# Transcriptional Signature of Mind-Body Interventions on Inflammatory Gene Expression: A Systematic Review and Meta-Analysis

Laszlo Pokorny

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# Transcriptional Signature of Mind-Body Interventions on Inflammatory Gene Expression:
## A Systematic Review and Meta-Analysis

by

Laszlo Pokorny

Department of Integrative Medicine

Post-Transplant Research Institute

New Jersey, USA

DOI: 10.5281/zenodo.18276385

2026
Copyright © 2026 by Laszlo Pokorny

All Rights Reserved
ABSTRACT

Mind-body interventions (MBIs) such as meditation, mindfulness, and yoga have demonstrated beneficial effects on psychological well-being and physical health; however, the molecular mechanisms underlying these effects remain incompletely characterized. This dissertation presents a systematic review and meta-analysis examining the transcriptional signature of mind-body interventions on inflammatory gene expression using publicly available datasets from the Gene Expression Omnibus (GEO). Grounded in the Quantum Psychoneuroimmunotheology (QPNIT) theoretical framework—a novel transdisciplinary model integrating psychoneuroimmunology, quantum physics, and theology—this study tests predictions regarding how contemplative practices modulate gene expression through psychoneuroimmunological pathways. Three GEO datasets meeting inclusion criteria were analyzed: GSE10041 (Relaxation Response training, 8 weeks), GSE108215 (Mindfulness Awareness Practice, 8 weeks), and GSE44777 (Sudarshan Kriya Yoga, 4 days), representing 236 blood samples from diverse populations. Differential expression analysis revealed that 2.7% to 4.4% of probes demonstrated nominally significant changes following interventions. Meta-analysis using Fisher's combined probability method identified 94 genes with consistent direction of regulation across studies, comprising 52 upregulated and 42 downregulated genes. Effect sizes were modest (log2 fold change range: 0.04–0.19), consistent with the expected magnitude of behavioral intervention effects. Pathway enrichment analysis revealed significant modulation of NF-κB signaling, inflammatory response, and stress response pathways, supporting QPNIT Proposition 3 regarding the measurable biological effects of spiritual and contemplative practices. These findings provide molecular-level evidence for the biological embeddedness of
mind-body intervention effects and identify potential transcriptional biomarkers for meditation response. Implications for integrative medicine, personalized healthcare, and future research directions are discussed.

*Keywords:* mind-body interventions, gene expression, inflammation, NF-κB, meditation, psychoneuroimmunology, QPNIT, meta-analysis
Table of Contents

<table><tr><td>ABSTRACT</td><td>3</td></tr><tr><td>CHAPTER 1: INTRODUCTION</td><td>21</td></tr><tr><td>Introduction to the Study</td><td>21</td></tr><tr><td>Background of the Problem</td><td>23</td></tr><tr><td>The Rise of Mind-Body Interventions in Healthcare</td><td>24</td></tr><tr><td>Historical Context: The Emergence of Psychoneuroimmunology</td><td>25</td></tr><tr><td>The Genomic Revolution: From Function to Gene Expression</td><td>28</td></tr><tr><td>The Need for Systematic Synthesis</td><td>29</td></tr><tr><td>Statement of the Problem</td><td>31</td></tr><tr><td>Purpose of the Study</td><td>33</td></tr><tr><td>Research Questions and Hypotheses</td><td>34</td></tr><tr><td>Table 1.1 Research Questions and Hypotheses</td><td>34</td></tr><tr><td>Theoretical Framework</td><td>36</td></tr><tr><td>Origins and Rationale for QPNIT</td><td>37</td></tr><tr><td>Core Propositions of QPNIT</td><td>39</td></tr><tr><td>QPNIT Proposition 3 and the Present Study</td><td>40</td></tr><tr><td>Figure 1.1 QPNIT Theoretical Framework Diagram</td><td>42</td></tr><tr><td>Nature of the Study</td><td>43</td></tr></table>
Transcriptional Signature

<table><tr><td>Data Sources and Selection</td><td>43</td></tr><tr><td>Analytical Approach</td><td>44</td></tr><tr><td>Significance of the Study</td><td>45</td></tr><tr><td>Theoretical Significance</td><td>45</td></tr><tr><td>Practical and Clinical Significance</td><td>46</td></tr><tr><td>Contribution to the Field</td><td>46</td></tr><tr><td>Definitions of Key Terms</td><td>47</td></tr><tr><td>Table 1.2 Definition of Key Terms</td><td>48</td></tr><tr><td>Assumptions, Limitations, and Delimitations</td><td>50</td></tr><tr><td>Assumptions</td><td>50</td></tr><tr><td>Limitations</td><td>51</td></tr><tr><td>Delimitations</td><td>52</td></tr><tr><td>Organization of the Dissertation</td><td>53</td></tr><tr><td>Chapter Summary</td><td>54</td></tr><tr><td>CHAPTER 2: LITERATURE REVIEW</td><td>57</td></tr><tr><td>Introduction</td><td>57</td></tr><tr><td>Purpose and Scope</td><td>58</td></tr><tr><td>Organization of the Chapter</td><td>59</td></tr><tr><td>Theoretical Framework: Quantum Psychoneuroimmunotheology (QPNIT)</td><td>60</td></tr><tr><td>Origins and Development of QPNIT</td><td>60</td></tr></table>
<table><tr><td>Core Propositions of QPNIT</td><td>62</td></tr><tr><td>Integration of PNI, Quantum Biology, and Consciousness Studies</td><td>64</td></tr><tr><td>Relevance of QPNIT to Mind-Body Research</td><td>66</td></tr><tr><td>Psychoneuroimmunology: Foundations and Mechanisms</td><td>68</td></tr><tr><td>Historical Development of Psychoneuroimmunology</td><td>68</td></tr><tr><td>The Hypothalamic-Pituitary-Adrenal Axis and Stress Response</td><td>70</td></tr><tr><td>Autonomic Nervous System Pathways</td><td>72</td></tr><tr><td>Cytokine Signaling and Immune-Brain Communication</td><td>74</td></tr><tr><td>Bidirectional Mind-Body Connections</td><td>76</td></tr><tr><td>Mind-Body Interventions: Definitions and Mechanisms</td><td>78</td></tr><tr><td>Meditation Practices</td><td>78</td></tr><tr><td>Yoga and Movement-Based Practices</td><td>81</td></tr><tr><td>Tai Chi and Qigong</td><td>82</td></tr><tr><td>Proposed Mechanisms of Action</td><td>83</td></tr><tr><td>Physiological and Psychological Effects</td><td>84</td></tr><tr><td>Gene Expression and Transcriptional Regulation</td><td>86</td></tr><tr><td>Basic Molecular Mechanisms of Gene Expression</td><td>87</td></tr><tr><td>Epigenetic Modifications</td><td>89</td></tr><tr><td>The Conserved Transcriptional Response to Adversity (CTRA)</td><td>91</td></tr><tr><td>Psychological States and Gene Expression</td><td>93</td></tr></table>
<table><tr><td>Social Genomics and the Biological Embedding of Experience</td><td>94</td></tr><tr><td>Inflammatory Pathways and Immune Function</td><td>95</td></tr><tr><td>The NF-κB Signaling Pathway</td><td>95</td></tr><tr><td>Pro-Inflammatory Cytokines: IL-6, TNF-α, and IL-1β</td><td>97</td></tr><tr><td>Anti-Inflammatory Mechanisms</td><td>99</td></tr><tr><td>Chronic Inflammation and Disease</td><td>100</td></tr><tr><td>Stress-Inflammation Connections</td><td>102</td></tr><tr><td>Empirical Research: Mind-Body Interventions and Gene Expression</td><td>103</td></tr><tr><td>Seminal Studies: Benson, Dusek, and the Relaxation Response</td><td>103</td></tr><tr><td>Cole, Creswell, and Social Genomics Approaches</td><td>105</td></tr><tr><td>Bower and Breast Cancer Survivors</td><td>106</td></tr><tr><td>Black and Caregiving Stress</td><td>107</td></tr><tr><td>Kaliman and Rapid Epigenetic Changes</td><td>108</td></tr><tr><td>Meditation and Transcriptional Changes</td><td>109</td></tr><tr><td>Yoga and Gene Expression</td><td>110</td></tr><tr><td>Comparative Studies and Dose-Response Relationships</td><td>111</td></tr><tr><td>Systematic Reviews and Meta-Analyses</td><td>112</td></tr><tr><td>Overview of Existing Reviews</td><td>113</td></tr><tr><td>The Buric Meta-Analysis of Molecular Signatures</td><td>114</td></tr><tr><td>Key Findings and Effect Sizes</td><td>115</td></tr></table>
<table><tr><td>Methodological Quality Assessment</td><td>116</td></tr><tr><td>Research Gaps and Future Directions</td><td>118</td></tr><tr><td>Methodological Limitations</td><td>118</td></tr><tr><td>Heterogeneity of Interventions and Populations</td><td>120</td></tr><tr><td>Mechanistic Gaps</td><td>121</td></tr><tr><td>Clinical Translation Gaps</td><td>122</td></tr><tr><td>Rationale for the Current Study</td><td>122</td></tr><tr><td>Chapter Summary</td><td>123</td></tr><tr><td>CHAPTER 3: METHODOLOGY</td><td>128</td></tr><tr><td>Introduction</td><td>128</td></tr><tr><td>Chapter Overview</td><td>129</td></tr><tr><td>Research Questions and Hypotheses Restated</td><td>130</td></tr><tr><td>Research Design</td><td>131</td></tr><tr><td>Systematic Review Methodology Rationale</td><td>132</td></tr><tr><td>Meta-Analysis Approach for Gene Expression Data</td><td>133</td></tr><tr><td>Alignment With PRISMA Guidelines</td><td>134</td></tr><tr><td>Data Sources</td><td>135</td></tr><tr><td>Gene Expression Omnibus (GEO) Database Description</td><td>136</td></tr><tr><td>Other Supplementary Databases</td><td>137</td></tr><tr><td>Rationale for Using Publicly Available Data</td><td>138</td></tr></table>
<table><tr><td>Table 3.1 Characteristics of Gene Expression Data Repositories</td><td>139</td></tr><tr><td>Search Strategy</td><td>140</td></tr><tr><td>Search Terms and Boolean Operators</td><td>140</td></tr><tr><td>Database-Specific Search Syntax</td><td>141</td></tr><tr><td>Date Range and Language Restrictions</td><td>142</td></tr><tr><td>Table 3.2 Complete Search Strategy by Database</td><td>143</td></tr><tr><td>Figure 3.1 Search Strategy Flowchart for Identification of Gene Expression Datasets</td><td>145</td></tr><tr><td>Eligibility Criteria</td><td>146</td></tr><tr><td>Inclusion Criteria (PICOS Framework)</td><td>146</td></tr><tr><td>Exclusion Criteria</td><td>148</td></tr><tr><td>Table 3.3 Inclusion and Exclusion Criteria Using PICOS Framework</td><td>149</td></tr><tr><td>Study Selection Process</td><td>149</td></tr><tr><td>Screening Procedures</td><td>150</td></tr><tr><td>Inter-Rater Reliability</td><td>151</td></tr><tr><td>Figure 3.2 PRISMA Flow Diagram (Template)</td><td>152</td></tr><tr><td>Data Extraction</td><td>153</td></tr><tr><td>Data Extraction Form Development</td><td>153</td></tr><tr><td>Variables Extracted</td><td>154</td></tr><tr><td>Table 3.4 Data Extraction Variables and Definitions</td><td>156</td></tr><tr><td>Quality Assessment</td><td>157</td></tr></table>
<table><tr><td>Quality Assessment Tools for Gene Expression Studies</td><td>157</td></tr><tr><td>MINSEQE Guidelines</td><td>158</td></tr><tr><td>Risk of Bias Assessment</td><td>159</td></tr><tr><td>Table 3.5 Quality Assessment Criteria for Gene Expression Studies of Mind-Body Interventions</td><td>159</td></tr><tr><td>Data Analysis</td><td>160</td></tr><tr><td>Bioinformatics Pipeline Overview</td><td>161</td></tr><tr><td>Normalization and Preprocessing</td><td>161</td></tr><tr><td>Differential Expression Analysis</td><td>163</td></tr><tr><td>Gene Set Enrichment Analysis (GSEA)</td><td>163</td></tr><tr><td>Pathway Analysis (KEGG, GO)</td><td>164</td></tr><tr><td>Meta-Analysis Statistical Methods</td><td>165</td></tr><tr><td>Heterogeneity Assessment</td><td>166</td></tr><tr><td>Software and Tools Used</td><td>167</td></tr><tr><td>Figure 3.3 Data Analysis Workflow/Pipeline for Systematic Review and Meta-Analysis</td><td>167</td></tr><tr><td>Table 3.6 Software and Bioinformatics Tools</td><td>169</td></tr><tr><td>Ethical Considerations</td><td>170</td></tr><tr><td>Use of Publicly Available Data</td><td>170</td></tr><tr><td>IRB Considerations</td><td>171</td></tr><tr><td>Data Privacy</td><td>172</td></tr></table>
<table><tr><td>Methodological Limitations</td><td>172</td></tr><tr><td>Anticipated Limitations</td><td>172</td></tr><tr><td>Mitigation Strategies</td><td>174</td></tr><tr><td>Chapter Summary</td><td>175</td></tr><tr><td>CHAPTER 4: RESULTS</td><td>178</td></tr><tr><td>Introduction</td><td>178</td></tr><tr><td>Organization of This Chapter</td><td>178</td></tr><tr><td>Study Selection Results</td><td>179</td></tr><tr><td>Database Search Results</td><td>179</td></tr><tr><td>PRISMA Flow Diagram</td><td>179</td></tr><tr><td>Figure 4.1. PRISMA 2020 flow diagram illustrating the systematic search and study selection process for the meta-analysis of mind-body interventions and gene expression.</td><td>181</td></tr><tr><td>Studies Included and Excluded</td><td>181</td></tr><tr><td>Table 4.1 PRISMA Study Selection Summary</td><td>181</td></tr><tr><td>Characteristics of Included Studies</td><td>182</td></tr><tr><td>Overview of GEO Datasets</td><td>182</td></tr><tr><td>Table 4.2 Characteristics of Included GEO Datasets</td><td>182</td></tr><tr><td>GSE10041: Relaxation Response Training</td><td>183</td></tr><tr><td>GSE108215: Mindfulness Awareness Practice</td><td>183</td></tr><tr><td>GSE44777: Sudarshan Kriya Yoga</td><td>184</td></tr></table>
<table><tr><td>Quality Assessment</td><td>184</td></tr><tr><td>Differential Expression Analysis Results</td><td>185</td></tr><tr><td>Overview of Differential Expression Findings</td><td>185</td></tr><tr><td>Table 4.3 Summary of Differentially Expressed Genes by Study</td><td>186</td></tr><tr><td>GSE10041: Relaxation Response Results</td><td>186</td></tr><tr><td>Figure 4.2. Volcano plot for GSE10041 (Relaxation Response) differential expression analysis. Red points indicate nominally significant genes (p &lt; .05). Horizontal dashed lines indicate p &lt; .05 and p &lt; .01 significance thresholds.</td><td>187</td></tr><tr><td>Table 4.4 Top 10 Differentially Expressed Probes in GSE10041 (Relaxation Response)</td><td>188</td></tr><tr><td>GSE108215: Mindfulness Awareness Practice Results</td><td>188</td></tr><tr><td>Figure 4.3. Volcano plot for GSE108215 (Mindfulness Awareness Practice) differential expression analysis. Red points indicate nominally significant genes (p &lt; .05).</td><td>189</td></tr><tr><td>Table 4.5 Top 10 Differentially Expressed Probes in GSE108215 (Mindfulness Awareness Practice)</td><td>190</td></tr><tr><td>GSE44777: Sudarshan Kriya Yoga Results</td><td>190</td></tr><tr><td>Figure 4.4. Volcano plot for GSE44777 (Sudarshan Kriya Yoga) differential expression analysis. Red points indicate nominally significant genes (p &lt; .05).</td><td>191</td></tr><tr><td>Table 4.6 Top 10 Differentially Expressed Probes in GSE44777 (Sudarshan Kriya Yoga)</td><td>192</td></tr><tr><td>Comparison of Differential Expression Patterns</td><td>192</td></tr></table>
<table><tr><td>Figure 4.5. Combined volcano plots comparing differential expression patterns across the three included studies. Each panel represents one study, with consistent axis scales to facilitate comparison.</td><td>193</td></tr><tr><td>Figure 4.6. Bar chart comparing counts of differentially expressed genes by direction across the three included studies. Blue bars indicate upregulated genes; orange bars indicate downregulated genes.</td><td>194</td></tr><tr><td>Gene Set Enrichment and Pathway Analysis</td><td>194</td></tr><tr><td>Enriched Biological Processes</td><td>194</td></tr><tr><td>Table 4.7 Enriched Pathways and GO Terms Across Studies</td><td>195</td></tr><tr><td>NF-κB and Inflammatory Pathway Findings</td><td>196</td></tr><tr><td>Figure 4.7. Heatmap of pathway enrichment scores across the three included studies. Rows represent biological pathways; columns represent studies. Color intensity indicates the magnitude of pathway enrichment.</td><td>197</td></tr><tr><td>Conserved Transcriptional Response to Adversity (CTRA)</td><td>197</td></tr><tr><td>Meta-Analysis Results</td><td>198</td></tr><tr><td>Combined Analysis Approach</td><td>198</td></tr><tr><td>Consistently Regulated Genes</td><td>198</td></tr><tr><td>Table 4.8 Meta-Analysis Results: Top Consistently Regulated Genes</td><td>199</td></tr><tr><td>Heterogeneity Assessment</td><td>199</td></tr></table>
<table><tr><td>Figure 4.8. Scatter plot comparing effect sizes (log2 fold change) between GSE10041 and GSE108215 studies. Each point represents one probe. The positive correlation indicates modest consistency in transcriptional effects across studies.</td><td>200</td></tr><tr><td>Heatmap of Top Meta-Analysis Genes</td><td>201</td></tr><tr><td>Figure 4.9. Heatmap of log2 fold changes for top genes from the meta-analysis. Rows represent individual probes; columns represent studies. Red indicates upregulation; blue indicates downregulation.</td><td>203</td></tr><tr><td>Forest Plot of Key Genes</td><td>203</td></tr><tr><td>Figure 4.10. Forest plot of effect sizes for selected genes related to NF-κB signaling and inflammatory response. Points represent log2 fold changes; error bars represent 95% confidence intervals.</td><td>203</td></tr><tr><td>Summary of Key Findings</td><td>204</td></tr><tr><td>Synthesis of Results</td><td>204</td></tr><tr><td>Table 4.9 Summary of Key Findings in Relation to Research Questions</td><td>204</td></tr><tr><td>Alignment with QPNIT Framework</td><td>204</td></tr><tr><td>Chapter Summary</td><td>205</td></tr><tr><td>CHAPTER 5: DISCUSSION</td><td>207</td></tr><tr><td>Introduction</td><td>207</td></tr><tr><td>Interpretation of Findings</td><td>208</td></tr><tr><td>Summary of Major Results</td><td>208</td></tr><tr><td>Meaning of Differential Expression Patterns</td><td>210</td></tr></table>
<table><tr><td>Significance of Pathway Findings: NF-κB and Inflammatory Genes</td><td>211</td></tr><tr><td>Interpretation of Meta-Analysis Results</td><td>213</td></tr><tr><td>Effect Size Considerations</td><td>214</td></tr><tr><td>Table 5.1 Summary of Key Findings and Interpretations</td><td>215</td></tr><tr><td>Findings in Relation to the Existing Literature</td><td>216</td></tr><tr><td>Comparison with Seminal Mind-Body Gene Expression Studies</td><td>216</td></tr><tr><td>Consistency with the Conserved Transcriptional Response to Adversity</td><td>219</td></tr><tr><td>Alignment with Psychoneuroimmunology Research</td><td>221</td></tr><tr><td>Novel Contributions to the Field</td><td>223</td></tr><tr><td>Table 5.2 Comparison with Previous Research</td><td>225</td></tr><tr><td>Theoretical Implications: The QPNIT Framework</td><td>225</td></tr><tr><td>Overview of QPNIT and Its Propositions</td><td>225</td></tr><tr><td>Support for Proposition 3: Spiritual Practice Effects</td><td>226</td></tr><tr><td>Implications for Mind-Body-Gene Connections</td><td>228</td></tr><tr><td>Integration with Psychoneuroimmunology Mechanisms</td><td>230</td></tr><tr><td>Refinement of the Theoretical Model</td><td>231</td></tr><tr><td>Figure 5.1 updated QPNIT conceptual model</td><td>233</td></tr><tr><td>Practical and Clinical Implications</td><td>234</td></tr><tr><td>Implications for Integrative Medicine</td><td>234</td></tr><tr><td>Potential Biomarkers for Intervention Efficacy</td><td>235</td></tr></table>
<table><tr><td>Personalized Medicine Considerations</td><td>237</td></tr><tr><td>Public Health Implications</td><td>238</td></tr><tr><td>Limitations</td><td>239</td></tr><tr><td>Methodological Limitations</td><td>239</td></tr><tr><td>Data Source Limitations</td><td>241</td></tr><tr><td>Heterogeneity of Interventions</td><td>241</td></tr><tr><td>Sample Size Considerations</td><td>242</td></tr><tr><td>Generalizability Concerns</td><td>243</td></tr><tr><td>Table 5.3 Study Limitations and Mitigation Strategies</td><td>244</td></tr><tr><td>Recommendations for Future Research</td><td>245</td></tr><tr><td>Methodological Improvements</td><td>245</td></tr><tr><td>Longitudinal Studies Needed</td><td>247</td></tr><tr><td>Mechanistic Investigations</td><td>248</td></tr><tr><td>Clinical Translation Research</td><td>249</td></tr><tr><td>Table 5.4 Future Research Agenda</td><td>251</td></tr><tr><td>Conclusions</td><td>252</td></tr><tr><td>Synthesis of Discussion</td><td>252</td></tr><tr><td>Significance of the Study</td><td>253</td></tr><tr><td>Final Reflections</td><td>254</td></tr><tr><td>CHAPTER 6: CONCLUSION</td><td>257</td></tr></table>
<table><tr><td>Introduction</td><td>257</td></tr><tr><td>Summary of the Study</td><td>258</td></tr><tr><td>Research Problem and Purpose</td><td>258</td></tr><tr><td>Theoretical Framework: Quantum Psychoneuroimmunotheology</td><td>259</td></tr><tr><td>Methodology Overview</td><td>260</td></tr><tr><td>Key Findings Summary</td><td>261</td></tr><tr><td>Conclusions by Research Question</td><td>262</td></tr><tr><td>Conclusions for Research Question 1: Transcriptional Signatures</td><td>262</td></tr><tr><td>Conclusions for Research Question 2: Inflammatory and Immune Pathways</td><td>263</td></tr><tr><td>Conclusions for Research Question 3: QPNIT Framework Support</td><td>264</td></tr><tr><td>Table 6.1 Research Questions, Hypotheses, and Conclusions</td><td>266</td></tr><tr><td>Contributions to Knowledge</td><td>266</td></tr><tr><td>Theoretical Contributions</td><td>266</td></tr><tr><td>Methodological Contributions</td><td>268</td></tr><tr><td>Empirical Contributions</td><td>269</td></tr><tr><td>Table 6.2 Summary of Contributions to Knowledge</td><td>270</td></tr><tr><td>Recommendations</td><td>271</td></tr><tr><td>Recommendations for Research</td><td>271</td></tr><tr><td>Recommendations for Practice</td><td>272</td></tr><tr><td>Recommendations for Policy</td><td>274</td></tr></table>
Transcriptional Signature

<table><tr><td>Final Reflections</td><td>275</td></tr><tr><td>Significance of Mind-Body Research</td><td>275</td></tr><tr><td>Vision for the Future of the Field</td><td>276</td></tr><tr><td>Closing Statement</td><td>278</td></tr><tr><td>REFERENCES</td><td>280</td></tr><tr><td>APPENDIX A: Data Analysis Code</td><td>316</td></tr><tr><td>D.1 Introduction</td><td>316</td></tr><tr><td>D.1.1 Software Requirements</td><td>316</td></tr><tr><td>D.2 R Code for Meta-Analysis</td><td>317</td></tr><tr><td>D.2.1 Package Loading and Setup</td><td>317</td></tr><tr><td>D.2.2 Data Preparation and Import</td><td>318</td></tr><tr><td>D.2.3 Effect Size Calculations</td><td>319</td></tr><tr><td>D.2.4 Random Effects Meta-Analysis</td><td>322</td></tr><tr><td>D.2.5 Forest Plot Generation</td><td>323</td></tr><tr><td>D.2.6 Publication Bias Assessment</td><td>325</td></tr><tr><td>D.2.7 Sensitivity Analysis</td><td>328</td></tr><tr><td>D.2.8 Heterogeneity Assessment</td><td>331</td></tr><tr><td>D.3 Python Code for GEO Data Processing</td><td>333</td></tr><tr><td>D.3.1 GEO Dataset Download</td><td>333</td></tr><tr><td>D.3.2 Data Preprocessing and Normalization</td><td>337</td></tr></table>
Transcriptional Signature

<table><tr><td>D.4 R/Python Code for Differential Expression Analysis</td><td>340</td></tr><tr><td>D.4.1 R limma Workflow</td><td>340</td></tr><tr><td>D.4.2 Python Differential Expression Analysis</td><td>343</td></tr><tr><td>D.4.3 Volcano Plot Generation</td><td>346</td></tr><tr><td>D.5 R Code for Gene Set Enrichment Analysis</td><td>350</td></tr><tr><td>D.5.1 clusterProfiler Analysis</td><td>350</td></tr><tr><td>D.5.2 fgsea Fast GSEA</td><td>354</td></tr><tr><td>D.6 Python Code for Data Visualization</td><td>356</td></tr><tr><td>D.6.1 Combined Multi-Study Volcano Plots</td><td>356</td></tr><tr><td>D.6.2 Effect Size Comparison Plots</td><td>359</td></tr><tr><td>D.6.3 Pathway Enrichment Heatmap</td><td>362</td></tr><tr><td>D.7 Supplementary Functions and Utility Scripts</td><td>365</td></tr><tr><td>D.7.1 Data Utility Functions</td><td>365</td></tr><tr><td>D.7.2 Session Information</td><td>372</td></tr></table>
# CHAPTER 1: INTRODUCTION

## Introduction to the Study

In a quiet hospital room, a cancer patient closes her eyes and begins a deep meditation practice. Across the city, a stressed executive attends his weekly mindfulness class. In a yoga studio, practitioners move through ancient postures while synchronizing breath and movement. These scenes, increasingly common in contemporary healthcare and wellness settings, represent humanity's enduring quest to harness the power of the mind to heal the body. What distinguishes the current moment from millennia of contemplative traditions is the unprecedented ability to peer beneath the surface of these practices—to observe, at the molecular level, how mental disciplines reshape cellular function and gene expression. This dissertation stands at the intersection of ancient wisdom and cutting-edge genomics, seeking to identify the transcriptional signature through which mind-body interventions influence inflammatory gene expression.

The past two decades have witnessed a remarkable convergence of contemplative science, psychoneuroimmunology, and genomic technologies that has transformed our understanding of the mind-body relationship. The discovery that psychological states and interventions can produce measurable changes in gene expression represents nothing less than a paradigm shift—one that challenges the long-held assumption that our genes are fixed determinants of biological destiny and instead reveals them as dynamic entities responsive to our experiences, relationships, and mental practices (Cole, 2014; Slavich & Cole, 2013). This paradigmatic transformation carries profound implications for medicine, psychology, and our fundamental understanding of what it means to be human. Where previous generations could only speculate about how the mind might influence the body, we now possess the technological
tools to measure these effects at the level of individual genes, transcription factors, and
molecular pathways.

The emergence of this field represents a critical juncture in the history of medicine—a
moment when the artificial boundaries between mind and body, between subjective experience
and objective biology, begin to dissolve under the weight of empirical evidence. Ancient healing
traditions across cultures have long maintained that mental states influence physical health, that
practices of contemplation and spiritual discipline promote healing. Modern science initially
dismissed such claims as superstition or relegated them to the category of "placebo effects" not
worthy of serious investigation. Yet the accumulating evidence from psychoneuroimmunology,
social genomics, and contemplative neuroscience has converged to reveal that the relationship
between psychological states and immune function is not merely correlational but operates
through identifiable molecular pathways that can be measured, quantified, and potentially
modified (Irwin & Cole, 2011; Cole, 2014).

The present study employs systematic review and meta-analysis methodology to
 synthesize gene expression data from studies examining the effects of meditation, mindfulness,
and yoga on the human transcriptome. By integrating evidence across multiple studies using
rigorous bioinformatics approaches, this research aims to identify convergent transcriptional
signatures that transcend individual study limitations and reveal the core molecular mechanisms
through which contemplative practices influence health. The investigation is grounded in the
Quantum Psychoneuroimmunotheology (QPNIT) theoretical framework (Pokorny, 2026), a
novel transdisciplinary model that provides conceptual integration of psychoneuroimmunology,
quantum physics, and theology to illuminate the mechanisms underlying mind-body-spirit
connections in human health and healing.
This introductory chapter establishes the foundation for the dissertation research. The chapter begins by articulating the background of the problem, situating the current investigation within the historical development of psychoneuroimmunology and the emergence of genomic approaches to studying mind-body effects. The statement of the problem delineates the specific gap in knowledge that this research addresses. Following the statement of purpose and research questions, the chapter presents the QPNIT theoretical framework that guides the investigation. Subsequent sections describe the nature of the study, its significance for theory and practice, operational definitions of key terms, and the assumptions, limitations, and delimitations that bound the research. The chapter concludes with an overview of the dissertation's organization.

## Background of the Problem

The exploration of the mind's influence over the body represents one of the most profound and enduring inquiries in both science and philosophy. While ancient healing traditions across cultures—from Traditional Chinese Medicine to Ayurveda to Indigenous healing practices—have long posited an intrinsic unity between mental states and physical health, the empirical validation of these connections has only recently begun to emerge within the rigorous framework of modern science (Kaptchuk, 2000; Lad, 2002). This section traces the historical development of our understanding of mind-body connections, examines the rise of mind-body interventions in contemporary healthcare, and articulates the gap between clinical practice and molecular understanding that motivates the present research. Understanding this background is essential for appreciating both the significance of the current investigation and its placement within the broader scientific discourse.
The Rise of Mind-Body Interventions in Healthcare

Mind-body interventions (MBIs) have emerged as one of the fastest-growing sectors in contemporary healthcare. The National Center for Complementary and Integrative Health (NCCIH) classifies MBIs as practices that "focus on the interactions among the brain, mind, body, and behavior, with the intent to use the mind to affect physical functioning and promote health" (NCCIH, 2021). This broad category encompasses meditation practices (including mindfulness meditation, Transcendental Meditation, and loving-kindness meditation), yoga in its various forms, tai chi, qigong, and guided imagery, among other practices. The prevalence of MBI use has increased dramatically over the past two decades, with national surveys indicating that approximately 14% of American adults practiced yoga and 14% engaged in meditation in 2017, representing increases of approximately 50% and 65%, respectively, from 2012 (Clarke et al., 2018).

The clinical efficacy of MBIs has been established across a remarkable range of conditions. Meta-analyses have documented beneficial effects for anxiety disorders (Hofmann et al., 2010), depression (Goyal et al., 2014), chronic pain (Hilton et al., 2017), cardiovascular risk factors (Rainforth et al., 2007), and immune function (Morgan et al., 2014). Mindfulness-Based Stress Reduction (MBSR), developed by Jon Kabat-Zinn at the University of Massachusetts Medical School in 1979, has been implemented in over 700 academic medical centers and healthcare settings worldwide (Kabat-Zinn, 2003). Similarly, yoga has become integrated into cardiac rehabilitation programs, cancer survivorship care, and mental health treatment protocols (Ross et al., 2013). The accumulating clinical evidence has prompted major healthcare organizations, including the American Heart Association and the American College of Physicians, to include mind-body practices in their clinical guidelines for specific conditions.
The economic implications of this shift toward integrative approaches are substantial. Americans spend approximately $30 billion annually on complementary health approaches, with meditation and yoga among the most common practices (Nahin et al., 2016). Healthcare systems increasingly invest in mind-body programs for employee wellness and chronic disease management, recognizing potential benefits for both health outcomes and healthcare costs. Major academic medical centers have established integrative medicine departments that incorporate mind-body approaches alongside conventional treatments. This mainstreaming of previously "alternative" practices represents a significant cultural and medical shift with implications for research, training, and healthcare delivery.

Despite this clinical integration, a fundamental disconnect persists between the therapeutic application of MBIs and our mechanistic understanding of how they produce their effects. Clinicians prescribe meditation for stress reduction, physicians recommend yoga for chronic pain, and healthcare systems invest in mindfulness programs for employee wellness—yet the molecular pathways through which these practices influence physiology remain incompletely characterized. This gap between practice and mechanism limits the ability to optimize interventions, identify biomarkers of treatment response, and personalize mind-body medicine approaches for individual patients. Addressing this gap requires bringing the full power of modern genomic technologies to bear on understanding how contemplative practices reshape biology at the molecular level.

## Historical Context: The Emergence of Psychoneuroimmunology

The scientific foundation for understanding how mental states influence physical health was established through the emergence of psychoneuroimmunology (PNI) as a formal discipline. The term itself, coined by Robert Ader in 1981, encapsulates the field's central premise: that the
Transcriptional Signature

psychological (psycho-), neurological (neuro-), and immunological (-immunology) systems
constitute an integrated network rather than separate entities (Ader, 1981). The historical
development of PNI spans from ancient observations about the influence of emotions on health
through the pioneering experiments that established the field's empirical foundation.

Understanding this history provides essential context for the present investigation into the
molecular basis of mind-body intervention effects.

While the formal discipline of PNI is relatively recent, observations about mind-body
connections date back to antiquity. Galen noted in the second century that melancholic women
were more susceptible to cancer than sanguine women. The 19th century saw systematic
observations by physicians like Claude Bernard and Walter Cannon regarding how emotional
states influence physiological function (Cannon, 1932). Hans Selye's work on the stress response
in the mid-20th century documented the profound physiological consequences of psychological
stressors, establishing the concept of the General Adaptation Syndrome and identifying the
hypothalamic-pituitary-adrenal (HPA) axis as a key mediator of stress effects (Selye, 1956).
These foundational observations set the stage for the formal emergence of PNI as an
interdisciplinary field.

The watershed moment for PNI arrived in 1975 with the serendipitous discovery by
Robert Ader and Nicholas Cohen at the University of Rochester. While studying conditioned
taste aversion in rats, they demonstrated that immunosuppression could be classically
conditioned—that is, the immune system could "learn" to respond to a neutral stimulus
(saccharin-flavored water) as if it were an immunosuppressive drug (Ader & Cohen, 1975). This
elegant experiment shattered the prevailing dogma that the immune system operated
autonomously, separate from nervous system influence. The finding that immune responses
could be conditioned just like salivary responses (as in Pavlov's famous experiments) implied
direct communication between the nervous and immune systems—a revolutionary concept that
challenged fundamental assumptions in both immunology and neuroscience.

The anatomical basis for these functional connections was subsequently established by David Felten and colleagues, who discovered dense networks of nerve fibers extending from the sympathetic nervous system directly into immune organs, with nerve terminals in close proximity to lymphocytes and macrophages (Felten et al., 1985). This "hard-wiring" between the nervous and immune systems provided the anatomical substrate for the functional interactions documented by Ader and Cohen. Additional research identified receptors for neurotransmitters on immune cells and discovered that immune cells themselves could produce neuropeptides and neurotransmitters, establishing the basis for bidirectional communication between these systems (Blalock, 1984).

The mechanisms of neuroimmune communication have been extensively elaborated in
subsequent decades. The hypothalamic-pituitary-adrenal (HPA) axis serves as a primary pathway
through which psychological stress influences immune function, with cortisol acting as a potent
immunomodulator (Sapolsky et al., 2000). The autonomic nervous system provides additional
pathways, including the cholinergic anti-inflammatory pathway mediated by the vagus nerve
(Tracey, 2002, 2007). This "inflammatory reflex" enables rapid neural control of systemic
inflammation through acetylcholine signaling to immune cells bearing nicotinic receptors.
Cytokines produced by immune cells signal back to the brain through both humoral and neural
routes, inducing sickness behavior and completing a bidirectional communication loop (Dantzer
et al., 2008). These discoveries established that mind-body connections operate through
identifiable, measurable biological pathways amenable to scientific investigation.
The Genomic Revolution: From Function to Gene Expression

The application of genomic technologies to PNI research has opened unprecedented
windows into the molecular mechanisms of mind-body connections. The human genome project,
completed in 2003, and the subsequent development of microarray and RNA sequencing
technologies enabled researchers to assess the activity of thousands of genes simultaneously,
providing comprehensive snapshots of cellular transcriptional states (Cole, 2014). The
application of these tools to studies of psychological experience revealed that our genes are not
static blueprints but dynamic entities whose expression patterns shift in response to social
conditions, emotional states, and behavioral practices. This realization—that experience becomes
biologically embedded through gene expression changes—represents a fundamental
reconceptualization of the relationship between mind, body, and heredity.

Steve Cole and colleagues at UCLA articulated the concept of "social genomics,"
demonstrating that social environmental conditions—including loneliness, social isolation, and
low socioeconomic status—produce characteristic patterns of gene expression that predispose
individuals to chronic inflammation and impaired antiviral immunity (Cole, 2014; Cole et al.,
2007). This research identified the Conserved Transcriptional Response to Adversity (CTRA), a
characteristic pattern of increased expression of pro-inflammatory genes (particularly those
driven by NF-κB transcription factors) and decreased expression of interferon response genes
observed in individuals experiencing chronic threat and adversity (Slavich & Cole, 2013). The
CTRA profile has been linked to increased risk of cardiovascular disease, cancer progression,
neurodegeneration, and mortality, establishing gene expression as a critical intermediate between
psychological experience and health outcomes.
Pioneering studies began applying these genomic approaches to mind-body interventions, with transformative results. Dusek et al. (2008) demonstrated that 8 weeks of Relaxation Response training produced significant changes in gene expression, with effects in pathways related to oxidative phosphorylation, cellular metabolism, and oxidative stress. The Relaxation Response, developed by Herbert Benson at Harvard, represents a physiological state opposite to the stress response, characterized by reduced sympathetic activity and metabolic rate. The finding that this mental practice produced widespread transcriptional changes provided molecular evidence for the biological significance of relaxation training.

Subsequent studies expanded these observations. Bhasin et al. (2013) identified specific transcriptional changes in long-term practitioners of mind-body practices compared to novices, with effects on energy metabolism, mitochondrial function, and insulin secretion pathways.

Black et al. (2013) showed that mindfulness meditation reduced expression of genes regulated by the pro-inflammatory transcription factor NF-κB, suggesting a molecular mechanism for the anti-inflammatory effects of contemplative practice. Kaliman et al. (2014) documented that a single day of intensive mindfulness practice produced rapid changes in expression of histone-modifying genes involved in epigenetic regulation, indicating that mind-body effects may extend to the epigenome. Collectively, these studies provided molecular-level evidence that contemplative practices produce measurable transcriptional changes with plausible relevance to health outcomes.

## The Need for Systematic Synthesis

Despite the growing number of studies examining gene expression changes following MBIs, several challenges have impeded mechanistic understanding and clinical translation. First, individual studies have employed heterogeneous intervention types, durations, and comparison
conditions, complicating synthesis across studies. Some studies examined meditation, others
mindfulness, others yoga—each with distinct techniques, training protocols, and proposed
mechanisms. Intervention durations have ranged from a single session to months of regular
practice. Comparison conditions have included waitlist controls, active comparators, and pre-
post within-subject designs. This heterogeneity makes it difficult to determine whether
seemingly inconsistent findings reflect true differences between practices or merely
methodological variation.

Second, differences in gene expression analysis methods, statistical thresholds, and pathway databases have produced seemingly inconsistent findings regarding which specific genes and pathways are affected. Studies have employed different microarray platforms, normalization procedures, and statistical approaches. Some studies focused on pre-specified candidate pathways while others took discovery-based approaches examining the entire transcriptome. The absence of standardized analytical pipelines has complicated comparison across studies and contributed to the perception of inconsistency in the literature.

Third, most studies have employed relatively small sample sizes, limiting statistical power to detect subtle but biologically meaningful effects. Gene expression changes from behavioral interventions are expected to be modest compared to pharmacological treatments, requiring adequate sample sizes for reliable detection. Individual studies typically included 20-50 participants, providing limited power for genome-wide analyses involving thousands of statistical tests. Small samples also limit ability to detect heterogeneity in treatment response or identify subgroups that may respond differently to intervention.

While narrative reviews have summarized individual study findings (e.g., Bower & Irwin, 2016; Black & Slavich, 2016), quantitative synthesis of gene expression data using
modern meta-analytic bioinformatics approaches has been notably absent. Such synthesis could
identify robust, reproducible signals amidst study-specific noise and generate hypotheses
regarding core molecular mechanisms of contemplative practice effects. Meta-analysis offers the
statistical power to detect consistent effects that individual studies may lack power to identify,
while also enabling formal assessment of heterogeneity across studies. The present study
addresses this critical gap through systematic review and meta-analysis of publicly available
gene expression datasets examining mind-body intervention effects on the human transcriptome.

## Statement of the Problem

The fundamental research problem addressed by this dissertation is the lack of
systematic, meta-analytic synthesis of gene expression data across mind-body intervention
studies to identify common transcriptional signatures. Despite the clinical integration of
meditation, mindfulness, and yoga into healthcare settings and the accumulating evidence from
individual genomic studies demonstrating that these practices produce measurable molecular
changes, no comprehensive quantitative synthesis has been conducted to identify convergent
patterns of gene expression change that transcend individual study limitations. This absence
represents a critical gap in the scientific literature with consequences for both theoretical
understanding and clinical application.

This gap in knowledge carries significant consequences for both scientific understanding
and clinical practice. Without identification of a robust transcriptional signature, the field lacks
molecular biomarkers that could predict treatment response, monitor intervention effectiveness,
or identify individuals most likely to benefit from specific mind-body approaches. Clinicians
implementing MBIs have no objective molecular measures to assess whether interventions are
producing their intended biological effects. Researchers lack validated endpoints for intervention
development and optimization studies. The absence of consensus on which genes and pathways
are affected impedes mechanistic understanding, limiting the development of targeted
interventions and evidence-based integration with conventional treatments.

Furthermore, the lack of quantitative synthesis reduces the field's ability to establish the consistency and magnitude of observed effects, undermining confidence in the biological plausibility of mind-body medicine approaches. Skeptics of mind-body medicine can point to apparently inconsistent findings across studies as evidence that observed effects are spurious or methodologically driven rather than reflecting genuine biology. Without meta-analytic evidence demonstrating reproducible effects, the field remains vulnerable to charges that positive findings represent selective reporting or false positives from underpowered studies. Establishing the robustness of transcriptional effects through rigorous meta-analysis is essential for advancing the scientific credibility of mind-body intervention research.

The specific gap in knowledge that this dissertation addresses can be articulated as
follows: While individual studies have documented gene expression changes following
meditation, mindfulness, and yoga interventions, with particular emphasis on inflammatory and
stress response pathways, no meta-analysis has synthesized these findings to determine (a)
whether a consistent transcriptional signature characterizes the molecular response to diverse
MBIs, (b) which specific genes and pathways demonstrate reproducible effects across studies,
and (c) what magnitude of effect can be expected from these interventions. Addressing this gap
requires the application of systematic review methodology combined with meta-analytic
bioinformatics approaches appropriate for transcriptomic data integration.
Purpose of the Study

The purpose of this study is to conduct a systematic review and meta-analysis of publicly
available gene expression datasets to identify a common transcriptional signature associated with
mind-body interventions, with particular emphasis on inflammatory and immune-regulatory gene
pathways. The investigation utilizes the Quantum Psychoneuroimmunotheology (QPNIT)
theoretical framework to guide hypothesis generation and interpretation of findings, specifically
testing predictions derived from QPNIT Proposition 3 regarding the measurable biological
effects of spiritual and contemplative practices. This research addresses the identified gap in
systematic synthesis by applying rigorous bioinformatics methodology to publicly available
transcriptomic data.

The specific aims of this study are to: (a) systematically identify and catalog all publicly
available gene expression datasets from the Gene Expression Omnibus (GEO) involving
meditation, mindfulness, yoga, or related mind-body interventions in human subjects; (b) apply
standardized bioinformatics analysis pipelines to individual datasets to identify differentially
expressed genes following interventions; (c) conduct gene-level and pathway-level meta-
analyses to identify convergent patterns of transcriptional change across studies; (d) characterize
effects on NF-κB target genes, inflammatory pathways, stress response genes, and antiviral
immune pathways; and (e) evaluate findings in relation to the QPNIT theoretical framework and
existing literature on mind-body-gene connections.

The scope of this study encompasses human studies examining genome-wide gene
expression changes in blood or peripheral blood mononuclear cell (PBMC) samples following
mind-body interventions, utilizing pre-post intervention designs or controlled comparisons. The
study synthesizes evidence using Fisher's combined probability method for gene-level meta-
analysis and examines pathway enrichment patterns across the identified transcriptional signature. By integrating evidence across heterogeneous studies using rigorous methodology, this research provides the quantitative synthesis necessary to advance mechanistic understanding and clinical application of mind-body interventions.

## Research Questions and Hypotheses

This dissertation is guided by three primary research questions and their corresponding hypotheses. These questions were developed based on the QPNIT theoretical framework, the existing empirical literature on mind-body interventions and gene expression, and the methodological considerations appropriate for meta-analysis of transcriptomic data. Table 1 presents the research questions and hypotheses in structured format.

<table><caption>**Table 1.1 Research Questions and Hypotheses**</caption><thead><tr><td>Research Question</td><td>Hypothesis</td></tr></thead><tbody><tr><td>RQ1: What are the common transcriptional signatures associated with mind-body interventions across multiple studies?</td><td>H1: A core set of genes will demonstrate consistent differential expression (same direction of effect) across multiple mind-body intervention studies, indicating a reproducible transcriptional signature of contemplative practice response.</td></tr><tr><td>RQ2: Which inflammatory and immune pathways are consistently affected by mind-body interventions?</td><td>H2: NF-κB target genes and pro-inflammatory pathway gene sets will show significant modulation following mind-body interventions, with predominant downregulation of inflammatory gene expression.</td></tr><tr><td>RQ3: How do the empirical findings support or</td><td>H3: The transcriptional signature of mind-body</td></tr></tbody></table>
<table><tr><td>refine the QPNIT theoretical framework, particularly Proposition 3?</td><td>interventions will demonstrate patterns consistent with QPNIT predictions, including modulation of stress response genes and inflammatory pathways through psychoneuroimmunological mechanisms.</td></tr><tr><td>RQ1 Rationale</td><td>Individual studies have reported diverse sets of differentially expressed genes; meta-analytic synthesis is required to identify convergent patterns.</td></tr><tr><td>RQ2 Rationale</td><td>NF-κB serves as a master regulator of inflammatory gene expression and has been identified in individual studies as a target of mind-body interventions.</td></tr><tr><td>RQ3 Rationale</td><td>QPNIT Proposition 3 predicts that contemplative practices produce measurable biological effects through identifiable psychoneuroimmunological pathways.</td></tr></table>

*Note.* QPNIT = Quantum Psychoneuroimmunotheology; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells.

Research Question 1 addresses the fundamental issue of reproducibility in the field. Individual studies have reported diverse sets of differentially expressed genes, but the extent to which these findings converge on a common signature remains unclear. Hypothesis 1 predicts that meta-analysis will reveal a core set of genes demonstrating consistent direction of effect across studies, indicating a reproducible transcriptional signature. This hypothesis derives from the theoretical expectation that diverse mind-body practices engage common
Transcriptional Signature

psychoneuroimmunological pathways and from the observation that individual studies have
identified overlapping gene sets despite methodological heterogeneity.

Research Question 2 tests a central prediction of the QPNIT framework and the broader PNI literature: that contemplative practices modulate inflammatory signaling pathways. The NF-κB transcription factor serves as a master regulator of inflammatory gene expression, controlling production of pro-inflammatory cytokines and other mediators (Hayden & Ghosh, 2008).

Chronic activation of NF-κB contributes to pathophysiology of cardiovascular disease, cancer, diabetes, and neurodegeneration. Hypothesis 2 predicts that NF-κB target genes and inflammatory pathway gene sets will demonstrate significant modulation in the meta-analysis.

This hypothesis derives from QPNIT's articulation of how mind-body practices engage the cholinergic anti-inflammatory pathway and HPA axis to suppress inflammatory signaling.

Research Question 3 addresses the theoretical implications of the empirical findings for
the QPNIT framework. QPNIT Proposition 3 specifically predicts that spiritual and
contemplative practices produce measurable biological effects through mechanisms including
modulation of stress-response systems, activation of relaxation responses, and alterations in gene
expression patterns (Pokorny, 2026). Hypothesis 3 predicts that the observed transcriptional
signatures will be consistent with these theoretical predictions, providing molecular-level
evidence supporting the QPNIT framework while potentially refining its mechanistic
propositions. The evaluation of findings against QPNIT predictions enables bidirectional
enrichment of theory and data.

Theoretical Framework

This dissertation is grounded in the Quantum Psychoneuroimmunotheology (QPNIT)
theoretical framework, a novel transdisciplinary model developed by Pokorny (2026) that
integrates psychoneuroimmunology, quantum physics, and theology to advance understanding of mind-body-spirit connections in human health and healing. QPNIT provides the conceptual foundation for understanding how contemplative practices may influence gene expression through psychoneuroimmunological pathways while situating these molecular mechanisms within a broader framework addressing consciousness, quantum processes, and spiritual experience. The framework represents a significant advancement in integrative theory, providing conceptual resources that transcend the limitations of any single disciplinary perspective.

## Origins and Rationale for QPNIT

The development of QPNIT emerged from the recognition that three relatively recent scientific developments provide foundations for theoretical integration that were previously unavailable. First, psychoneuroimmunology established during the late 20th century demonstrated that psychological states, neural processes, and immune function constitute an integrated network with bidirectional communication pathways (Ader & Cohen, 1975; Ader, 2007). The documentation of neural innervation of immune organs, identification of neurotransmitter receptors on immune cells, and demonstration of conditioned immune responses established the empirical foundation for understanding how mind influences body through identifiable biological mechanisms.

Second, quantum biology emerged as a frontier discipline demonstrating that quantum phenomena play functional roles in biological systems, challenging classical assumptions about biological mechanisms (Lambert et al., 2013). Evidence for quantum coherence in photosynthesis, quantum tunneling in enzyme catalysis, and quantum effects in olfaction and avian navigation suggested that living systems may exploit quantum phenomena in ways not captured by classical biology. The possibility that quantum processes occur in neural systems
opened new avenues for understanding consciousness and its potential to influence biological
systems at fundamental levels.

Third, consciousness research documented measurable effects of contemplative practices
and intentional mental states on physiological processes, raising profound questions about
mechanisms that transcend conventional reductionist explanations (Davidson & Lutz, 2008). The
placebo effect demonstrated that belief and expectation produce objectively measurable
biological changes. Studies of meditation documented alterations in brain structure and function,
immune parameters, and gene expression. These findings suggested that consciousness possesses
causal efficacy in physical systems, challenging eliminativist positions that reduce mind to
neural computation.

QPNIT proposes that the complex interactions between mind, body, and spirit cannot be
fully comprehended through traditional reductionist approaches. The framework seeks to
construct a comprehensive model that honors the multidimensionality of human existence by
integrating insights across disciplinary boundaries. The term itself encapsulates this
multidimensional nature: "Psycho-" refers to the realm of the mind, including thoughts,
emotions, consciousness, and psychological states; "-Neuro-" pertains to the nervous system, the
biological hardware through which the mind interfaces with the body; "-Immuno-" denotes the
immune system, which is profoundly sensitive to neural and psychological signals; and "-
Theology" addresses ultimate reality, meaning, and the individual's relationship with the
transcendent.
Core Propositions of QPNIT

The QPNIT framework articulates four core propositions that organize its theoretical content and generate testable predictions. These propositions represent the substantive claims of the framework regarding mind-body-spirit-quantum connections:

Proposition 1: Consciousness interfaces with physical reality at the quantum level, providing a mechanism for mental states to influence biological processes. This proposition draws on quantum theories of consciousness, including the Orchestrated Objective Reduction (Orch-OR) theory of Penrose and Hameroff (2014), which proposes that consciousness arises from quantum computations in neuronal microtubules. QPNIT extends these ideas to propose that conscious intention may influence quantum-level processes that subsequently affect cellular function. While speculative, this proposition provides a theoretical framework for understanding how mental states might exert causal influence on physical processes without violating natural law.

Proposition 2: Immune system function involves quantum biological processes susceptible to modulation through the consciousness-quantum interface. Evidence for quantum effects in biological systems—including quantum coherence in photosynthesis, quantum tunneling in enzyme catalysis, and quantum effects in olfaction—suggests that living systems exploit quantum phenomena in ways not captured by classical biology (Engel et al., 2007; Lambert et al., 2013). QPNIT proposes that immune cell function may similarly involve quantum processes amenable to modulation, providing a mechanistic link between consciousness and immunity that complements classical neuroimmune pathways.

Proposition 3: Spiritual practices produce measurable biological effects through mechanisms including modulation of stress-response systems, activation of relaxation responses,
and alterations in gene expression patterns. This proposition directly addresses the focus of the present dissertation. QPNIT identifies several psychoneuroimmunological pathways through which contemplative practices may influence gene expression: activation of the parasympathetic nervous system and the cholinergic anti-inflammatory pathway (Tracey, 2002, 2007); modulation of the HPA axis and glucocorticoid signaling; reduction of sympathetic nervous system activity and β-adrenergic receptor signaling; and engagement of positive emotional states that activate distinct neurobiological pathways. These mechanisms operate through established biological pathways amenable to empirical investigation.

**Proposition 4:** Consciousness may possess non-local properties relevant to healing phenomena that transcend conventional spatiotemporal limitations. This proposition addresses phenomena such as distant healing and intercessory prayer that, while controversial, have been subjects of scientific investigation (Schlitz et al., 2012). While Proposition 4 lies beyond the scope of the present investigation, it completes the theoretical architecture of QPNIT by acknowledging phenomena that challenge conventional scientific paradigms.

## QPNIT Proposition 3 and the Present Study

The present dissertation provides a direct empirical test of QPNIT Proposition 3 by examining whether mind-body interventions produce consistent, measurable changes in gene expression consistent with the framework's predictions. Proposition 3 generates several specific predictions relevant to transcriptional analysis: (a) contemplative practices should produce detectable changes in gene expression measurable using genomic technologies; (b) these changes should involve pathways related to stress response, inflammation, and immune function; (c) pro-inflammatory gene expression, particularly genes regulated by NF-κB, should be modulated toward reduced inflammatory signaling; and (d) patterns of gene expression change should be
broadly consistent across diverse contemplative practices that engage similar
psychoneuroimmunological mechanisms.

The QPNIT framework provides theoretical justification for expecting convergent transcriptional effects across diverse MBIs. Despite surface differences between meditation, mindfulness, and yoga practices, QPNIT proposes that these interventions engage overlapping psychoneuroimmunological pathways—parasympathetic activation, HPA axis modulation, reduced sympathetic tone, positive emotional engagement—that converge on common molecular targets. This theoretical expectation motivates the meta-analytic approach of the present study, which seeks to identify the convergent transcriptional signature underlying diverse contemplative practices. The framework predicts that this signature will reflect modulation of inflammatory and stress response genes through the identified neuroimmune communication pathways.
<figure><img src="image_2.png" /><figcaption>Figure 1.1 QPNIT Theoretical Framework Diagram</figcaption></figure>

Figure 1.1 The Quantum Psychoneuroimmunotheology (QPNIT) framework illustrating the integration of psychological, neurological, immunological, and quantum domains. Mind-body interventions engage psychoneuroimmunological pathways (HPA axis, autonomic nervous system, cholinergic anti-inflammatory pathway) to modulate gene expression in immune cells. The present study tests QPNIT Proposition 3, which addresses the measurable biological effects of contemplative practices operating through identified psychoneuroimmunological mechanisms. Arrows indicate bidirectional communication pathways between domains.
## Nature of the Study

This study employs a systematic review and meta-analysis research design combining qualitative synthesis of intervention characteristics with quantitative meta-analysis of gene expression data. The systematic review methodology provides a rigorous, transparent, and reproducible approach to identifying, appraising, and synthesizing all relevant evidence addressing the research questions (Moher et al., 2009). Meta-analysis extends systematic review by applying statistical methods to combine results across studies, increasing statistical power and precision of effect estimates while enabling formal assessment of heterogeneity (Borenstein et al., 2009). The integration of these approaches is essential for achieving the study objectives of identifying convergent transcriptional signatures across the body of mind-body intervention gene expression research.

## Data Sources and Selection

The primary data source for this study is the Gene Expression Omnibus (GEO), a public repository maintained by the National Center for Biotechnology Information (NCBI) that archives functional genomics data including microarray and high-throughput sequencing datasets (Barrett et al., 2013). GEO contains over 170,000 curated studies representing billions of data points across diverse experimental conditions. The repository provides standardized data formats, quality control procedures, and metadata annotation that facilitate re-analysis and meta-analysis of deposited datasets. Supplementary searches of PubMed were conducted to identify published studies with associated GEO deposits.

Studies were included in the meta-analysis if they met the following criteria: (a) examined human subjects; (b) employed a mind-body intervention including meditation, mindfulness, yoga, or related contemplative practice; (c) collected blood or peripheral blood
mononuclear cell (PBMC) samples; (d) utilized genome-wide gene expression profiling (microarray or RNA sequencing); (e) employed a pre-post intervention design or controlled comparison; and (f) deposited raw or processed data in GEO or another public repository enabling re-analysis. Studies were excluded if they examined non-human subjects, used tissue types other than blood, employed targeted gene expression approaches rather than genome-wide profiling, or lacked publicly available data.

## Analytical Approach

Bioinformatics analyses were conducted using standardized pipelines implemented in R/Bioconductor. Individual datasets were processed using platform-appropriate normalization methods (RMA for Affymetrix arrays, quantile normalization for Illumina arrays). Differential expression analysis employed the limma package with paired analyses for pre-post designs, generating log2 fold change estimates and moderated t-statistics for each probe or gene. Multiple testing correction was applied using the Benjamini-Hochberg false discovery rate (FDR) procedure.

Meta-analysis across studies utilized Fisher's combined probability method, which aggregates p-values from individual studies to identify genes with consistent evidence of differential expression. This approach is particularly appropriate for transcriptomic meta-analysis because it accommodates heterogeneity in effect sizes while identifying genes with reproducible statistical signals. In addition to gene-level meta-analysis, pathway enrichment analysis was conducted using Gene Ontology biological processes and KEGG pathways to identify functional themes among the convergent gene signature. This multilevel approach enables identification of both specific genes and broader biological processes affected by mind-body interventions.
## Significance of the Study

This study offers significant contributions across theoretical, methodological, and practical dimensions. The identification of a robust transcriptional signature of mind-body intervention response advances mechanistic understanding, provides potential biomarkers for clinical application, and strengthens the empirical foundation for integrating contemplative practices into evidence-based healthcare.

## Theoretical Significance

Theoretically, this study provides molecular-level evidence directly relevant to the QPNIT framework, particularly Proposition 3 regarding the measurable biological effects of spiritual and contemplative practices. The identification of consistent transcriptional changes across diverse MBIs supports the framework's claim that these practices engage overlapping psychoneuroimmunological pathways converging on common molecular targets. Furthermore, characterization of effects on NF-κB signaling, inflammatory pathways, and stress response genes tests specific mechanistic predictions derived from QPNIT's integration of contemplative practice, autonomic function, and immune modulation.

Beyond QPNIT, this study contributes to the broader theoretical discourse on gene-environment interactions and the molecular embedding of experience. The demonstration that voluntary mental practices produce reproducible transcriptional changes has implications for understanding how psychological and social experiences become biologically embodied, extending the social genomics paradigm articulated by Cole (2014) and Slavich and Cole (2013). The findings inform theoretical understanding of the mechanisms through which lifestyle and behavioral interventions influence health trajectories at the molecular level, potentially transforming our understanding of the relationship between experience and biology.
## Practical and Clinical Significance

From a practical perspective, identification of a transcriptional signature of MBI response provides several potential applications. First, genes demonstrating consistent differential expression may serve as biomarkers for monitoring intervention effectiveness, providing objective measures to complement self-report outcomes. Second, baseline expression patterns might predict treatment response, enabling personalized selection of mind-body approaches for individual patients. Third, the specific pathways identified may suggest targets for developing enhanced interventions that more effectively engage beneficial molecular mechanisms.

For clinical practice, this study strengthens the empirical foundation for integrating MBIs into conventional healthcare. Demonstration that meditation, mindfulness, and yoga produce consistent, biologically plausible molecular effects—particularly in inflammation-related pathways—supports their use in conditions characterized by immune dysregulation and chronic inflammation. The findings provide mechanistic rationale for mind-body interventions in conditions ranging from cardiovascular disease to autoimmune disorders to depression, where inflammatory processes play pathophysiological roles. This evidence base supports insurance coverage, clinical guideline inclusion, and healthcare system investment in mind-body programs.

## Contribution to the Field

Methodologically, this study demonstrates the application of meta-analytic bioinformatics approaches to mind-body intervention research, establishing procedures for future synthesis studies in this domain. The systematic review and meta-analysis methodology provides a template for ongoing synthesis as additional datasets become available, enabling cumulative knowledge building in a field that has previously relied primarily on narrative review. The
Transcriptional Signature

demonstration of feasibility and utility of this approach may stimulate additional meta-analyses
as the genomic literature continues to grow.

The study contributes to reducing the gap between mind-body intervention practice and molecular understanding. While MBIs have achieved substantial clinical integration based on behavioral and symptomatic outcomes, the absence of mechanistic evidence has limited acceptance among some healthcare providers and researchers. Identification of a reproducible transcriptional signature provides the molecular evidence necessary to advance the field from phenomenological observation to mechanistic understanding, positioning mind-body medicine within the framework of molecular biomedicine while honoring its distinctive philosophical and practical dimensions.

## Definitions of Key Terms

Clear operational definitions are essential for systematic review and meta-analysis, where
consistent application of terms determines study eligibility and interpretation of findings. This
section provides definitions for key terms used throughout the dissertation. Table 2 presents
these definitions in systematic format.
<table><caption>**Table 1.2 Definition of Key Terms**</caption><thead><tr><td>Term</td><td>Operational Definition</td></tr></thead><tbody><tr><td>Mind-Body Intervention (MBI)</td><td>Practices that focus on the interactions among the brain, mind, body, and behavior, with the intent to use the mind to affect physical functioning and promote health (NCCIH, 2021). Includes meditation, mindfulness practices, yoga, tai chi, qigong, and related contemplative disciplines.</td></tr><tr><td>Gene Expression</td><td>The process by which information encoded in DNA is converted into functional products, typically proteins. Gene expression profiling measures the transcription of genes into messenger RNA (mRNA) as an indicator of gene activity.</td></tr><tr><td>Transcriptional Signature</td><td>A characteristic pattern of gene expression changes that distinguishes one condition, treatment, or phenotype from another. In this study, refers to genes consistently differentially expressed following mind-body interventions.</td></tr><tr><td>Differential Expression</td><td>A statistically significant change in gene expression between conditions (e.g., pre- vs. post-intervention). Typically quantified as fold change with associated statistical significance.</td></tr><tr><td>NF-κB (Nuclear Factor Kappa B)</td><td>A transcription factor that serves as a master regulator of inflammatory gene expression, controlling production of pro-inflammatory cytokines, chemokines, and other immune mediators (Hayden & Ghosh, 2008).</td></tr></tbody></table>
<table><tr><td>Psychoneuroimmunology (PNI)</td><td>The study of interactions between psychological processes, the nervous system, and immune function. PNI examines bidirectional communication pathways linking brain, behavior, and immunity (Ader, 2007).</td></tr><tr><td>CTRA</td><td>Conserved Transcriptional Response to Adversity—a characteristic gene expression pattern observed in individuals experiencing chronic stress, featuring upregulation of pro-inflammatory genes and downregulation of antiviral genes (Slavich & Cole, 2013).</td></tr><tr><td>Meta-Analysis</td><td>A statistical approach that combines results from multiple studies to derive a pooled estimate of effect, increase statistical power, and assess consistency of findings across studies (Borenstein et al., 2009).</td></tr><tr><td>GEO</td><td>Gene Expression Omnibus—a public repository maintained by NCBI that archives and provides free access to functional genomics datasets including microarray and sequencing studies (Barrett et al., 2013).</td></tr><tr><td>PBMCs</td><td>Peripheral Blood Mononuclear Cells—a population of blood cells including lymphocytes and monocytes, commonly used in gene expression studies examining immune function.</td></tr><tr><td>QPNIT</td><td>Quantum Psychoneuroimmunotheology—a transdisciplinary theoretical framework integrating psychoneuroimmunology, quantum physics, and theology to understand mind-body-spirit connections (Pokorny, 2026).</td></tr></table>
<table><tr><td>Log2 Fold Change</td><td>A measure of gene expression change magnitude, calculated as the logarithm (base 2) of the ratio of expression levels between conditions. A log2FC of 1 indicates a 2-fold increase.</td></tr></table>

## Assumptions, Limitations, and Delimitations

### Assumptions

Several assumptions underlie the present research. First, it is assumed that gene expression in blood and PBMCs reflects systemic biological responses to mind-body interventions. While blood represents the most accessible tissue for human research, gene expression patterns may differ across tissues. However, blood-based transcriptional profiling has demonstrated relevance to diverse health outcomes and serves as a window into systemic immune and stress response processes relevant to MBI effects.

Second, it is assumed that publicly available GEO datasets provide adequate quality data for meta-analysis. GEO datasets undergo quality review prior to deposit, and the bioinformatics pipeline employed includes quality control steps. However, the original investigators' decisions regarding sample processing, normalization, and data cleaning introduce heterogeneity that may affect results. This assumption is addressed through quality assessment of included studies and sensitivity analyses.

Third, it is assumed that diverse mind-body interventions engage sufficiently overlapping molecular mechanisms to produce detectable convergent signatures in meta-analysis. The QPNIT framework provides theoretical justification for this assumption, proposing that meditation, mindfulness, and yoga engage common psychoneuroimmunological pathways
despite surface differences. The validity of this assumption is empirically tested through the
meta-analysis itself.

Limitations

The study acknowledges several limitations. First, the systematic search identified a
limited number of datasets meeting inclusion criteria (n = 3), constraining the statistical power
and generalizability of meta-analytic findings. This limitation reflects the current state of
publicly available mind-body intervention transcriptomics data and highlights the need for
additional well-designed studies with data sharing. The modest number of included studies limits
ability to conduct subgroup analyses examining effects of specific intervention types, durations,
or populations.

Second, the meta-analysis synthesizes studies employing different microarray platforms, which introduces technical heterogeneity beyond biological variability. While the analytical approach accommodates platform differences through separate normalization and gene-level synthesis, platform effects may contribute to heterogeneity in observed results. Cross-platform integration remains a methodological challenge in transcriptomic meta-analysis.

Third, the included studies varied in intervention characteristics including type
(Relaxation Response, mindfulness, yoga), duration (4 days to 8 weeks), and comparison
condition (pre-post within-subjects). This heterogeneity complicates interpretation of convergent
findings and limits ability to identify optimal intervention parameters. However, the
identification of consistent effects despite heterogeneity strengthens confidence in the robustness
of observed signatures.

Fourth, effect sizes for gene expression changes are modest (log2 fold change: 0.04–
0.19), consistent with the expected magnitude of behavioral intervention effects but potentially
reflecting limited biological impact. Small effect sizes increase vulnerability to type I and type II
errors and limit the clinical utility of identified genes as biomarkers. However, modest individual
gene effects may aggregate into meaningful pathway-level changes with biological significance.

Delimitations

Delimitations represent boundaries intentionally established to define research scope.

This study is delimited to human studies examining blood or PBMC gene expression, excluding studies using other tissues (brain, saliva, skin), animal models, or cell culture systems. This delimitation focuses the research on clinically accessible biomarkers while acknowledging that tissue-specific effects may not be captured.

The study is delimited to genome-wide expression profiling studies, excluding targeted
approaches such as RT-PCR studies examining specific candidate genes. This delimitation
enables unbiased discovery of transcriptional signatures but excludes studies that may have
examined relevant genes through targeted methods. The study is further delimited to publicly
available datasets, excluding proprietary data that may exist but cannot be accessed for
independent re-analysis.

Finally, the study is delimited to examination of gene expression (mRNA levels) as the
primary outcome, excluding other molecular measures such as protein levels, DNA methylation,
or histone modifications. While epigenetic mechanisms likely mediate MBI effects on gene
expression, comprehensive integration of multi-omic data lies beyond the scope of this
systematic review. The focus on transcription provides a tractable entry point for meta-analysis
while acknowledging that gene expression represents one level in a complex regulatory cascade.
# Organization of the Dissertation

This dissertation is organized into six chapters that progressively develop the theoretical foundation, methodology, findings, and implications of the systematic review and meta-analysis. This organizational structure follows conventions for dissertation research while accommodating the specific requirements of systematic review reporting.

Chapter 1, the present chapter, has established the foundation for the dissertation research. The chapter articulated the background of the problem, including the rise of mind-body interventions, the emergence of psychoneuroimmunology, and the application of genomic approaches to studying contemplative practices. The statement of the problem identified the gap in systematic synthesis of transcriptomic data across MBI studies. The purpose and research questions specified the study objectives, and the theoretical framework section introduced QPNIT with particular attention to Proposition 3. Subsequent sections addressed the nature of the study, its significance, key definitions, and assumptions, limitations, and delimitations.

Chapter 2 provides a comprehensive literature review synthesizing scholarship from psychoneuroimmunology, social genomics, contemplative neuroscience, and the QPNIT theoretical framework. The review traces the historical development of PNI, examines mechanisms of neuroimmune communication, reviews evidence on mind-body intervention effects on gene expression, and critically evaluates existing reviews and meta-analyses. The chapter establishes the theoretical and empirical foundation for the dissertation research and identifies specific gaps addressed by the present study.

Chapter 3 presents the methodology employed in the systematic review and meta-analysis. The chapter details the research design rationale, data sources, search strategy, eligibility criteria, study selection process, data extraction procedures, quality assessment
Transcriptional Signature

methods, and analytical approaches including the bioinformatics pipeline for individual study
analysis and the meta-analytic methods for cross-study synthesis. The methodology chapter
provides sufficient detail for replication and establishes the rigor of the research procedures.

Chapter 4 presents the results of the systematic review and meta-analysis. The chapter reports the study selection process and PRISMA flow diagram, characteristics of included studies, differential expression analysis findings for each individual dataset, gene set enrichment and pathway analysis results, and meta-analytic synthesis across studies. Results are presented in relation to the research questions and hypotheses with appropriate tables and figures.

Chapter 5 provides a comprehensive discussion of the findings, interpreting results in relation to existing literature and the QPNIT theoretical framework. The chapter addresses the meaning of differential expression patterns, pathway-level effects, theoretical implications for QPNIT Proposition 3, practical and clinical implications, and limitations of the research.

Recommendations for future research directions are articulated based on the findings and their implications.

Chapter 6 concludes the dissertation with a synthesis of contributions, definitive conclusions regarding the research questions, recommendations for future research and practice, and reflections on the significance of the work for advancing understanding of the mind-body-gene nexus. The chapter provides final assessment of how the findings support or refine the QPNIT framework and articulates a vision for the future of mind-body genomics research.

Chapter Summary

This introductory chapter has established the foundation for a systematic review and
meta-analysis examining the transcriptional signature of mind-body interventions on
inflammatory gene expression. The chapter began by situating the research at the intersection of
ancient contemplative wisdom and cutting-edge genomics, highlighting the paradigm shift represented by the discovery that mental practices can produce measurable molecular changes in gene expression patterns.

The background section traced the rise of mind-body interventions in contemporary healthcare, documenting their increasing prevalence and clinical integration. The historical development of psychoneuroimmunology was examined, from the foundational work of Ader and Cohen demonstrating conditioned immunosuppression through the elaboration of neuroimmune communication pathways involving the HPA axis, autonomic nervous system, and cytokine signaling. The application of genomic technologies to studying contemplative practice effects was reviewed, highlighting pioneering studies that documented transcriptional changes following meditation and mindfulness interventions.

The statement of the problem identified the critical gap addressed by this research: the absence of meta-analytic synthesis of gene expression data across MBI studies, which limits identification of robust transcriptional biomarkers and mechanistic understanding. The purpose statement and research questions articulated the study's objectives: to identify a common transcriptional signature associated with mind-body interventions, characterize effects on inflammatory and immune-regulatory pathways, and evaluate findings in relation to the QPNIT theoretical framework.

The theoretical framework section introduced Quantum Psychoneuroimmunotheology (QPNIT) as the conceptual foundation guiding this investigation. Particular attention was given to QPNIT Proposition 3, which predicts that spiritual and contemplative practices produce measurable biological effects through identified psychoneuroimmunological mechanisms. The
framework provides theoretical justification for expecting convergent transcriptional effects
across diverse MBIs that engage overlapping molecular pathways.

The nature of the study section described the systematic review and meta-analysis
methodology, including data sources (Gene Expression Omnibus), inclusion criteria, and
analytical approaches. The significance section articulated theoretical, practical, and
methodological contributions of the research. Operational definitions provided clarity regarding
key terms, and the assumptions, limitations, and delimitations section established appropriate
bounds on interpretation and generalization of findings.

With the foundation established in this introductory chapter, the dissertation now
proceeds to Chapter 2, which provides a comprehensive review of the literature spanning
psychoneuroimmunology, social genomics, contemplative neuroscience, and the QPNIT
theoretical framework that guides this investigation into the molecular signatures of mind-body
transformation.
# CHAPTER 2: LITERATURE REVIEW

## Introduction

The exploration of the mind's influence over the body represents one of the most profound and enduring inquiries in science and philosophy. While ancient healing traditions have long posited an intrinsic unity between mental states and physical health, the empirical validation of these connections has only recently begun to emerge within the rigorous framework of modern science. This literature review is situated at the confluence of several rapidly evolving disciplines—psychology, neuroscience, immunology, and genomics—to explore the transcriptional signature of mind-body interventions (MBIs) on inflammatory gene expression. The theoretical lens through which this complex interplay will be examined is Quantum Psychoneuroimmunotheology (QPNIT), a novel integrative theoretical framework proposed to provide a comprehensive explanatory model for the phenomena under investigation (Pokorny, 2026).

The accumulating evidence from psychoneuroimmunology (PNI), social genomics, and contemplative neuroscience has converged to reveal that the relationship between psychological states and immune function is not merely correlational but operates through identifiable molecular pathways that can be measured, quantified, and potentially modified (Irwin & Cole, 2011; Cole, 2014). Central to this understanding is the recognition that our genes are not static determinants of our biological fate but rather dynamic entities whose expression patterns shift in response to our experiences, relationships, and mental practices (Slavich & Cole, 2013). The discovery that psychological interventions such as meditation, yoga, and mindfulness can produce measurable changes in the expression of genes governing inflammation and immune
function represents a paradigm shift in our understanding of the mind-body relationship (Bower
et al., 2015; Creswell et al., 2012).

The purpose of this chapter is to provide a comprehensive and critical review of the scholarly literature that forms the foundation for this dissertation's systematic review and meta-analysis of transcriptional signatures associated with mind-body interventions. This review synthesizes evidence from multiple disciplinary perspectives to establish the theoretical rationale, empirical foundation, and methodological considerations that guide the present research. By examining the historical development of key fields, the mechanisms underlying mind-body-immune connections, and the current state of empirical evidence, this chapter demonstrates both what is known and what remains to be discovered regarding how contemplative practices influence inflammatory gene expression.

Purpose and Scope

This literature review serves multiple interconnected purposes that collectively establish
the foundation for the dissertation research. First, it provides a comprehensive examination of the
theoretical frameworks that underpin our understanding of mind-body-immune interactions, with
particular emphasis on the novel QPNIT framework that guides this investigation. Second, it
traces the historical development of psychoneuroimmunology from its origins to its current status
as a rigorous interdisciplinary science. Third, it examines the specific mechanisms through which
psychological states and interventions can influence immune function and gene expression.
Fourth, it reviews the empirical evidence demonstrating that mind-body interventions produce
measurable transcriptional changes, with particular attention to inflammatory pathways. Fifth, it
critically evaluates existing systematic reviews and meta-analyses to identify methodological
strengths and limitations. Finally, it articulates the research gaps that justify the present study and
positions this dissertation within the broader scholarly discourse.

The scope of this review encompasses literature from psychoneuroimmunology, social genomics, contemplative neuroscience, molecular biology, immunology, and integrative medicine. While the primary focus is on human studies examining gene expression changes following mind-body interventions, foundational animal research and mechanistic studies are included where they illuminate the biological pathways under investigation. The temporal scope extends from the founding experiments of PNI in the 1970s through the most recent empirical studies and reviews, with emphasis on research from the past two decades that has employed genomic technologies to assess transcriptional changes.

## Organization of the Chapter

This chapter is organized into nine major substantive sections following this introduction.
The second section presents the theoretical framework of Quantum
Psychoneuroimmunotheology (QPNIT), examining its origins, core propositions, and relevance
to mind-body research. The third section provides a comprehensive review of
psychoneuroimmunology, tracing its historical development and elucidating the mechanisms of
neuroimmune communication. The fourth section examines mind-body interventions, including
their definitions, proposed mechanisms, and documented physiological and psychological
effects. The fifth section explores gene expression and transcriptional regulation, including
epigenetic mechanisms and the Conserved Transcriptional Response to Adversity (CTRA). The
sixth section details inflammatory pathways and immune function, with particular emphasis on
NF-κB signaling and pro-inflammatory cytokines. The seventh section synthesizes empirical
research demonstrating that mind-body interventions alter inflammatory gene expression. The
eighth section reviews existing systematic reviews and meta-analyses in this domain. The ninth section identifies research gaps and articulates future directions. The chapter concludes with a summary that integrates key findings and transitions to the methodology chapter.

## Theoretical Framework: Quantum Psychoneuroimmunotheology (QPNIT)

The Quantum Psychoneuroimmunotheology (QPNIT) framework represents a paradigmatic advancement in understanding the intricate connections between psychological processes, the nervous system, the immune system, quantum processes, and spiritual experience (Pokorny, 2026). This novel transdisciplinary theoretical framework proposes that the complex interactions between mind, body, and spirit cannot be fully comprehended through traditional reductionist approaches. Instead, QPNIT seeks to construct a comprehensive model that honors the multidimensionality of human existence by integrating insights from psychoneuroimmunology, quantum physics, consciousness studies, and theology. The term itself encapsulates the multidimensional nature of the mind-body relationship: "Psycho-" refers to the realm of the mind, including thoughts, emotions, consciousness, and psychological states; "-Neuro-" pertains to the nervous system, the biological hardware through which the mind interfaces with the body; "-Immuno-" denotes the immune system, the body's intricate defense network that is profoundly sensitive to neural and psychological signals; and "-Theology," in this context, is used not in a dogmatic religious sense, but in its broader philosophical meaning concerning the study of ultimate reality, purpose, meaning, and the individual's relationship with the whole (Pokorny, 2026).

## Origins and Development of QPNIT

The development of QPNIT emerged from the recognition that three relatively recent scientific developments provide foundations for theoretical integration that were previously
unavailable (Pokorny, 2026). First, psychoneuroimmunology emerged during the late 20th
century as a field explicitly devoted to understanding bidirectional communication between the
nervous system and immune system, demonstrating that psychological states, neural processes,
and immune function constitute an integrated network rather than separate systems (Ader &
Cohen, 1975; Ader, 2007). PNI research documented neural innervation of lymphoid organs,
identified receptors for neurotransmitters on immune cells, demonstrated that stress and
depression suppress immune function, and showed that psychological interventions can enhance
immunity (Irwin & Cole, 2011; Segerstrom & Miller, 2004). This body of evidence established
the scientific legitimacy of mind-body connections while raising profound questions about
mechanisms.

Second, quantum biology has emerged as a frontier discipline investigating whether
quantum phenomena—traditionally considered relevant only at microscopic scales and ultracold
temperatures—play functional roles in living systems (Lambert et al., 2013; Marais et al., 2018).
Evidence for quantum effects in photosynthesis, enzyme catalysis, olfaction, bird navigation, and
potentially neural microtubules challenges classical assumptions about biological mechanisms
and suggests that quantum coherence, superposition, tunneling, and entanglement may constitute
fundamental features of life (Arndt et al., 2009; Engel et al., 2007). The possibility that quantum
processes occur in the brain opens new avenues for understanding consciousness and its potential
to influence biological systems, providing a potential mechanism for the observed effects of
intention and mental states on physiological processes.

Third, the persistent "hard problem" of consciousness (Chalmers, 1995) and the
documented efficacy of contemplative practices in promoting health continue to point toward
dimensions of human experience that resist purely materialistic explanations (Davidson & Lutz,
2008). Ancient healing traditions developed across diverse cultures—including Traditional Chinese Medicine, Ayurveda, and Indigenous healing practices—consistently conceptualized health as arising from harmony among physical, mental, emotional, and spiritual dimensions of human existence (Kaptchuk, 2000; Lad, 2002). These systems, refined through millennia of clinical observation, assert that mental states influence physical health, that spiritual practices support healing, and that the person cannot be adequately understood through analysis of isolated parts. Major religious and philosophical traditions similarly emphasize the integration of material and spiritual dimensions (Wallace, 2007).

## Core Propositions of QPNIT

The QPNIT framework articulates four core theoretical propositions that provide the conceptual architecture for understanding mind-body-spirit-quantum connections in human health and healing (Pokorny, 2026). These propositions are derived from systematic analysis of convergence points across psychoneuroimmunology, quantum theory, and theology, and they generate testable predictions that can be examined through empirical research. The propositions are not merely speculative philosophical claims but are grounded in empirical observations from multiple disciplines that, when viewed together, suggest an integrated model of human health and consciousness.

**Proposition 1:** Consciousness interfaces with physical reality at the quantum level, providing a mechanism for mental states to influence biological processes (Pokorny, 2026; Stapp, 2011). This proposition draws upon quantum consciousness theories, particularly the Orchestrated Objective Reduction (Orch OR) theory proposed by Hameroff and Penrose (2014), which suggests that quantum processes in neural microtubules may play a role in consciousness. From this perspective, the collapse of the quantum wave function through conscious observation
provides a point of contact between the subjective realm of experience and the objective realm of
physical matter. While speculative, this proposition offers a potential mechanism through which
subjective mental states could exert causal influence on objective biological processes without
invoking supernatural explanations.

Proposition 2: Immune system function involves quantum biological processes susceptible to modulation through the consciousness-quantum interface (Pokorny, 2026). Evidence for quantum effects in biological systems—including photosynthesis (Engel et al., 2007), enzyme catalysis (Klinman & Kohen, 2013), olfaction (Turin, 1996), and avian navigation (Ritz et al., 2004)—challenges classical assumptions and suggests that quantum coherence, superposition, tunneling, and entanglement may constitute fundamental features of life (Lambert et al., 2013; Marais et al., 2018). If immune cells utilize quantum processes in their signaling and function, then consciousness-mediated quantum effects could provide a pathway for mental states to influence immunity. Recent research has begun to explore quantum effects in immune cell signaling, though this area remains in its early stages.

Proposition 3: Spiritual practices produce measurable biological effects through mechanisms including quantum coherence enhancement, modulation of stress-response systems, and activation of relaxation responses (Pokorny, 2026). Research has documented that meditation and contemplative practices are associated with changes in brain activity, autonomic nervous system function, stress hormone levels, and inflammatory markers (Davidson & Lutz, 2008; Black & Slavich, 2016; Bower & Irwin, 2016). QPNIT proposes that these practices may enhance quantum coherence in neural systems, facilitating more effective consciousness-mediated modulation of physiological processes. This proposition generates testable predictions about the biological effects of spiritual practices that can be examined using current genomic and
Transcriptional Signature

neuroimaging methodologies. The present dissertation directly tests aspects of this proposition by examining whether mind-body interventions produce consistent transcriptional changes in inflammatory pathways.

Proposition 4: Consciousness may possess non-local properties relevant to healing phenomena transcending conventional spatiotemporal limitations (Pokorny, 2026; Radin, 2006). While the most speculative of QPNIT's propositions, this concept is included to maintain theoretical comprehensiveness and to address phenomena such as intercessory prayer and distant healing that have been subjects of scientific investigation, albeit with mixed results (Masters et al., 2006). For the present dissertation, this proposition is less directly relevant, as the focus is on an individual's own mind-body practices rather than purported non-local effects. Nevertheless, the inclusion of this proposition within the broader QPNIT framework reflects its commitment to addressing the full range of phenomena that have been reported in the mind-body-spirit literature.

Integration of PNI, Quantum Biology, and Consciousness Studies

A central contribution of the QPNIT framework is its systematic integration of findings from psychoneuroimmunology, quantum biology, and consciousness studies (Pokorny, 2026). This integration is not merely additive but synergistic, with each domain illuminating aspects of the others. PNI provides the empirical foundation demonstrating that psychological states can influence immune function through identifiable neuroendocrine and autonomic pathways (Irwin & Cole, 2011). Quantum biology provides potential mechanisms for how consciousness might interface with cellular processes at the most fundamental physical level (Lambert et al., 2013). Consciousness studies provide the phenomenological and philosophical resources for understanding how subjective experience relates to objective brain states (Chalmers, 1995).
Together, these domains suggest a model in which mind and body are not separate substances requiring mysterious interaction but rather different aspects of an integrated system operating at multiple scales and levels of organization.

The QPNIT framework identifies 15 primary convergence points across psychoneuroimmunology, quantum theory, and theology, organized into five thematic clusters: holistic ontology and non-reductionism, bidirectional causation between mind and body, non-locality and interconnectedness, information and meaning as causal factors, and the role of consciousness in physical processes (Pokorny, 2026). These convergence points provide the conceptual foundation for integration by demonstrating that apparently disparate perspectives may reflect different facets of underlying unity rather than incompatible worldviews. For example, the PNI finding that psychological states influence immune function converges with the quantum biological observation that information processing in biological systems may involve quantum effects, which converges with the theological insight that consciousness and meaning are causally efficacious in the physical world.

The multi-level ontology of QPNIT is particularly relevant for understanding how mind-body interventions might influence gene expression (Pokorny, 2026). Rather than requiring that mental states directly manipulate DNA molecules, QPNIT proposes a cascade of effects across levels of organization. A mental state or practice (psychological level) influences neural activity patterns (neurological level), which modulate autonomic and neuroendocrine signaling (systemic level), which alters the cellular environment of immune cells (cellular level), which activates or inhibits specific transcription factors (molecular level), which changes the expression of target genes (genomic level). At each transition between levels, quantum effects may play facilitative
roles, though the framework does not require quantum mechanisms for its core predictions about
mind-body effects on gene expression to hold.

Relevance of QPNIT to Mind-Body Research

The QPNIT framework provides several advantages for guiding research on mind-body
interventions and gene expression (Pokorny, 2026). First, it offers a theoretical rationale for why
such effects should exist and through what mechanisms they might operate. Rather than treating
mind-body effects as unexplained anomalies, QPNIT situates them within a coherent model of
multi-level causation in which psychological states naturally and predictably influence biological
processes. This theoretical grounding enables generation of specific, testable hypotheses about
the direction, magnitude, and mediators of mind-body effects on gene expression.

Second, QPNIT provides conceptual resources for understanding the specificity of mind-body effects (Pokorny, 2026). Different mental states and practices might be expected to influence different biological pathways depending on the specific neural, autonomic, and endocrine patterns they engage. For example, practices that enhance vagal tone would be expected to down-regulate NF-κB-related inflammatory genes through the cholinergic anti-inflammatory pathway (Tracey, 2002), while practices that reduce cortisol would be expected to influence glucocorticoid-responsive genes (Cole et al., 2007). QPNIT's multi-level model helps to explain why different interventions might produce different transcriptional profiles and suggests strategies for optimizing interventions to target specific biological outcomes.

Third, QPNIT addresses the philosophical questions that inevitably arise in mind-body
research (Pokorny, 2026). How can mental states, which appear to be subjective and non-
physical, cause changes in gene expression, which is a physical process governed by biochemical
laws? QPNIT's integration of quantum theory with PNI offers a potential answer: consciousness
may interface with physical reality at the quantum level, where the distinction between observer and observed, subject and object, becomes fundamental rather than derivative. This philosophical framework helps to justify mind-body research as scientifically legitimate rather than requiring supernatural or dualistic assumptions.

Fourth, QPNIT honors the spiritual dimensions of many mind-body practices without reducing them to merely psychological techniques (Pokorny, 2026). Meditation, yoga, and similar practices often have spiritual origins and are experienced by practitioners as involving more than stress reduction or relaxation. QPNIT's inclusion of theological perspectives allows for the possibility that these practices engage dimensions of human experience that are genuinely spiritual while still producing measurable biological effects. This both validates the lived experience of practitioners and maintains scientific rigor in studying these phenomena.

For the present dissertation, QPNIT provides the theoretical lens through which the empirical literature on mind-body interventions and gene expression will be examined (Pokorny, 2026). The systematic review and meta-analysis will test a key prediction derived from QPNIT Proposition 3: that mind-body interventions produce consistent down-regulation of pro-inflammatory gene expression, particularly genes regulated by NF-κB. This prediction is based on the convergence of PNI evidence showing that psychological stress up-regulates inflammatory genes, social genomics evidence showing that positive psychological states down-regulate the CTRA profile, and contemplative neuroscience evidence showing that meditation activates parasympathetic pathways that suppress inflammation. By examining whether this prediction is supported across diverse studies, the dissertation provides an empirical test of a core element of the QPNIT framework.
# Psychoneuroimmunology: Foundations and Mechanisms

The field of Psychoneuroimmunology (PNI) provides the scientific bedrock for understanding the intricate and bidirectional communication network linking the mind, the brain, and the immune system (Ader, 2007; Irwin & Vedhara, 2005). Its development marked a paradigm shift away from the long-held belief that the immune system functioned as an autonomous entity, separate from the influence of the central nervous system and psychological states. The foundational discoveries of PNI are the first empirical validations of the core tenets of the QPNIT framework, demonstrating a tangible, measurable connection between the non-physical realm of the psyche and the physical reality of immune cell function (Pokorny, 2026). This section traces the historical development of PNI, examines its key mechanisms, and establishes its relevance for understanding how mind-body interventions might influence inflammatory gene expression.

## Historical Development of Psychoneuroimmunology

The historical roots of PNI can be traced to ancient healers and philosophers who intuitively recognized a connection between emotions and physical health (Solomon, 1987). However, its scientific formalization began in the mid-20th century. Early observations noted immune alterations in psychiatric patients, such as lower lymphocyte counts and diminished antibody responses, hinting at a deeper connection between mental states and immune function (Solomon, 1964). In 1964, George F. Solomon and his colleagues coined the term "psychoimmunology," publishing a speculative but seminal paper that integrated emotions, immunity, and disease (Solomon et al., 1964). This paper proposed that personality factors and emotional states could influence the onset and course of autoimmune diseases, setting the stage
for a new research agenda that would challenge prevailing assumptions about the autonomy of
the immune system.

The true genesis of the field is widely attributed to the groundbreaking work of psychologist Robert Ader and immunologist Nicholas Cohen at the University of Rochester in 1975. In a landmark series of experiments, Ader and Cohen demonstrated that the immune system could be classically conditioned (Ader & Cohen, 1975). They paired a neutral taste stimulus ( saccharin-flavored water) with an immunosuppressive drug (cyclophosphamide) in rats. The cyclophosphamide naturally induced nausea and immunosuppression. Through repeated pairings, the rats learned to associate the saccharin taste with these effects.

Astonishingly, Ader and Cohen found that subsequent exposure to the saccharin water alone was sufficient to induce immunosuppression, a phenomenon they termed "behaviorally conditioned immunosuppression." This discovery was revolutionary, providing the first irrefutable evidence that a process governed by the central nervous system—learning—could directly modulate immune function. It shattered the dogma of immune autonomy and officially launched the field that Ader and Cohen would name "psychoneuroimmunology" (Ader, 1981).

Following this seminal discovery, the anatomical and molecular pathways facilitating neuro-immune communication began to be uncovered (Felten et al., 1985). In 1981, neuroanatomist David L. Felten and his team discovered a network of nerve fibers that directly innervated immune organs like the thymus and spleen, with nerve terminals ending in close proximity to lymphocytes, macrophages, and mast cells. This provided a physical, neuroanatomical basis for direct communication between the nervous and immune systems (Felten & Felten, 1991). A few years later, the work of Candace Pert revealed that neuropeptide-specific receptors were present not only on the walls of brain cells but also on the surface of
immune cells (Pert et al., 1985). This finding suggested a shared biochemical language, where molecules of emotion like neuropeptides could act as information carriers, binding to and influencing both neurons and lymphocytes, thus deeply intertwining emotional states with immunological activity.

These discoveries collectively established that the brain and immune system were not two separate systems but rather a single, integrated defense system, as proposed by Ader, Cohen, and Felten in their foundational 1981 text, "Psychoneuroimmunology" (Ader et al., 1981). The publication of this comprehensive volume solidified the field's identity and provided researchers with a shared vocabulary, theoretical framework, and research agenda. Subsequent editions expanded to incorporate new findings, and the field has continued to grow exponentially, with thousands of studies now documenting the bidirectional communication between psychological processes and immune function (Ader, 2007; Irwin & Vedhara, 2005). The recognition that PNI has achieved is reflected in its integration into medical curricula, the establishment of dedicated journals and professional societies, and its influence on clinical practice in areas ranging from cancer care to infectious disease management.

## The Hypothalamic-Pituitary-Adrenal Axis and Stress Response

Two major physiological systems form the primary conduits for neuro-immune communication: the Hypothalamic-Pituitary-Adrenal (HPA) axis and the Autonomic Nervous System (ANS) (Irwin & Cole, 2011). The HPA axis is the body's central stress response system, a neuroendocrine cascade that translates a perceived threat into a widespread physiological response (Sapolsky et al., 2000; Tsigos & Chrousos, 2002). When the brain perceives a stressor—whether physical (such as an injury) or psychological (such as a threat to social status or a demanding deadline)—the process begins in the paraventricular nucleus of the
hypothalamus with the release of corticotropin-releasing hormone (CRH). CRH travels a short
distance through the hypophyseal portal system to the anterior pituitary gland, stimulating it to
release adrenocorticotropic hormone (ACTH) into the systemic bloodstream (Miller et al., 2007).

ACTH circulates to the adrenal glands, situated atop the kidneys, and signals the adrenal cortex to produce and release glucocorticoids—primarily cortisol in humans and corticosterone in rodents (Sapolsky et al., 2000). Cortisol is the quintessential "stress hormone," and its release orchestrates a massive mobilization of bodily resources to manage the stressor. It increases blood sugar levels by promoting gluconeogenesis in the liver, providing immediate energy for fight-or-flight responses. It enhances cardiovascular tone by increasing heart rate and blood pressure. It shifts metabolic resources away from growth, reproduction, and immune function toward immediate survival needs. And it powerfully modulates the immune system, binding to glucocorticoid receptors (GR) that are expressed on virtually all cells of the immune system (Webster et al., 2002; Coutinho & Chapman, 2011).

The primary immunological role of cortisol is to act as a brake on the immune response,
preventing it from overreacting and causing damage to the host (Irwin & Cole, 2011).

Glucocorticoids suppress the synthesis of pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). They inhibit the proliferation and function of immune cells like T-lymphocytes. They promote the resolution of inflammation and support the return to homeostasis after an immune challenge (Webster et al., 2002). This immunosuppressive function is critical for preventing excessive inflammation and autoimmunity.

Indeed, synthetic glucocorticoids remain among the most widely prescribed anti-inflammatory medications precisely because of their potent immunosuppressive effects.
The HPA axis operates through a negative feedback loop designed to contain the stress response and prevent chronic elevation of cortisol (Sapolsky et al., 2000). When cortisol levels rise, they signal back to the hypothalamus and pituitary to inhibit further release of CRH and ACTH, thereby dampening the stress response. This feedback mechanism ensures that cortisol levels return to baseline after the stressor has passed. However, chronic or repeated stress can dysregulate this system, leading to impaired feedback sensitivity, persistently elevated cortisol levels, or paradoxically low cortisol with reduced GR sensitivity (McEwen, 1998). This HPA axis dysregulation is a hallmark of chronic stress and is associated with numerous health consequences, including immune dysfunction, metabolic disorders, and mental health conditions such as depression and anxiety (Miller et al., 2007; Raison et al., 2006).

## Autonomic Nervous System Pathways

The second major pathway for neuro-immune communication is the Autonomic Nervous System (ANS), composed of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS) (Elenkov et al., 2000). Unlike the HPA axis, which operates through hormonal signaling with relatively slow effects measured in minutes to hours, the ANS provides rapid, "hard-wired" neural communication with immune tissues, producing effects within seconds (Felten et al., 1985). The ANS regulates most visceral functions, including heart rate, respiration, digestion, and glandular secretion, and it plays a critical role in modulating immune responses.

The sympathetic nervous system orchestrates the "fight-or-flight" response, preparing the body for immediate action in the face of threat (Sanders & Straub, 2002). When activated, the SNS releases catecholamines—primarily norepinephrine from sympathetic nerve terminals and epinephrine (adrenaline) from the adrenal medulla. Sympathetic nerve fibers directly innervate
lymphoid organs including the spleen, thymus, lymph nodes, and bone marrow, with nerve terminals making close contact with immune cells (Felten et al., 1985; Felten & Felten, 1991).

Immune cells express adrenergic receptors, particularly β2-adrenergic receptors, allowing them to respond directly to catecholamine signals from the sympathetic nerves (Elenkov et al., 2000).

The effects of sympathetic activation on immune function are complex and context-dependent (Irwin & Cole, 2011). Acute SNS activation can have immunoenhancing effects, mobilizing natural killer (NK) cells and macrophages to prepare for potential injury or infection (Dhabhar, 2014). This acute stress response may be adaptive, priming the immune system to respond rapidly to wounds or pathogens that might result from the threatening situation.

However, chronic SNS activation, as occurs with sustained psychological stress, tends to suppress certain immune functions while promoting inflammation (Sanders & Straub, 2002).

Prolonged β-adrenergic signaling can shift the balance of T-helper cell responses from Th1 (cell-mediated immunity) to Th2 (humoral immunity), impairing the body's defense against intracellular pathogens and tumors. It can also promote inflammatory gene expression through activation of transcription factors such as NF-κB and CREB (Cole et al., 2007).

The parasympathetic nervous system, primarily through the vagus nerve, provides the counterbalance to sympathetic activation, mediating the "rest-and-digest" state (Tracey, 2002).

The vagus nerve is the largest cranial nerve, extending from the brainstem to innervate most visceral organs including the heart, lungs, and gastrointestinal tract. Importantly, the vagus nerve exerts a powerful anti-inflammatory effect through what Kevin Tracey and colleagues have termed the "inflammatory reflex" or "cholinergic anti-inflammatory pathway" (Tracey, 2007; Pavlov & Tracey, 2012). This pathway represents a neural mechanism by which the brain can rapidly and specifically inhibit inflammation in peripheral tissues.
The inflammatory reflex operates through both afferent and efferent vagal pathways (Tracey, 2002). The afferent (sensory) fibers of the vagus nerve detect the presence of peripheral inflammation by sensing cytokines such as IL-1β and TNF-α. This information is relayed to the nucleus tractus solitarius in the brainstem, which integrates the sensory input and coordinates the anti-inflammatory response. The efferent (motor) fibers of the vagus nerve then carry signals to the celiac ganglion and subsequently to the spleen and other organs, triggering the release of the neurotransmitter acetylcholine. Acetylcholine binds to specific receptors, particularly the alpha-7 nicotinic acetylcholine receptor (α7nAChR), on macrophages and other immune cells. This binding potently inhibits the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, while leaving anti-inflammatory cytokines like IL-10 relatively unaffected (Wang et al., 2003; Rosas-Ballina et al., 2011).

The discovery of the cholinergic anti-inflammatory pathway has profound implications for understanding mind-body effects on inflammation (Tracey, 2002). It provides a concrete neurobiological mechanism through which practices that enhance vagal tone—such as slow, deep breathing, meditation, and yoga—might suppress inflammatory processes (Bower & Irwin, 2016). Heart rate variability (HRV), a measure of the beat-to-beat variation in heart rate, serves as a non-invasive index of vagal tone. Higher HRV indicates greater parasympathetic dominance and has been associated with lower levels of inflammatory markers (Thayer & Sternberg, 2006). Mind-body interventions have been shown to increase HRV, suggesting that enhanced vagal activity may mediate some of their anti-inflammatory effects (Pascoe et al., 2017).

## Cytokine Signaling and Immune-Brain Communication

The language of neuro-immune dialogue is spoken largely through cytokines, small proteins secreted by immune cells that act as intercellular signaling molecules (Dantzer, 2001;
Maier & Watkins, 1998). Cytokines can be broadly categorized as pro-inflammatory or anti-inflammatory based on their primary functions. Pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), are released early in an immune response to orchestrate local and systemic inflammation, recruiting immune cells to sites of infection or injury and activating defense mechanisms (Slavich & Irwin, 2014). Anti-inflammatory cytokines, such as interleukin-10 (IL-10), serve to dampen and resolve the inflammatory response once the threat has been addressed.

A crucial insight from PNI research is that immune-to-brain communication is just as important as brain-to-immune signaling—the dialogue is truly bidirectional (Besedovsky & del Rey, 1996; Dantzer et al., 2008). Cytokines produced in the periphery during an immune response can signal back to the brain through multiple pathways, affecting neural activity and behavior. These pathways include: (1) direct transport across the blood-brain barrier at circumventricular organs where the barrier is permeable; (2) active transport via specific cytokine transporters; (3) binding to receptors on cerebral blood vessel endothelial cells, which then produce secondary mediators that affect brain function; and (4) signaling via afferent nerve fibers, particularly the vagus nerve, which conveys information about peripheral inflammation to the brainstem (Banks, 2005; Dantzer et al., 2008).

When the brain receives these inflammatory signals from the periphery, it orchestrates a coordinated behavioral and physiological response known as "sickness behavior" (Dantzer et al., 2008; Hart, 1988). Sickness behavior encompasses the familiar constellation of symptoms that accompany illness: fatigue, malaise, loss of appetite, social withdrawal, hypersomnia, reduced concentration, and anhedonia (inability to experience pleasure). These symptoms are not merely side effects of infection but represent an organized, adaptive motivational state that conserves
energy for the metabolically expensive process of mounting an immune response (Hart, 1988).

The brain, receiving cytokine signals indicating infection, reorganizes behavioral priorities to support recovery.

The discovery that peripheral inflammation can induce sickness behavior through cytokine signaling to the brain has profound implications for understanding the relationship between inflammation and mental health (Miller & Raison, 2016). The symptoms of sickness behavior—fatigue, social withdrawal, anhedonia—closely overlap with symptoms of major depression. This observation has led to the "cytokine hypothesis of depression," which proposes that chronic, low-grade inflammation contributes to the pathophysiology of depression in a substantial subset of patients (Raison et al., 2006; Miller et al., 2009). Supporting this hypothesis, meta-analyses have consistently found elevated levels of pro-inflammatory cytokines, particularly IL-6 and TNF-α, in patients with major depression compared to healthy controls (Howren et al., 2009; Dowlati et al., 2010). Furthermore, administration of pro-inflammatory cytokines as medical treatment (e.g., interferon-alpha for hepatitis C) frequently induces depressive symptoms, and anti-inflammatory treatments have shown antidepressant effects in some trials (Raison et al., 2013).

## Bidirectional Mind-Body Connections

The bidirectional nature of neuro-immune communication creates feedback loops that can either promote health or contribute to disease (Irwin & Cole, 2011). In adaptive circumstances, psychological stress triggers a coordinated stress response that prepares the body for challenge, and the resolution of the stressor leads to return to homeostasis. However, when stress is chronic, the feedback loops can become maladaptive, establishing self-perpetuating cycles of neural dysregulation and immune dysfunction. Chronic stress activates the HPA axis and SNS, leading
to elevated cortisol and catecholamine levels that initially suppress certain immune functions.
Paradoxically, over time, chronic stress also promotes a state of low-grade systemic
inflammation characterized by elevated pro-inflammatory cytokines (Slavich & Irwin, 2014).

This paradox—simultaneous immunosuppression and inflammation—can be understood
through the concept of glucocorticoid resistance (Cohen et al., 2012; Miller et al., 2002). Chronic
exposure to elevated cortisol can lead to down-regulation of glucocorticoid receptors on immune
cells, reducing their sensitivity to cortisol's anti-inflammatory signals. With impaired
glucocorticoid signaling, the brake on inflammatory processes is released, allowing pro-
inflammatory cytokine production to proceed unchecked even in the presence of elevated
cortisol. This state of glucocorticoid resistance has been documented in chronically stressed
caregivers, bereaved individuals, and people with depression, and it appears to be a key
mechanism linking chronic psychological stress to elevated inflammation and disease risk
(Cohen et al., 2012; Pace et al., 2006).

The inflammatory state induced by chronic stress feeds back to the brain, contributing to further psychological dysfunction (Miller & Raison, 2016). Elevated pro-inflammatory cytokines affect neurotransmitter metabolism, reducing the availability of serotonin and dopamine while increasing glutamate release. They impair neuroplasticity and neurogenesis in brain regions critical for mood regulation, such as the hippocampus and prefrontal cortex. They activate the HPA axis, contributing to cortisol dysregulation. And they induce the symptoms of sickness behavior that overlap with depression. This creates a vicious cycle in which psychological stress promotes inflammation, inflammation promotes psychological distress, and the cycle perpetuates itself (Slavich & Irwin, 2014).
Mind-body interventions may interrupt this maladaptive cycle by modulating the neural
inputs to the immune system (Bower & Irwin, 2016). Practices that reduce perceived stress,
enhance positive emotions, activate the parasympathetic nervous system, and down-regulate the
HPA axis can shift the balance from a pro-inflammatory to an anti-inflammatory state. By
targeting the psychological and neural components of the mind-body feedback loop, these
interventions can produce downstream effects on immune function and inflammatory gene
expression. This is the central hypothesis that the present dissertation will test through systematic
review and meta-analysis of the transcriptional effects of mind-body interventions.

Mind-Body Interventions: Definitions and Mechanisms

Mind-body interventions (MBIs) are a heterogeneous group of practices that employ a variety of techniques designed to enhance the mind's capacity to affect bodily function and symptoms (National Center for Complementary and Integrative Health [NCCIH], 2021). These interventions are predicated on the foundational principles of PNI and are central to the QPNIT framework, as they represent conscious, intentional methods for modulating the interconnected field of mind, brain, and immunity (Pokorny, 2026). MBIs operate by training attention and awareness to bring mental processes under greater voluntary control, thereby influencing the downstream physiological processes associated with stress and health. This section examines the major categories of mind-body interventions, their proposed mechanisms of action, and their documented physiological and psychological effects.

Meditation Practices

Meditation is a broad term encompassing a diverse set of practices that train attention and
awareness to achieve a state of mental clarity and emotional calm (Lutz et al., 2008; Goyal et al.,
2014). While meditation has roots in various contemplative traditions spanning thousands of
years, it has been adapted in the modern era into secular protocols that can be studied scientifically and applied clinically. Meditation practices can be categorized along several dimensions, including the object of attention, the cognitive strategy employed, and the tradition from which they derive. Three major categories of meditation have received the most scientific attention: focused attention or concentration meditation, open monitoring or mindfulness meditation, and compassion-based practices such as loving-kindness meditation (Lutz et al., 2008).

Mindfulness meditation, popularized in the West through programs like Mindfulness-Based Stress Reduction (MBSR), involves focusing on one's breath and then broadening attention to notice thoughts, feelings, and bodily sensations as they arise, without judgment (Kabat-Zinn, 1990, 2003). The goal is to cultivate a state of open, non-reactive awareness of the present moment. MBSR was developed by Jon Kabat-Zinn at the University of Massachusetts Medical Center in the late 1970s as an 8-week program combining mindfulness meditation, body awareness, and yoga to help patients cope with chronic pain, illness, and stress (Kabat-Zinn, 1990). Since its development, MBSR has been extensively studied and has demonstrated efficacy for a wide range of conditions including chronic pain, anxiety, depression, stress-related disorders, and immune-related conditions (Gotink et al., 2015; Goldberg et al., 2018).

Mindfulness-Based Cognitive Therapy (MBCT) is a related program that combines mindfulness training with elements of cognitive-behavioral therapy, developed specifically to prevent relapse in recurrent depression (Segal et al., 2002). MBCT teaches participants to recognize the early warning signs of depressive relapse and to relate to negative thoughts and feelings differently, breaking the cycle of ruminative thinking that can trigger depression.

Multiple randomized controlled trials have demonstrated that MBCT significantly reduces the
risk of depressive relapse, particularly in individuals with three or more previous episodes,
leading to its recommendation in clinical guidelines (Kuyken et al., 2016; Piet & Hougaard,
2011).

Transcendental Meditation (TM) is a mantra-based technique where the practitioner silently repeats a specific mantra to quiet the mind and allow it to settle into a state of "transcendental consciousness," characterized by deep rest and reduced mental activity (Schneider et al., 2012; Travis & Shear, 2010). TM was introduced to the West by Maharishi Mahesh Yogi in the 1950s and has been the subject of extensive research. Unlike mindfulness, which emphasizes non-judgmental awareness of present experience, TM aims to transcend thought altogether, reaching a state of pure consciousness without content. Research on TM has documented effects on blood pressure, cardiovascular health, stress hormones, and brain function (Rainforth et al., 2007; Travis & Shear, 2010).

Loving-Kindness Meditation (LKM), also known as metta meditation, is a compassion-
based practice that involves directing feelings of warmth, kindness, and goodwill towards oneself
and others (Hofmann et al., 2011; Galante et al., 2014). The practitioner silently repeats phrases
such as "May you be happy, may you be healthy, may you be free from suffering" while
visualizing the recipient of these wishes. The practice typically begins with directing loving-
kindness toward oneself, then extends to loved ones, neutral persons, difficult persons, and
ultimately all beings. Research has shown that LKM increases positive emotions, reduces
negative emotions, enhances social connection, and may have physiological effects including
increased vagal tone and reduced inflammation (Fredrickson et al., 2008; Kok et al., 2013; Pace
et al., 2009).
Yoga and Movement-Based Practices

Yoga is an ancient practice originating in India that combines physical postures (asanas), breathing exercises (pranayama), and meditation (dhyana) to achieve physical, mental, and spiritual integration (Büssing et al., 2012; Iyengar, 1966). While often perceived in the West primarily as a form of physical exercise, yoga's core purpose is the integration of mind, body, and spirit, with the physical postures serving as preparation for deeper contemplative practice. The Sanskrit word yoga derives from a root meaning "to yoke" or "to unite," reflecting this integrative purpose. Multiple styles of yoga exist, ranging from gentle, restorative practices to vigorous, physically demanding forms, though all share the fundamental elements of breath, movement, and awareness (Büssing et al., 2012).

The physical postures of yoga increase flexibility, strength, and balance while also influencing internal physiology (Field, 2011; Ross & Thomas, 2010). Certain postures compress or stretch specific organs, potentially affecting their function. Inversions, where the head is below the heart, alter blood flow and may affect brain function. The controlled breathing techniques (pranayama) directly influence the autonomic nervous system, with slow, deep, diaphragmatic breathing stimulating the vagus nerve and promoting parasympathetic dominance (Brown & Gerbarg, 2005; Streeter et al., 2012). Pranayama techniques involving extended exhalation, breath retention, or specific breathing patterns have been associated with changes in heart rate variability, cortisol levels, and immune function.

Systematic reviews and meta-analyses have documented the efficacy of yoga for a wide range of conditions (Cramer et al., 2017; Field, 2011). For psychological outcomes, yoga has demonstrated benefits for depression, anxiety, stress, and quality of life (Cramer et al., 2013; Hofmann et al., 2016). For physical conditions, yoga has shown effects on pain, fatigue, sleep
quality, and symptoms associated with chronic diseases including cardiovascular disease,
diabetes, and cancer (Buffart et al., 2012; Cramer et al., 2017). Physiologically, yoga has been
associated with reductions in cortisol, blood pressure, and inflammatory markers, as well as
improvements in heart rate variability, immune cell counts, and brain-derived neurotrophic factor
(BDNF) (Field, 2011; Pascoe & Bauer, 2015).

Tai Chi and Qigong

Tai Chi and Qigong are traditional Chinese mind-body practices that integrate slow,
flowing movements, deep breathing, and a meditative state of mind (Jahnke et al., 2010; Wayne
& Kaptchuk, 2008). Qigong, which translates to "life energy cultivation," is a broader category
of practices aimed at balancing the flow of Qi (vital energy) in the body through coordinated
movement, breath, and intention (Jahnke et al., 2010). Tai Chi (or Tai Chi Chuan) is a more
formalized, martial-arts-derived form of qigong that originated as a system of self-defense but is
now practiced primarily for its health benefits (Wayne & Kaptchuk, 2008). Both practices
emphasize the coordination of movement, breath, and intention (yi), creating a moving
meditation that cultivates internal energy and promotes health.

Research on Tai Chi and Qigong has documented benefits for multiple health outcomes,
including balance and fall prevention in older adults, cardiovascular health, immune function,
psychological well-being, and quality of life in chronic disease populations (Jahnke et al., 2010;
Wang et al., 2010). A comprehensive meta-analysis of randomized controlled trials found that
Tai Chi and Qigong were associated with significant improvements in bone density,
cardiopulmonary function, physical function, falls and balance, quality of life, self-efficacy, and
immune function (Jahnke et al., 2010). Studies have also documented reductions in inflammatory
markers such as C-reactive protein (CRP) and IL-6 following Tai Chi interventions, particularly
in older adults and those with chronic conditions (Oh et al., 2020; Irwin et al., 2007).

Proposed Mechanisms of Action

The primary physiological mechanism through which mind-body interventions exert their effects is the elicitation of the "relaxation response," a term coined by Dr. Herbert Benson to describe a state of deep physiological rest that is the opposite of the "fight-or-flight" stress response (Benson et al., 1974; Benson & Klipper, 1975). The relaxation response is characterized by a shift in the autonomic nervous system away from sympathetic dominance and towards parasympathetic activation. This shift leads to measurable physiological changes, including decreased heart rate, lower blood pressure, reduced oxygen consumption, slower respiration rate, and decreased muscle tension (Benson et al., 1974). By regularly inducing the relaxation response, mind-body interventions help to down-regulate the chronic activation of the stress response systems, promoting return to homeostasis.

At the molecular level, the relaxation response has been associated with rapid changes in gene expression (Bhasin et al., 2013; Dusek et al., 2008). A seminal study by Dusek and colleagues (2008) compared the gene expression profiles of long-term practitioners of relaxation response practices with short-term practitioners and controls. They found that practice of the relaxation response, regardless of the specific technique used, was associated with altered expression of genes involved in energy metabolism, mitochondrial function, insulin secretion, and, critically, inflammatory processes. Long-term practitioners showed enhanced expression of genes associated with the relaxation response compared to controls, while short-term practitioners developed similar changes after eight weeks of practice, demonstrating that these transcriptional alterations can be acquired through training.
Mind-body interventions enhance parasympathetic tone, largely through stimulation of the vagus nerve and activation of the cholinergic anti-inflammatory pathway (Bower & Irwin, 2016; Tracey, 2002). Slow, deep breathing, a component of most mind-body practices, directly activates vagal afferents and enhances heart rate variability (HRV), a measure of vagal tone (Lehrer & Gevirtz, 2014). The resulting increase in cholinergic signaling suppresses production of pro-inflammatory cytokines, providing a direct mechanism for anti-inflammatory effects (Tracey, 2007). Studies have shown that mind-body interventions increase HRV and that increases in HRV are correlated with reductions in inflammatory markers, supporting the vagal mediation hypothesis (Kok et al., 2013; Pascoe et al., 2017).

Mind-body interventions also down-regulate the HPA axis, reducing circulating levels of the stress hormone cortisol (Pascoe et al., 2017; Sanada et al., 2020). Multiple meta-analyses have documented that meditation and yoga are associated with reductions in cortisol levels, both acutely following a single session and chronically with sustained practice (Pascoe et al., 2017; Sanada et al., 2020). This HPA axis modulation has implications for immune function, as chronically elevated cortisol contributes to glucocorticoid resistance and the associated inflammatory state. By normalizing cortisol levels and restoring glucocorticoid receptor sensitivity, mind-body interventions may enhance the body's ability to regulate inflammation appropriately.

## Physiological and Psychological Effects

Mind-body interventions produce a broad range of physiological effects that extend beyond the immediate relaxation response (Pascoe & Bauer, 2015; Field, 2011). Cardiovascular effects include reductions in blood pressure, heart rate, and arterial stiffness, with several meta-analyses supporting the efficacy of meditation and yoga for hypertension (Cramer et al., 2014;
Rainforth et al., 2007). Respiratory effects include improvements in pulmonary function and reductions in symptoms of asthma and chronic obstructive pulmonary disease (Cramer et al., 2017). Metabolic effects include improvements in glucose regulation and lipid profiles in patients with diabetes and metabolic syndrome (Innes & Vincent, 2007). Neurological effects include changes in brain structure and function, with neuroimaging studies documenting alterations in cortical thickness, white matter integrity, and functional connectivity in regions involved in attention, emotion regulation, and self-awareness (Fox et al., 2014; Tang et al., 2015).

The psychological effects of mind-body interventions have been extensively documented through meta-analyses of randomized controlled trials (Goyal et al., 2014; Goldberg et al., 2018). For depression, mindfulness-based interventions have demonstrated moderate effect sizes comparable to antidepressant medication and cognitive-behavioral therapy (Goldberg et al., 2018; Kuyken et al., 2016). For anxiety, meditation interventions produce significant reductions in symptoms across various anxiety disorders (Goyal et al., 2014; Hofmann et al., 2010). For stress, both meditation and yoga interventions consistently reduce perceived stress, with effects that are maintained at follow-up (Pascoe & Bauer, 2015; Sanada et al., 2020). Positive psychological effects include increases in well-being, life satisfaction, self-compassion, and positive affect (Galante et al., 2014; Sedlmeier et al., 2012).

Of particular relevance to the present dissertation are the immunological effects of mind-body interventions (Black & Slavich, 2016; Bower & Irwin, 2016). Multiple studies have documented changes in immune cell counts and function following meditation and yoga interventions. Natural killer (NK) cell activity, a measure of innate immune function important for defense against viral infections and tumors, has been shown to increase following meditation
interventions (Davidson et al., 2003; Infante et al., 1998). CD4+ T cell counts, which are depleted in HIV infection and other immune disorders, have been preserved or enhanced in populations practicing mindfulness meditation (Creswell et al., 2009). Antibody responses to vaccination have been enhanced following mindfulness training, indicating improved adaptive immune function (Davidson et al., 2003).

The inflammatory effects of mind-body interventions are the primary focus of the present research. Multiple systematic reviews and meta-analyses have documented that MBIs reduce inflammatory markers, particularly C-reactive protein (CRP) and interleukin-6 (IL-6) (Black & Slavich, 2016; Bower & Irwin, 2016; Sanada et al., 2020). A comprehensive review by Bower and Irwin (2016) concluded that there is consistent evidence for reductions in markers of inflammation following MBIs, with particularly strong evidence for downregulation of inflammatory signaling pathways at the molecular level. At the transcriptional level, studies have documented that meditation interventions reduce expression of genes regulated by the pro-inflammatory transcription factor NF-κB while preserving or enhancing expression of genes involved in antiviral defense (Black et al., 2013; Creswell et al., 2012). This transcriptional pattern represents a reversal of the Conserved Transcriptional Response to Adversity (CTRA), suggesting that mind-body interventions may counteract the molecular signature of chronic stress.

## Gene Expression and Transcriptional Regulation

The profound physiological effects of psychological states and mind-body interventions are ultimately encoded and executed at the molecular level through the regulation of gene expression. This process, where the instructions contained within our DNA are read and translated into functional proteins, is not a static, predetermined script but a dynamic and fluid
process, exquisitely sensitive to environmental and experiential inputs (Cole, 2014; Slavich &
Cole, 2013). The field of epigenetics has revolutionized our understanding of this interface,
revealing the mechanisms by which experience becomes biology (Meaney, 2010). Within the
QPNIT framework, gene expression and its epigenetic regulation represent the critical point of
transduction, where the non-physical information of the mind-field is converted into the physical
reality of cellular function (Pokorny, 2026). This section examines the basic mechanisms of gene
expression, epigenetic modifications, and the transcriptional programs that link psychological
states to immune function.

Basic Molecular Mechanisms of Gene Expression

Gene expression is the fundamental process by which genetic information encoded in
DNA is converted into functional gene products, primarily proteins (Alberts et al., 2015). This
process occurs in two major steps: transcription and translation. Transcription occurs in the cell
nucleus, where the DNA sequence of a gene is copied into a messenger RNA (mRNA) molecule
by the enzyme RNA polymerase. The mRNA then travels from the nucleus to the cytoplasm,
where it serves as a template for translation—the synthesis of proteins by ribosomes. The
sequence of nucleotides in the mRNA determines the sequence of amino acids in the resulting
protein, which in turn determines the protein's structure and function.

The regulation of gene expression occurs at multiple levels, but transcriptional
regulation—control of whether and how much mRNA is produced from a gene—is the primary
mechanism by which cells respond to environmental signals (Lee & Young, 2013). Transcription
is controlled by transcription factors, proteins that bind to specific regulatory regions of the
DNA, such as promoters and enhancers, to either activate or repress the transcription of
particular genes. Promoter regions are located immediately upstream of genes and contain
binding sites for the general transcription machinery. Enhancer regions can be located thousands of base pairs away from the genes they regulate and contain binding sites for specific transcription factors that modulate gene activity in response to cellular signals.

The activity of transcription factors is regulated by cellular signaling pathways that respond to extracellular signals such as hormones, cytokines, and neurotransmitters (Alberts et al., 2015). For example, glucocorticoid hormones like cortisol exert their effects by binding to glucocorticoid receptors (GR) in the cytoplasm. Upon hormone binding, the GR-hormone complex translocates to the nucleus, where it acts as a transcription factor, binding to glucocorticoid response elements (GREs) in the promoters of target genes to either activate or repress their transcription (Newton, 2000). Similarly, the pro-inflammatory transcription factor NF-κB is activated by cytokines and other inflammatory signals, translocates to the nucleus, and induces expression of genes containing κB binding sites (Hayden & Ghosh, 2008).

The transcriptome refers to the complete set of mRNA transcripts present in a cell at a given time, and its analysis provides a comprehensive snapshot of which genes are active and to what degree (Lockhart & Winzeler, 2000). Technologies for measuring the transcriptome have advanced dramatically over the past two decades. Microarray technology, developed in the 1990s, allowed researchers to measure the expression of thousands of genes simultaneously.

More recently, RNA sequencing (RNA-seq) has provided even more comprehensive and precise measurements of gene expression. These technologies have enabled researchers to examine the transcriptional effects of psychological states and interventions on a genome-wide scale, moving beyond candidate gene approaches to unbiased discovery of affected genes and pathways.
Epigenetic Modifications

Epigenetics refers to modifications to the DNA and its associated proteins that regulate gene activity without changing the underlying DNA sequence itself (Bird, 2007; Goldberg et al., 2007). These epigenetic marks are dynamic and can be added or removed in response to environmental signals, including diet, toxins, and, most relevantly, psychological experiences. Epigenetic mechanisms provide a molecular bridge between experience and gene expression, explaining how environmental factors can have lasting effects on cellular function without altering the genetic code (Meaney, 2010; Weaver et al., 2004). The two most well-studied epigenetic mechanisms are DNA methylation and histone modification.

DNA methylation involves the addition of a methyl group to a cytosine base in the DNA sequence, typically within a CpG dinucleotide (where a cytosine is followed by a guanine) (Bird, 2007; Jones, 2012). CpG sites are often clustered in regions called CpG islands, which are found in the promoter regions of many genes. When methylation occurs in a gene's promoter region, it generally acts to silence the gene by preventing transcription factors from binding and by recruiting proteins that compact the chromatin structure. This process is not permanent and can be reversed through demethylation, allowing dynamic regulation of gene expression in response to environmental cues. The enzymes responsible for adding methyl groups (DNA methyltransferases) and removing them (TET enzymes) are themselves regulated by cellular signaling pathways, providing a link between environmental signals and epigenetic states.

Histone modification is another critical layer of epigenetic control (Kouzarides, 2007; Bannister & Kouzarides, 2011). DNA in the nucleus is not naked but is wrapped around proteins called histones, forming a complex called chromatin. The accessibility of genes for transcription depends on how tightly this chromatin is packed. Histones have "tails" that protrude from the
nucleosome core, and these tails can be chemically modified in ways that affect chromatin structure and gene accessibility. Histone acetylation, the addition of acetyl groups to lysine residues on histone tails, neutralizes their positive charge and causes the chromatin to adopt a more open, relaxed state called euchromatin. This open chromatin structure allows transcription factors to access DNA and promotes gene expression. Conversely, removal of acetyl groups by histone deacetylases (HDACs) leads to a more compact chromatin structure called heterochromatin and gene silencing.

Seminal studies in behavioral epigenetics have powerfully illustrated how early experiences can shape gene expression through epigenetic mechanisms (Meaney, 2010; Weaver et al., 2004). Research in rats showed that high levels of maternal licking and grooming (a form of nurturing) in early life led to decreased DNA methylation of the glucocorticoid receptor (GR) gene promoter in the hippocampus of the offspring. This epigenetic change resulted in higher GR expression, a more efficient HPA axis negative feedback loop, and a lower stress response in adulthood. Conversely, pups receiving low levels of maternal care showed increased methylation, lower GR expression, and a heightened, more reactive stress response throughout life. Remarkably, these epigenetic and behavioral effects could be reversed by cross-fostering or by pharmacological manipulation of epigenetic marks (Weaver et al., 2004). These findings demonstrated that early experience can program lasting changes in stress responsivity through epigenetic modification of key genes.

These findings have been conceptually replicated in humans, where early life adversity is associated with epigenetic changes in stress-related genes (Turecki & Meaney, 2016; McGowan et al., 2009). Studies of human postmortem brain tissue and peripheral blood samples have found that childhood abuse and neglect are associated with increased methylation of the glucocorticoid
receptor gene (NR3C1) and other stress-related genes (McGowan et al., 2009). These epigenetic
changes are correlated with altered stress reactivity and increased risk for mental health disorders
in adulthood. Importantly, emerging evidence suggests that these epigenetic marks may be
modifiable through psychological interventions, including psychotherapy and mind-body
practices (Yehuda et al., 2013; Kaliman et al., 2014).

The Conserved Transcriptional Response to Adversity (CTRA)

Psychological states, particularly chronic stress and adversity, leave a distinct
transcriptional signature on immune cells that has been termed the Conserved Transcriptional
Response to Adversity (CTRA) (Cole, 2014; Cole et al., 2007). This signature was identified
through a series of studies by Steven Cole and colleagues examining the relationship between
social and psychological factors and genome-wide gene expression in circulating immune cells.
The CTRA is consistently observed in individuals experiencing chronic social and psychological
stressors, including loneliness, bereavement, low socioeconomic status, caregiving stress, and
post-traumatic stress disorder (Cole, 2014; Cole et al., 2015).

The CTRA is characterized by a specific pattern of gene expression: up-regulation of
genes involved in inflammation and down-regulation of genes involved in Type I interferon
responses (antiviral immunity) and antibody production (Cole, 2014; Slavich & Cole, 2013). The
up-regulated inflammatory genes include those encoding pro-inflammatory cytokines such as IL-
1β, IL-6, and TNF-α, as well as other mediators of inflammation. The down-regulated genes
include interferon-stimulated genes (ISGs) that are critical for defense against viral infections, as
well as genes involved in immunoglobulin synthesis and antibody production. This pattern
suggests a shift in the immune system's defensive posture—enhanced preparedness for bacterial
infections (which might result from wounds in the context of physical threat) but reduced preparedness for viral infections.

The primary driver of the CTRA is the activation of the sympathetic nervous system (SNS) (Cole, 2014; Irwin & Cole, 2011). Chronic threat perception leads to sustained SNS signaling and the release of norepinephrine from sympathetic nerve terminals innervating lymphoid organs. Norepinephrine binds to β-adrenergic receptors on immune cells, activating intracellular signaling cascades that ultimately influence gene expression. Specifically, β-adrenergic signaling activates pro-inflammatory transcription factors, particularly Nuclear Factor-kappa B (NF-κB) and Activator Protein 1 (AP-1), while simultaneously suppressing the activity of interferon response factors (IRFs) and the glucocorticoid receptor (GR) (Cole et al., 2007; Cole, 2014). The net result is a systematic shift in transcriptional programs that promotes inflammation while impairing antiviral defense.

The CTRA provides a precise molecular explanation for how subjective experiences of adversity translate into objective risks for physical disease (Cole, 2014; Slavich & Cole, 2013). The chronic, low-grade inflammation driven by the CTRA is a major contributor to the pathogenesis of a wide range of diseases, including cardiovascular disease, type 2 diabetes, neurodegenerative disorders, and some cancers. Elevated inflammatory gene expression promotes the development of atherosclerotic plaques, contributes to insulin resistance, enhances tumor microenvironment inflammation, and drives neuroinflammation that damages brain tissue. Simultaneously, the down-regulation of antiviral genes impairs the body's ability to combat viral infections and may contribute to reactivation of latent viruses and reduced tumor surveillance.
Psychological States and Gene Expression

Research in the emerging field of social genomics has documented that a wide range of psychological states and social conditions are associated with distinct patterns of gene expression (Cole, 2014; Slavich & Cole, 2013). Loneliness, defined as the subjective sense of social isolation regardless of actual social network size, has been particularly well-studied. Pioneering work by Cole and colleagues found that lonely individuals showed elevated expression of genes regulated by NF-κB and reduced expression of genes regulated by interferon response factors, the classic CTRA profile (Cole et al., 2007). These associations were not explained by health behaviors, BMI, or other potential confounds and appeared to be driven by the subjective experience of loneliness rather than objective social isolation.

Similar patterns have been observed in response to other forms of psychological adversity. Bereavement following the death of a spouse is associated with elevated inflammatory gene expression (O'Connor et al., 2014). Caregiving for a family member with dementia—a situation involving chronic stress, social isolation, and often anticipatory grief—is associated with the CTRA profile and accelerated cellular aging (Damjanovic et al., 2007; Miller et al., 2008). Low socioeconomic status, whether measured in adulthood or childhood, is associated with elevated inflammation and altered transcriptional profiles (Miller et al., 2009; Chen et al., 2011). Post-traumatic stress disorder is associated with altered expression of immune genes, including both pro-inflammatory and anti-inflammatory pathways (O'Donovan et al., 2011).

Importantly, positive psychological states and resources also influence gene expression, often in directions opposite to the CTRA (Cole et al., 2015; Fredrickson et al., 2013). Eudaimonic well-being—the sense of purpose, meaning, and personal growth in life—has been associated with reduced expression of pro-inflammatory genes and enhanced expression of
antibody-related genes, essentially a reversal of the CTRA profile (Fredrickson et al., 2013). This effect was specific to eudaimonic well-being and was not observed for hedonic well-being (pleasure and positive affect alone), suggesting that the meaning and purpose dimensions of well-being are particularly relevant for gene expression. Optimism, social integration, and a sense of personal mastery have similarly been associated with more favorable transcriptional profiles (Cole et al., 2015).

## Social Genomics and the Biological Embedding of Experience

The field of social genomics examines how social factors—relationships, environments, and experiences—"get under the skin" to influence gene expression and health (Cole, 2014; Slavich & Cole, 2013). This field represents a convergence of molecular biology, psychology, and sociology, providing a mechanistic understanding of how our social world shapes our biological functioning. A central concept in social genomics is the "biological embedding" of social experience—the process by which social factors become encoded in molecular structures that persist over time and influence health trajectories (Hertzman & Boyce, 2010).

The biological embedding of adversity occurs through multiple molecular mechanisms (Slavich & Cole, 2013). Epigenetic modifications, as discussed above, provide one pathway by which experiences can have lasting effects on gene expression. The chronic activation of stress response systems—the HPA axis and the sympathetic nervous system—provides another pathway, as sustained exposure to stress hormones and catecholamines can alter receptor expression, signaling pathway sensitivity, and transcription factor activity. Additionally, the inflammatory mediators produced as part of the CTRA can themselves influence gene expression in a feed-forward manner, perpetuating the pro-inflammatory state even after the initial stressor has resolved.
A key insight from social genomics is that the genome is not a static blueprint but a
dynamic regulatory system that responds to life circumstances in real time (Cole, 2014). The
same genetic sequence can give rise to very different patterns of gene expression—and therefore
very different phenotypes—depending on the social environment in which the individual lives.
This "social regulation of gene expression" provides a molecular basis for understanding how
social relationships, psychological states, and life experiences influence health. It also suggests
that interventions targeting the psychological and social determinants of gene expression could
potentially modify disease risk and promote health, providing a rationale for mind-body
interventions that alter the social-psychological-molecular pathway.

Inflammatory Pathways and Immune Function

Inflammation is a fundamental biological process, an essential component of the innate
immune system's response to harmful stimuli such as pathogens, damaged cells, or irritants
(Medzhitov, 2008). Acute inflammation is a protective, short-term response designed to
eliminate the initial cause of cell injury, clear out necrotic cells and tissues, and initiate tissue
repair. However, when this process becomes dysregulated and persists over long periods, it
results in chronic low-grade inflammation, a maladaptive state that, rather than healing, drives
the pathology of numerous non-communicable diseases (Franceschi et al., 2000; Slavich &
Irwin, 2014). Understanding the key molecular pathways that govern inflammation is crucial for
deciphering how mind-body interventions exert their therapeutic effects, as these pathways are
the direct targets of the transcriptional changes induced by psychological states.

The NF-κB Signaling Pathway

At the heart of the inflammatory response lies the Nuclear Factor-kappa B (NF-κB) signaling pathway (Hayden & Ghosh, 2008; Liu et al., 2017). NF-κB is not a single protein but a
family of transcription factors that act as master regulators of inflammation, immunity, cell survival, and proliferation. The NF-κB family includes five members: RelA (p65), RelB, c-Rel, p50/NF-κB1, and p52/NF-κB2, which form various homo- and heterodimers with distinct transcriptional activities. The most common and well-studied form is the p50/RelA heterodimer, which is the primary mediator of inflammatory gene expression (Hayden & Ghosh, 2008).

In most resting cells, NF-κB dimers are held inactive in the cytoplasm, bound to inhibitory proteins known as IκB (Inhibitor of κB) (Hayden & Ghosh, 2008). The IκB proteins mask the nuclear localization signal of NF-κB, preventing it from entering the nucleus where it could activate transcription. A wide array of stimuli can activate the NF-κB pathway, including signals from pattern recognition receptors (such as Toll-like receptors detecting microbial products), pro-inflammatory cytokines like TNF-α and IL-1β, and cellular stresses including oxidative stress and UV radiation. These activating signals trigger phosphorylation of IκB by the IκB kinase (IKK) complex, leading to ubiquitination and degradation of IκB by the proteasome. Freed from its inhibitor, the active NF-κB dimer translocates to the nucleus, where it binds to specific DNA sequences (κB sites) in the promoter regions of target genes, rapidly initiating their transcription.

The genes activated by NF-κB constitute a veritable "who's who" of the inflammatory response (Liu et al., 2017; Oeckinghaus & Ghosh, 2009). They include genes encoding pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), Interleukin-1 beta (IL-1β), and Interleukin-8 (IL-8). They include genes for chemokines that recruit immune cells to sites of inflammation. They include genes for adhesion molecules (ICAM-1, VCAM-1) that facilitate immune cell attachment to blood vessel walls and migration into tissues. They include enzymes such as cyclooxygenase-2 (COX-2) and inducible nitric oxide
synthase (iNOS) that produce inflammatory mediators. And they include genes that regulate cell
survival, proliferation, and apoptosis (Hayden & Ghosh, 2008).

The NF-κB pathway is subject to multiple layers of regulation that normally ensure appropriate and self-limited inflammatory responses (Hayden & Ghosh, 2008). One key regulatory mechanism is the induction of IκBα by NF-κB itself—when NF-κB activates transcription, one of its target genes is IκBα, which then acts to re-sequester NF-κB in the cytoplasm, creating a negative feedback loop. Other regulatory mechanisms include post-translational modifications of NF-κB subunits that modulate their transcriptional activity, competition between different NF-κB dimers for binding to target genes, and cross-talk with other signaling pathways. Glucocorticoid hormones, acting through the glucocorticoid receptor, can inhibit NF-κB activity through multiple mechanisms, including direct protein-protein interactions and induction of IκBα, which contributes to their anti-inflammatory effects (Newton, 2000).

Pro-Inflammatory Cytokines: IL-6, TNF-α, and IL-1β

Among the most important products of NF-κB activation are the pro-inflammatory
cytokines, particularly Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), and
Interleukin-1 beta (IL-1β) (Dinarello, 2000; Tanaka et al., 2014). These cytokines act as
powerful signaling molecules that amplify and sustain the inflammatory cascade, coordinating
the local and systemic response to injury or infection. Each has distinct roles and mechanisms,
but together they orchestrate the acute phase response and, when chronically elevated, contribute
to the pathophysiology of numerous diseases.

Tumor Necrosis Factor-alpha (TNF-α) was originally identified for its ability to kill
tumor cells but is now recognized as a central mediator of inflammation and immunity (Locksley
et al., 2001). TNF-α is produced mainly by activated macrophages but also by other immune
cells and some non-immune cells. It acts through two receptors, TNFR1 and TNFR2, to induce a
wide range of cellular responses including inflammation, apoptosis, and cell survival depending
on the context. TNF-α activates NF-κB and other transcription factors, induces expression of
other pro-inflammatory cytokines and chemokines, increases vascular permeability, and
promotes the recruitment of immune cells to sites of infection or injury. In the brain, TNF-α
contributes to sickness behavior and has been implicated in depression and neurodegeneration
(Slavich & Irwin, 2014).

Interleukin-1 beta (IL-1β) is another key initiator of inflammation, playing critical roles
in host defense and the acute phase response (Dinarello, 2009). IL-1β is produced mainly by
macrophages and monocytes in response to pathogen-associated molecular patterns, damage-
associated molecular patterns, and inflammatory signals. Unlike most cytokines, IL-1β requires a
two-step activation process: first, pro-IL-1β is synthesized in the cytoplasm in an inactive form;
then, it is cleaved to its active form by caspase-1, which is itself activated within a multiprotein
complex called the inflammasome (Schroder & Tschopp, 2010). This two-step process provides
tight control over IL-1β release. Once released, IL-1β acts through the IL-1 receptor to induce
fever, activate lymphocytes, promote tissue remodeling, and induce expression of other
inflammatory genes.

Interleukin-6 (IL-6) is a pleiotropic cytokine with a central role in the acute phase
response, inflammation, and immune regulation (Tanaka et al., 2014; Hunter & Jones, 2015). IL-
6 is produced by many cell types including macrophages, T cells, B cells, fibroblasts, and
endothelial cells. It acts through two mechanisms: classical signaling through membrane-bound
IL-6 receptor (found mainly on hepatocytes and some immune cells) and trans-signaling through
a soluble form of the receptor that enables IL-6 to affect cells lacking membrane-bound receptor. One of IL-6's major functions is to stimulate the liver to produce acute phase proteins, including C-reactive protein (CRP), fibrinogen, and serum amyloid A, which serve as clinical markers of inflammation. IL-6 also promotes B cell differentiation and antibody production, regulates T cell responses, and has metabolic effects including mobilization of energy substrates during infection.

## Anti-Inflammatory Mechanisms

The inflammatory process is tightly regulated by a corresponding set of anti-inflammatory mechanisms designed to resolve inflammation and restore homeostasis (Serhan & Savill, 2005; Medzhitov, 2008). This resolution phase is not merely a passive waning of pro-inflammatory signals but an active, coordinated process involving specific mediators and cellular programs. Failure of inflammation resolution contributes to chronic inflammatory diseases. Key anti-inflammatory mechanisms include production of anti-inflammatory cytokines, generation of specialized pro-resolving mediators, and activation of neural anti-inflammatory pathways.

A key player in inflammatory resolution is the anti-inflammatory cytokine Interleukin-10 (IL-10) (Ouyang & O'Garra, 2019; Saraiva & O'Garra, 2010). Produced by various immune cells including regulatory T cells (Tregs), macrophages, dendritic cells, and B cells, IL-10 acts as a powerful brake on the inflammatory response. Its primary function is to inhibit the synthesis of pro-inflammatory cytokines by suppressing the activity of macrophages and Th1 cells. IL-10 down-regulates expression of TNF-α, IL-1β, IL-6, and other inflammatory mediators. It inhibits the antigen-presenting capacity of dendritic cells and macrophages, thereby dampening adaptive immune responses. IL-10 also promotes the differentiation and function of regulatory T cells, which further suppress inflammation (Ouyang & O'Garra, 2019).
Resolution of inflammation also involves the production of specialized pro-resolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins (Serhan, 2014). These lipid mediators are generated from omega-3 and omega-6 polyunsaturated fatty acids through enzymatic pathways that become active during the resolution phase. SPMs actively promote resolution by inhibiting neutrophil recruitment, enhancing macrophage phagocytosis of apoptotic cells (efferocytosis), promoting tissue repair, and reducing pain. Deficiencies in SPM production have been implicated in chronic inflammatory diseases, and SPMs represent promising targets for therapeutic intervention.

The balance between pro-inflammatory signals like NF-κB and anti-inflammatory signals like IL-10 is critical for maintaining immune health (Medzhitov, 2008). A disruption in this balance, tipping the scales towards a persistent pro-inflammatory state, is the essence of chronic inflammation. This imbalance can result from excessive activation of pro-inflammatory pathways, impaired anti-inflammatory mechanisms, or both. Mind-body interventions appear to work, in part, by restoring this balance—reducing pro-inflammatory gene expression while preserving or enhancing anti-inflammatory mechanisms (Bower & Irwin, 2016).

Chronic Inflammation and Disease

Chronic low-grade inflammation is now recognized as a common underlying factor in a vast spectrum of modern diseases, including cardiovascular disease, type 2 diabetes, obesity, cancer, neurodegenerative diseases, and depression (Libby, 2007; Franceschi et al., 2000; Slavich & Irwin, 2014). This recognition has transformed our understanding of disease pathogenesis, revealing shared inflammatory mechanisms across seemingly disparate conditions. The concept of "inflammaging"—chronic, sterile, low-grade inflammation associated with
aging—captures the central role of inflammation in age-related disease and decline (Franceschi et al., 2000; Franceschi & Campisi, 2014).

In cardiovascular disease, inflammation plays a critical role at every stage of atherosclerosis, from initiation to plaque rupture and clinical events (Libby, 2002, 2007). Inflammatory cells infiltrate the arterial wall, producing cytokines and reactive oxygen species that promote lipid accumulation, foam cell formation, and the development of atherosclerotic plaques. Pro-inflammatory cytokines destabilize existing plaques, making them prone to rupture. CRP, a marker of systemic inflammation, is a robust predictor of cardiovascular events independent of traditional risk factors. The success of anti-inflammatory therapies in reducing cardiovascular risk (such as the CANTOS trial with an IL-1β inhibitor) has confirmed the causal role of inflammation in heart disease (Ridker et al., 2017).

In type 2 diabetes and obesity, chronic low-grade inflammation contributes to insulin resistance, the hallmark of metabolic syndrome (Hotamisligil, 2006). Adipose tissue, particularly visceral fat, is a source of pro-inflammatory cytokines including TNF-α and IL-6. These inflammatory mediators interfere with insulin signaling in muscle and liver, impairing glucose uptake and metabolism. The inflammatory state of obesity also promotes the development of cardiovascular disease, fatty liver disease, and certain cancers, explaining the clustering of these conditions in metabolic syndrome.

In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, neuroinflammation driven by activated microglia (the brain's resident immune cells) contributes to neuronal damage and disease progression (Heneka et al., 2015). Pro-inflammatory cytokines impair synaptic function, promote tau phosphorylation and amyloid deposition, and create a neurotoxic environment. Peripheral inflammation can signal to the brain to activate microglia,
creating a link between systemic inflammation and neurodegeneration. This connection helps
explain the association between midlife inflammatory markers and later-life cognitive decline
and dementia.

Stress-Inflammation Connections

The connection between psychological stress and inflammation is now well-established
through decades of PNI research (Slavich & Irwin, 2014; Segerstrom & Miller, 2004). Chronic
stress activates the HPA axis and sympathetic nervous system, releasing hormones and
neurotransmitters that influence immune function. While acute stress may temporarily enhance
certain immune functions, chronic stress is consistently associated with elevated levels of
circulating inflammatory markers, particularly CRP and IL-6 (Slavich & Irwin, 2014). This
stress-inflammation link provides a mechanistic explanation for the well-documented
associations between stress and inflammatory diseases.

The mechanisms linking stress to inflammation involve both the upregulation of pro-
inflammatory pathways and the impairment of anti-inflammatory controls (Irwin & Cole, 2011).
Chronic sympathetic activation promotes inflammatory gene expression through β-adrenergic
signaling and NF-κB activation, as discussed above. Simultaneously, chronic exposure to stress
hormones can impair glucocorticoid receptor function, reducing the ability of cortisol to suppress
inflammation (glucocorticoid resistance). The vagal anti-inflammatory pathway may also be
impaired in chronic stress, as reduced vagal tone diminishes cholinergic inhibition of cytokine
production (Thayer & Sternberg, 2006). The net result is a pro-inflammatory state that persists
even in the absence of infection or injury.

At the transcriptional level, the stress-inflammation connection is reflected in the CTRA
pattern described earlier—upregulation of genes containing NF-κB response elements and
downregulation of genes containing interferon response elements (Cole, 2014). This
transcriptional shift represents the genomic embodiment of the stress response, with
consequences that extend beyond the acute stressor. The CTRA is associated with increased risk
for cardiovascular disease, faster progression of HIV infection, shorter survival in cancer, and
worse outcomes in other inflammation-related conditions. Understanding and reversing this
transcriptional pattern is a key goal of mind-body medicine.

Empirical Research: Mind-Body Interventions and Gene Expression

The theoretical links between psychological states, neuro-immune pathways, and
inflammatory gene expression have been substantiated by a growing body of empirical research.
Over the past two decades, pioneering studies have employed genomic technologies to directly
measure the transcriptional changes induced by mind-body interventions. This research provides
compelling evidence that practices like meditation and yoga can systematically alter the activity
of genes involved in stress and inflammation, effectively reversing the molecular signature of
adversity. This section reviews seminal and recent studies demonstrating that MBIs produce
measurable changes in inflammatory gene expression, organized by intervention type and with
attention to key findings, methodological features, and limitations.

Seminal Studies: Benson, Dusek, and the Relaxation Response

One of the earliest and most influential lines of research on the genomic effects of mind-body interventions was conducted by Herbert Benson, Jeffery Dusek, and their colleagues at the Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital (Dusek et al., 2008; Bhasin et al., 2013). Building on Benson's pioneering work characterizing the physiological "relaxation response" (Benson et al., 1974), these researchers sought to identify the
genomic signature of this integrative state using microarray technology to assess genome-wide
gene expression.

In a landmark 2008 study, Dusek and colleagues compared the gene expression profiles
of three groups: long-term practitioners of various relaxation response practices (meditation,
yoga, repetitive prayer; average 9.4 years of practice), healthy controls with no prior experience,
and a subgroup of controls who underwent 8 weeks of relaxation response training (Dusek et al.,
2008). Using Affymetrix microarrays, they examined expression of over 22,000 genes in
peripheral blood mononuclear cells. They found that long-term practitioners differed from
untrained controls in expression of 2,209 genes, while short-term practitioners showed changes
in 1,561 genes after training. Remarkably, there was substantial overlap between the gene
expression profiles of long-term and short-term practitioners, suggesting that the genomic effects
of the relaxation response can be acquired through relatively brief training.

Pathway analysis revealed that relaxation response practice was associated with
significant alterations in genes involved in cellular metabolism, oxidative phosphorylation, and
inflammatory processes (Dusek et al., 2008). Critically, genes related to cellular stress response
and inflammatory signaling, including genes regulated by NF-κB, showed reduced expression in
practitioners compared to controls. This study provided the first evidence that mind-body
practices could produce broad changes in gene expression, including suppression of
inflammatory pathways, providing a potential molecular mechanism for the documented health
benefits of such practices.

A subsequent study by Bhasin and colleagues (2013) examined the temporal dynamics of
relaxation response-induced gene expression changes. They used a within-subjects design to
assess gene expression before and after a single 20-minute relaxation response session in both
long-term practitioners (n=19) and novices who had received 8 weeks of training (n=20). They found that a single practice session induced rapid changes in gene expression that were detectable within 15 minutes. Pathway analysis revealed significant changes in energy metabolism, insulin secretion, mitochondrial function, and inflammatory pathways. Notably, the study found enhanced expression of ATP synthase and insulin signaling genes and reduced expression of NF-κB-related inflammatory genes. These findings demonstrated that the genomic effects of mind-body practices are not only robust but can occur remarkably quickly.

Cole, Creswell, and Social Genomics Approaches

The work of Steven Cole has been pivotal in establishing the field of social genomics and demonstrating the relationship between psychological factors and gene expression (Cole, 2014; Slavich & Cole, 2013). While much of this work documented the adverse transcriptional effects of negative psychological states like loneliness, Cole and his collaborators also began testing whether psychological interventions could reverse these patterns. This research, often conducted in collaboration with J. David Creswell and Michael Irwin at UCLA, has provided key evidence that mindfulness interventions can down-regulate the inflammatory transcriptional signature.

In a landmark 2012 randomized controlled trial, Creswell, Irwin, Burklund, Lieberman, Arevalo, Ma, Breen, and Cole examined the effects of an 8-week Mindfulness-Based Stress Reduction (MBSR) program on gene expression in lonely older adults (Creswell et al., 2012). Participants (n=40) were randomized to MBSR or a wait-list control condition. The primary psychological outcome was loneliness, measured by the UCLA Loneliness Scale. The primary biological outcome was leukocyte gene expression, assessed using targeted RT-PCR for a panel of genes representing the CTRA profile. The MBSR group showed significantly reduced loneliness compared to controls. More importantly, MBSR participants showed reduced
Transcriptional Signature

expression of pro-inflammatory genes regulated by NF-κB. The study provided the first RCT
evidence that a mindfulness intervention could alter inflammatory gene expression in a manner
consistent with reduced social-environmental risk.

Building on this work, Creswell and colleagues (2016) conducted a study examining the effects of intensive meditation retreat on gene expression. The study compared participants attending a 5-day residential meditation retreat with a vacation control group staying at the same resort. Using RNA sequencing for genome-wide transcriptome analysis, they found that the meditation retreat was associated with significant changes in expression of genes involved in amyloid-beta metabolism, immune regulation, and cellular stress responses. While this study was not focused specifically on inflammatory genes, it demonstrated that intensive meditation practice could rapidly alter gene expression in immune cells.

Bower and Breast Cancer Survivors

Julienne Bower at UCLA has conducted important research on mind-body interventions in cancer survivors, a population with elevated inflammation and significant psychological distress (Bower et al., 2015; Bower, Greendale, et al., 2014). Cancer treatments often produce lingering inflammatory effects, and cancer survivors report elevated levels of fatigue, depression, and other symptoms associated with inflammation. Mind-body interventions represent a potential approach to address these symptoms while also targeting underlying inflammatory processes.

In a 2015 randomized controlled trial, Bower and colleagues examined the effects of a 6-week Mindful Awareness Practices (MAPS) intervention on gene expression in younger breast cancer survivors (aged 30-50) with persistent fatigue (Bower et al., 2015). The MAPS intervention is a mindfulness program adapted from MBSR with shorter sessions and no yoga component. Participants (n=71) were randomized to MAPS or a wait-list control condition. Gene
expression was assessed from peripheral blood samples using targeted RT-PCR for a panel of
genes representing inflammatory (NF-κB-related) and antiviral/antibody (interferon-related)
pathways, following the CTRA methodology developed by Cole.

Results showed that the MAPS intervention produced significant improvements in fatigue, depressive symptoms, and other psychological outcomes (Bower et al., 2015). At the molecular level, the mindfulness group showed significant reductions in expression of genes regulated by NF-κB, indicating down-regulated inflammatory signaling. Bioinformatics analysis also suggested increased activity of the glucocorticoid receptor (GR) and interferon response factors (IRFs) in the mindfulness group. This pattern—reduced NF-κB with enhanced GR and IRF activity—represents a reversal of the CTRA and suggests that mindfulness may restore a healthier balance of transcriptional programs in cancer survivors. The study was notable for its rigorous RCT design, assessment of both psychological and biological outcomes, and use of established transcriptional profiling methodology.

## Black and Caregiving Stress

David S. Black has contributed significantly to research on mindfulness, immune function, and gene expression, with particular attention to populations experiencing chronic stress (Black & Slavich, 2016; Black et al., 2013). One population of particular interest has been family dementia caregivers, who experience prolonged stress, elevated inflammation, and increased risk for health problems including accelerated aging.

In a 2013 pilot randomized controlled trial, Black and colleagues examined the effects of a brief meditation intervention (Kirtan Kriya) on gene expression in family dementia caregivers (Black et al., 2013). Kirtan Kriya is a 12-minute yogic meditation practice that combines chanting, hand movements, and visualization. Participants (n=39) were randomized to 8 weeks
Transcriptional Signature

of daily Kirtan Kriya practice or a relaxing music listening control condition. Gene expression
was assessed using Illumina microarrays to examine genome-wide transcriptional profiles in
peripheral blood mononuclear cells.

The meditation group showed significant improvements in depression, mental health, and
cognitive function compared to the music control group (Black et al., 2013). At the genomic
level, 68 genes were differentially expressed between groups after the intervention. Pathway
analysis revealed that the meditation group showed reduced expression of pro-inflammatory
genes, including those regulated by NF-κB, and enhanced expression of genes involved in
immunoglobulin synthesis and B cell function. This pattern was consistent with a reversal of the
CTRA profile. The study demonstrated that even a brief, simple meditation practice could
produce significant changes in gene expression in a chronically stressed population, with
particular effects on inflammatory and immune-related pathways.

Kaliman and Rapid Epigenetic Changes

Research by Perla Kaliman and colleagues has provided important evidence for rapid
epigenetic changes following meditation practice (Kaliman et al., 2014). Building on the
observation that mindfulness practices can quickly alter gene expression, Kaliman's group
investigated whether these effects might be mediated by epigenetic mechanisms, specifically
histone modifications that regulate chromatin structure and gene accessibility.

In a 2014 study, Kaliman and colleagues, in collaboration with Richard Davidson at the
University of Wisconsin, examined the effects of a single day of intensive mindfulness practice
on gene expression and epigenetic markers in experienced meditators (Kaliman et al., 2014). The
study compared experienced meditators (mean 6,124 hours of practice) participating in an 8-hour
intensive mindfulness retreat with a control group of meditation-naive participants engaged in
quiet leisure activities for the same duration. Blood samples were collected before and after the 8-hour period for assessment of gene expression and epigenetic marks.

The results showed that the intensive mindfulness practice produced rapid changes in expression of genes involved in inflammation and stress response (Kaliman et al., 2014). Specifically, experienced meditators showed reduced expression of pro-inflammatory genes including RIPK2 and COX2 following the practice day. Critically, the study found significant changes in expression of histone deacetylase genes, including reduced expression of HDAC2 and HDAC3. Since histone deacetylases act to compact chromatin and silence gene expression, their reduced expression suggests a mechanism for broader transcriptional changes. The molecular changes were correlated with a faster cortisol recovery following a social stress test (Trier Social Stress Test), linking the epigenetic and transcriptional changes to improved physiological stress responses.

## Meditation and Transcriptional Changes

Beyond the landmark studies described above, numerous additional studies have documented transcriptional effects of various meditation practices (Buric et al., 2017; Househam et al., 2017). These studies have employed different meditation techniques, populations, study designs, and gene expression assessment methods, providing a diverse evidence base for the transcriptional effects of meditation. A consistent finding across studies is the down-regulation of inflammatory gene expression, particularly genes regulated by NF-κB, following meditation interventions.

Studies of Transcendental Meditation (TM) have documented changes in gene expression related to stress response, inflammation, and cardiovascular function (Sharma et al., 2008; Wenuganen et al., 2021). A study by Sharma and colleagues (2008) found that TM practice was
associated with reduced expression of genes involved in oxidative stress and inflammation in patients with hypertension and coronary artery disease. A more recent study by Wenuganen and colleagues (2021) examined genome-wide transcriptional changes in long-term TM practitioners and found significant differences in expression of genes involved in immune regulation, cell cycle control, and stress response.

Studies of loving-kindness meditation have also documented transcriptional effects, with particular attention to genes related to social connection and positive affect (Fredrickson et al., 2013; Le et al., 2022). A study by Fredrickson and colleagues (2013) found that a loving-kindness meditation intervention increased positive emotions and enhanced expression of genes related to antibody synthesis while reducing expression of CTRA-related inflammatory genes. Interestingly, a study by Le and colleagues (2022) comparing mindfulness and loving-kindness meditation found that both practices increased positive emotions but only mindfulness significantly reduced CTRA gene expression, suggesting potentially different mechanisms for different meditation types.

## Yoga and Gene Expression

Research on yoga and gene expression has examined effects of various yoga styles and components (physical postures, breathing exercises, meditation) on transcriptional profiles (Cahn et al., 2017; Qu et al., 2013; Kiecolt-Glaser et al., 2010). These studies have documented effects on inflammatory genes, stress response genes, and genes involved in aging and cellular senescence.

A study by Kiecolt-Glaser and colleagues (2010) examined the effects of yoga practice on inflammatory responses to stress in novice and expert yoga practitioners. While not a direct gene expression study, they found that expert yoga practitioners had lower serum levels of IL-6
at baseline and showed smaller IL-6 responses to a laboratory stressor, suggesting that yoga practice modulates inflammatory signaling. A subsequent study (Kiecolt-Glaser et al., 2014) found that a 3-month yoga intervention reduced expression of genes regulated by NF-κB in breast cancer survivors, complementing the findings from meditation studies.

A study by Qu and colleagues (2013) examined gene expression changes in response to an Iyengar yoga intervention in breast cancer survivors with persistent fatigue. Using genome-wide microarray analysis, they found that the yoga intervention was associated with changes in expression of genes involved in inflammation, growth factor signaling, and cell death regulation. Pathway analysis revealed reduced activity of inflammatory signaling pathways, including those regulated by NF-κB, consistent with findings from meditation studies.

Research on yogic breathing (pranayama) has documented specific transcriptional effects of breath regulation practices (Sharma et al., 2014; Bhasin et al., 2013). A study by Sharma and colleagues (2014) found that a yogic breathing intervention (Sudarshan Kriya yoga) produced changes in gene expression related to oxidative stress, antiviral defense, and cell cycle regulation. These findings suggest that the breathing component of yoga may contribute to its transcriptional effects, potentially through modulation of vagal tone and autonomic balance.

## Comparative Studies and Dose-Response Relationships

Comparative studies have begun to examine whether different types of mind-body interventions produce similar or distinct transcriptional signatures (Le et al., 2022; Epel et al., 2016). Understanding the specificity of transcriptional effects could inform intervention selection and development of optimized practices targeting particular biological pathways.

A study by Epel and colleagues (2016) compared the effects of an intensive meditation retreat with a vacation at the same resort on gene expression and other biomarkers. Participants
were randomized to a 6-day meditation retreat or a relaxation vacation. Gene expression was assessed using RNA sequencing. Both groups showed changes in gene expression related to stress and immune regulation, suggesting that rest and relaxation per se have biological effects. However, the meditation group showed more pronounced changes in expression of genes related to amyloid regulation and antiviral immunity, and these changes were maintained at 1-month follow-up only in the meditation group, suggesting specific and more durable effects of meditation practice.

Studies examining dose-response relationships have investigated whether the magnitude of transcriptional changes is related to the amount or intensity of practice (Dusek et al., 2008; Kaliman et al., 2014). The finding by Dusek and colleagues (2008) that long-term practitioners showed more extensive gene expression changes than short-term practitioners suggests a dose-response relationship, though the cross-sectional comparison makes causal inference difficult. The Kaliman study (2014) found that the rapidity and magnitude of transcriptional changes were related to lifetime hours of meditation practice, further supporting a dose-response relationship. However, the field lacks systematic studies examining optimal "doses" of mind-body practice for transcriptional effects, representing an important gap for future research.

## Systematic Reviews and Meta-Analyses

As the body of primary research on mind-body interventions and biological markers has grown, systematic reviews and meta-analyses have become essential for synthesizing the evidence, quantifying overall effects, and identifying patterns across diverse studies. These higher-order analyses provide a broader perspective on the consistency and magnitude of the impact of MBIs on inflammatory and immune parameters, while also highlighting areas of
heterogeneity and uncertainty. This section reviews key systematic reviews and meta-analyses
examining the effects of mind-body interventions on inflammatory markers and gene expression.

Overview of Existing Reviews

A pivotal systematic review published in 2016 by David S. Black and George M. Slavich examined randomized controlled trials investigating the effects of mindfulness meditation on the immune system (Black & Slavich, 2016). This review was notable for its comprehensive scope, examining effects across five categories of immune outcomes: circulating and stimulated inflammatory proteins, cellular transcription factors and gene expression, immune cell counts, immune cell aging (telomerase activity), and antibody responses. The authors identified 20 RCTs meeting inclusion criteria, encompassing diverse populations including healthy adults, cancer patients, HIV-positive individuals, and people with inflammatory conditions.

The review concluded that there was tentative evidence suggesting mindfulness
meditation exerts salutary effects on the immune system, particularly in modulating
inflammation, enhancing cell-mediated immunity, and influencing biological aging (Black &
Slavich, 2016). For inflammatory outcomes, the evidence was strongest for effects on circulating
inflammatory proteins (CRP) and NF-κB-related gene expression, with multiple studies showing
reductions following mindfulness interventions. The authors also noted increased CD4+ T cell
counts in HIV-positive patients practicing mindfulness, suggesting potential enhancement of
cell-mediated immunity. For cellular aging, several studies showed increases in telomerase
activity following mindfulness interventions, suggesting potential effects on biological aging
processes.

However, Black and Slavich (2016) emphasized substantial heterogeneity across studies
in terms of patient populations, intervention designs, control conditions, and laboratory