Brain Structural Differences in Adults Reporting Localized Chronic Pains Mediate Risk for Suicidal Behaviors
Authors: Bhatt Ravi R. , Haddad Elizabeth , Zhu Alyssa H. , Thompson Paul M. , Gupta Arpana , Mayer Emeran A. , Jahanshad Neda 
Published: October 2022

Background

Chronic pain is a global health priority. Mapping pain occurring at different body sites, and variability in brain circuitry related to widespread chronic pain, can elucidate nuanced roles of the central nervous system underlying chronic pain conditions. Chronic pain triples suicide risk; however, whether brain circuitry can inform this risk relationship has not been investigated.

Methods

11,298 participants (mean age: 64 years (range: 58-70), 55% female) with brain MRI from the UK Biobank with pain for more than 3 months in the head, neck/shoulders, back, abdomen, or hips and knees, were age-and-sex-matched to 11,298 pain-free controls. Regression models assessed cortical and subcortical structure differences between individuals reporting chronic pain and those without; mediation models determined the relationship between pain, brain structure and history of attempted suicide.

Outcomes

Chronic pain, regardless of site was associated with, lower surface area throughout the cortex, lower volume in the brainstem, ventral diencephalon, cerebellum, and pallidum, lower cortical thickness in the anterior insula, and greater cortical thickness in the superior parietal cortex. When differentiated by pain site, participants with chronic headaches distinctly showed an overall thicker cortex compared with controls. Chronic pain was associated with an elevated risk for suicide attempt and this relationship was mediated by lower cerebellum volume.

Interpretation

There are shared cortical mechanisms underlying chronic pain across body sites. An extensive thicker cortex in chronic headache was consistent with previous research. Cerebellum volume mediates the relationship between chronic pain and suicide attempt, serving as a potential biomarker prognostic for suicidal behaviors in chronic pain patients.

Funding

National Science Foundation, National Institutes of Health

Research in Context

Evidence before this study

Chronic pain is the leading cause of disability and disease burden globally, and its prevalence is increasing. As perception of pain occurs in the brain, alterations in brain structure have been investigated in various chronic pain conditions. However, published works, to date, report inconsistent findings, and typically do not compare a wide range of chronic pain types within the same study. Chronic pain is a risk factor for suicidal ideation, which can occur in up to 41% of individuals with chronic pain, but the role of specific brain systems in mediating the relationship between chronic pain and suicide has not been investigated.

Added value of this study

The present study reports alterations of brain structure in the largest and most well-powered sample reporting chronic pain to date (N = 11,298) compared to 11,298 pain-free controls, while taking into account age, sex, socioeconomic status, anxiety and depression. The effect of chronic pain on the brain is also evaluated as a function of pain across one or more of six different sites in the body (i.e. headaches, neck and shoulder, back, abdominal, hip and knee pain). Lower cortical surface area throughout the brain was related to chronic pain, and shown to be far more extensive than previously recognized. We, for the first time, show that participants with chronic headaches compared to controls have, on average, thicker gray matter throughout the cortex, a distinct and opposite pattern of effects than when individuals with other systemic pain conditions are compared to controls. A higher prevalence of suicide attempt history was noted in participants reporting chronic pain than controls. The relationship between chronic pain and suicide attempt, was mediated by the volume of the cerebellum, implicating spinocerebellar mechanisms.

Implications of all the available evidence

Brain structure plays a key role in chronic pain, and mediates the role between pain and suicidal behaviors, independent of commonly presenting comorbidities. Our results highlight the concept of central sensitization and the role of the brain’s interacting networks in the presence of chronic pain. The thicker cortical gray matter in chronic headaches vs. controls - compared to other chronic pain conditions - indicates different mechanisms underlie these conditions and suggests that a clinically different approach to treatment is warranted. The cerebellum volume is a reliable mediator between chronic pain and suicide attempt, a finding that provides insight into potential underlying spinocerebellar mechanisms and to how treatments such as ketamine infusions may be beneficial in chronic pain and suicidal risk behavior management. Our work shows reliable neurobiological support for the multiple brain networks impacted and in regulating mood in the chronic pain phenotype.