bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive Reserve in Model Systems for Mechanistic Discovery: The Importance of Longitudinal Studies
Authors: McQuail Joseph A. , Dunn Amy R. , Stern Yaakov , Barnes Carol A. , Kempermann Gerd , Rapp Peter R. , Kaczorowski Catherine C. , Foster Thomas C.
Published: January 2021

The goal of this review article is to provide a resource for longitudinal studies, using animal models, directed at understanding and modifying the relationship between cognition and brain structure and function throughout life. We propose that forthcoming longitudinal studies will build upon a wealth of knowledge gleaned from prior cross-sectional designs to identify early predictors of variability in cognitive function during aging, and characterize fundamental neurobiological mechanisms that underlie the vulnerability to, and the trajectory of, cognitive decline. Finally, we present examples of biological measures that may differentiate mechanisms of the cognitive reserve at the molecular, cellular, and network level.
Mini Review: Correlations of Cognitive Domains With Cerebrospinal Fluid α-Synuclein Levels in Patients With Parkinson's Disease
Authors: Murakami Hidetomo , Ono Kenjiro , Shiraishi Tomotaka , Umehara Tadashi , Omoto Shusaku , Iguchi Yasuyuki
Published: January 2021

The level of α-synuclein, a component of Lewy bodies, in cerebrospinal fluid (CSF) in Parkinson's disease (PD) has attracted recent attention. Most meta-analyses conclude that CSF levels of α-synuclein are decreased in PD. Patients with PD present with cognitive impairment, including frontal/executive dysfunction in the early phase and later emergence of visuospatial and mnemonic deficits. To examine whether CSF α-synuclein levels reflect the activities of various cognitive domains, we reviewed reports examining the association of these levels with cognitive performance in each domain in PD. Among 13 cross-sectional studies, five showed that a lower CSF α-synuclein level was associated with worse cognitive function. In four of these five reports, frontal/executive function showed this association, suggesting a link of the pathophysiology with Lewy bodies. In three other reports, a higher CSF α-synuclein level was associated with temporal-parieto-occipital cognitive deterioration such as memory. In the other five reports, the CSF α-synuclein level did not correlate with cognitive performance for any domain. In four longitudinal studies, a higher baseline CSF α-synuclein level was associated with a worse cognitive outcome, including cognitive processing speed, visuospatial function and memory in two, but not with any cognitive outcome in the other two. The different associations may reflect the heterogeneous pathophysiology in PD, including different pathogenic proteins, neurotransmitters. Thus, more studies of the association between cognitive domains and CSF levels of pathogenic proteins are warranted.
Lipopolysaccharide Pre-conditioning Attenuates Pro-inflammatory Responses and Promotes Cytoprotective Effect in Differentiated PC12 Cell Lines via Pre-activation of Toll-Like Receptor-4 Signaling Pathway Leading to the Inhibition of Caspase-3/Nuclear Factor-κappa B Pathway
Authors: Sangaran Pushpa Gandi , Ibrahim Zaridatul Aini , Chik Zamri , Mohamed Zahurin , Ahmadiani Abolhassan
Published: January 2021

Lipopolysacharide (LPS) pre-conditioning (PC), has been shown to exert protective effects against cytotoxic effects. Therefore, we hypothesized, the tolerance produced by LPS PC will be resulted by the alterations and modifications in gene and protein expression. With reference to the results of MTT assays, AO/PI staining, and Annexin V-FITC analyses of LPS concentration (0.7815–50 μg/mL) and time-dependent (12–72 h) experiments, the pre-exposure to 3 μg/mL LPS for 12 h protected the differentiated PC12 cells against 0.75 mg/mL LPS apoptotic concentration. LPS-treated cells secreted more inflammatory cytokines like IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-17, IFN-γ, and TNF-α than LPS-PC cells. The production of inflammatory mediators ROS and NO was also higher in the LPS-induced cells compared to LPS-PC cells. Conversely, anti-inflammatory cytokines (like IL-10, IL-13, CNTF, and IL-1Ra) were upregulated in the LPS-PC cells but not in the LPS-induced cells. Meanwhile, the LPS initiated caspase-8 which in turn activates effector caspase 3/7. When the activities of caspases in the LPS-induced cells were inhibited using z-VADfmk and z-DEVDfmk, the expressions of c-MYC and Hsp70 were increased, but p53 was reduced. The potential molecules associated with protective and destructive effect was measured by RT2 Profiler PCR array to elucidate the signaling pathways and suggested inhibition NF-κB/caspase-3 signaling pathway regulates the cytoprotective genes and proto-oncogenes. In conclusion, this study provides a basis for future research to better understand the molecular mechanism underlying LPS pre-conditioning /TLR4 pre-activation and its functional role in offering cytoprotective response in neuronal environment.
Resting-State Co-activation Patterns as Promising Candidates for Prediction of Alzheimer’s Disease in Aged Mice
Authors: Adhikari Mohit H. , Belloy Michaël E. , Van der Linden Annemie , Keliris Georgios A. , Verhoye Marleen
Published: January 2021

Alzheimer’s disease (AD), a neurodegenerative disorder marked by accumulation of extracellular amyloid-β (Aβ) plaques leads to progressive loss of memory and cognitive function. Resting-state fMRI (RS-fMRI) studies have provided links between these two observations in terms of disruption of default mode and task-positive resting-state networks (RSNs). Important insights underlying these disruptions were recently obtained by investigating dynamic fluctuations in RS-fMRI signals in old TG2576 mice (a mouse model of amyloidosis) using a set of quasi-periodic patterns (QPP). QPPs represent repeating spatiotemporal patterns of neural activity of predefined temporal length. In this article, we used an alternative methodology of co-activation patterns (CAPs) that represent instantaneous and transient brain configurations that are likely contributors to the emergence of commonly observed RSNs and QPPs. We followed a recently published approach for obtaining CAPs that divided all time frames, instead of those corresponding to supra-threshold activations of a seed region as done traditionally, to extract CAPs from RS-fMRI recordings in 10 TG2576 female mice and eight wild type littermates at 18 months of age. Subsequently, we matched the CAPs from the two groups using the Hungarian method and compared the temporal (duration, occurrence rate) and the spatial (lateralization of significantly co-activated and co-deactivated voxels) properties of matched CAPs. We found robust differences in the spatial components of matched CAPs. Finally, we used supervised learning to train a classifier using either the temporal or the spatial component of CAPs to distinguish the transgenic mice from the WT. We found that while duration and occurrence rates of all CAPs performed the classification with significantly higher accuracy than the chance-level, blood oxygen level-dependent (BOLD) signals of significantly activated voxels from individual CAPs turned out to be a significantly better predictive feature demonstrating a near-perfect classification accuracy. Our results demonstrate resting-state co-activation patterns are a promising candidate in the development of a diagnostic, and potentially, prognostic RS-fMRI biomarker of AD.
Nonlinear Control in the Nematode C. elegans
Authors: Morrison Megan , Fieseler Charles , Kutz J. Nathan
Published: January 2021

Recent whole-brain calcium imaging recordings of the nematode C. elegans have demonstrated that the neural activity associated with behavior is dominated by dynamics on a low-dimensional manifold that can be clustered according to behavioral states. Previous models of C. elegans dynamics have either been linear models, which cannot support the existence of multiple fixed points in the system, or Markov-switching models, which do not describe how control signals in C. elegans neural dynamics can produce switches between stable states. It remains unclear how a network of neurons can produce fast and slow timescale dynamics that control transitions between stable states in a single model. We propose a global, nonlinear control model which is minimally parameterized and captures the state transitions described by Markov-switching models with a single dynamical system. The model is fit by reproducing the timeseries of the dominant PCA mode in the calcium imaging data. Long and short time-scale changes in transition statistics can be characterized via changes in a single parameter in the control model. Some of these macro-scale transitions have experimental correlates to single neuro-modulators that seem to act as biological controls, allowing this model to generate testable hypotheses about the effect of these neuro-modulators on the global dynamics. The theory provides an elegant characterization of control in the neuron population dynamics in C. elegans. Moreover, the mathematical structure of the nonlinear control framework provides a paradigm that can be generalized to more complex systems with an arbitrary number of behavioral states.
The Medial Thalamus Plays an Important Role in the Cognitive and Emotional Modulation of Orofacial Pain: A Functional Magnetic Resonance Imaging-Based Study
Authors: Jin Yu , Yang Hong , Zhang Feifei , Wang Jue , Liu He , Yang Xin , Long Hu , Li Fei , Gong Qiyong , Lai Wenli
Published: January 2021

The thalamus plays a critical role in the perception of orofacial pain. We investigated the neural mechanisms of orofacial pain by exploring the intrinsic functional alterations of the thalamus and assessing the changes in functional connectivity (FC) between the thalamic subregions with significant functional alterations and other brain regions in orofacial pain using the seed-based FC approach. There were 49 participants in the orofacial pain group and 49 controls. Orofacial pain was caused by orthodontic separators. The resting-state functional magnetic resonance imaging data of the two groups were analyzed to obtain the fractional amplitude of low-frequency fluctuations (fALFF) of the thalamus; the thalamic subregions with significant fALFF abnormalities were used as seeds for FC analysis. Student's t-tests were used for comparisons. Pearson's correlation analysis was performed using SPM software. Forty-four participants with orofacial pain (mean age, 21.0 ± 0.9 years; 24 women) and 49 age- and sex-matched controls (mean age, 21.0 ± 2.6 years; 27 women) were finally included. Compared with the control group, the orofacial pain group demonstrated the following: (1) increased function in the dorsal area of the thalamus and decreased function in the medial thalamus; (2) decreased FC between the medial thalamus and 12 brain regions (p < 0.05, family-wise error corrected, voxel > 100); and (3) potential positive and negative correlations between the medial thalamus-seeded FC and visual analog scale score changes (p < 0.05, AlphaSim corrected). The findings show that the medial and dorsal thalami play important roles in orofacial pain perception, and that the medial thalamus likely plays an important role in the cognitive and emotional modulation of orofacial pain.
Blood–Brain Barrier Disruption and Hemorrhagic Transformation in Acute Ischemic Stroke: Systematic Review and Meta-Analysis
Authors: Arba Francesco , Rinaldi Chiara , Caimano Danilo , Vit Federica , Busto Giorgio , Fainardi Enrico
Published: January 2021

Introduction: Hemorrhagic transformation (HT) is a complication of reperfusion therapy for acute ischemic stroke. Blood–brain barrier (BBB) disruption is a crucial step toward HT; however, in clinical studies, there is still uncertainty about this relation. Hence, we conducted a systematic review and meta-analysis to summarize the current evidence.

Methods: We performed systematic review and meta-analysis of observational studies from January 1990 to March 2020 about the relation between BBB disruption and HT in patients with acute ischemic stroke with both computed tomography (CT) and magnetic resonance (MR) assessment of BBB. The outcome of interest was HT at follow-up imaging evaluation (within 48 h from symptom onset). We pooled data from available univariate odds ratios (ORs) in random-effects models with DerSimonian–Laird weights and extracted cumulative ORs.

Results: We included 30 eligible studies (14 with CT and 16 with MR), N = 2,609 patients, with 88% and 70% of patients included in CT and MR studies treated with acute stroke therapy, respectively. The majority of studies were retrospective and had high or unclear risk of bias. BBB disruption was measured with consistent methodology in CT studies, whereas in MR studies, there was more variability. All CT studies provided a BBB disruption cutoff predictive of HT. Four CT and 10 MR studies were included in the quantitative analysis. We found that BBB disruption was associated with HT with both CT (OR = 3.42; 95%CI = 1.62–7.23) and MR (OR = 9.34; 95%CI = 3.16–27.59). There was a likely publication bias particularly for MR studies.

Conclusion: Our results confirm that BBB disruption is associated with HT in both CT and MR studies. Compared with MR, CT has been more uniformly applied in the literature and has resulted in more consistent results. However, more efforts are needed for harmonization of protocols and methodology for implementation of BBB disruption as a neuroradiological marker in clinical practice.
Anti-CD20 B Cell Treatment for Relapsing Multiple Sclerosis
Authors: Roach Charles A. , Cross Anne H.
Published: January 2021

Several clinical trials have demonstrated the efficacy of lytic therapies targeting B cells in the treatment of relapsing multiple sclerosis (MS). More modest efficacy has been noted in the primary progressive subtype of MS. Clinical success has increased interest in the role of B cells in the pathogenesis of MS and in ways to potentially improve upon current B cell therapies. In this mini review, we will critically review previous and ongoing clinical trials of anti-CD20 monoclonal antibodies in MS, including rituximab, ocrelizumab, ofatumumab, and ublituximab. Side effects and adverse event profiles will be discussed. Studies examining the proposed mechanisms of action of B cell depleting therapies will also be reviewed.
Duration of Treatment Effect Using IncobotulinumtoxinA for Upper-limb Spasticity: A Post-hoc Analysis
Authors: Kaňovský Petr , Elovic Elie P. , Hanschmann Angelika , Pulte Irena , Althaus Michael , Hiersemenzel Reinhard , Marciniak Christina
Published: January 2021

The efficacy and safety of incobotulinumtoxinA ≤400 U was demonstrated in subjects with post-stroke upper-limb spasticity in a randomized, double-blind Phase 3 study with an open-label extension (OLEX; EudraCT number 2005-003951-11, NCT00432666). We report a post-hoc analysis of the duration of the treatment effect. Subjects completing the placebo-controlled main period (single injection cycle with 12–20-week observation) entered the OLEX and received a maximum of five further treatments (maximum duration 69 weeks) with incobotulinumtoxinA ≤400 U at flexible intervals with a minimum duration of 12 weeks, based on clinical need. Intervals between two consecutive incobotulinumtoxinA injections, excluding treatment intervals prior to the end-of-study visit, were evaluated. Of 437 incobotulinumtoxinA treatment intervals, 415 received by 136 subjects were included in the post-hoc analysis. More than half (52.3%; 217/415) of all incobotulinumtoxinA reinjections were administered at Week ≥14, 31.1% (129/415) at Week ≥16, 19.0% (79/415) at Week ≥18, and 11.6% (48/415) at Week ≥20. The duration of effect may vary and can exceed 20 weeks or more, which was observed in at least one injection cycle in 29.4% (40/136) subjects over the course of their treatment. Data show that incobotulinumtoxinA retreatment for upper-limb spasticity may not be required at 12-week intervals and provides evidence for flexible treatment intervals beyond this time frame.
Preoperative Applications of Navigated Transcranial Magnetic Stimulation
Authors: Haddad Alexander F. , Young Jacob S. , Berger Mitchel S. , Tarapore Phiroz E.
Published: January 2021

Preoperative mapping of cortical structures prior to neurosurgical intervention can provide a roadmap of the brain with which neurosurgeons can navigate critical cortical structures. In patients undergoing surgery for brain tumors, preoperative mapping allows for improved operative planning, patient risk stratification, and personalized preoperative patient counseling. Navigated transcranial magnetic stimulation (nTMS) is one modality that allows for highly accurate, image-guided, non-invasive stimulation of the brain, thus allowing for differentiation between eloquent and non-eloquent cortical regions. Motor mapping is the best validated application of nTMS, yielding reliable maps with an accuracy similar to intraoperative cortical mapping. Language mapping is also commonly performed, although nTMS language maps are not as highly concordant with direct intraoperative cortical stimulation maps as nTMS motor maps. Additionally, nTMS has been used to localize cortical regions involved in other functions such as facial recognition, calculation, higher-order motor processing, and visuospatial orientation. In this review, we evaluate the growing literature on the applications of nTMS in the preoperative setting. First, we analyze the evidence in support of the most common clinical applications. Then we identify usages that show promise but require further validation. We also discuss developing nTMS techniques that are still in the experimental stage, such as the use of nTMS to enhance postoperative recovery. Finally, we highlight practical considerations when utilizing nTMS and, importantly, its safety profile in neurosurgical patients. In so doing, we aim to provide a comprehensive review of the role of nTMS in the neurosurgical management of a patient with a brain tumor.
Patient Reported Outcomes Measurements Information System in Stroke Patients in Full and Shortened Format
Authors: Lens Charlotte , Demeestere Jelle , Vanhaecht Kris , Lemmens Robin
Published: January 2021

Introduction: The modified Rankin Scale (mRS) after 90 days documents outcome in stroke patients, but focusses only on activities of daily living. Here we studied stroke outcome beyond these activities by the Dutch-Flemish version of the Patient Reported Outcomes Measurement Information System (PROMIS) questionnaire.

Patients and Methods: We documented the mRS at day 90 in stroke patients who filled out a questionnaire on pain intensity and seven PROMIS domains: physical function, ability to participate in social roles, anxiety, fatigue, depression, sleep disturbance, pain interference. In a subgroup of patients this questionnaire was reduced to one overall question per PROMIS domain. We correlated these findings with the mRS.

Results: We received 102 questionnaires and identified physical function as the most affected PROMIS domain. The strongest correlation with mRS was found for the health domains of physical function (ρs = 0.70, p < 0.001) and ability to participate in social roles (ρs = 0.61, p < 0.001). The other domains with substantial proportions of patients with worse scores compared to the general population (19–44%) correlated weakly with the mRS. We identified a strong correlation between the single question per health domain and the overall score per PROMIS domain.

Discussion and Conclusion: PROMIS better reflects the overall health status of stroke patients beyond functional outcome as measured by the mRS. Simplification of the questionnaire with a single question per PROMIS domain could potentially replace the full questionnaire, but needs further validation.
A Functional Near-Infrared Spectroscopy Examination of the Neural Correlates of Cognitive Shifting in Dimensional Change Card Sort Task
Authors: Li Hui , Wu Dandan , Yang Jinfeng , Xie Sha , Luo Jiutong , Chang Chunqi
Published: January 2021

This study aims to examine the neural correlates of cognitive shifting during the Dimensional Change Card Sort Task (DCCS) task with functional near-infrared spectroscopy. Altogether 49 children completed the DCCS tasks, and 25 children (Mage = 68.66, SD = 5.3) passing all items were classified into the Switch group. Twenty children (Mage = 62.05, SD = 8.13) committing more than one perseverative errors were grouped into the Perseverate group. The Switch group had Brodmann Area (BA) 9 and 10 activated in the pre-switch period and BA 6, 9, 10, 40, and 44 in the post-switch period. In contrast, the Perseverate group had BA 9 and 10 activated in the pre-switch period and BA 8, 9, 10 in the post-switch period. The general linear model results afford strong support to the “V-shape curve” hypothesis by identifying a significant decrease–increase cycle in BA 9 and 44, the neural correlations of cognitive shifting.
Neural Basis and Motor Imagery Intervention Methodology Based on Neuroimaging Studies in Children With Developmental Coordination Disorders: A Review
Authors: Irie Keisuke , Matsumoto Amiri , Zhao Shuo , Kato Toshihiro , Liang Nan
Published: January 2021

Although the neural bases of the brain associated with movement disorders in children with developmental coordination disorder (DCD) are becoming clearer, the information is not sufficient because of the lack of extensive brain function research. Therefore, it is controversial about effective intervention methods focusing on brain function. One of the rehabilitation techniques for movement disorders involves intervention using motor imagery (MI). MI is often used for movement disorders, but most studies involve adults and healthy children, and the MI method for children with DCD has not been studied in detail. Therefore, a review was conducted to clarify the neuroscientific basis of the methodology of intervention using MI for children with DCD. The neuroimaging review included 20 magnetic resonance imaging studies, and the neurorehabilitation review included four MI intervention studies. In addition to previously reported neural bases, our results indicate decreased activity of the bilateral thalamus, decreased connectivity of the sensory-motor cortex and the left posterior middle temporal gyrus, bilateral posterior cingulate cortex, precuneus, cerebellum, and basal ganglia, loss of connectivity superiority in the abovementioned areas. Furthermore, reduction of gray matter volume in the right superior frontal gyrus and middle frontal gyrus, lower fractional anisotropy, and axial diffusivity in regions of white matter pathways were found in DCD. As a result of the review, children with DCD had less activation of the left brain, especially those with mirror neurons system (MNS) and sensory integration functions. On the contrary, the area important for the visual space processing of the right brain was activated. Regarding of characteristic of the MI methods was that children observed a video related to motor skills before the intervention. Also, they performed visual-motor tasks before MI training sessions. Adding action observation during MI activates the MNS, and performing visual-motor tasks activates the basal ganglia. These methods may improve the deactivated brain regions of children with DCD and may be useful as conditioning before starting training. Furthermore, we propose a process for sharing the contents of MI with the therapist in language and determining exercise strategies.
Effects of Long-Term Meditation Practices on Sensorimotor Rhythm-Based Brain-Computer Interface Learning
Authors: Jiang Xiyuan , Lopez Emily , Stieger James R. , Greco Carol M. , He Bin
Published: January 2021

Sensorimotor rhythm (SMR)-based brain–computer interfaces (BCIs) provide an alternative pathway for users to perform motor control using motor imagery. Despite the non-invasiveness, ease of use, and low cost, this kind of BCI has limitations due to long training times and BCI inefficiency—that is, the SMR BCI control paradigm may not work well on a subpopulation of users. Meditation is a mental training method to improve mindfulness and awareness and is reported to have positive effects on one’s mental state. Here, we investigated the behavioral and electrophysiological differences between experienced meditators and meditation naïve subjects in one-dimensional (1D) and two-dimensional (2D) cursor control tasks. We found numerical evidence that meditators outperformed control subjects in both tasks (1D and 2D), and there were fewer BCI inefficient subjects in the meditator group. Finally, we also explored the neurophysiological difference between the two groups and showed that the meditators had a higher resting SMR predictor, more stable resting mu rhythm, and a larger control signal contrast than controls during the task.
Presenilin-Deficient Neurons and Astrocytes Display Normal Mitochondrial Phenotypes
Authors: Contino Sabrina , Suelves Nuria , Vrancx Céline , Vadukul Devkee M. , Payen Valery L. , Stanga Serena , Bertrand Luc , Kienlen-Campard Pascal
Published: January 2021

Presenilin 1 (PS1) and Presenilin 2 (PS2) are predominantly known as the catalytic subunits of the γ-secretase complex that generates the amyloid-β (Aβ) peptide, the major constituent of the senile plaques found in the brain of Alzheimer's disease (AD) patients. Apart from their role in γ-secretase activity, a growing number of cellular functions have been recently attributed to PSs. Notably, PSs were found to be enriched in mitochondria-associated membranes (MAMs) where mitochondria and endoplasmic reticulum (ER) interact. PS2 was more specifically reported to regulate calcium shuttling between these two organelles by controlling the formation of functional MAMs. We have previously demonstrated in mouse embryonic fibroblasts (MEF) an altered mitochondrial morphology along with reduced mitochondrial respiration and increased glycolysis in PS2-deficient cells (PS2KO). This phenotype was restored by the stable re-expression of human PS2. Still, all these results were obtained in immortalized cells, and one bottom-line question is to know whether these observations hold true in central nervous system (CNS) cells. To that end, we carried out primary cultures of PS1 knockdown (KD), PS2KO, and PS1KD/PS2KO (PSdKO) neurons and astrocytes. They were obtained from the same litter by crossing PS2 heterozygous; PS1 floxed (PS2+/−; PS1flox/flox) animals. Genetic downregulation of PS1 was achieved by lentiviral expression of the Cre recombinase in primary cultures. Strikingly, we did not observe any mitochondrial phenotype in PS1KD, PS2KO, or PSdKO primary cultures in basal conditions. Mitochondrial respiration and membrane potential were similar in all models, as were the glycolytic flux and NAD+/NADH ratio. Likewise, mitochondrial morphology and content was unaltered by PS expression. We further investigated the differences between results we obtained here in primary nerve cells and those previously reported in MEF cell lines by analyzing PS2KO primary fibroblasts. We found no mitochondrial dysfunction in this model, in line with observations in PS2KO primary neurons and astrocytes. Together, our results indicate that the mitochondrial phenotype observed in immortalized PS2-deficient cell lines cannot be extrapolated to primary neurons, astrocytes, and even to primary fibroblasts. The PS-dependent mitochondrial phenotype reported so far might therefore be the consequence of a cell immortalization process and should be critically reconsidered regarding its relevance to AD.
Single Low Dose of Cocaine–Structural Brain Injury Without Metabolic and Behavioral Changes
Authors: Nicolucci Camilla , Pais Mariana Lapo , Santos A. C. , Ribeiro Fabiana M. , Encarnação Pedro M. C. C. , Silva Ana L. M. , Castro I. F. , Correia Pedro M. M. , Veloso João F. C. A. , Reis Julie , Lopes Marina Z. , Botelho Maria F. , Pereira Frederico C. , Priolli Denise G.
Published: January 2021

Chronic cocaine use has been shown to lead to neurotoxicity in rodents and humans, being associated with high morbidity and mortality rates. However, recreational use, which may lead to addictive behavior, is often neglected. This occurs, in part, due to the belief that exposure to low doses of cocaine comes with no brain damage risk. Cocaine addicts have shown glucose metabolism changes related to dopamine brain activity and reduced volume of striatal gray matter. This work aims to evaluate the morphological brain changes underlying metabolic and locomotor behavioral outcome, in response to a single low dose of cocaine in a pre-clinical study. In this context, a Balb-c mouse model has been chosen, and animals were injected with a single dose of cocaine (0.5 mg/kg). Control animals were injected with saline. A behavioral test, positron emission tomography (PET) imaging, and anatomopathological studies were conducted with this low dose of cocaine, to study functional, metabolic, and morphological brain changes, respectively. Animals exposed to this cocaine dose showed similar open field activity and brain metabolic activity as compared with controls. However, histological analysis showed alterations in the prefrontal cortex and hippocampus of mice exposed to cocaine. For the first time, it has been demonstrated that a single low dose of cocaine, which can cause no locomotor behavioral and brain metabolic changes, can induce structural damage. These brain changes must always be considered regardless of the dosage used. It is essential to alert the population even against the consumption of low doses of cocaine.
Diffusion Basis Spectrum Imaging Detects Axonal Loss After Transient Dexamethasone Treatment in Optic Neuritis Mice
Authors: Lin Tsen-Hsuan , Zhan Jie , Song Chunyu , Wallendorf Michael , Sun Peng , Niu Xuan , Yang Ruimeng , Cross Anne H. , Song Sheng-Kwei
Published: January 2021

Optic neuritis is a frequent first symptom of multiple sclerosis (MS) for which corticosteroids are a widely employed treatment option. The Optic Neuritis Treatment Trial (ONTT) reported that corticosteroid treatment does not improve long-term visual acuity, although the evolution of underlying pathologies is unclear. In this study, we employed non-invasive diffusion basis spectrum imaging (DBSI)-derived fiber volume to quantify 11% axonal loss 2 months after corticosteroid treatment (vs. baseline) in experimental autoimmune encephalomyelitis mouse optic nerves affected by optic neuritis. Longitudinal DBSI was performed at baseline (before immunization), after a 2-week corticosteroid treatment period, and 1 and 2 months after treatment, followed by histological validation of neuropathology. Pathological metrics employed to assess the optic nerve revealed axonal protection and anti-inflammatory effects of dexamethasone treatment that were transient. Two months after treatment, axonal injury and loss were indistinguishable between PBS- and dexamethasone-treated optic nerves, similar to results of the human ONTT. Our findings in mice further support that corticosteroid treatment alone is not sufficient to prevent eventual axonal loss in ON, and strongly support the potential of DBSI as an in vivo imaging outcome measure to assess optic nerve pathology.
Galanin Receptor 2 Is Involved in Galanin-Induced Analgesic Effect by Activating PKC and CaMKII in the Nucleus Accumbens of Inflammatory Pain Rats
Authors: Li Mengnan , Zhang Xiaomin , Li Chongyang , Liu Yanan , Yang Shuang , Xu Shilian
Published: January 2021

It has been reported that galanin has an analgesic effect via activating galanin receptors (GALRs). This study focused on the involvement of GALR2 in the galanin-induced analgesic effect and its signaling mechanism in the nucleus accumbens (NAc) of inflammatory rats. Animal models were established through injecting carrageenan into the plantar of rats’ left hind paw. The results showed that GALR2 antagonist M871 weakened partially the galanin-induced increases in hind paw withdrawal latency (HWL) to thermal stimulation and hind paw withdrawal threshold (HWT) to mechanical stimulation in NAc of inflammatory rats. Moreover, the GALR2 agonist M1145 prolonged the HWL and HWT, while M871 blocked the M1145-induced increases in HWL and HWT. Western blotting showed that the phosphorylation of calcium/calmodulin-dependent protein kinase II (p-CaMKII) and protein kinase C (p-PKC) in NAc were upregulated after carrageenan injection, while p-PKC and p-CaMKII were downregulated after intra-NAc administration of M871. Furthermore, the CaMKII inhibitor KN93 and PKC inhibitor GO6983 attenuated M1145-induced increases in HWL and HWT in NAc of rats with inflammatory pain. These results prove that GALR2 is involved in the galanin-induced analgesic effect by activating CaMKII and PKC in NAc of inflammatory pain rats, implying that GALR2 agonists probably are potent therapeutic options for inflammatory pain.
Lateral Hypothalamic GABAergic Neurons Encode and Potentiate Sucrose's Palatability
Authors: Garcia Aketzali , Coss Alam , Luis-Islas Jorge , Puron-Sierra Liliana , Luna Monica , Villavicencio Miguel , Gutierrez Ranier
Published: January 2021

Sucrose is attractive to most species in the animal kingdom, not only because it induces a sweet taste sensation but also for its positive palatability (i.e., oromotor responses elicited by increasing sucrose concentrations). Although palatability is such an important sensory attribute, it is currently unknown which cell types encode and modulate sucrose's palatability. Studies in mice have shown that activation of GABAergic LHAVgat+ neurons evokes voracious eating; however, it is not known whether these neurons would be driving consumption by increasing palatability. Using optrode recordings, we measured sucrose's palatability while VGAT-ChR2 transgenic mice performed a brief access sucrose test. We found that a subpopulation of LHAVgat+ neurons encodes palatability by increasing (or decreasing) their activity as a function of the increment in licking responses evoked by sucrose concentrations. Optogenetic gain of function experiments, where mice were able to choose among available water, 3% and 18% sucrose solutions, uncovered that opto-stimulation of LHAVgat+ neurons consistently promoted higher intake of the most palatable stimulus (18% sucrose). In contrast, if they self-stimulated near the less palatable stimulus, some VGAT-ChR2 mice preferred water over 18% sucrose. Unexpectedly, activation of LHAVgat+ neurons increased quinine intake but only during water deprivation, since in sated animals, they failed to promote quinine intake or tolerate an aversive stimulus. Conversely, these neurons promoted overconsumption of sucrose when it was the nearest stimulus. Also, experiments with solid foods further confirmed that these neurons increased food interaction time with the most palatable food available. We conclude that LHAVgat+ neurons increase the drive to consume, but it is potentiated by the palatability and proximity of the tastant.
Case Report: PNPLA2 Gene Complex Heterozygous Mutation Leading to Neutral Lipid Storage Disease With Myopathy
Authors: Shi Jiejing , Qu Qianqian , Liu Haiyan , Zhang Yan , Cui Wenhao , Chen Ping , Lv Haidong
Published: January 2021

Objective: To investigate the clinical features, skeletal muscle imaging, muscle pathology, blood smear and so on of neutral lipid storage disease with myopathy (NLSDM) caused by PNPLA2 gene mutation.

Methods: The clinical data, skeletal muscle imaging, pathological data, and genetic test results of a patient with NLSDM treated in our hospital were collected in detail, and the previous literature was reviewed and compared.

Results: The main symptoms were muscle weakness and muscular atrophy. Pathological findings of muscle biopsy showed fat deposition in muscle fibers with border cavitation. Fatty droplets were seen in the cytoplasm of neutrophils in peripheral blood. Magnetic resonance imaging of the muscles of both lower extremities showed that muscle in the thigh vastus intermedius, lateral muscles, biceps, and the muscle abdominal area of the middle leg were filled or replaced by fat. Genetic test results suggested mutations in the PNPLA2 gene.

Conclusion: NLSDM is a rare clinical myopathy with abnormal lipid metabolism. Characteristic changes can be seen in skeletal muscle imaging and pathology. The detection of PNPLA2 gene mutation is an important basis for diagnosing NLSDM. Asymmetry and progressive limb weakness are the clinical features. Muscle MRI is mainly involved in the posterior group of the lower limbs. Jordans bodies in the peripheral blood smear and a large number of coarse-grained lipid deposits with rimmed vacuoles in muscle fibers are the characteristic pathological changes.
Mitochondrial Content, but Not Function, Is Altered With a Multimodal Resistance Training Protocol and Adequate Protein Intake in Leucine-Supplemented Pre/Frail Women
Authors: Jacob Kathryn J. , Sonjak Vita , Spendiff Sally , Hepple Russell T. , Chevalier Stéphanie , Perez Anna , Morais José A.
Published: January 2021

Background: Frailty is a clinical condition associated with loss of muscle mass and strength (sarcopenia). Mitochondria are centrally implicated in frailty and sarcopenia. Leucine (Leu) can alter mitochondrial content in myocytes, while resistance training (RT) is the strongest stimulus to counteract sarcopenia and may enhance mitochondrial biogenesis.

Objective: We determined the effects of Leu supplementation and RT on mitochondrial content and function in pre/frail elderly women in a randomized double-blinded placebo-controlled study.

Methods: Nineteen pre/frail elderly women (77.5 ± 1.3 y, BMI: 25.1 ± 0.9 kg/m2), based on the Frailty Phenotype, underwent 3-months of RT 3×/week with protein-optimized diet and were randomized to 7.5 g/d of Leu supplementation or placebo alanine (Ala). Pre/post-intervention mitochondrial respiration, reactive oxygen species (ROS) production, calcium retention capacity (CRC), time to permeability transition pore (mPTP) opening, mitochondrial voltage-dependent anion channel (VDAC) protein content, leg press 1-repetition maximum (1RM), and 6-min walk test (6MWT) were measured.

Results: No time, supplementation, or interaction effects were observed for respiration, ROS, time to mPTP opening, and CRC. VDAC levels significantly increased in the Leu group post-intervention (p = 0.012). Both groups significantly increased leg press 1RM and 6MWT, with no effect of supplementation.

Discussion: Leu supplementation with 3 months of RT increased mitochondrial content. Future studies should investigate if there is an increase in mitochondrial turnover or a shift in quality control (mitophagy) in leucine supplemented pre/frail elderly women who undergo 12 weeks of RT.

Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT01922167.
Comprehensive Characterization of Immunological Profiles and Clinical Significance in Hepatocellular Carcinoma
Authors: Tao Ping , Hong Liang , Tang Wenqing , Lu Qun , Zhao Yanrong , Zhang Si , Ma Lijie , Xue Ruyi
Published: January 2021

Background

Therapies targeting immune molecules have rapidly been adopted and advanced the treatment of hepatocellular carcinoma (HCC). Nonetheless, no studies have reported a systematic analysis between immunological profiles and clinical significance in HCC.

Methods

We comprehensively investigated immune patterns and systematically correlated 22 types of both adaptive and innate immune cells with genomic characteristics and clinical outcomes based on 370 HCC patients from The Cancer Genome Atlas (TCGA) database through a metagene approach (known as CIBERSORT). Based on the Quantitative Pathology Imaging and Analysis System coupled with integrated high-dimensional bioinformatics analysis, we further independently validated six immune subsets (CD4+ T cells, CD8+ T cells, CD20+ B cells, CD14+ monocytes, CD56+ NK cells, and CD68+ macrophages), and shortlisted three (CD4+ T cells, CD8+ T cells, and CD56+ NK cells) of which to investigate their association with clinical outcomes in two independent Zhongshan cohorts of HCC patients (n = 258 and n = 178). Patient prognosis was further evaluated by Kaplan-Meier analysis and univariate and multivariate regression analysis.

Results

By using the CIBERSORT method, the immunome landscape of HCC was constructed based on integrated transcriptomics analysis and multiplexed sequential immunohistochemistry. Further, the patients were categorized into four immune subgroups featured with distinct clinical outcomes. Strikingly, significant inter-tumoral and intra-tumoral immune heterogeneity was further identified according to the in-depth interrogation of the immune landscape.

Conclusion

This work represents a potential useful resource for the immunoscore establishment for prognostic prediction in HCC patients.
Development of an Immune-Related Gene Signature for Prognosis in Melanoma
Authors: Zhang Jia-An , Zhou Xu-Yue , Huang Dan , Luan Chao , Gu Heng , Ju Mei , Chen Kun
Published: January 2021

Melanoma remains a potentially deadly malignant tumor. The incidence of melanoma continues to rise. Immunotherapy has become a new treatment method and is widely used in a variety of tumors. Original melanoma data were downloaded from TCGA. ssGSEA was performed to classify them. GSVA software and the "hclust" package were used to analyze the data. The ESTIMATE algorithm screened DEGs. The edgeR package and Venn diagram identified valid immune-related genes. Univariate, LASSO and multivariate analyses were used to explore the hub genes. The "rms" package established the nomogram and calibrated the curve. Immune infiltration data were obtained from the TIMER database. Compared with that of samples in the high immune cell infiltration cluster, we found that the tumor purity of samples in the low immune cell infiltration cluster was higher. The immune score, ESTIMATE score and stromal score in the low immune cell infiltration cluster were lower. In the high immune cell infiltration cluster, the immune components were more abundant, while the tumor purity was lower. The expression levels of TIGIT, PDCD1, LAG3, HAVCR2, CTLA4 and the HLA family were also higher in the high immune cell infiltration cluster. Survival analysis showed that patients in the high immune cell infiltration cluster had shorter OS than patients in the low immune cell infiltration cluster. IGHV1-18, CXCL11, LTF, and HLA-DQB1 were identified as immune cell infiltration-related DEGs. The prognosis of melanoma was significantly negatively correlated with the infiltration of CD4+ T cells, CD8+ T cells, dendritic cells, neutrophils and macrophages. In this study, we identified immune-related melanoma core genes and relevant immune cell subtypes, which may be used in targeted therapy and immunotherapy of melanoma.
Long Non-Coding RNA PCAT6 Induces M2 Polarization of Macrophages in Cholangiocarcinoma via Modulating miR-326 and RhoA-ROCK Signaling Pathway
Authors: Tu Jianfei , Wu Fazong , Chen Li , Zheng Liyun , Yang Yang , Ying Xihui , Song Jingjing , Chen Chunmiao , Hu Xianghua , Zhao Zhongwei , Ji Jiansong
Published: January 2021

LncRNAs can act crucial roles in multiple tumors including cholangiocarcinoma (CCA). M2 polarization of macrophages is crucial for their biological roles in immunologic tolerance, which is able to induce tumorigenesis. Given that increasing evidence have suggested that lncRNAs could participate in modulating immune cell differentiation and function. Our current study was aimed to identify the underlying mechanism of lncRNA prostate cancer-associated transcript 6 (PCAT6) in CCA progression via regulating M2 macrophage polarization. PCAT6 has been reported as an oncogene in many cancers. In our work, we observed increased expression of PCAT6 in CCA patients. PCAT6 expression in various types of immune cells derived from CCA patients was tested by quantitative real-time PCR (qRT-PCR). It was revealed that PCAT6 was highly expressed in macrophages, which indicated that PCAT6 might regulate the function of macrophages to promote CCA progression. Then, via establishing CCA xenograft mouse model, we found loss of PCAT6 obviously triggered the immune response and reduced the in vivo tumor growth. In addition, overexpression of PCAT6 led to the M2 polarization of THP-1-differentiated macrophages. Moreover, miR-326 was predicted and proved as a target for PCAT6. In addition, down-regulation of PCAT6 repressed M2 polarization of macrophages, which was reversed by miR-326 inhibitors. The increase of PCAT6 induced the accumulation of ROS, mitochondrial and metabolic dysfunction in macrophages and mimics of miR-326 exhibited an opposite process. RohA has been recognized as a significant regulator of immune cell function. In our current work, we observed that RohA function as a downstream target for miR-326. In conclusion, our study highlighted a significant role of PCAT6/miR-326/RohA in immune response of macrophages in CCA and indicated PCAT6 as a potential target of immunotherapy in CCA.
Surgical Management of Tentorial Notch Meningioma Guided by Further Classification: A Consecutive Study of 53 Clinical Cases
Authors: Qin Chaoying , Wang Junquan , Long Wenyong , Xiao Kai , Wu Changwu , Yuan Jian , Pan Yimin , Zhang Chi , Su Jun , Yuan Xianrui , Liu Qing
Published: January 2021

Background

Management of tentorial notch meningiomas (TNM) remains a challenge for neurosurgeons. We demonstrate the clinical characteristics and surgical experiences of TNM based on our cases according to a proposed further classification.

Methods

We retrospectively analyzed clinical and follow-up data in a consecutive series of 53 TNM patients who underwent microsurgical operation from 2011 to 2019 in our institution. The operations were performed using various approaches. Clinical history, preoperative and postoperative neurofunction, imaging results, and surgical outcomes were collected for further classification of TNM.

Results

All TNM cases were divided into anterior (T1), middle (T2), and posterior notch (T3). According to the direction of tumor extension and correlation with the neurovascular structures, detailed subtypes of anterior TNMs were identified as the central (T1a), posterior (T1b), and medial type (T1c). The middle TNMs were divided into the infratentorial (T2a), supratentorial (T2b), and supra-infratentorial type (T2c). The posterior TNMs were divided into superior (T3a), inferior (T3b), lateral (T3c), and straight sinus type (T3d) in reference to Bassiouni’s classification. Total removal of the tumor was achieved in 46 cases, with five cases of subtotal and two cases of partial removal without any recorded deaths in our series. In total, five subtotal resected cases underwent gamma-knife treatment and achieved stable disease. Postoperative aggravation or new onset cranial nerve dysfunction occurred in some individual cases, with incidences ranging from 3.77 to 15.10% and improved preoperative neurological deficits ranging from 0 to 100%.

Conclusion

Further, TNM classification based on the intracranial location, extension direction, relationship with brainstem, and neurovascular structures guides preoperative evaluation, rational surgical approach selection, and surgical strategy formulation. Taking microsurgery as the main body, a satisfactory outcome of TNM treatment can be achieved for complicated tumors by combining stereotactic radiotherapy. This study demonstrates the surgical outcomes and complications in detail. Further classification might be helpful for treatment decisions in the future.