Melanopsin gene polymorphism and volumetric change in the left hippocampal dentate gyrus following light therapy in mood disorders: An exploratory study
Aug 2026· Frontiers in Psychiatry· Vol 17· 0 citations· 21 references
Medicine
TL;DR
The findings of this study suggest that rs1079610 in OPN4 might be a potential SNP that affects volumetric change in the left DG following light therapy in mood disorders.
Abstract
Introduction Bright light therapy (BLT) is an effective treatment for mood disorders. We previously reported that four weeks of bright light (BL) exposure in patients with mood disorders led to increased volume of the left dentate gyrus (DG). We propose a novel hypothesis that the extent of light-induced volumetric increase in the left DG may be influenced by individual genetic variation in the OPN4 gene, especially rs1079610. This exploratory study aimed to test this hypothesis. Methods We recontacted 21 patients with mood disorders who had previously participated in a 4-week, randomized controlled trial comparing BL (10,000 lux) and dim light (DL; 50 lux). All participants underwent magnetic resonance imaging and 18F-fluorodeoxyglucose (FDG) positron emission tomography at baseline and after 4 weeks of light exposure. Blood samples were collected for genotyping of two Single-Nucleotide Polymorphisms (SNPs) in OPN4 (rs1079610 and rs2675703), which are expressed in intrinsically photosensitive retinal ganglion cells. The primary outcome was the main effect of the rs1079610 genotype for percentage change volume (%ΔV) of the left DG. Analysis of covariance was conducted using a general linear model. Results The final sample size was 21 (BL group, n = 11; DL group, n = 10). A significant main effect of rs1079610 genotype (C allele carriers versus TT) was observed (F (1,17) = 7.16, P = 0.016, partial η2 = 0.3). Sensitivity analyses were performed with sequential adjustment for potential confounders. The association between rs1079610 genotype and %ΔV of the left DG remained statistically significant after adjustment for age, sex, baseline left DG volume, and diagnosis (F (1,13) = 4.8, P = 0.047, partial η2 = 0.27). Discussion The findings of this study suggest that rs1079610 in OPN4 might be a potential SNP that affects volumetric change in the left DG following light therapy in mood disorders.
The findings suggest that I394T‐C carriers exhibit features of the circadian phenotype commonly observed in older cohorts, including reduced rhythm robustness and lower melatonin levels, and support a role for this variant in interindividual differences in light sensitivity and circadian function.
Jesús Vicente-Martínez, M. Bonmati-Carrion, Ana María López-Parra et al.· Journal of Pineal Research· 0 citations
Electroconvulsive therapy (ECT) is an effective treatment for major depressive disorder (MDD), yet its underlying mechanisms remain unclear. This study investigated the antidepressant effects of ECT through a multimodal neuroimage meta-analysis combined with functional, genetic, and neurotransmitter assessments. Resting-state functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM) data were analyzed using seed-based d mapping with permutation of subject images (SDM-PSI) to identify changes in spontaneous brain activity and gray matter volume (GMV) before and after ECT. Further analysis of regions with altered activation and GMV was conducted using Neurosynth, postmortem gene expression data, and receptor/transporter distribution maps to explore molecular underpinnings. The whole-brain multimodal meta-analysis included 291 patients from resting-state fMRI studies and 302 patients from VBM studies. The results showed convergent increases in spontaneous activity and GMV in the left angular gyrus (AG) following ECT. Functional annotation linked the left AG to memory, attention, and perceptual processing. Gene expression analysis identified TFAP2B and OTX2 as the most highly expressed genes in this region. Notably, ECT-associated changes in spontaneous brain activity and GMV were positively correlated with 5-HT1a receptor and dopamine transporter distribution. These findings suggest the left AG is a key region mediating ECT's effects. Neurotransmitter analysis further indicates that ECT may exert its antidepressant action by modulating neurotransmitter systems, offering insights into the neural and molecular basis of its therapeutic efficacy in MDD.
Ruifeng Shi, Yikai Dou, Ying He et al.· Progress in Neuro-psychophar...· 0 citations
Episodic Migraine (EM) is a highly prevalent and disabling neurological disorder. Recent therapeutic advances have targeted the calcitonin gene-related peptide (CGRP), a neuropeptide implicated in the pathophysiology of migraine. Promising outcomes have been obtained with monoclonal antibodies and, more recently, with a new class of drugs consisting of small-molecule CGRP receptor antagonists, known as gepants. Atogepant, an oral agent of the gepant class, has demonstrated efficacy in migraine prevention, yet its effects on central brain activity and neurotransmitter circuits remain largely unclear. This exploratory study investigates changes in brain functional connectivity and changes related to key neurotransmitter systems, following 12 weeks of treatment with atogepant in a group of EM patients.
This is an exploratory single-arm longitudinal study assessing clinical and neuroimaging changes before and after 12 weeks of atogepant treatment. We enrolled patients diagnosed with EM according to ICHD-3 criteria, without prior exposure to anti-CGRP therapies. Participants underwent clinical assessments (monthly migraine days MMD, acute drugs intake MAM) and resting-state functional MRI (rs-fMRI) before and after 12 weeks of treatment with atogepant 60 mg once daily. Longitudinal functional connectivity analyses were performed at the whole-brain level with a region-of-interest analysis. Additionally, longitudinal neurotransmitter-related functional connectivity was investigated within the serotoninergic and the dopaminergic systems.
A total of 15 patients completed the evaluation. A significant group-level reduction in MMD (T = −7.09,
p
< 0.001) and MAM (T = −6.35,
p
< 0.001) following 12 weeks of atogepant treatment was observed, accompanied by a reduction of allodynia symptoms, albeit not statistically significant. Patients exhibited significant longitudinally increased functional connectivity, involving the right superior frontal gyrus, bilateral putamen, left pallidum, left anterior and bilateral posterior cingulate cortex. The greater the longitudinal increase in anterior–posterior cingulate cortices connectivity, the larger the improvement in MMD, MAM, and allodynia symptoms after treatment. Additionally, longitudinal connectivity changes were observed within the orbitofrontal cortex in the mesocorticolimbic dopaminergic system.
In this exploratory cohort, significant clinical improvement after atogepant treatment was accompanied by longitudinal functional connectivity changes in EM patients. These preliminary findings may reflect either direct or indirect central modulation linked to atogepant treatment. A deeper understanding of the observed central changes may help to clarify the mechanisms underlying anti-CGRP therapies for migraine.
D. Montisano, Davide Fedeli, G. Demichelis et al.· Frontiers in Neurology· 0 citations
Background. Bipolar disorder (BD) is characterized by circadian rhythm disruptions, contributing to mood instability and recurrence. These rhythms are regulated by clock genes in the suprachiasmatic nucleus, including the CLOCK 3111T/C (rs1801260) polymorphism that has been linked to delayed sleep phase, insomnia, and altered circadian expression. Both circadian disruption and adverse childhood experiences (ACEs) correlate with white matter (WM) abnormalities. We hypothesized that rs1801260 moderates ACE effects on WM microstructure in BD. Methods. We enrolled 137 BD patients in depressive episodes. Participants underwent 3T MRI, rs1801260 genotyping and completed the Childhood Trauma Questionnaire. Moderation (PROCESS) tested genotype–ACE interactions on whole-brain fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) values; voxel-wise TBSS (FSL Randomize) localized effects, with sex-stratified and GLZ analyses for genotype–sex interactions. Results. Significant rs1801260 × ACE interactions emerged for FA and RD across physical abuse, physical neglect, and emotional neglect. Higher ACEs were associated with lower FA/higher RD only in CLOCK rs1801260*C carriers, mainly females. TBSS showed physical abuse × rs1801260 interaction in the corpus callosum, internal capsule and corona radiata. A GLZ model with separate slopes confirmed physical abuse × sex × rs1801260 interactions on FA/RD, with effects specific to female CLOCK rs1801260*C carriers but genotype-independent in males. Conclusions. rs1801260 moderates the impact of early-life stress on WM integrity in BD, particularly in emotion-regulation tracts, with CLOCK rs1801260*C carriers showing greater vulnerability. Effects are genotype-specific in females but genotype-independent in males, possibly reflecting sex-dimorphic neurodevelopment driven by estrogen–androgen modulation of clock genes, HPA axis, and myelination.
F. Nozza, B. Bravi, L. Fortaner-Uyá et al.· Genes· 0 citations
BACKGROUND
The neurocognitive dysfunction observed in Alcohol Use Disorder (AUD) is related to a complex interplay between genetic, neurobiological, and environmental factors. The μ-opioid receptor (MOR), encoded by the OPRM1 gene, modulates reward processing, stress responsivity, and excitatory-inhibitory activity within prefrontal-limbic and hippocampal circuits implicated in neurocognition. The common A118G (Asn40Asp, rs1799971) polymorphism alters MOR expression and signaling, but its contribution to domain-specific cognitive functioning in AUD, particularly among Veterans, has received limited investigation.
METHODS
Veterans (n = 127) in residential treatment for AUD completed a neurocognitive battery assessing the following domains of functioning: auditory-verbal and visuospatial learning and memory, executive function, and working memory. Participants were genotyped for OPRM1 A118G, and A homozygotes and G-allele carriers (AG/GG) were compared on the above measures, using bootstrapped generalized linear models, adjusted for age, education, biological sex, race, pre-study alcohol consumption, and brain-derived neurotrophic factor (BDNF) (rs6265) and catechol-O-methyltransferase (COMT) (rs4680) genotypes, which have been previously shown to be associated with neurocognition.
RESULTS
G-allele carriers demonstrated significantly worse performance than A homozygotes on measures of auditory-verbal learning and memory, cognitive flexibility/set shifting, auditory working memory, and on a composite average of all measures. BDNF or COMT genotypes were not associated with any measure, and there were no significant interactions among OPRM1, BDNF, and COMT genotypes.
CONCLUSIONS
Findings suggest that altered MOR signaling in G-allele carriers may be associated with differences in prefrontal network efficiency, potentially justifying future studies investigating the relationship between OPRM1 and glutamatergic plasticity. The results highlight a potential genetically influenced contributor to the neurocognitive heterogeneity in AUD and underscore the possible value of integrating MOR-related biological markers into neurocognitive assessment of individuals with AUD.
Roberto Andrade, M. W. McNerney, Eric P Kraybill et al.· Alcohol, clinical & experime...· 0 citations
Major depressive disorder (MDD) is characterized by dysfunction in higher-order cortical regions involved in emotional and cognitive processes; however, its neurobiological basis remains unclear. Pharmacological treatments, including esketamine and sertraline, produce rapid antidepressant effects. We investigated the local intrinsic neural dynamics underlying these antidepressant effects using intrinsic neural timescales (INT), which measure the duration and capacity of information integration in localized brain regions.
A total of 57 healthy controls and 41 patients with MDD were included. All patients with MDD received six intravenous infusions of esketamine (0.25 mg/kg) and two weeks of sertraline treatment. All participants underwent resting-state fMRI to quantify INT alterations at the voxel and brain network levels, followed by spatial correlation analyses linking autocorrelation metrics of INT signals to transcriptomic data from the Allen Human Brain Atlas and PET-derived neurotransmitter receptor maps. The spatial correlation between PLS2 scores and case–control t-statistic maps did not pass rigorous spin permutation testing (
r
= 0.484,
p
= 0.068) and did not meet the conventional significance threshold of 0.05. Accordingly, all subsequent enrichment analyses based on PLS2 results are presented as exploratory preliminary observations for hypothesis generation.
Compared with healthy controls, patients with MDD exhibited significantly elevated INT levels in the left and right precuneus. Following treatment, patients with MDD showed significantly increased INT in the left occipital midline region and left calcarine cortex. At the brain network level, INT levels were significantly reduced in the default mode network (DMN) in patients with MDD compared with healthy controls. Compared with the pre-treatment state, the cerebellar network (CN) showed significantly elevated INT levels after treatment. Partial least squares regression analysis suggested potential associations between INT alterations and spatial gene expression gradients particularly those associated with immune responses, hormonal regulation, neutrophils, regulatory T cells, and glutamatergic synapses. Cell-type enrichment analysis identified excitatory and inhibitory neurons as key cellular contributors. Alterations in INT also correlated with cortical 5-HT1b and NAT receptor density, suggesting a role for inhibitory neurotransmission in temporal integration deficits.
This study advances understanding of treatment-related brain abnormalities in patients with MDD from the perspective of local neural dynamics. These findings support a multiscale pathophysiological framework involving brain connectivity dynamics, molecular architecture, and neurochemical regulation in MDD.
Xiang Liu, Yuanzhi He, Lifeng Li et al.· BMC Psychiatry· 0 citations
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