The molecular and neurochemical basis of altered intrinsic neural timescales in major depressive disorder: a multimodal imaging-transcriptomic investigation of esketamine and sertraline treatment
A multiscale pathophysiological framework involving brain connectivity dynamics, molecular architecture, and neurochemical regulation in patients with MDD is supported, suggesting a role for inhibitory neurotransmission in temporal integration deficits.
Abstract
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.
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, Yi-Kai Dou, Ying He et al.· Progress in Neuro-psychophar...· 0 citations
Schizophrenia is a severe psychiatric disorder marked by widespread brain abnormalities. Recent studies suggest that pathological changes may originate from focal 'epicenter' regions and subsequently spread to other brain areas strongly connected to them. Investigating drug-naïve first-episode schizophrenia (dn-FES) patients may help characterize early-stage regional functional abnormalities and their potential neurochemical underpinnings. Resting-state functional magnetic resonance imaging data were acquired from 50 dn-FES patients and 50 age- and sex-matched healthy controls (HCs). Static regional homogeneity (sReHo) and dynamic ReHo (dReHo) were compared between groups, and correlations with psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). We further used the JuSpace toolbox to test whether spatial patterns of ReHo alterations were associated with specific neurotransmitter receptor/transporter densities. Compared with HCs, dn-FES patients showed reduced sReHo in the bilateral postcentral/precentral gyri, bilateral paracentral lobules and right supplementary motor area, and increased dReHo in the left lingual gyrus. sReHo in the right postcentral gyrus was inversely correlated with PANSS positive scores, whereas dReHo in the left lingual gyrus was negatively correlated with PANSS general scores. Schizophrenia-related sReHo alterations showed significant spatial associations with serotonergic, dopaminergic, noradrenergic and cholinergic systems, whereas dReHo alterations were associated with serotonergic, dopaminergic, cannabinoid and opioid systems. Taken together, this study identifies abnormal static and dynamic local functional connectivity in sensorimotor and visual regions in drug-naïve first-episode schizophrenia, and the spatial correspondence between these alterations and receptor/transporter distributions may offer insight into the molecular substrates associated with these functional abnormalities.
Ziyu Wang, Kangkang Xue, Yan Zhang et al.· Progress in Neuro-psychophar...· 0 citations
Background: Adolescents with depression pose a significant public health challenge, yet individual variability in treatment response to accelerated intermittent theta-burst stimulation (iTBS) for depression remains substantial. This study aims to integrate metabolomics with multimodal neuroimaging techniques to identify objective biomarkers of response to iTBS treatment and investigate the relationship between brain and metabolism. Methods: Patients received an accelerated iTBS protocol targeting the left dorsolateral prefrontal cortex. Assessments included plasma metabolomic profiling, resting-state and naturalistic functional magnetic resonance imaging, and clinical scale evaluations conducted at baseline and post-treatment. Results: The study enrolled 85 adolescents with depression and 48 healthy controls. 53 adolescent patients with depression completed the full course of iTBS treatment and provided blood samples for biomarker detection and analysis. Seventeen differential metabolites were identified that distinguished patients from controls and changed significantly after iTBS treatment. The area under the curve (AUC) for the metabolites 3-hydroxymethylglutaric acid, malonic acid, N-acetylphenylalanine, norepinephrine and tryptophanamide exceeds 0.8. The metabolites isovalerylcarnitine, taurochenodeoxycholic acid, taurodeoxycholic acid, and valerylcarnitine were significantly correlated with the reduction in scores on the Hamilton Depression Rating scale (HAMD). Furthermore, alterations in the metabolites 3-Indolepropionic acid, N-acetylphenylalanine, 3-Methylhistidine, Norepinephrine, Ortho-hydroxyphenylacetic acid, 3-Hydroxymethylglutaric acid and Indole-3-carboxaldehyde were associated with functional changes in key prefrontal regions, specifically, the Amplitude of Low-Frequency Fluctuations (ALFF) and Regional Homogeneity (ReHo) in the left superior frontal gyrus, and ReHo in the left middle frontal gyrus. Conclusions: This study uncovers preliminary evidence of a distinct metabolic signature in adolescent depression that normalizes following iTBS treatment and correlates with both prefrontal functional recovery and clinical improvement. The identified metabolites serve as potential candidate biomarkers and shed light on the brain-metabolism relationship. These findings offer preliminary candidate biomarkers for future investigations into interindividual variability in iTBS treatment response and offer a tentative framework for developing personalized neuromodulation strategies for adolescent depression. Clinical Trial Registration: The study has been registered on https://www.chictr.org.cn/ (registration number: ChiCTR2500106503 and ChiCTR2500113926; registration link: https://www.chictr.org.cn/showproj.html?proj=279390 and https://www.chictr.org.cn/showproj.html?proj=279455).
Ze-Yang Zhao, Tao Leng, Pei-Ying Li et al.· ALPHA PSYCHIATRY· 0 citations
The findings show that first-episode drug-naïve or minimally treated schizophrenia patients are characterized by disrupted intrinsic neural timescales with distinct cortical-subcortical alterations, which may represent a candidate neurobiological marker of early-stage schizophrenia.
Xia-Wei Liu, Fei-Wen Wang, Yi-Ju Wang et al.· Asian Journal of Psychiatry· 0 citations
Major Depressive Disorder (MDD) is a psychiatric disorder associated with altered neuro-metabolism. This study investigated the effect of antidepressant therapy on the metabolism of the right hippocampus and anterior cingulate cortex (ACC) in patients with MDD, using in vivo proton magnetic resonance spectroscopy (MRS) at 3.0 T. MRS was performed in 42 patients with MDD (at baseline and after 8 weeks of antidepressant therapy) and 35 healthy controls (HCs). Metabolite concentrations were quantified using Osprey software with partial-volume corrections. The Hamilton Depression Rating Scale (HDRS) was used to assess response to antidepressant therapy. Patients with MDD who had a > 50% reduction in HDRS scores were classified as remitted, and those with a < 50% reduction were grouped as non-remitted after therapy. Compared with HCs, baseline levels of hippocampal total N-acetylaspartate (tNAA), total creatine (tCr), total choline (tCho), and myo-inositol (mI) were reduced. Baseline levels of ACC tNAA and tCr were higher in patients with MDD than in HCs. After antidepressant therapy, a significant increase in tNAA and tCr levels was observed in the hippocampus of patients with remitted MDD, indicating a positive impact of therapy on energy metabolism and neurodegenerative processes, thereby supporting remission. Hippocampal metabolite levels remained unaltered after therapy in the non-remitted subgroup. ACC metabolites remained unaltered after therapy in both remitted and non-remitted subgroups. Thus, findings highlighted the importance of hippocampal metabolism in MDD and the possibility that metabolite levels may serve as biomarkers of antidepressant therapy response.
Deepti Upadhyay, Vishwa Rawat, G. Hans et al.· Magnetic Resonance Imaging· 0 citations
Abstract Background Electroconvulsive therapy (ECT) is among the most effective treatments for severe and treatment-resistant depression. Despite more than 90 years of clinical use, its underlying neurobiological mechanisms remain incompletely understood. One prominent hypothesis suggests that ECT induces neuroplastic changes, supported by evidence of volumetric brain alterations in regions implicated in depression and increases in peripheral neurotrophins [1,2]. In contrast, critical perspectives interpret post-ECT volumetric changes as transient oedema or raise concerns about potential neuronal damage. Aims & Objectives The present prospective study aimed to investigate ECT-associated changes in brain structure and functional connectivity using magnetic resonance imaging (MRI), alongside cerebrospinal fluid (CSF) markers of neuronal and glial injury, in patients with severe depression. Method Thirteen hospitalized patients with treatment-resistant depression (mean age 41 ± 9.6 years; baseline Hamilton Depression Rating Scale (HAMD17) score 26 ± 3.1, indicating severe depression) underwent a course of eight bilateral ECT sessions. ECT was administered using a Thymatron IV device under general anesthesia with either methohexital or ketofol and succinylcholine as muscle relaxant; stimulus dosing was determined via individual seizure threshold titration. All patients remained on stable antidepressant medication throughout the treatment period. Structural and resting-state MRI scans were acquired before the first and after the eighth ECT session using a Siemens MAGNETOM Prisma 3T scanner, accompanied by lumbar puncture at both time points. Gray matter volume changes were assessed using a repeated-measures analysis of covariance (rmANCOVA) with age and sex as covariates. Brain segmentation was performed with FreeSurfer 7.1, and statistical analyses were conducted using SPSS Version 25. Resting-state functional connectivity analyses focused on the default mode network (DMN) as a seed region, with preprocessing performed in SPM12. CSF concentrations of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified using single molecule array (SIMOA) technology, with statistical analyses conducted in RStudio. Given the exploratory nature of the study, results are reported without correction for multiple comparisons. Results Following ECT, depressive symptoms significantly improved, as reflected by a marked reduction in HAMD17 scores (t = 6.1, p < 0.001). Structural MRI revealed a significant, uncorrected increase in gray matter volume confined to the left precuneus (F = 6.016, p = 0.044). Functional connectivity analyses demonstrated reduced connectivity between the DMN and the cerebellum (t = 6.61, p < 0.001) as well as the middle occipital gyrus (t = 5.85, p = 0.002) following ECT. Importantly, no significant changes in CSF levels of NfL (p = 0.213) or GFAP (p = 0.362) were observed. Discussion & Conclusions Consistent with previous neuroimaging findings, ECT was associated with alterations in brain structure and DMN connectivity – a network critically involved in the pathophysiology of depression [3]. Notably, the absence of changes in CSF markers of neuronal or glial injury provides no evidence for ECT-related neuronal damage in this cohort. Whether the observed neuroimaging changes represent a necessary component of ECT’s antidepressant efficacy remains an open question. The small sample size and exploratory design constitute important limitations and warrant replication in larger, controlled studies.
P. Baldinger-Melich, S. Riessland, B. Spurny-Dworak et al.· International Journal of Neu...· 0 citations
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