Depressive disorders have been consistently associated with elevated levels of mind-wandering and self-focused negative rumination. Separate tracks of research have implicated brain structures within the default mode network (DMN) in both mind-wandering and depression. In this study, we hypothesized that diminished mind-wandering and fewer depressive symptoms would co-occur in individuals with damage to the DMN. To test this hypothesis, we used a k-means clustering algorithm to identify a target group of patients with reduced mind-wandering and fewer depressive symptoms relative to brain-damaged comparison subjects (n = 37 of 68; ps < .001). The anatomical localization of lesions for this target group was predominantly within the medial prefrontal cortex (mPFC). Structural and functional lesion network mapping results revealed that lesions of the target group had significantly greater connectivity with DMN and limbic regions. Taken together, these results suggest that brain injury affecting the mPFC and DMN is associated with both reduced mind-wandering and fewer depressive symptoms. Further investigation of neuroanatomical substrates that mediate a causal relationship between mind-wandering and mood may facilitate the identification of new therapeutic targets for neuromodulation in patients with disorders characterized by maladaptive mind-wandering, such as rumination.

Vascular depression (VaDep), which was proposed over two decades ago, is a distinct subtype of depression primarily observed in patients with stroke and cerebral small-vessel disease and is characterized by white matter hyperintensities; however, the lack of standardized diagnostic criteria and consensus limits its clinical application. This review explores the pathological conditions and vascular risk factors that may precipitate VaDep, particularly in relation to stroke and cerebral small-vessel disease. VaDep is distinguished by unique pathophysiological mechanisms and treatment responses. We categorize these mechanisms into three groups: 1) macroscopic mechanisms, including vascular aging, cerebral hypoperfusion, blood-brain barrier disruption, and neural circuit dysfunction; 2) microscopic mechanisms, involving the inflammatory response, hypothalamic-pituitary-adrenal axis dysregulation, impaired monoamine synthesis, and mitochondrial dysfunction; and 3) undetermined mechanisms, such as microbiota-gut-brain axis dysbiosis. These insights support VaDep as a distinct depression subtype, differentiating it from late-life depression and major depressive disorder. Treatment is challenging, as patients with VaDep often exhibit resistance to conventional antidepressants. Addressing vascular risk factors and protecting vascular integrity are essential for effective management. Future research should validate these mechanisms and develop novel diagnostic and therapeutic approaches to improve VaDep outcomes.

Parkinson's disease (PD) presents with a variety of non-motor symptoms such as sleep disorders, hyposmia, pain, cognitive dysfunction, neuropsychiatric and autonomic symptoms. One of the most neglected motor symptoms is the impairment of eye movements, which occurs in 75% of PD patients. The aim of our study was to investigate the relationship between the severity of non-motor symptoms and the impairment of different types of eye movements.

We conducted a cross-sectional study with idiopathic PD patients in which non-motor symptoms were assessed using standardised scales. The impairment of smooth pursuit, saccades, antisaccades and visually-guided saccades was evaluated with eye-tracker analysis, using battery of tests.

The mean age of our subjects was 65.06 (± 9.135; 43-80) years with a median disease duration of 4 (2-7) years. The duration of PD correlated positively with visually-guided memory saccades. We found moderate positive correlations between scales for sleep quality, depression, anxiety, and nonmotor experiences of daily living (PDSS-2, RBDSQ, BAI, BDI-II, MDS-UPDRS I) with deviation of fast smooth pursuit movements and latency of saccades and antisaccades. Number of correct answers in different trials testing visually-guided memory saccades were most strongly negatively correlated with scales assessing depression, sleep quality and cognitive functions (MoCA).

Different types of eye movement parameters correlate with scales assessing non-motor symptoms, possibly caused by the same pathophysiological mechanism in PD. Further research that addresses these challenges and focuses on the relationship between eye movements and specific non-motor symptoms in PD could provide valuable insights into the comprehensive management of this complex disease.

Serotonin is strongly involved in the regulation of brain development, including the proper formation of neuronal circuits and synaptic plasticity. One of the factors that can affect brain serotonin levels is exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, the first-line pharmacological treatment for depression and anxiety in the pediatric population. The safety of early-life FLX treatment is still questionable. Women are more prone to anxiety and depression from a young age. We hypothesized that juvenile FLX treatment influences the brain maturation and behavior of adolescent females.

On postnatal days 20 to 28, juvenile female rats were injected once daily with FLX. Five days later, anxiety- and fear-related behaviors and amphetamine-induced locomotor activity were assessed. On postnatal day 40, the numbers of neurons and glial cells in the medial prefrontal cortex (mPFC) and hippocampus were estimated via stereological methods. Additionally, the mRNA expression of cell survival/apoptosis and synaptic plasticity markers was evaluated via RT‒qPCR.

FLX-treated females showed decreased anxiety level, freezing behavior during fear conditioning and amphetamine-induced locomotor activity when compared to control females. Simultaneously, FLX-injected females presented greater regional volume and numbers of neurons and astrocytes in specific subregions of the mPFC when compared to the control group. Additionally, FLX-treated females showed increased expression of genes regulating cell survival and reduced mRNA levels of AMPA glutamate receptors in the mPFC.

Juvenile FLX affects the maturation of the mPFC and attenuates anxiety-like behavior, fear memory and the locomotor response to amphetamine in adolescent females.

Observational studies suggest white matter (WM) microstructural anomalies are linked to bulimia nervosa (BN), but a direct causal relationship remains unestablished. This study aimed to investigate the causal impact of BN on WM microstructure.

We analyzed genome-wide association study (GWAS) summary data from 2442 individuals to identify genetically predicted BN. Diffusion MRI were obtained from the UK Biobank. After assessing instrumental variable validity, we conducted Mendelian randomization (MR) using inverse variance weighting (IVW) as the primary method, followed by pleiotropy and heterogeneity tests.

The MR analysis from BN to brain imaging-derived phenotypes showed that BN had significant causal effects on a union set of nine tracts (including a total of 18 image-derived phenotypes) (IVW, P < 0.05): brainstem tracts (pontine crossing tract, bilateral medial lemniscus, left superior cerebellar peduncle, and middle cerebellar peduncle), sensory-related tracts (right retrolenticular part of the internal capsule and left inferior longitudinal fasciculus), and emotion-related tracts (left anterior corona radiata and right cingulum hippocampus).

This study revealed that BN has a causal effect on WM microstructure, which extends the reports of association to causation for WM and BN. These causal effects may explain the deficits in feeding, taste, vision, and emotion regulation that are often observed in patients with BN. Level of evidence III well-designed cohort analytic study.

This study was aimed at assessing the protective effect of the 80% ethanolic extract of Synurus deltoides (EESD) on chronic unpredictable mild stress (CUMS)-induced depressive-like behavior dysfunction. The bioactive compounds of S. deltoides were identified as quinic acid, chlorogenic acid, rutin, 1,3-dicaffeoylquinic acid, and dicaffeoylsuccinoylquinic acid. EESD and bioactive compounds in EESD significantly protected corticosterone-induced hippocampal cellular death and reactive oxygen species (ROS) contents compared to vitamin C in HT22 cells. By conducting the sucrose preference test, forced swimming test, open field test, and tail suspension test, EESD was found to significantly suppress depression-like behavior. EESD effectively reduced mitochondrial dysfunction by regulating cerebral ROS levels, mitochondrial membrane potential, and ATP contents. EESD showed a considerable regulatory effect by regulating serum stress hormones including corticosterone, norepinephrine, serotonin, 5-hydroxyindoleacetic acid, and melatonin. In addition, EESD significantly suppressed stress-related CRF pathway, inflammatory TLR pathway, and apoptotic signal in cerebral tissues. These results suggest that EESD might be a natural plant substance that improves CUMS-induced behavior abnormality by regulating inflammation and hormonal changes in brain tissue. In the future, additional clinical trials or efficacy evaluations of individual compounds of EESD will be needed to confirm the bioactivity ability and usability of EESD.

Cognitive-behavioral therapy (CBT) is a primary treatment for depression. Although previous research has underscored the significant roles of white matter (WM) alterations and maladaptive parenting in depression risk, their associations with CBT response remain largely unknown. This longitudinal study investigated the interplay of WM integrity changes over time, treatment response, and parenting style in patients with depression. Diffusion-tensor-imaging and clinical data were assessed in n = 65 (55% female) patients with depression before and after 20 CBT sessions and n = 65 (68% female) healthy controls (HC) in a naturalistic design. Linear-mixed-effect models compared changes in fractional anisotropy (FA) between groups and tested associations between FA changes and symptom changes. It was investigated whether parenting style predicts depressive symptoms at follow-up and whether FA changes mediate this association. Patients showed differential FA changes over time in the corpus callosum and corona radiata compared to HC (ptfce-FWE = 0.008). Increases in FA in the corpus callosum, corona radiata and superior longitudinal fasciculus were linked to symptom improvement after CBT in patients (ptfce-FWE = 0.023). High parental care (pFDR = 0.010) and low maternal overprotection (pFDR = 0.001) predicted fewer depressive symptoms at follow-up. The association between maternal overprotection and depressive symptoms at follow-up was mediated by FA changes (pFDR = 0.044). Robustness checks-controlling for outliers, non-linear age effects, clinical characteristics, and patient subgroups-supported these results. Overall, patients with depression show changes in WM integrity following CBT, which are linked to treatment response. The results highlight the significance of early life adversities and related microstructural changes in the effectiveness of CBT for treating depression.

This paper assesses the correlation between tinnitus and mental health, including depression, anxiety, stress, insomnia, and suicide through meta-analysis.

Web of Science, Embase, PubMed, and Cochrane databases were searched until January 2024. After article screening, data extraction, and quality evaluation, meta-analysis was performed using Stata 15.1.

22 papers were enrolled, including 5 case-control studies, 8 cohort studies, and 9 cross-sectional studies. Meta-analysis uncovered that tinnitus was associated with depression (OR = 1.92, 95 % CI: 1.56, 2.36), anxiety (OR = 1.63, 95 % CI: 1.34, 1.98), stress (OR = 1.17, 95 % CI: 1.01, 1.36), insomnia (OR = 3.07, 95 % CI: 2.36, 3.98), and suicide (OR = 5.31, 95 % CI: 4.34, 6.51).

A correlation is indicated between tinnitus and mental health. Therefore, it is critical to incorporate psychological interventions in tinnitus treatment and to implement a comprehensive treatment program.

Trace amines are physiologically active amines present in all organisms. They are structurally identical to traditional monoamines and are rapidly metabolized by monoamine oxidases. The mammalian neurological system generates these molecules at rates equivalent to traditional monoamines, but because of their short half-life, they are only observable in trace quantities. Their receptors are G protein-coupled receptors present in both the CNS and peripheral locations, with trace amine-associated receptor 1 (TAAR1) being the most researched. TAAR1's capacity to regulate glutamatergic and monoaminergic neurotransmission has made it a viable therapeutic target for neuropsychiatric illnesses. Although the TAAR1 role in schizophrenia and other neuropsychiatric disorders is well established, its role in the pathology of neurodegenerative and neurotraumatic disorders recently got attention. This review discusses the role of TAAR1 in neurodegenerative, neurodevelopment, and neurotraumatic disorders and explores its potential to be a novel therapeutic target in these disorders.

Neurologic impairment is common in patients with acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. While patients with severe COVID have a higher prevalence of neurologic symptoms, as many as one in five patients with mild COVID may also be affected, exhibiting impaired memory as well as other cognitive dysfunctions.

To characterize the effect of COVID on the brain, the current study recruited a group of adults with post-COVID cognitive complaints but with mild, non-hospitalized cases. They were then evaluated through formal neuropsychological testing and underwent functional MRI of the brain. The participants in our study performed nearly as expected for cognitively intact individuals. Additionally, we characterized the functional connectivity of the default mode network (DMN), which is known for cognitive functions including memory as well as the attention functions involved in normal aging and degenerative diseases.

Along with the retention of functional connectivity in the DMN, our results found the DMN to be associated with neurocognitive performance through region-of-interest and whole-brain analyses. The connectivity between key nodes of the DMN was positively correlated with cognitive scores (r = 0.51, p = 0.02), with higher performers exhibiting higher DMN connectivity.

Our findings provide neuroimaging evidence of the functional connectivity of brain networks among individuals experiencing cognitive deficits beyond the recovery of mild COVID. These imaging outcomes indicate expected functional trends in the brain, furthering understanding and guidance of the DMN and neurocognitive deficits in patients recovering from COVID.

Scopolamine is a muscarinic receptor antagonist and is widely utilized as a "memory-loss model." However, its impact across different memory and attention tasks and using different modes of administration has yet to be clearly evaluated. This systematic review and meta-analysis investigates the effect of scopolamine, across all routes of administration and across different dosages, on memory and attention performance in healthy humans (PROSPERO ID: CRD42024531634).

Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched (on 20 April 2024) for studies that utilized scopolamine and assessed memory and/or attention. Random-effects meta-analyses were conducted across a range of memory and attention tasks using "Comprehensive Meta-Analysis," Version 3, to evaluate differential pharmacological effects on cognitive tasks between the scopolamine and placebo groups.

Forty-six studies fulfilled the inclusion and exclusion criteria. Scopolamine negatively impaired performance on all memory tasks (immediate memory, delayed recall, digit span, Buschke selective reminding task, and recognition memory) and led to slower reaction times for three of the five attention tasks examined (choice reaction time, simple reaction time, and rapid visual information processing) compared to placebo. Scopolamine's negative effect on memory and attention was greater with injectable (e.g., intramuscular, intravenous, and subcutaneous) compared to non-injectable routes of administration (e.g., intranasal, oral, and transdermal).

This study supports the use of scopolamine as a "memory-loss model," particularly when given by an injectable route of administration. Future clinical trials should evaluate the bioavailability of scopolamine across different routes of administration to ensure therapeutic benefits outweigh any potential adverse cognitive effects.

Common variants in the FKBP5 gene have been implicated in recurrence of major depressive disorder (MDD) and response to antidepressant treatment. Although the relationship between FKBP5 and MDD has been revealed through several studies, the detailed molecular mechanisms by which FKBP5 regulates responsiveness to antidepressants have not been fully understood. Here, we aimed to elucidate the molecular mechanisms of FKBP5 in autophagy initiation and its potential role in the antidepressant response. We found that FKBP5 deficiency impaired the initiation of basal and stress-induced autophagy, accompanied by reduced protein levels of the PIK3C3/VPS34 complex, which is essential for autophagy initiation. Mechanistically, we demonstrated that FKBP5 physically binds to the VPS34 complex components, facilitating their assembly and subsequent autophagy initiation. Particularly, our study revealed that FKBP5 mediates antidepressant-induced autophagy by promoting the VPS34 complex assembly. These findings were consistent in neuronal cells, where FKBP5 depletion resulted in decreased autophagy and impaired the VPS34 complex assembly. Understanding the interplay between FKBP5, autophagy, and MDD may provide new insights into more effective treatments for MDD and related disorders.

Chronic stress induces neural dysfunctions and risks mental illnesses. Clinical and preclinical studies have established the roles of brain regions underlying emotional and cognitive functions in stress and depression. However, neural pathways to perceive sensory stimuli as stress to cause behavioral disturbance remain unknown. Using whole-brain imaging of Arc-dVenus neuronal response reporter mice and machine learning analysis, here we unbiasedly demonstrated different patterns of contribution of widely distributed brain regions to neural responses to acute and chronic social defeat stress (SDS). Among these brain regions, multiple sensory cortices, especially the piriform (olfactory) cortex, primarily contributed to classifying neural responses to chronic SDS. Indeed, SDS-induced activation of the piriform cortex was augmented with repetition of SDS, accompanied by impaired odor discrimination. Axonal tracing and chemogenetic manipulation showed that excitatory neurons in the piriform cortex directly project to the lateral septum and activate it in response to chronic SDS, thereby inducing behavioral disturbance. These results pave the way for identifying a spatially defined sequence of neural consequences of stress and the roles of sensory pathways in perceiving chronic stress in mental illness pathology.

This study was conducted to clarify patterns of cortico-limbic volume abnormalities in late life depression (LLD) relative to non-depressed (ND) adults matched for amyloid β (Aβ) deposition and to evaluate the relationship of volume abnormalities with cognitive performance. Participants included 116 LLD and 226 ND. Classification accuracy of LLD status was estimated using area under the receiver operator characteristic curve. Twenty-one percent of LLD and ND participants were Aβ positive and the groups did not differ on white matter hyperintensity volume (WMH (logscale); β = 0.12, p = 0.28). Compared to ND, the LLD group exhibited significantly lower bilateral volume in the lateral orbitofrontal cortex, hippocampus, accumbens area, superior temporal lobe, temporal pole, and amygdala after multiple comparison correction (p < 0.009 for all). Cortico-limbic volumes significantly improved classification of LLD beyond demographic characteristics, Aβ status, and WMH (AUCVol = 0.71, AUCWMH, Aβ = 0.62, AUC difference, 0.09 [0.03 to 0.15]). LLD exhibited poorer performance on measures of global cognition, set shifting, and verbal learning and memory relative to ND. Cognitive function was positively associated with cortico-limbic volumes and these relationships did not differ by group. Secondary analyses with an ND sample additionally matched for Mild Cognitive Impairment (MCI) diagnosis showed a similar but attenuated pattern of volume abnormalities. Overall, our results support LLD as being associated with cortico-limbic volume abnormalities that are distinct from Aβ and white matter pathologies and that these volume abnormalities are important factors associated with cognitive dysfunction in LLD.

Depression is a heterogeneous disorder with diverse clinical presentations and etiological underpinnings, necessitating the identification of distinct subtypes to enhance targeted interventions. Dissociative symptoms, commonly observed in major depressive disorder (MDD) and linked to early life trauma, may represent a unique clinical dimension associated with specific neurocognitive deficits. Although emerging research has begun to explore the role of dissociation in depression, most studies have provided only descriptive analyses, leaving the mechanistic interplay between these phenomena underexplored. The primary objective of this study is to determine whether MDD patients with prominent dissociative symptoms differ from those without such symptoms in clinical presentation, neurocognitive performance, and markers of functional connectivity. This investigation will be the first to integrate comprehensive clinical evaluations, advanced neurocognitive testing, and high-resolution brain imaging to delineate the contribution of dissociative symptoms in MDD.

We will recruit fifty participants for each of three groups: (1) depressive patients with dissociative symptoms, (2) depressive patients without dissociative symptoms, and (3) healthy controls. Diagnostic assessments will be performed using the Structured Clinical Interview for DSM-5 (SCID) alongside standardized scales for depression severity, dissociation, and childhood trauma. Neurocognitive performance will be evaluated through a battery of tests assessing memory, attention, executive function, and processing speed. Structural and functional magnetic resonance imaging (MRI) will be conducted on a 3 Tesla scanner, focusing on the connectivity of the Default Mode Network with key regions such as the orbitofrontal cortex, insula, and posterior cingulate cortex. Data analyses will employ SPM-12 and Matlab-based CONN and PRONTO tools, with multiclass Gaussian process classification applied to differentiate the three groups based on clinical, cognitive, and imaging data.

The results of this study will introduce a novel perspective on understanding the connection between major depressive disorder and dissociation. It could also aid in pinpointing a distinct form of depression associated with dissociative symptoms and early childhood stressors.

Future research, aiming to forecast the response to biological and psychological interventions for depression, anticipates this subtype and provides insights.

Mood disorders, including major depressive disorder and bipolar disorder, are among the most prevalent mental health conditions globally, yet their underlying mechanisms remain incompletely understood. This review critically examines the neuronal atrophy hypothesis, which posits that chronic stress and associated neurobiological changes lead to structural and functional deficits in critical brain regions, contributing to mood disorder pathogenesis. Key mechanisms explored include dysregulation of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), elevated glucocorticoids from stress responses, neuroinflammation mediated by cytokines, and mitochondrial dysfunction disrupting neuronal energy metabolism. These processes collectively impair synaptic plasticity, exacerbate structural atrophy, and perpetuate mood dysregulation. Emerging evidence from neuroimaging, genetic, and epigenetic studies underscores the complexity of these interactions and highlights the role of environmental factors such as early-life stress and urbanization. Furthermore, therapeutic strategies targeting neuroplasticity, including novel pharmacological agents, lifestyle interventions, and anti-inflammatory treatments, are discussed as promising avenues for improving patient outcomes. Advancing our understanding of the neuronal atrophy hypothesis could lead to more effective, sustainable interventions for managing mood disorders and mitigating their global health burden.

Heart failure (HF) is a complex and debilitating syndrome that affects millions of people worldwide. In addition to the syndrome-related functional limitations, such as exercise intolerance and dyspnea, patients frequently suffer from various comorbidities. Neuropsychiatric conditions, including autonomic dysfunction, cognitive impairment, and depression, are important albeit underrecognized comorbidities in HF. Autonomic dysfunction, which is expressed as sympathetic predominance and decreased parasympathetic tone, is a key contributor to HF progression. Depression and cognitive impairment are highly prevalent in HF patients, affecting adherence to medical treatment and increasing morbidity and mortality risk. Stress cardiomyopathy, a usually reversible form of left ventricular dysfunction triggered by emotional or physical stress, is another clinical manifestation of the interplay between the heart and the brain. Early recognition and management of these comorbidities in HF patients are crucial for improving outcomes. This narrative review provides an overview of the pathophysiological mechanisms linking HF and brain disorders and discusses clinical perspectives of heart-brain interactions in the context of HF.

Brain dynamics offer a more direct insight into brain function than network structure, providing a profound understanding of dysregulation and control mechanisms within intricate brain systems. This study investigates the dynamics of functional brain networks in major depressive disorder (MDD) patients to decipher the mechanisms underlying brain dysfunction during depression and assess the impact of repetitive transcranial magnetic stimulation (rTMS) intervention.

We employed energy landscape analysis of functional magnetic resonance imaging (fMRI) data to examine the dynamics of functional brain networks in MDD patients. The analysis focused on key dynamical indicators of the default mode network (DMN), the salience network (SN), and the central execution network (CEN). The effects of rTMS intervention on these networks were also evaluated.

Our findings revealed notable dynamical alterations in the pDMN, the vDMN, and the aSN, suggesting their potential as diagnostic and therapeutic markers. Particularly striking was the altered activity observed in the dDMN in the MDD group, indicative of patterns associated with depressive rumination. Notably, rTMS intervention partially reverses the identified dynamical alterations.

Our results shed light on the intrinsic dysfunction mechanisms of MDD from a dynamic standpoint and highlight the effects of rTMS intervention. The identified alterations in brain network dynamics provide promising analytical markers for the diagnosis and treatment of MDD. Future studies should further explore the clinical applications of these markers and the comprehensive dynamical effects of rTMS intervention.

Esketamine has demonstrated acute antidepressant effects in patients with major depressive disorder (MDD). This study investigated whether these effects associate with reversible white matter fiber integrity recovery using diffusion imaging.

Twenty patients with MDD and 20 healthy controls received 2-week esketamine treatment. Patients received 0.25 mg/kg intravenous esketamine. Emotional and cognitive recovery were assessed. Diffusion tensor imaging and tract-based spatial statistics evaluated white matter fiber integrity pre/post-treatment. Correlation analyses examined associations between white matter changes and clinical scales.

Compared to controls, patients with MDD exhibited decreased fractional anisotropy (FA) values of cerebral white matter fibers involving the association fibers, the commissural fibers and projection fibers. Esketamine effectively reduced depression, anxiety, and suicidal ideation scores while improving cognitive function. However, no reversible recovery of compromised white matter integrity was observed after 2 weeks of esketamine treatment. FA reductions in projection fibers correlated with anxiety and suicidal ideation severity.

Concurrent sertraline use and lack of placebo control limited our ability to isolate esketamine's effects. The wide age range may have introduced response variability. We used minimal effective dosages based on previous research. The small sample size limited statistical power. Larger, more controlled studies are needed to validate these preliminary findings.

This study enhances MDD neuropathological understanding, with widespread white matter impairment and associations between projection fibers and symptom severity. While producing significant antidepressant effects, short-term esketamine did not recover compromised white matter microstructure.

Considerable research has mapped the human brain networks implicated in anxiety. Yet, less is known about the intrinsic features of the brain implicated in adolescent anxiety and their generalizability to affective and behavioral problems. To this end, we investigated the intrinsic functional connectomes associated with anxiety, their associations with behavioral phenotypes of clinical interest, and the cross-syndrome overlap between the anxiety network and other affective syndromes in an adolescent sample.

We used the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) dataset which comprises 203 clinical and healthy adolescents aged 14-17. Participants underwent a resting-state magnetic resonance imaging scan and completed the Child Behavior Checklist (CBCL) and Behavioral Inhibition/Activation System scale. Using network-based statistics, we identified functional networks associated with anxiety and other behavioral syndromes. The anxiety network strengths were then correlated with behavioral measures.

A significant resting-state functional network associated with anxiety was identified, largely characterized by hyperconnectivity between the somatomotor and both the default mode network and subcortical regions. Network strengths derived from the anxiety network were significantly correlated to various behavioral syndromes, including internalizing and externalizing tendencies. Cross-syndrome overlapping edges were also observed in networks of internalizing disorders, more prominently post-traumatic stress syndromes.

Our results revealed the functional connectomes characteristic of anxiety in adolescents. This resting-state functional network was also predictive of and shared similar features with behavioral syndromes typically associated with anxiety-related disorders, providing evidence that the high comorbidity of anxiety with other clinical conditions may have a neurobiological basis.

Suicide risk is a major concern for patients with major depressive disorder (MDD). Neuroimaging studies have demonstrated that patients with MDD with suicidal ideation or suicide attempt (MDD-S) are accompanied by neurostructural or functional abnormalities, but there is no consensus of opinion on neural substrate alterations involved in MDD-S.

We performed a whole-brain multimodal meta-analysis of existing magnetic resonance imaging (MRI) studies to identify conjoint and separate alterations of grey matter volume (GMV) and spontaneous brain activity characteristics (regional homogeneity and amplitude of low-frequency fluctuations) between patients with MDD-S and patients with MDD without suicidal ideation or suicidal attempt (MDD-NS) via the seed-based d mapping software. We excluded studies that used other modalities, had overlapping data, or had insufficient information.

Our systematic search identified 13 structural MRI studies (471 patients with MDD-S and 508 patients with MDD-NS) and 16 resting-state functional MRI studies (704 patients with MDD-S and 554 patients with MDD-NS) published up to Dec. 5, 2023. Compared with patients with MDD-NS, those with MDD-S showed increased GMV with hypoactivity in the left postcentral gyrus, decreased GMV with hypoactivity in the right inferior parietal gyri, decreased GMV with hyperactivity in the right insula, and separate GMV and functional changes within the bilateral parietal, occipital, and frontal lobes, and the left thalamus.

We were unable to analyze the association between brain features and clinical detail because of a lack of data. Included studies showed considerable heterogeneity and publication bias.

These findings provide a comprehensive overview of brain morphological and spontaneous functional impairments linked to impulsivity, impaired positive reward modulation, emotional disturbances, abnormal emotional processing, and cognitive deficits in MDD-S. These results support an understanding of the relationship between neural substrates and clinical symptoms in MDD-S, and these alterations provide useful insight into pathophysiological mechanisms and intervention strategies to decrease suicide risk in MDD.

Stressful experiences can affect both daily life and long-term health outcomes in a variety of ways. Acute challenges may be adaptive, promoting arousal and enhancing memory and cognitive function. Importantly, however, chronic stress dysregulates the body's physiological regulatory mechanisms consisting of complex hormone interactions throughout the peripheral and central nervous systems. This disrupted signaling consequently alters the balance of synapse formation, maturation and pruning, processes which regulate neural communication, plasticity, learning, cognitive flexibility and adaptive behaviors - hallmarks of a healthy, functional brain. The chronically stressed brain state, therefore, is one which may be uniquely vulnerable. To understand the development of this state, how it is sustained and how behavior and neural function are transiently or indelibly impacted by it, we can turn to a number of advanced approaches in animal models which offer unprecedented insights. This has been the aim of my recent work within the field and the goal of my new independent research program. To achieve this, I have employed methods to uncover how key brain circuits integrate information to support motivated behaviors, how stress impacts their ability to perform this process and how best to operationalize behavioral readouts. Here I present an overview of research contributions that I find most meaningful for advancing our understanding of the impact of stress and propose new avenues which will guide my own framework to address the salient outstanding questions within the field.

Psychedelic compounds have gained renewed interest due to their rapid and long-lasting therapeutic effects on stress-related disorders. While the underlying mechanisms of therapeutic actions of psychedelic compounds are still unclear, these drugs are thought to modulate the activity of the serotonergic system, primarily through activating serotonin type 2A receptor (5-HT2AR) and studies have focused on these actions in the medial prefrontal cortex (mPFC). 25CN-NBOH, a synthetic psychedelic compound with a high binding affinity for 5-HT2ARs and anti-anxiety actions, has emerged as a valuable tool for investigating the physiological functions mediated by this receptor. This study aimed to investigate the electrophysiological effects of 25CN-NBOH on pyramidal mPFC neurons using whole-cell patch clamp recordings in mouse brain slices. We recorded synaptic events and action potential rates during acute and long-term exposure to two concentrations of 25CN-NBOH. Acute application of 10 µM 25CN-NBOH increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) that was reliant on activation of 5-HT2AR, and which was not seen upon chronic exposure. A similar effect of 200 nM 25CN-NBOH was not noted. Surprisingly, both 10 µM and 200 nM 25CN-NBOH significantly suppressed the firing rate following acute as well as a longer-term exposure of 1 h. This suppression was independent of 5-HT2AR activation but was mediated by M-current channels, as evidenced by the reversal of suppression with the M-current blocker XE-991. Our data suggest a complicated dual action of 25CN-NBOH in enhancing excitatory transmission while also reducing excitability. Our data contribute to knowledge regarding the cellular consequence of 5-HT2AR agonism and contribute to widening our understanding of the potential mechanisms underlying the therapeutic actions of serotonergic psychedelics.

Suicide is a complex behavior strongly associated with depression. Despite extensive research, an objective biomarker for evaluating suicide risk precisely and timely is still lacking. Using the precision resting-state fMRI method, we studied 61 depressive patients with suicide ideation (SI) or suicide attempt (SA), and 35 patients without SI to explore functional biomarkers of suicide risk. Among them, 21 participants also completed electroconvulsive therapy (ECT) treatment, allowing the examination of functional changes across different risk states within the same individual. Functional networks were localized in each subject using resting-state fMRI and then an individualized connectome was constructed to represent the subject's functional brain organization. We identified a set of connections that track suicide risk (r = 0.41, p = 0.001) and found that these risk-associated connections were hyper-connected in the frontoparietal network (FPN, p = 0.008, Cohen's d = 0.58) in patients with suicide risk compared to those without. Moreover, ECT treatment significantly reduced (p = 0.001, Cohen's d = 0.56) and normalized these FPN hyper-connections. These findings suggest that connections involving FPN may constitute an important biomarker for evaluating suicide risk and may provide potential targets for interventions such as non-invasive brain stimulation.

The emotion regulation network (ERN) in the brain provides a framework for understanding the neuropathology of affective disorders. Although previous neuroimaging studies have investigated the neurobiological correlates of the ERN in major depressive disorder (MDD), whether patients with MDD exhibit abnormal functional connectivity (FC) patterns in the ERN and whether the abnormal FC in the ERN can serve as a therapeutic response signature remain unclear.

A large functional magnetic resonance imaging dataset comprising 709 patients with MDD and 725 healthy controls (HCs) recruited across five sites was analyzed. Using a seed-based FC approach, we first investigated the group differences in whole-brain resting-state FC of the 14 ERN seeds between participants with and without MDD. Furthermore, an independent sample (45 MDD patients) was used to evaluate the relationship between the aforementioned abnormal FC in the ERN and symptom improvement after 8 weeks of antidepressant monotherapy.

Compared to the HCs, patients with MDD exhibited aberrant FC between 7 ERN seeds and several cortical and subcortical areas, including the bilateral middle temporal gyrus, bilateral occipital gyrus, right thalamus, calcarine cortex, middle frontal gyrus, and the bilateral superior temporal gyrus. In an independent sample, these aberrant FCs in the ERN were negatively correlated with the reduction rate of the HAMD17 score among MDD patients.

These results might extend our understanding of the neurobiological underpinnings underlying unadaptable or inflexible emotional processing in MDD patients and help to elucidate the mechanisms of therapeutic response.

Maternal prenatal depression can affect child brain and behavioral development. Specifically, altered limbic network structure and function is a likely mechanism through which prenatal depression impacts the life-long mental health of exposed children. While developmental trajectories are influenced by many factors that exacerbate risk or promote resiliency, the role of child age and sex in the relationship between prenatal depression and the child brain remains unclear. Here, we review studies of associations between prenatal depression and brain structure and function, with a focus on the role of age and sex in these relationships. After exposure to maternal prenatal depression, altered amygdala, hippocampal, and frontal cortical structure, as well as changes in functional and structural connectivity within the limbic network, are evident during the fetal, infant, preschool, childhood, and adolescent stages of development. Sex appears to play a key role in this relationship, with evidence of differential findings particularly in infants, with males showing smaller and females larger hippocampal and amygdala volumes following prenatal depression. Longitudinal studies in this area have only begun to emerge within the last 5 years and will be key to understanding critical windows of opportunity. Future research focused on the role of age and sex in this relationship is essential to further inform screening, policy, and interventions for children exposed to prenatal depression, interrupt the intergenerational transmission of depression, and ultimately support healthy brain development.

Psychiatric diseases are bringing heavy burdens for both individual health and social stability. The accurate and timely diagnosis of the diseases is essential for effective treatment and intervention. Thanks to the rapid development of brain imaging technology and machine learning algorithms, diagnostic classification of psychiatric diseases can be achieved based on brain images. However, due to divergences in scanning machines or parameters, the generalization capability of diagnostic classification models has always been an issue. We propose Meta-learning with Meta batch normalization and Distance Constraint (M2DC) for training diagnostic classification models. The framework can simulate the train-test domain shift situation and promote intra-class cohesion, as well as inter-class separation, which can lead to clearer classification margins and more generalizable models. To better encode dynamic brain graphs, we propose a concatenated spatiotemporal attention graph isomorphism network (CSTAGIN) as the backbone. The network is trained for the diagnostic classification of major depressive disorder (MDD) based on multi-site brain graphs. Extensive experiments on brain images from over 3261 subjects show that models trained by M2DC achieve the best performance on cross-site diagnostic classification tasks compared to various contemporary domain generalization methods and SOTA studies. The proposed M2DC is by far the first framework for multi-source closed-set domain generalizable training of diagnostic classification models for MDD and the trained models can be applied to reliable auxiliary diagnosis on novel data.

Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) are prevalent comorbidities related to a greater likelihood of poor treatment outcomes and prolonged treatment for Reward Deficiency Syndrome (RDS) behaviors. The current exploratory case study of a small cohort (n=3; f=2 m=1) used novel neurotechnology to treat co-occurring MDD and GAD with a multifaceted intervention that combines the novel bio-resonance neurotechnology (BRNT) referred to as NuCalm®, to restore autonomic nervous system balance and dual hemispheric repetitive transcranial magnetic stimulation (rTMS) of the ipsilateral Dorsal Lateral Prefrontal Cortex (DLPFC) to treat the disrupted structural components of the brain. Neuroacoustic brainwave entrainment, electromagnetic frequency bio-resonance, and light-blocking combine to place patients into a parasympathetic dominant state. The paired t-tests indicated a significant decrease in comparing before and after the intervention. The Patient Health Questionnaire PHQ-9 scores from the first to the last time-point (mean difference = 20, t(2) = 6.55, p = 0.0226), with a 95% confidence interval of mean difference ranging from 6.86 to 33.14. Similarly, there was a significant decrease in General Anxiety Disorder GAD-7 questionnaire scores from the first to the last time point (mean difference = 18.67, t(2) = 12.85, p = 0.0060), with a 95% confidence interval of the mean difference ranging from 12.42 to 24.92. After applying the Bonferroni correction, the corrected p-values for PHQ-9 and GAD-7 are 0.0452 and 0.0120, respectively. Cohen's d standardized effect size indicated that the main effect size was 5.47 and 13.8 times the noise (variability), respectively, for the initial versus final PHQ-9 and GAD-7. Further, more extensive, much larger sham-controlled and blinded studies are required to confirm these encouraging results and explore this multifaceted intervention.

Besides seizures, a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy, which further debilitates their quality of life. This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses, respectively, on corneal kindling-induced generalized seizures and behavioral alterations. Furthermore, observed convulsive frequency and behavioral changes were correlated to post-kindling-induced changes in the activity of markers of oxidative stress.

Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz electrical stimulations (3 mA) for 3 s for 12 days until animals reached a fully kindled state. After the kindling procedure, animals were tested using a set of behavioral tests, and neurochemical alterations were assessed.

Corneal-kindled animals exhibited intense generalized convulsions, altered behavioral phenotypes typified by positive symptoms (hyperlocomotion), negative symptoms (anxiety and anhedonia), and deficits in semantic and working memory. BRV 10 + RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4-5 seizures and improved phenotypical deficits, that is, anxiety, depression, and memory impairments. Moreover, this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult.

Based on our outcomes, this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.

Magnetic resonance imaging (MRI) offers non-invasive assessments of brain structure and function for analyzing brain disorders. With the increasing accumulation of multimodal MRI data in recent years, integrating information from various modalities has become an effective strategy for improving the detection of brain disorders. This study focuses on identifying major depressive disorder (MDD) by using arterial spin labeling (ASL) perfusion MRI in conjunction with structural MRI data. We collected ASL and structural MRI data from 260 participants, including 169 MDD patients and 91 healthy controls. We developed an explainable fusion method to identify MDD, utilizing cerebral blood flow (CBF) data from ASL perfusion MRI and brain tissue volumes from structural MRI. The fusion model, which integrates multimodal data, demonstrated superior predictive performance for MDD. By combining MRI regional volumes with CBF data, we achieved more effective results than using each modality independently. Additionally, we analyzed feature importance and interactions to explain the fusion model. We identified fourteen important features, comprising eight regional volumes and six regional CBF measures, that played a crucial role in the identification of MDD. Furthermore, we found three feature interactions among the important features and seven interactions between structural and functional features, which were particularly prominent in the model. The results of this study suggest that the fusion learning approach, which integrates ASL and structural MRI data, is effective in detecting MDD. Moreover, the study demonstrates that the model explanation method can reveal key features that influence the decisions of models, as well as potential interactions among these key features or between functional and structural features in identifying MDD.

The dried succulent stems of Cistanche tubulosa (Schenk) Wight are utilized in traditional medicine for tonifying kidney yang, which have shown to be effective in alleviating depression-like behaviors or male sexual dysfunction, respectively. However, the pharmacological effects and mechanisms of C. tubulosa and its combinations in the treatment of depression in comorbid with sexual dysfunction remain unclear.

This study aims to elucidate the pharmacological effects and mechanisms of C. tubulosa aqueous extract (CTE) and its combination with fluoxetine (FLX) on depression in comorbid with sexual dysfunction.

A mouse model of depression in comorbid with sexual dysfunction was created using the chronic unpredictable mild stress (CUMS) procedure. The therapeutic effects of CTE and its combination with FLX were assessed using depressive-like and mating behavior experiments, histopathological analysis, and hypothalamic-pituitary-gonadal (HPG) axis function evaluation. The mechanisms were explored by integrated serum and testicular metabolomics combined with network correlation analysis.

CTE was confirmed to significantly improve depressive-like behaviors, reduce mating abilities, testicular histopathological damage, and HPG axis hormone secretion disorders in CUMS mice. Subsequently, mechanism exploration findings indicated that CTE might exert its effect by regulating potential efficacy-related biomarkers (isobutyrylglycine, citric acid, D-galactose) to improve certain metabolic pathways centered around steroid hormone biosynthesis and tricarboxylic acid (TCA) cycle. Furthermore, the combination of CTE and FLX exhibited stronger antidepressant effects than FLX alone, and ameliorated the exacerbated sexual dysfunction induced by FLX. These effects were achieved through the regulation of potential efficacy-related biomarkers (17α-hydroxypregnenolone, tetrahydrodeoxy-corticosterone, sphingosine, cortol, thymine, and L-histidine), thereby improving disorders in glycerophospholipid and histidine metabolism.

In conclusion, the amelioration effects of CTE and its combination with FLX on depression in comorbid with sexual dysfunction were confirmed for the first time. This key mechanism may be achieved by modulating the levels of potential efficacy-related biomarkers, and then emphatically intervene in steroid hormone biosynthesis, TCA cycle, glycerophospholipid and histidine metabolism. The study offers a new perspective for the development and utilization of C. tubulosa.

Major depressive disorder (MDD) is a prevalent mental illness characterized by persistent sadness, loss of interest in activities, and significant functional impairment. It poses severe risks to individuals' physical and psychological well-being. The development of automated diagnostic systems for MDD is essential to improve diagnostic accuracy and efficiency. Electroencephalography (EEG) has been extensively utilized in MDD diagnostic research. However, studies employing deep learning methods still face several challenges, such as difficulty in extracting effective information from EEG signals and risks of data leakage due to experimental designs. These issues result in limited generalization capabilities when models are tested on unseen individuals, thereby restricting their practical application. In this study, we propose a novel deep learning approach, termed TSF-MDD, which integrates temporal, spatial, and frequency-domain information. TSF-MDD first applies a data reconstruction scheme to obtain a four-dimensional temporal-spatial-frequency representation of EEG signals. These data are then processed by a model based on 3D-CNN and CapsNet, enabling comprehensive feature extraction across domains. Finally, a subject-independent data partitioning strategy is employed during training and testing to eliminate data leakage. The proposed approach achieves an accuracy of 92.1%, precision of 90.0%, recall of 94.9%, and F1-score of 92.4%, respectively, on the Mumtaz2016 public dataset. The results demonstrate that TSF-MDD exhibits excellent generalization performance.

The basolateral complex of the amygdala is a crucial neurobiological site for Pavlovian conditioning. Investigations into volumetric alterations of the basolateral amygdala in individuals with major depressive disorder (MDD) have yielded conflicting results. These may be reconciled in an inverted U-shape allostatic growth trajectory. This hypothesized trajectory unfolds with an initial phase of volumetric expansion, driven by enhanced dendritic arborization and synaptic plasticity. The increase in volume is followed by a reduction phase, as glucocorticoid exposure cumulatively results in excitotoxic damage, reflecting allostatic load.

7T magnetic resonance brain imaging was conducted on a total of 84 participants (mean age 38 ± 12 years), comprising 20 unmedicated and 20 medicated individuals with MDD, 21 individuals suffering from bipolar disorder and 23 healthy controls. We employed FreeSurfer 7.3.2 for automatic high-resolution segmentation of nine amygdala subnuclei. We conducted analyses of covariance, with volumes of the basolateral complex, the lateral nucleus and, exploratively, the whole amygdala, as dependent variables, while controlling for the total intracranial volume and sex. Quadratic regressions were computed within the MDD group and in relevant subgroups to investigate the presence of a U-shaped relationship between the number of preceding major depressive episodes or the duration of the disease since the first episode and the dependent variables.

Diagnostic groups did not exhibit statistically significant differences in the volumes of the basolateral amygdala (left F (3,75) = 0.66, p >.05; right F (3,76) = 1.80, p >.05), the lateral nucleus (left F (3,75) = 1.22, p >.05; right F (3,76) = 2.30, p >.05)), or the whole amygdala (left F (3,75) = 0.48, p >.05; right F (3,76) = 1.58, p >.05). No quadratic associations were observed between surrogate parameters of disease progression and any of the examined amygdala volumes. There were no significant correlations between subregion volumes and clinical characteristics.

We found no evidence for the hypothesis of an inverted U-shaped volumetric trajectory of the basolateral amygdala in MDD. Future research with larger sample sizes, including the measurement of genetic and epigenetic markers, will hopefully further elucidate this compelling paradigm.

Medial Forebrain Bundle Deep Brain Stimulation (MFB-DBS) can have rapid and long lasting antidepressant effects in Treatment Resistant Depression (TRD) patients. The mechanisms are not well understood, but one hypothesis stipulates that modulation of the dopaminergic (DAergic) fibers contribute to the therapeutic outcome. Acute DBS effects on DA release have been studied; however, longitudinal studies with acute-repetitive DBS are lacking. Long-Evans accumbal DA release and Ventral Tegmental Area (VTA) calcium tonic and phasic signaling to different mfb-DBS parameters were measured using fiber photometry over 8 weeks, following acute and repetitive stimulation in behaving and non-behaving animals. DBS-induced release was observed in both targets, with increased frequency and DBS duration. 130 Hz stimulation increased phasic and tonic DA response over time, with the latter being a potential mechanism for its long-term clinical effectiveness. VTA calcium transients decreased, while phasic activity increased with frequency. Pulse width (PW)-mediated differential peak release timing also suggests potential parallel activation of diverse fiber types. Additionally, decreased DA transients rate during Elevated Plus Maze (EPM) suggests context and stimulation duration-dependent DA release. The data confirm chronic antidromic/orthodromic DAergic responses with stimulation parameter dependent variability, providing novel insights into temporal adaptations, connectivity and fiber recruitment on mfb DBS.

While patients with major depressive disorder (MDD) and bipolar disorder (BD) exhibited default mode network (DMN) dysfunction revealed by aberrant resting-state functional connectivity (rsFC) patterns, previous findings have been inconsistent. Little is known about the similarities and differences in DMN rsFC between MDD and BD.

A voxel-wise meta-analysis of seed-based DMN rsFC studies on MDD or BD was performed using the Seed-based d Mapping software with permutation of subject images (SDM-PSI). Aberrant DMN rsFC in both disorders was investigated separately, followed by conjunction and between-disorder comparison analyses. Functional decoding was performed to implicate the psychophysiological underpinnings of derived brain abnormalities.

Thirty-four studies comparing 1316 MDD patients with 1327 HC, and 22 studies comparing 1059 BD patients with 1396 HC were included. Compared to HC, MDD patients exhibited DMN hyperconnectivity with frontolimbic systems, and hypoconnectivity with temporal lobe and posterior cingulate cortex. BD patients displayed increased DMN connectivity with bilateral precuneus, and reduced connectivity with prefrontal cortex and middle temporal gyrus. No common patterns of DMN rsFC abnormalities were observed between MDD and BD. Compared to BD, MDD patients showed DMN hyperconnectivity with triangular part of the left inferior frontal gyrus and left fusiform gyrus. Functional decoding found that patterns of DMN rsFC alteration between MDD and BD were primarily related to action and perception domains.

Distinct DMN dysfunction patterns in MDD and BD enhance current understanding of the neural substrates of mood disorders and may provide a potential biomarker for differentiation.

Recent genetic studies have linked numerous loci to psychiatric disorders. However, the biological pathways that connect these genetic associations to psychiatric disorders' specific pathophysiological processes are largely unclear. Endophenotypes, first defined over five decades ago, are heritable traits, independent of disease state that are associated with a disease, encompassing a broad range of neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, and neuropsychological characteristics. Considering the advancements in genetics and genomics over recent decades, we propose a revised definition of endophenotypes as 'genetically influenced phenotypes linked to disease or treatment characteristics and their related events.' We also updated endophenotype criteria to include (1) reliable measurement, (2) association with the disease or its related events, and (3) genetic mediation. 'Genetic mediation' is introduced to differentiate between causality and pleiotropic effects and allows non-linear relationships. Furthermore, this updated Endophenotype 2.0 framework expands to encompass genetically regulated responses to disease-related factors, including environmental risks, illness progression, treatment responses, and resilience phenotypes, which may be state-dependent. This broadened definition paves the way for developing new endophenotypes crucial for genetic analyses in psychiatric disorders. Integrating genetics, genomics, and diverse endophenotypes into multi-dimensional mechanistic models is vital for advancing our understanding of psychiatric disorders. Crucially, elucidating the biological underpinnings of endophenotypes will enhance our grasp of psychiatric genetics, thereby improving disease risk prediction and treatment approaches.