Towards a neurodevelopmental model of bipolar disorder: a critical review of trait- and state-related functional neuroimaging in adolescents and young adults.

Neurodevelopmental mechanisms are increasingly implicated in bipolar disorder (BD), highlighting the importance of their study in young persons. Neuroimaging studies have demonstrated a central role for frontotemporal corticolimbic brain systems that subserve processing and regulation of emotions, and processing of reward in adults with BD. As adolescence and young adulthood (AYA) is a time when fully syndromal BD often emerges, and when these brain systems undergo dynamic maturational changes, the AYA epoch is implicated as a critical period in the neurodevelopment of BD. Functional magnetic resonance imaging (fMRI) studies can be especially informative in identifying the functional neuroanatomy in adolescents and young adults with BD (BDAYA) and at high risk for BD (HR-BDAYA) that is related to acute mood states and trait vulnerability to the disorder. The identification of early emerging brain differences, trait- and state-based, can contribute to the elucidation of the developmental neuropathophysiology of BD, and to the generation of treatment and prevention targets. In this critical review, fMRI studies of BDAYA and HR-BDAYA are discussed, and a preliminary neurodevelopmental model is presented based on a convergence of literature that suggests early emerging dysfunction in subcortical (e.g., amygdalar, striatal, thalamic) and caudal and ventral cortical regions, especially ventral prefrontal cortex (vPFC) and insula, and connections among them, persisting as trait-related features. More rostral and dorsal cortical alterations, and bilaterality progress later, with lateralization, and direction of functional imaging findings differing by mood state. Altered functioning of these brain regions, and regions they are strongly connected to, are implicated in the range of symptoms seen in BD, such as the insula in interoception, precentral gyrus in motor changes, and prefrontal cortex in cognition. Current limitations, and outlook on the future use of neuroimaging evidence to inform interventions and prevent the onset of mood episodes in BDAYA, are outlined.

Predicting depressed and elevated mood symptomatology in bipolar disorder using brain functional connectomes.

BACKGROUND: The study is aimed to identify brain functional connectomes predictive of depressed and elevated mood symptomatology in individuals with bipolar disorder (BD) using the machine learning approach Connectome-based Predictive Modeling (CPM). METHODS: Functional magnetic resonance imaging data were obtained from 81 adults with BD while they performed an emotion processing task. CPM with 5000 permutations of leave-one-out cross-validation was applied to identify functional connectomes predictive of depressed and elevated mood symptom scores on the Hamilton Depression and Young Mania rating scales. The predictive ability of the identified connectomes was tested in an independent sample of 43 adults with BD. RESULTS: CPM predicted the severity of depressed [concordance between actual and predicted values (r = 0.23, pperm (permutation test) = 0.031) and elevated (r = 0.27, pperm = 0.01) mood. Functional connectivity of left dorsolateral prefrontal cortex and supplementary motor area nodes, with inter- and intra-hemispheric connections to other anterior and posterior cortical, limbic, motor, and cerebellar regions, predicted depressed mood severity. Connectivity of left fusiform and right visual association area nodes with inter- and intra-hemispheric connections to the motor, insular, limbic, and posterior cortices predicted elevated mood severity. These networks were predictive of mood symptomatology in the independent sample (r ⩾ 0.45, p = 0.002). CONCLUSIONS: This study identified distributed functional connectomes predictive of depressed and elevated mood severity in BD. Connectomes subserving emotional, cognitive, and psychomotor control predicted depressed mood severity, while those subserving emotional and social perceptual functions predicted elevated mood severity. Identification of these connectome networks may help inform the development of targeted treatments for mood symptoms.

Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium.

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.

The differential association between local neurotransmitter levels and whole-brain resting-state functional connectivity in two distinct cingulate cortex subregions.

We examined the association between rsFC and local neurotransmitter levels in the pregenual anterior cingulate cortex (pgACC) and the anterior mid-cingulate cortex (aMCC) by varying rsFC-strengths at the whole-brain level. Our results showed region-dependent directionality of associations in the investigated ACC subdivisions.

Dorsal bed nucleus of stria terminalis in depressed and nondepressed temporal lobe epilepsy patients.

OBJECTIVE: Temporal lobe epilepsy (TLE) and depression are common comorbid disorders whose underlying shared neural network has yet to be determined. Although animal studies demonstrate a role for the dorsal bed nucleus of the stria terminalis (dBNST) in both seizures and depression, and human clinical studies demonstrate a therapeutic effect of stimulating this region on treatment-resistant depression, the role of the dBNST in depressed and nondepressed TLE patients is still unclear. Here, we tested the hypothesis that this structure is morphologically abnormal in these epilepsy patients, with an increased abnormality in TLE patients with comorbid depression. METHODS: In this case-controlled study, 3-T structural magnetic resonance imaging scans were obtained from TLE patients with no depression (TLEonly), TLE patients with depression (TLEdep), and healthy control (HC) subjects. TLE subjects were recruited from the Yale University Comprehensive Epilepsy Center, diagnosed with the International League Against Epilepsy 2014 Diagnostic Guidelines, and confirmed by video-electroencephalography. Diagnosis of major depressive disorder was confirmed by a trained neuropsychologist through a Mini International Neuropsychiatric Interview based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. The dBNST was delineated manually by reliable raters using Bioimage Suite software. RESULTS: The number of patients and subjects included 35 TLEonly patients, 20 TLEdep patients, and 102 HC subjects. Both TLEonly and TLEdep patients had higher dBNST volumes compared to HC subjects, unilaterally in the left hemisphere in the TLEonly patients (p = .003) and bilaterally in the TLEdep patients (p < .0001). Furthermore, the TLEdep patients had a higher dBNST volume than the TLEonly patients in the right hemisphere (p = .02). SIGNIFICANCE: Here, we demonstrate an abnormality of the dBNST in TLE patients, both without depression (left enlargement) and with depression (bilateral enlargement). Our results demonstrate this region to underlie TLE both with and without depression, implicating it as a target in treating the comorbidity between these two disorders.

A graph theory-based whole brain approach to assess mood state differences in adolescents and young adults with bipolar disorder.

OBJECTIVES: Identifying hubs of brain dysfunction in adolescents and young adults with Bipolar I Disorder (BDAYA ) could provide targets for early detection, prevention, and treatment. Previous neuroimaging studies across mood states of BDAYA are scarce and often examined limited brain regions potentially prohibiting detection of other important regions. We used a data-driven whole-brain Intrinsic Connectivity Distribution (ICD) approach to investigate dysconnectivity hubs across mood states in BDAYA . METHODS: Functional magnetic resonance imaging whole-brain ICD data were investigated for differences across four groups: BDAYA -depressed (n = 22), BDAYA -euthymic (n = 45), BDAYA -elevated (n = 24), and healthy controls (HC, n = 111). Clusters of ICD differences were assessed for regional dysconnectivity and mood symptom relationships. Analyses were also performed for BDAYA overall (vs. HC) ICD differences persisting across mood states. RESULTS: ICD was higher in the BDAYA- depressed group than other groups in bilateral ventral/rostral/dorsal prefrontal cortex (PFC) and right lenticular nucleus (LN) (pcorrected  <0.05). In BDAYA -depressed, functional connectivity (FC) was increased between these regions with their contralateral homologues and PFC-medial temporal FC was more negative (p < 0.005). PFC-related findings correlated with depression scores (p < 0.05). The overall BDAYA group showed ICD increases in more ventral left PFC and right cerebellum, present across euthymia and acute mood states. CONCLUSIONS: This ICD approach supports a PFC hub of inter- and intra-hemispheric frontotemporal dysconnectivity in BDAYA with potential trait features and disturbances of higher magnitude during depression. Hubs were also revealed in LN and cerebellum, less common foci of BD research. The hubs are potential targets for early interventions to detect, prevent, and treat BD.

Localized Prediction of Glutamate from Whole-Brain Functional Connectivity of the Pregenual Anterior Cingulate Cortex.

Local measures of neurotransmitters provide crucial insights into neurobiological changes underlying altered functional connectivity in psychiatric disorders. However, noninvasive neuroimaging techniques such as magnetic resonance spectroscopy (MRS) may cover anatomically and functionally distinct areas, such as p32 and p24 of the pregenual anterior cingulate cortex (pgACC). Here, we aimed to overcome this low spatial specificity of MRS by predicting local glutamate and GABA based on functional characteristics and neuroanatomy in a sample of 88 human participants (35 females), using complementary machine learning approaches. Functional connectivity profiles of pgACC area p32 predicted pgACC glutamate better than chance (R2 = 0.324) and explained more variance compared with area p24 using both elastic net and partial least-squares regression. In contrast, GABA could not be robustly predicted. To summarize, machine learning helps exploit the high resolution of fMRI to improve the interpretation of local neurometabolism. Our augmented multimodal imaging analysis can deliver novel insights into neurobiology by using complementary information.SIGNIFICANCE STATEMENT Magnetic resonance spectroscopy (MRS) measures local glutamate and GABA noninvasively. However, conventional MRS requires large voxels compared with fMRI, because of its inherently low signal-to-noise ratio. Consequently, a single MRS voxel may cover areas with distinct cytoarchitecture. In the largest multimodal 7 tesla machine learning study to date, we overcome this limitation by capitalizing on the spatial resolution of fMRI to predict local neurotransmitters in the PFC. Critically, we found that prefrontal glutamate could be robustly and exclusively predicted from the functional connectivity fingerprint of one of two anatomically and functionally defined areas that form the pregenual anterior cingulate cortex. Our approach provides greater spatial specificity on neurotransmitter levels, potentially improving the understanding of altered functional connectivity in mental disorders.

Emotion processing and regulation in major depressive disorder: A 7T resting-state fMRI study.

Dysfunctions in bottom-up emotion processing (EP), as well as top-down emotion regulation (ER) are prominent features in pathophysiology of major depressive disorder (MDD). Nonetheless, it is not clear whether EP- and ER-related areas are regionally and/or connectively disturbed in MDD. In addition, it is yet to be known how EP- and ER-related areas are interactively linked to regulatory behavior, and whether this interaction is disrupted in MDD. In our study, regional amplitude of low frequency fluctuations (ALFF) and whole-brain functional connectivity (FC) of meta-analytic-driven EP- and ER-related areas were compared between 32 healthy controls (HC) and 20 MDD patients. Then, we aimed to investigate whether the EP-related areas can predict the ER-related areas and regulatory behavior in both groups. Finally, the brain-behavior correlations between the EP- and ER-related areas and depression severity were assessed. We found that: (a) affective areas are regionally and/or connectively disturbed in MDD; (b) EP-ER interaction seems to be disrupted in MDD; overburden of emotional reactivity in amygdala may inversely affect cognitive control processes in prefrontal cortices, which leads to diminished regulatory actions. (c) Depression severity is correlated with FC of affective areas. Our findings shed new lights on the neural underpinning of affective dysfunctions in depression.

Altered frontal cortex functioning in emotion regulation and hopelessness in bipolar disorder.

OBJECTIVES: Emotion regulation difficulties precipitate and exacerbate acute mood symptoms in individuals with bipolar disorder (BD), and contribute to suicidal behavior. However, few studies have examined regional brain responses in explicit emotion regulation during acute BD mood states, or hopelessness, a major suicide risk factor. We assessed brain responses during explicit emotion regulation, and their relationship with hopelessness, in acutely symptomatic and euthymic individuals with BD. METHODS: Functional MRI data were obtained from individuals with BD who were either in acute negative (BD-A; n = 24) or euthymic (BD-E; n = 24) mood states, and from healthy volunteers (HV; n = 55), while participants performed a paradigm that instructed them to downregulate their responses to fearful (EmReg-Fear) and happy (EmReg-Happy) facial stimuli. Emotion regulation-related differences in brain responses during negative and euthymic BD states, as well as their associations with negative affective symptoms (hopelessness and depression), were examined. RESULTS: Decreased responses were observed in ventral and dorsal frontal regions, including medial orbitofrontal (mOFC) and dorsal anterior cingulate cortices, during EmReg-Fear across symptomatic and euthymic states in participants with BD relative to HVs. The lowest responses were observed in the BD-A group. Across BD participants, negative associations were observed between mOFC responses and hopelessness, particularly due to loss of motivation. Differences were not significant during EmReg-Happy. CONCLUSIONS: Lesser emotion regulation-related ventral and dorsal frontal engagement in BD could represent a trait abnormality that worsens during acute negative states. The reduced mOFC engagement in BD during explicit regulation of negative emotions may contribute to hopelessness particularly in the context of diminished motivation.

Telehealth Social Rhythm Therapy to Reduce Mood Symptoms and Suicide Risk Among Adolescents and Young Adults With Bipolar Disorder.

OBJECTIVE: Social rhythm irregularities are associated with increased bipolar disorder symptoms and suicide risk. This study was the first to examine the feasibility and acceptability of a 12-week social rhythm therapy (SRT) delivered predominantly via telehealth (three in-person sessions, nine via video teleconferencing) to adolescents and young adults with bipolar disorder. The primary aim was to determine the feasibility and acceptability of SRT delivered predominantly via telehealth. Secondary aims were to explore the intervention's impacts on social rhythm regularity, mood symptoms, and suicide propensity. METHODS: Thirteen adolescents and young adults with bipolar disorder received a modified SRT called Brain Emotion circuitry-targeted Self-Monitoring And Regulation Therapy for Daily Rhythms (BE-SMART-DR) administered mostly remotely, adjunctive to treatment as usual. Retention rates, client satisfaction, therapeutic alliance, and pre- to postintervention changes in social rhythm regularity, mood symptoms, and suicide propensity were assessed. RESULTS: BE-SMART-DR was associated with high retention rates (77%), high mean±SD scores on the Client Satisfaction Questionnaire (29.4±2.7), and high participant global scores on the Working Alliance Inventory (231.3±8.1), indicative of strong therapeutic alliance. Secondary outcome measures on social rhythm irregularities, mood symptoms, and suicide propensity decreased from pre- to posttherapy. Increased social rhythm regularity was associated with reduced suicide propensity after analyses were controlled for reductions in mood symptoms. CONCLUSIONS: These preliminary results indicate that SRT delivered largely by telemedicine is feasible and acceptable. The intervention appeared to reduce mood symptoms, and suicide propensity independent of mood symptoms, among adolescents and young adults with bipolar disorder.

Local glutamate in cingulate cortex subregions differentially correlates with affective network activations during face perception.

The cingulate cortex is involved in emotion recognition/perception and regulation. Rostral and caudal subregions belong to different brain networks with distinct roles in affective perception. Despite recent accounts of the relevance of cingulate cortex glutamate (Glu) on blood-oxygen-level-dependent (BOLD) responses, the specificity of the subregional Glu levels during emotional tasks remains unclear. Seventy-two healthy participants (age = 27.33 ± 6.67, 32 women) performed an affective face-matching task and underwent magnetic resonance spectroscopy (MRS) at 7 Tesla. Correlations between the BOLD response during emotion perception and Glu concentration in the pregenual anterior cingulate cortex (pgACC) and anterior midcingulate cortex (aMCC) were compared on a whole-brain level. Post hoc specificity of the association with an affect was assessed. Lower Glu in the pgACC correlated with stronger activation differences between negative and positive faces in the left inferior and superior frontal gyrus (L IFG and L SFG). In contrast, lower Glu in the aMCC correlated with BOLD contrasts in the posterior cingulate cortex (PCC). Furthermore, negative face detection was associated with prolonged response time (RT). Our results demonstrate a subregion-specific involvement of cingulate cortex Glu in interindividual differences during viewing of affective facial expressions. Glu levels in the pgACC were correlated with frontal area brain activations, whereas Glu in the salience network component aMCC modulated responses in the PCC-precuneus. We show that region-specific metabolite mapping enables specific activation of different BOLD signals in the brain underlying emotional perception.

Default mode network connectivity change corresponds to ketamine's delayed glutamatergic effects.

Ketamine exerts rapid antidepressant effects peaking 24 h after a single infusion, which have been suggested to be reflected by both reduced functional connectivity (FC) within default mode network (DMN) and altered glutamatergic levels in the perigenual anterior cingulate cortex (pgACC) at 24 h. Understanding the interrelation and time point specificity of ketamine-induced changes of brain circuitry and metabolism is thus key to future therapeutic developments. We investigated the correlation of late glutamatergic changes with FC changes seeded from the posterior cingulate cortex (PCC) and tested the prediction of the latter by acute fractional amplitude of low-frequency fluctuations (fALFF). In a double-blind, randomized, placebo-controlled study of 61 healthy subjects, we compared effects of subanesthetic ketamine infusion (0.5 mg/kg over 40 min) on resting-state fMRI and MR-Spectroscopy at 7 T 1 h and 24 h post-infusion. FC decrease between PCC and dorsomedial prefrontal cortex (dmPFC) was found at 24 h post-infusion (but not 1 h) and this FC decrease correlated with glutamatergic changes at 24 h in pgACC. Acute increase in fALFF was found in ventral PCC at 1 h which was not observed at 24 h and inversely correlated with the reduced dPCC FC towards the dmPFC at 24 h. The correlation of metabolic and functional markers of delayed ketamine effects and their temporal specificity suggest a potential mechanistic relationship between glutamatergic modulation and reconfiguration of brain regions belonging to the DMN.

GAD65 Promoter Polymorphism rs2236418 Modulates Harm Avoidance in Women via Inhibition/Excitation Balance in the Rostral ACC.

Anxiety disorders are common and debilitating conditions with higher prevalence in women. However, factors that predispose women to anxiety phenotypes are not clarified. Here we investigated potential contribution of the single nucleotide polymorphism rs2236418 in GAD2 gene to changes in regional inhibition/excitation balance, anxiety-like traits, and related neural activity in both sexes. One hundred and five healthy individuals were examined with high-field (7T) multimodal magnetic resonance imaging (MRI); including resting-state functional MRI in combination with assessment of GABA and glutamate (Glu) levels via MR spectroscopy. Regional GABA/Glu levels in anterior cingulate cortex (ACC) subregions were assessed as mediators of gene-personality interaction for the trait harm avoidance and moderation by sex was tested. In AA homozygotes, with putatively lower GAD2 promoter activity, we observed increased intrinsic neuronal activity and higher inhibition/excitation balance in pregenual ACC (pgACC) compared with G carriers. The pgACC drove a significant interaction of genotype, region, and sex, where inhibition/excitation balance was significantly reduced only in female AA carriers. This finding was specific for rs2236418 as other investigated single nucleotide polymorphisms of the GABA synthesis related enzymes (GAD1, GAD2, and GLS) were not significant. Furthermore, only in women there was a negative association of pgACC GABA/Glu ratios with harm avoidance. A moderated-mediation model revealed that pgACC GABA/Glu also mediated the association between the genotype variant and level of harm avoidance, dependent on sex. Our data thus provide new insights into the neurochemical mechanisms that control emotional endophenotypes in humans and constitute predisposing factors for the development of anxiety disorders in women.SIGNIFICANCE STATEMENT Anxiety disorders are among the most common and burdensome psychiatric disorders, with higher prevalence rates in women. The causal mechanisms are, however, poorly understood. In this study we propose a neurobiological basis that could help to explain female bias of anxiety endophenotypes. Using magnetic resonance brain imaging and personality questionnaires we show an interaction of the genetic variation rs2236418 in the GAD2 gene and sex on GABA/glutamate (Glu) balance in the pregenual anterior cingulate cortex (pgACC), a region previously connected to affect regulation and anxiety disorders. The GAD2 gene polymorphism further influenced baseline neuronal activity in the pgACC. Importantly, GABA/Glu was shown to mediate the relationship between the genetic variant and harm avoidance, however, only in women.

Concepts and Dysfunctions of Emotion in Neuropsychiatric Research.

This chapter aims to provide a perspective of the complex formation of emotion and its operational usage in neuroscience. In the first section, the essence and function of emotion will be introduced from different perspectives. After an overview of historical and ongoing debates in the second section, the neuroscientific findings regarding emotional instances in healthy subjects and psychiatric patients will be outlined throughout the third and fourth sections. In the last section, a comprehensive approach of the newly developing field of computational psychiatry to emotion will be introduced.

Factors Influencing the Cardiovascular Response to Subanesthetic Ketamine: A Randomized, Placebo-Controlled Trial.

Background: The increasing use of ketamine as a potential rapid-onset antidepressant necessitates a better understanding of its effects on blood pressure and heart rate, well-known side effects at higher doses. For the subanesthetic dose used for depression, potential predictors of these cardiovascular effects are important factors influencing clinical decisions. Since ketamine influences the sympathetic nervous system, we investigated the impact of autonomic nervous system-related factors on the cardiovascular response: a genetic polymorphism in the norepinephrine transporter and gender effects. Methods: Blood pressure and heart rate were monitored during and following administration of a subanesthetic dose of ketamine or placebo in 68 healthy participants (mean age 26.04 ±5.562 years) in a double-blind, randomized, controlled, parallel-design trial. The influences of baseline blood pressure/heart rate, gender, and of a polymorphism in the norepinephrine transporter gene (NET SLC6A2, rs28386840 [A-3081T]) on blood pressure and heart rate changes were investigated. To quantify changes in blood pressure and heart rate, we calculated the maximum change from baseline (ΔMAX) and the time until maximum change (TΔMAX). Results: Systolic and diastolic blood pressure as well as heart rate increased significantly upon ketamine administration, but without reaching hypertensive levels. During administration, the systolic blood pressure at baseline (TP0Sys) correlated negatively with the time to achieve maximal systolic blood pressure (TΔMAXSys, P<.001). Furthermore, women showed higher maximal diastolic blood pressure change (ΔMAXDia, P<.001) and reached this peak earlier than men (TΔMAXDia, P=.017) at administration. NET rs28386840 [T] carriers reached their maximal systolic blood pressure during ketamine administration significantly earlier than [A] homozygous (TΔMAXSys, P=.030). In a combined regression model, both genetic polymorphism and TP0Sys were significant predictors of TΔMAXSys (P<.0005). Conclusions: Subanesthetic ketamine increased both blood pressure and heart rate without causing hypertensive events. Furthermore, we identified gender and NET rs28386840 genotype as factors that predict increased cardiovascular sequelae of ketamine administration in our young, healthy study population providing a potential basis for establishing monitoring guidelines.

A spectroscopic approach toward depression diagnosis: local metabolism meets functional connectivity.

Abnormal anterior insula (AI) response and functional connectivity (FC) is associated with depression. In addition to clinical features, such as severity, AI FC and its metabolism further predicted therapeutic response. Abnormal FC between anterior cingulate and AI covaried with reduced glutamate level within cingulate cortex. Recently, deficient glial glutamate conversion was found in AI in major depression disorder (MDD). We therefore postulate a local glutamatergic mechanism in insula cortex of depressive patients, which is correlated with symptoms severity and itself influences AI's network connectivity in MDD. Twenty-five MDD patients and 25 healthy controls (HC) matched on age and sex underwent resting state functional magnetic resonance imaging and magnetic resonance spectroscopy scans. To determine the role of local glutamate-glutamine complex (Glx) ratio on whole brain AI FC, we conducted regression analysis with Glx relative to creatine (Cr) ratio as factor of interest and age, sex, and voxel tissue composition as nuisance factors. We found that in MDD, but not in HC, AI Glx/Cr ratio correlated positively with AI FC to right supramarginal gyrus and negatively with AI FC toward left occipital cortex (p < 0.05 family wise error). AI Glx/Cr level was negatively correlated with HAMD score (p < 0.05) in MDD patients. We showed that the local AI ratio of glutamatergic-creatine metabolism is an underlying candidate subserving functional network disintegration of insula toward low level and supramodal integration areas, in MDD. While causality cannot directly be inferred from such correlation, our finding helps to define a multilevel network of response-predicting regions based on local metabolism and connectivity strength.

Increased levels of 5HT2A receptor mRNA expression in peripheral blood mononuclear cells of patients with major depression: correlations with severity and duration of illness.

BACKGROUND: Neuroimaging, immunologic, and pharmacologic studies have emphasized the role of 5-HT2A and 5-HT3A serotonin receptors in the pathophysiology of major depression. AIM: The aim of this study was to measure the relative expression of 5-HT2A and 5-HT3A receptor mRNA in peripheral blood mononuclear cells (PBMCs) of patients with major depressive disorder (MDD). METHOD: 5-HT2A and 5-HT3A receptor mRNA expressions were examined in PBMCs of 25 medication-naïve-patients with MDD, 25 medication-free MDD patients, and 25 healthy controls. 5-HT2A and 5-HT3A receptor mRNA expressions were measured using real-time quantitative PCR. This study evaluated patients' clinical symptoms using the Hamilton Depression Rating Scale-17 items (HDRS) and the Beck Depression Inventory (BDI). RESULTS: Relative 5-HTR2A mRNA expression was significantly higher in PBMCs of all MDD patients when compared with healthy controls (Z = -3.875, p < 0.05). However, there was no significant difference in the relative levels of 5-HTR3A mRNA expression in PBMCs of all MDD patients when compared with healthy controls (Z = -1.328, p > 0.05). MDD patients showed significant correlations between 5-HTR2A mRNA expression and HDRS scores (rs = 0.902, p < 0.001) and BDI scores (rs = 0.878, p < 0.001). CONCLUSION: This study showed that depressed patients, irrespective of treatment, have higher 5-HTR2A mRNA levels in PBMCs than healthy subjects. It also provided evidence that 5-HTR2A mRNA levels in PBMCs of MDD patients could be associated with the severity of depression and the duration of the illness.

Corrigendum to "Cross-sectional study of retrospective self-reported childhood emotional neglect and inhibitory neurometabolite levels in the pregenual anterior cingulate cortex in adult humans" [Neurobiol. Stress, 25 (July 2023), 100556].

[This corrects the article DOI: 10.1016/j.ynstr.2023.100556.].

Gut microbiome in atypical depression.

BACKGROUND: Recent studies showed that immunometabolic dysregulation is related to unipolar major depressive disorder (MDD) and that it more consistently maps to MDD patients endorsing an atypical symptom profile, characterized by energy-related symptoms including increased appetite, weight gain, and hypersomnia. Despite the documented influence of the microbiome on immune regulation and energy homeostasis, studies have not yet investigated microbiome differences among clinical groups in individuals with MDD. METHODS: Fifteen MDD patients with atypical features according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)-5, forty-four MDD patients not fulfilling the DSM-5 criteria for the atypical subtype, and nineteen healthy controls were included in the study. Participants completed detailed clinical assessment and stool samples were collected. Samples were sequenced for the prokaryotic 16S rRNA gene, in the V3-V4 variable regions. Only samples with no antibiotic exposure in the previous 12 months and a minimum of >2000 quality-filtered reads were included in the analyses. RESULTS: There were no statistically significant differences in alpha- and beta-diversity between the MDD groups and healthy controls. However, within the atypical MDD group, there was an increase in the Verrucomicrobiota phylum, with Akkermansia as the predominant bacterial genus. LIMITATIONS: Cross-sectional data, modest sample size, and significantly increased body mass index in the atypical MDD group. CONCLUSIONS: There were no overall differences among the investigated groups. However, differences were found at several taxonomic levels. Studies in larger longitudinal samples with relevant confounders are needed to advance the understanding of the microbial influences on the clinical heterogeneity of depression.

Psychological distress among individuals with a suicide attempt or suicidal ideation and suicide attempts patterns: first two years of the pandemic.

Background: The COVID-19 pandemic and related restrictions may have led to increased stress, particularly in people with mental health problems. Since stress factors play important role in the emergence of suicide attempts (SA) and suicidal ideation (SI), they may have been exacerbated by the pandemic, which could have led to an increased number of suicide attempts. Thus, we first investigated whether the pandemic affected personal stress experiences and appraisal of coping potential in individuals with and without SA and SI. In a second step, we analyzed the frequency and dynamics of SAs by patients admitted to a psychiatric university clinic over a period of four years. Methods: We examined stress experiences and appraisal of coping resources of inpatients recruited between March 2021 and February 2022 with SA (n=38), SI (n=27), and with mood disorder without SA or SI (n=45). In the second study, we investigated the time course of prospectively recorded patients with a suicide attempt (n=399) between January 1st 2018 and December 31st 2021 using interrupted time-series Poisson regression models. Results: There was a significant main effect of group (F[2,107]=6.58, p=0.002) regarding psychological stress levels, which was significantly higher in the SA and SI groups than in the psychiatric control group. No significant differences were found in the appraisal of coping resources or in the frequency of SAs before and during pandemic. However, the pandemic had a significant impact on the seasonal pattern of SAs. Conclusions: The pandemic increased psychological stress levels in individuals with SA and SI, which may be related to SI and do not necessarily result in SA. The pandemic did not affect the overall frequency of SA between March 2020 and December 2021, but interfered with the seasonal pattern of SA occurrence. Effective intervention strategies during a pandemic should include programs to strengthen the psychological resilience of people who are susceptible to mental health problems.