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Background and objectives Substance use disorder (SUD) includes maladaptive patterns of substance use despite negative consequences. Previous structural neuroimaging studies showed some structural alterations in SUD, but it remains unknown whether these alterations are specifically associated with SUD or common comorbidities. This study attempts to validate the findings of structural differences between SUD, healthy controls (HC), and psychiatric controls (PC). Methods We used HC (N = 86) matched for demographics, and PC (N = 86) matched for demographics and psychiatric diagnoses to a group of SUD patients (N = 86). We assessed the group differences of subcortical volumes, cortical volumes, thickness, and surface areas between SUD and HC. We then analyzed the group differences between SUD and PC within regions showing differences between SUD and HC. Results SUD had smaller left nucleus accumbens, right thalamus, right hippocampus, left caudal anterior cingulate cortex (ACC) volume, and larger right caudal ACC volume, and right caudal ACC, right caudal middle frontal gyrus (MFG), and right posterior cingulate cortex (PCC) surface than HC. Increased right caudal ACC volume and right PCC surface in SUD were the only findings when compared with PC. Several areas showed thickness alterations between SUD and HC, but none survived multiple comparisons vs PC. Discussion and conclusions Our findings suggest that cingulate structures may be altered in SUD compared with both HC and PC. Scientific significance These results are among the first to indicate that some structural alterations may be SUD-specific, and highlight a cautionary note about using HC in psychiatric biomarker research. (Am J Addict 2020;00:00-00).

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

The gut microbiota has recently gained attention as a possible modulator of brain activity. A number of reports suggest that the microbiota may be associated with neuropsychiatric conditions such as major depressive disorder, autism and anxiety. The gut microbiota is thought to influence the brain via vagus nerve signalling, among other possible mechanisms. The insula processes and integrates these vagal signals. To determine if microbiota diversity and structure modulate brain activity, we collected faecal samples and examined insular function using resting state functional connectivity (RSFC). Thirty healthy participants (non-smokers, tobacco smokers and electronic cigarette users, n = 10 each) were studied. We found that the RSFC between the insula and several regions (frontal pole left, lateral occipital cortex right, lingual gyrus right and cerebellum 4, 5 and vermis 9) were associated with bacterial microbiota diversity and structure. In addition, two specific bacteria genera, Prevotella and Bacteroides, were specifically different in tobacco smokers and also associated with insular connectivity. In conclusion, we show that insular connectivity is associated with microbiome diversity, structure and at least two specific bateria genera. Furthemore, this association is potentially modulated by tobacco smoking, although the sample sizes for the different smoking groups were small and this result needs validation in a larger cohort. While replication is necessary, the microbiota is a readily accessible therapeutic target for modulating insular connectivity, which has previously been shown to be abnormal in anxiety and tobacco use disorders.

Objective About 80% of patients who commit suicide do not report suicidal ideation the last time they speak to their mental health provider, highlighting the need to identify biomarkers of suicidal behavior. Our goal is to identify suicidal behavior neural biomarkers to classify suicidal psychiatric inpatients. Methods Eighty percent of our sample [suicidal (n = 63) and non-suicidal psychiatric inpatients (n = 65)] was used to determine significant differences in structural and resting-state functional connectivity measures throughout the brain. These measures were used in a random forest classification model on 80% of the sample for training the model. Results The model built on 80% of the patients had sensitivity = 79.4% and specificity = 72.3%. This model was tested on an independent sample (20%; n = 32) with sensitivity = 81.3% and specificity = 75.0% for confirming the generalizability of the model. Altered resting-state functional connectivity features from frontal and middle temporal regions, as well as the amygdala, parahippocampus, putamen, and vermis were found to generalize best. Conclusion This work demonstrates neuroimaging (an unbiased biomarker) can be used to classify suicidal behavior in psychiatric inpatients without observing any clinical features.

Background Many research papers claim that patients with specific psychiatric disorders (major depressive disorder, posttraumatic stress disorder, borderline personality disorder, alcohol use disorder, and others) have smaller hippocampi, but most of those reports compared patients to healthy controls. We hypothesized that if psychiatrically matched controls (psychiatric control, matched for demographics and psychiatric comorbidities) were used, much of the biomarker literature in psychiatric research would not replicate. We used hippocampus and amygdala volume only as examples, as these are very commonly replicated results in psychiatry biomarker research. We propose that psychiatry biomarker research could benefit from using psychiatric controls, as the use of healthy controls results in data that are not disorder-specific. Method Hippocampus/amygdala volumes were compared between major depressive disorder, sex-/age-/race-matched healthy control, and psychiatric control (N = 126/group). Similar comparisons were performed for posttraumatic stress disorder (N = 67), borderline personality disorder (N = 111), and alcohol use disorder (N = 136). Results Major depressive disorder patients had smaller left (p = 8.79 × 10 −3 ) and right (p = 3.13 × 10 −3 ) hippocampal volumes than healthy control. Posttraumatic stress disorder had smaller left (p = 0.018) and right (p = 8.64 × 10 −4 ) hippocampi than healthy control. Borderline personality disorder had smaller right hippocampus (p = 7.90 × 10 −3 ) and amygdala (p = 1.49 × 10 −3 ) than healthy control. Alcohol use disorder had smaller right hippocampus (p = 0.034) and amygdala (p = .024) than healthy control. No differences were found between any of the four diagnostic groups and psychiatric control. Conclusion When psychiatric controls were used, there was no difference in hippocampal or amygdalar volume between any of the diagnoses studied and controls. This strategy (keeping all possible relevant variables matched between experimental groups) has been used to advance science for hundreds of years, and we propose should also be used in biomarker psychiatry research.

Background Linking human genetics and brain imaging data is extremely challenging, among other reasons because both fields suffer from multiple comparison problems. New method ProcessGeneLists (PGL) links genetics and human brain imaging by using genes associated with a disease and calculating a normalized mRNA expression average of those genes in each brain region. Brain regions in which those genes are most co-expressed become regions of interest (ROIs) to perform brain imaging in participants with and without the disease, decreasing multiple comparisons. Once a region is identified as “imaging-relevant”, the genes most responsible for that ROI being highlighted can be genotyped in the imaged sample. This allows to re-analyze imaging data under the light of likely relevant genetics, to study possible brain imaging/gene variant interactions. Results As proof-of-concept, we created two lists of genes expressed in the habenula and the striatum, to verified that PGL would highlight those regions. Next, we used a list of genes likely important in alcohol abuse from the literature, which identified several brain regions previously associated with alcohol abuse such as the striatum, habenula, and hippocampus. Comparison with existing methods To our knowledge there is no current method to obtain brain regions of interest from genetics data. Conclusions Genetics typically asks “which genes are associated with a disease?” while human brain imaging typically asks “which brain regions are associated with a disease?” PGL asks “which genes, via modulation within specific brain regions, are found to be associated with a disease?”.

PURPOSE: Despite anorexia nervosa having the highest mortality rate of mental illnesses, little is known regarding the brain mechanisms involved. Given that lack of interest for food in anorexic patients is related to alterations in the reward system, we tested the hypothesis that patients with past anorexia nervosa (pAN) have altered resting state functional connectivity (RSFC) between the habenula (a major component of the reward system) and its targets. METHODS: RSFC between the habenula and major targets (locus coeruleus, median and dorsal raphe nuclei, substantia nigra, and ventral tegmental area) was studied in 14 psychiatric inpatients with pAN and 14 psychiatric inpatient controls (PC, never-anorexic patients in same clinic, matched for comorbidities). Next, we tested possible correlations between RSFC and suicidal ideation, depression, and anxiety as determined by self-report questionnaires. RESULTS: Left habenula/locus coeruleus RSFC was lower in pAN patients compared to PC..The left habenula/locus coeruleus RSFC was positively correlated with suicidal ideation (past two months) in pAN patients but not in controls. CONCLUSIONS: pAN patients showed long lasting alterations in habenular connectivity. This may have clinical implications, possibly including future evaluation of the habenula as a therapeutic target and the need to carefully monitor suicidality in pAN patients. NO LEVEL OF EVIDENCE: basic science.

Background: Avoidant personality disorder (AvPD) is a condition typified by social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation. AvPD has a high comorbidity rate with other personality disorders and other psychological diagnostic categories. There is very little research investigating subcortical volumetry in AvPD. We studied subcortical brain morphometry in AvPD as compared to both healthy controls and comorbidity-matched psychiatric controls (patients in the same clinic matched for age, sex and all psychiatric diagnoses except for AvPD). Methods: We compared volumetric measures of 9 bilateral subcortical brain regions between AvPD patients, healthy controls, and psychiatric controls (n = 100 each group). The Bonferroni correction was used to control for multiple comparisons across regions (p Results: Compared to healthy controls, AvPD patients had lower volume of the left accumbens and left thalamus. However, no significant results were found when comparing AvPD patients and psychiatric controls. An exploratory study of cortical regions showed similar results: statistically significant differences between HC and AvPD (left lateral occipital, left and right pericalcarine smaller in AvPD) but no differences between AvPD and PC. Limitations: MRI and neuroimaging provides correlational information, and no causal claims can be made. Conclusions: These results suggest there may be no overt subcortical volumetric differences specific to AvPD, and provide strong cautionary advice when comparing patients to healthy controls, a common practice in psychiatry biomarker research.

Substance abuse is commonly defined as the persistence of drug use despite negative consequences. Recent preclinical work has shown that higher input from the orbitofrontal cortex (OFC) to the dorsal striatum was associated with compulsive reward-seeking behavior despite negative effects. It remains unknown whether drug use is associated with the connectivity between the OFC and dorsal striatum in humans. We studied the resting state functional connectivity (RSFC) between the OFC, dorsal striatum, and habenula (and the whole brain in a separate analysis) in psychiatric inpatients with high (PU, problem users) and low (LU, low users) substance use. We matched PU and LU for psychiatric comorbidities. We found that PU showed higher RSFC between the left OFC and the left dorsal striatum than LU. RSFC between the habenula and both OFC and dorsal striatum was also higher in PU, which suggests the habenula may be a part of the same circuit. Finally, higher RSFC between the OFC and insula was also observed in PU. Our data shows that OFC, habenula, dorsal striatum, and insula may play an important role in PU. Furthermore, we postulate that the habenula may link the mesolimbic and cortico-striatal systems, which are altered in PU.

Previous magnetic resonance imaging studies of post-traumatic stress disorder (PTSD) have reported cortical volume alterations in the parahippocampal, anterior cingulate cortex, and temporal pole. It is unclear, however, if these cortical regions are specifically associated with PTSD or associated with common comorbidities. Here, we present the result of cortical volume differences between PTSD and healthy and psychiatric controls. In this study, healthy controls (n = 67) were matched for demographic characteristics (age, sex, race) and psychiatric controls (n = 67) were matched for demographic characteristics plus all other psychiatric diagnoses (past and current) to a group of PTSD patients (N = 67). We assessed group differences of 34 bilateral cortical structure volumes using statistically defined brain regions-of-interest from FreeSurfer between PTSD patients and healthy controls. We found 10 regions to be significantly different between PTSD and healthy controls and analyzed the group differences between PTSD and psychiatric controls within these regions. The right temporal pole volume in PTSD was found to be significantly smaller than both healthy and psychiatry controls. Our finding suggests only right temporal pole volume reduction is specifically associated with PTSD, and also highlights the need for using appropriate controls in psychiatry research.

Suicide is a leading cause of death in America, with over 40,000 reported suicides per year. Mental illness is a major risk factor for suicidality. This study attempts to validate findings of volumetric differences from studies on suicidality. Psychiatric inpatients classified as having mildly severe or severe depression were separated into two groups: suicide attempted in the past two months (SA; n = 20), non-suicidal control group (DA; n = 20); these patients were all depressed and not significantly different for age, gender, race, marital status, education level, anxiety level, and substance abuse. Healthy controls (HC; n = 20) were not significantly different from the suicidal groups for age and gender. Volunteers underwent MRI to assess volumes of cortical lobes, corpus callosum, and subcortical regions of interest, including the thalamus, insula, limbic structures, and basal ganglia. The right hippocampal volume of the SA group was significantly reduced compared to healthy controls. The frontal and temporal lobe volumes of the SA group were significantly decreased compared to the DA group. These volumetric reductions confirm previous findings and support the hypothesis that fronto-temporal function may be altered in suicidal patients.