Multi-modal risk factors differentiate suicide attempters from ideators in military veterans with major depressive disorder.

BACKGROUND: The suicide rate for United States military veterans is 1.5× higher than that of non-veterans. To meaningfully advance suicide prevention efforts, research is needed to delineate factors that differentiate veterans with suicide attempt/s, particularly in high-risk groups, e.g., major depressive disorder (MDD), from those with suicidal ideation (no history of attempt/s). The current study aimed to identify clinical, neurocognitive, and neuroimaging variables that differentiate suicide-severity groups in veterans with MDD. METHODS: Sixty-eight veterans with a DSM-5 diagnosis of MDD, including those with no ideation or suicide attempt (N = 21; MDD-SI/SA), ideation-only (N = 17; MDD + SI), and one-or-more suicide attempts (N = 30; MDD + SA; aborted, interrupted, actual attempts), participated in this study. Participants underwent a structured diagnostic interview, neurocognitive assessment, and 3 T-structural/diffusion tensor magnetic-resonance-imaging (MRI). Multinomial logistic regression models were conducted to identify variables that differentiated groups with respect to the severity of suicidal behavior. RESULTS: Relative to veterans with MDD-SI/SA, those with MDD + SA had significantly higher left cingulum fractional anisotropy, decreased attentional control on emotional-Stroop, and faster response time with intact accuracy on Go/No-Go. Relative to MDD + SI, MDD + SA had higher left cingulum fractional anisotropy and faster response time with intact accuracy on Go/No-Go. LIMITATIONS: Findings are based on retrospective, cross-sectional data and cannot identify causal relationships. Also, a healthy control group was not included given the study's focus on differentiating suicide profiles in MDD. CONCLUSIONS: This study suggests that MRI and neurocognition differentiate veterans with MDD along the suicide-risk spectrum and could inform suicide-risk stratification and prevention efforts in veterans and other vulnerable populations.

Characterization of the extracellular free water signal in schizophrenia using multi-site diffusion MRI harmonization.

Studies applying Free Water Imaging have consistently reported significant global increases in extracellular free water (FW) in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time course of free water elevations across illness stages. Moreover, the relationship between FW and duration of illness has yet to be directly tested. Leveraging our multi-site diffusion magnetic resonance imaging(dMRI) harmonization approach, we analyzed dMRI scans collected by 12 international sites from 441 healthy controls and 434 individuals diagnosed with schizophrenia-spectrum disorders at different illness stages and ages (15-58 years). We characterized the pattern of age-related FW changes by assessing whole brain white matter in individuals with schizophrenia and healthy controls. In individuals with schizophrenia, average whole brain FW was higher than in controls across all ages, with the greatest FW values observed from 15 to 23 years (effect size range = [0.70-0.87]). Following this peak, FW exhibited a monotonic decrease until reaching a minima at the age of 39 years. After 39 years, an attenuated monotonic increase in FW was observed, but with markedly smaller effect sizes when compared to younger patients (effect size range = [0.32-0.43]). Importantly, FW was found to be negatively associated with duration of illness in schizophrenia (p = 0.006), independent of the effects of other clinical and demographic data. In summary, our study finds in a large, age-diverse sample that participants with schizophrenia with a shorter duration of illness showed higher FW values compared to participants with more prolonged illness. Our findings provide further evidence that elevations in the FW are present in individuals with schizophrenia, with the greatest differences in the FW being observed in those at the early stages of the disorder, which might suggest acute extracellular processes.

Neural correlates of impulsivity in bipolar disorder: A systematic review and clinical implications.

Impulsivity is a common feature of bipolar disorder (BD) with ramifications for functional impairment and premature mortality. This PRISMA-guided systematic review aims to integrate findings on the neurocircuitry associated with impulsivity in BD. We searched for functional neuroimaging studies that examined rapid-response impulsivity and choice impulsivity using the Go/No-Go Task, Stop-Signal Task, and Delay Discounting Task. Findings from 33 studies were synthesized with an emphasis on the effect of mood state of the sample and affective salience of the task. Results suggest trait-like brain activation abnormalities in regions implicated in impulsivity that persist across mood states. During rapid-response inhibition, BD exhibit under-activation of key frontal, insular, parietal, cingulate, and thalamic regions, but over-activation of these regions when the task involves emotional stimuli. Delay discounting tasks with functional neuroimaging in BD are lacking, but hyperactivity of orbitofrontal and striatal regions associated with reward hypersensitivity may be related to difficulty delaying gratification. We propose a working model of neurocircuitry dysfunction underlying behavioral impulsivity in BD. Clinical implications and future directions are discussed.

Smaller rostral cingulate volume and psychosocial correlates in veterans at risk for suicide.

Suicide research/clinical work remain in dire need of effective tools that can better predict suicidal behavior. A growing body of literature has started to focus on the role that neuroimaging may play in helping explain the path towards suicide. Specifically, structural alterations of rostral anterior cingulate cortex (rost-ACC) may represent a biological marker and/or indicator of suicide risk in Major Depressive Disorder (MDD). Furthermore, the construct of "grit," defined as perseverance for goal-attainment and shown to be associated with suicidality, is modulated by rost-ACC. The aim was to examine relationships among rost-ACC gray matter volume, grit, and suicidality in U.S. Military Veterans. Participants were age-and-sex-matched Veterans with MDD: with suicide attempt (MDD+SA:n = 23) and without (MDD-SA:n = 37). Groups did not differ in depression symptomatology. Participants underwent diagnostic interview, clinical symptom assessment, and 3T-MRI-scan. A Group (SA-vs.-No-SA) x Cingulate-region (rostral-caudal-posterior) x Hemisphere (left-right) mixed-model-multivariate-ANOVA was conducted. Left-rost-ACC was significantly smaller in MDD+SA, Group x Cingulate-region x Hemisphere-interaction. Lower grit and less left-rost-ACC gray matter each predicted suicide attempt history, but grit level was a more robust predictor of SA. Both structural alterations of rost-ACC and grit level represent potentially valuable tools for suicide risk assessment.

Frontal lobe fALFF measured from resting-state fMRI as a prognostic biomarker in first-episode psychosis.

Clinical response to antipsychotic drug treatment is highly variable, yet prognostic biomarkers are lacking. The goal of the present study was to test whether the fractional amplitude of low-frequency fluctuations (fALFF), as measured from baseline resting-state fMRI data, can serve as a potential biomarker of treatment response to antipsychotics. Patients in the first episode of psychosis (n = 126) were enrolled in two prospective studies employing second-generation antipsychotics (risperidone or aripiprazole). Patients were scanned at the initiation of treatment on a 3T MRI scanner (Study 1, GE Signa HDx, n = 74; Study 2, Siemens Prisma, n = 52). Voxelwise fALFF derived from baseline resting-state fMRI scans served as the primary measure of interest, providing a hypothesis-free (as opposed to region-of-interest) search for regions of the brain that might be predictive of response. At baseline, patients who would later meet strict criteria for clinical response (defined as two consecutive ratings of much or very much improved on the CGI, as well as a rating of ≤3 on psychosis-related items of the BPRS-A) demonstrated significantly greater baseline fALFF in bilateral orbitofrontal cortex compared to non-responders. Thus, spontaneous activity in orbitofrontal cortex may serve as a prognostic biomarker of antipsychotic treatment.

Cognitive deficits, clinical variables, and white matter microstructure in schizophrenia: a multisite harmonization study.

Cognitive deficits are among the best predictors of real-world functioning in schizophrenia. However, our understanding of how cognitive deficits relate to neuropathology and clinical presentation over the disease lifespan is limited. Here, we combine multi-site, harmonized cognitive, imaging, demographic, and clinical data from over 900 individuals to characterize a) cognitive deficits across the schizophrenia lifespan and b) the association between cognitive deficits, clinical presentation, and white matter (WM) microstructure. Multimodal harmonization was accomplished using T-scores for cognitive data, previously reported standardization methods for demographic and clinical data, and an established harmonization method for imaging data. We applied t-tests and correlation analysis to describe cognitive deficits in individuals with schizophrenia. We then calculated whole-brain WM fractional anisotropy (FA) and utilized regression-mediation analyses to model the association between diagnosis, FA, and cognitive deficits. We observed pronounced cognitive deficits in individuals with schizophrenia (p < 0.006), associated with more positive symptoms and medication dosage. Regression-mediation analyses showed that WM microstructure mediated the association between schizophrenia and language/processing speed/working memory/non-verbal memory. In addition, processing speed mediated the influence of diagnosis and WM microstructure on the other cognitive domains. Our study highlights the critical role of cognitive deficits in schizophrenia. We further show that WM is crucial when trying to understand the role of cognitive deficits, given that it explains the association between schizophrenia and cognitive deficits (directly and via processing speed).

Cingulate and hippocampal subregion abnormalities in combat-exposed veterans with PTSD.

BACKGROUND: The hippocampus and cingulate gyrus are strongly interconnected brain regions that have been implicated in the neurobiology of post-traumatic stress disorder (PTSD). These brain structures are comprised of functionally distinct subregions that may contribute to the expression of PTSD symptoms or associated cardio-metabolic markers, but have not been well investigated in prior studies. METHODS: Two divisions of the cingulate cortex (i.e., rostral and caudal) and 11 hippocampal subregions were investigated in 22 male combat-exposed veterans with PTSD and 22 male trauma-exposed veteran controls (TC). Cardio-metabolic measures included cholesterol, body mass index, and mean arterial pressure. RESULTS: Individuals with PTSD had less caudal cingulate area compared to TC even after controlling for caudal cingulate thickness. Total hippocampus volume was lower in PTSD compared to TC, accounted for by differences in CA1-CA4, granule cell layer of the dentate gyrus, molecular layer, and subiculum. Individuals with PTSD had higher mean arterial pressure compared to TC, which correlated with hippocampus volume only in the PTSD group. LIMITATIONS: Sample size, cross-sectional analysis, no control for medications and findings limited to males. CONCLUSIONS: These data demonstrate preferential involvement of caudal cingulate area (vs. thickness) and hippocampus subregions in PTSD. The inverse association between hippocampus volume and mean arterial pressure may contribute to accelerated aging known to be associated with PTSD.

Frontotemporal thalamic connectivity in schizophrenia and schizotypal personality disorder.

Schizotypal personality disorder (SPD) resembles schizophrenia, but with attenuated brain abnormalities and the absence of psychosis. The thalamus is integral for processing and transmitting information across cortical regions and widely implicated in the neurobiology of schizophrenia. Comparing thalamic connectivity in SPD and schizophrenia could reveal an intermediate schizophrenia-spectrum phenotype to elucidate neurobiological risk and protective factors in psychosis. We used rsfMRI to investigate functional connectivity between the mediodorsal nucleus (MDN) and pulvinar, and their connectivity with frontal and temporal cortical regions, respectively in 43 healthy controls (HCs), and individuals in the schizophrenia-spectrum including 45 psychotropic drug-free individuals with SPD, and 20 individuals with schizophrenia-related disorders [(schizophrenia (n = 10), schizoaffective disorder (n = 8), schizophreniform disorder (n = 1) and psychosis NOS (n = 1)]. Individuals with SPD had greater functional connectivity between the MDN and pulvinar compared to individuals with schizophrenia. Thalamo-frontal (i.e., between the MDN and rostral middle frontal cortex) connectivity was comparable in SPD and HCs; in SPD greater connectivity was associated with less symptom severity. Individuals with schizophrenia had less thalamo-frontal connectivity and thalamo-temporal (i.e., pulvinar to the transverse temporal cortex) connectivity compared with HCs. Thalamo-frontal functional connectivity may be comparable in SPD and HCs, but abnormal in schizophrenia, and that this may be protective against psychosis in SPD.

Improving the predictive potential of diffusion MRI in schizophrenia using normative models-Towards subject-level classification.

Diffusion MRI studies consistently report group differences in white matter between individuals diagnosed with schizophrenia and healthy controls. Nevertheless, the abnormalities found at the group-level are often not observed at the individual level. Among the different approaches aiming to study white matter abnormalities at the subject level, normative modeling analysis takes a step towards subject-level predictions by identifying affected brain locations in individual subjects based on extreme deviations from a normative range. Here, we leveraged a large harmonized diffusion MRI dataset from 512 healthy controls and 601 individuals diagnosed with schizophrenia, to study whether normative modeling can improve subject-level predictions from a binary classifier. To this aim, individual deviations from a normative model of standard (fractional anisotropy) and advanced (free-water) dMRI measures, were calculated by means of age and sex-adjusted z-scores relative to control data, in 18 white matter regions. Even though larger effect sizes are found when testing for group differences in z-scores than are found with raw values (p < .001), predictions based on summary z-score measures achieved low predictive power (AUC < 0.63). Instead, we find that combining information from the different white matter tracts, while using multiple imaging measures simultaneously, improves prediction performance (the best predictor achieved AUC = 0.726). Our findings suggest that extreme deviations from a normative model are not optimal features for prediction. However, including the complete distribution of deviations across multiple imaging measures improves prediction, and could aid in subject-level classification.

Right parahippocampal volume deficit in an older population with posttraumatic stress disorder.

BACKGROUND: Posttraumatic Stress Disorder (PTSD) is an increasingly prevalent condition among older adults and may escalate further as the general population including veterans from recent conflicts grow older. Despite growing evidence of higher medical comorbidity, cognitive impairment and dementia, and disability in older individuals with PTSD, there are very few studies examining brain cortical structure in this population. Hence, we examined cortical volumes in a cross-sectional study of veterans and civilians aged ≥50 years, of both sexes and exposed to trauma (interpersonal, combat, non-interpersonal). METHODS: Cortical volumes were obtained from T1-weighted structural MRI and compared between individuals with PTSD and Trauma Exposed Healthy Controls (TEHC) adjusting for age, sex, estimated intracranial volume, depression severity, and time elapsed since trauma exposure. RESULTS: The PTSD group (N = 55) had smaller right parahippocampal gyrus compared to TEHC (N = 36), corrected p(pFWER) = 0.034, with an effect size of 0.75 (Cohen's d), with no significant group differences in other cortical areas. CONCLUSIONS: These findings are different from the structural brain findings reported in studies in younger age groups (larger parahippocampal volume in PTSD patients), suggesting a possible significant change in brain structure as PTSD patients age. These results need replication in longitudinal studies across the age-span to test whether they are neuroanatomical markers representing disease vulnerability, trauma resilience or pathological neurodegeneration associated with cognitive impairment and dementia.