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.

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

Evaluation of Cardiovascular Autonomic Function during Inpatient Rehabilitation following Traumatic Spinal Cord Injury.

Assessment of the degree of impaired autonomic nervous system (ANS) function is not part of routine clinical practice during inpatient rehabilitation following traumatic spinal cord injury (SCI). The goal of this investigation was to determine the utility of the International Standards for Neurologic Classification of SCI (ISNCSCI) and the recently revised International Standards to document remaining Autonomic Function after SCI (ISAFSCI) in documenting cardiovascular ANS impairment during inpatient rehabilitation following traumatic SCI. Beat-to-beat recording of supine heart rate (HR) and blood pressure (BP) were collected at the bedside for estimation of total cardiovascular ISAFSCI score, cardio-vagal modulation (i.e., high frequency HR variability [HFHRV]) and sympathetic vasomotor regulation (i.e., Mayer wave component of systolic BP [SBPmayer]). A total of 41 participants completed baseline testing, which was conducted 11 ± 5 days from the admission ISNCSCI examination. There were no differences in supine HR or BP based on the ISNCSCI or ISAFSCI assessments. The HFHRV was generally lower with more distal lesions (r2 = 0.15; p = 0.01), and SBPmayer was significantly lower in those with American Spinal Injury Association Impairment Scale (AIS) A compared with AIS B, C, D (Cohen's d = -1.4; p < 0.001). There were no significant differences in HFHRV or SBPmayer in patients with or without ISAFSCI evidence of cardiovascular ANS impairment. These preliminary data suggest that neither the ISNCSCI nor the ISAFSCI are sensitive to changes in ANS cardiovascular function following traumatic SCI. Bedside assessment of HR and BP variabilities may provide insight, but are not readily available in the clinical setting. Further research is required to evaluate methods that accurately assess the degree of ANS impairment following traumatic SCI.

Orthostatic systemic and cerebral hemodynamics in newly injured patients with spinal cord injury.

BACKGROUND: Low blood pressure (BP) may lead to reduced cerebral blood flow velocity (CBFv) during an orthostatic challenge in newly injured patients with traumatic spinal cord injury (SCI), which, may relate to the neurological level of injury (NLI) as documented on the International Standards for the Neurologic Classification of SCI (ISNCSCI), or to evidence of cardiovascular autonomic impairment as determined by the International Standards to document remaining Autonomic Function after SCI (ISAFSCI). OBJECTIVE: To examine the influence of patient demographics, ISNCSCI and ISAFSCI scores on hemodynamic responses to a bedside sit-up test in newly injured patients with SCI. DESIGN: Cross-sectional, prospective analysis. METHODS: A modified sit-up test was conducted at the bedside with the hips at an angle between 45° and 90° and the legs horizontal, level with the hips. Heart rate, BP, and CBFv were recorded for 10 min in the supine and seated positions. RESULTS: Fifty-three newly injured patients (median 39.5 days post-injury) with traumatic SCI were enrolled. Overall, 28 (53%) patients met ISAFSCI criteria, and the number of criteria met (total score) was significantly related to orthostatic changes in CBFv. Change in SBP and change in CBFv were not significantly related, but NLI and total sensory score from the ISNCSCI were significant predictors of the change in CBFv. CONCLUSIONS: Total ISAFSCI score, NLI and sensory scores were positively associated with orthostatic changes in CBFv. Long term follow-up should be considered to determine the consequences of diminished CBFv on cognitive function and quality of life following SCI.

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.

Reprint of: F-18Fluorodeoxyglucose positron emission tomography studies of the schizophrenia spectrum: The legacy of Monte S. Buchsbaum, M.D.

This is a selective review of the work of Buchsbaum and colleagues. It revisits and pays tribute to four decades of publications employing positron emission tomography (PET) with F-18fluorodeoxyglucose (FDG) to examine the neurobiology of schizophrenia-spectrum disorders (including schizotypal personality disorder (SPD) and schizophrenia). Beginning with a landmark FDG-PET study in 1982 reporting hypofrontality in unmedicated schizophrenia patients, Buchsbaum and colleagues published high-impact work on regional glucose metabolic rate (GMR) abnormalities in the spectrum. Several key discoveries were made, including the delineation of schizophrenia-spectrum abnormalities in frontal and temporal lobe, cingulate, thalamus, and striatal regions using three-dimensional mapping with coregistered MRI and PET. These findings indicated that SPD patients have less marked frontal lobe and striatal dysfunction compared with schizophrenia patients, possibly mitigating frank psychosis. Additionally, these investigations were among the first to conduct early seed-based functional connectivity analyses with FDG-PET, showing aberrant cortical-subcortical circuitry and, in particular, revealing a thalamocortical circuitry abnormality in schizophrenia. Finally, pioneering work employing the first double-blind randomized antipsychotic (haloperidol) vs. placebo FDG-PET study design in schizophrenia indicated that GMR in the striatum, more than in any other region, was related to clinical response.

F-18Fluorodeoxyglucose positron emission tomography studies of the schizophrenia spectrum: The legacy of Monte S. Buchsbaum, M.D.

This is a selective review of the work of Buchsbaum and colleagues. It revisits and pays tribute to four decades of publications employing positron emission tomography (PET) with F-18fluorodeoxyglucose (FDG) to examine the neurobiology of schizophrenia-spectrum disorders (including schizotypal personality disorder (SPD) and schizophrenia). Beginning with a landmark FDG-PET study in 1982 reporting hypofrontality in unmedicated schizophrenia patients, Buchsbaum and colleagues published high-impact work on regional glucose metabolic rate (GMR) abnormalities in the spectrum. Several key discoveries were made, including the delineation of schizophrenia-spectrum abnormalities in frontal and temporal lobe, cingulate, thalamus, and striatal regions using three-dimensional mapping with coregistered MRI and PET. These findings indicated that SPD patients have less marked frontal lobe and striatal dysfunction compared with schizophrenia patients, possibly mitigating frank psychosis. Additionally, these investigations were among the first to conduct early seed-based functional connectivity analyses with FDG-PET, showing aberrant cortical-subcortical circuitry and, in particular, revealing a thalamocortical circuitry abnormality in schizophrenia. Finally, pioneering work employing the first double-blind randomized antipsychotic (haloperidol) vs. placebo FDG-PET study design in schizophrenia indicated that GMR in the striatum, more than in any other region, was related to clinical response.