Clinical and electrophysiological correlates of hopelessness in the context of suicide risk✰.

Hopelessness is a key risk factor for suicide. This analysis explored whether hopelessness indicates a recent suicide crisis state and is linked with magnetoencephalography (MEG) oscillatory power and effective connectivity differences. Change in hopelessness ratings and effective connectivity post-ketamine were also evaluated in a subsample of high-risk individuals to evaluate correlates of dynamic changes over time. Participants (66F;44 M;1 transgender) included individuals with suicide crisis in the last two weeks (High Risk (HR), n = 14), those with past suicide attempt but no recent suicide ideation (SI) (Low Risk (LR), n = 37), clinical controls (CC, n = 33), and healthy volunteers at minimal risk (MinR, n = 27). MEG oscillatory power and clinical hopelessness ratings (via the Beck Hopelessness Scale (BHS)) were evaluated across groups. Dynamic casual modeling (DCM) evaluated connectivity within and between the anterior insula (AI) and anterior cingulate cortex (ACC). A subsample of HR individuals who received ketamine (n = 10) were evaluated at Day 1 post-infusion. The HR group reported the highest levels of hopelessness, even when adjusting for SI. MEG results linked hopelessness with reduced activity across frequency bands in salience network regions, with no group or group-by-interaction effects. Using DCM, the HR group had reduced intrinsic drive from granular Layer IV stellate cells to superficial pyramidal cells in the ACC and AI. In the pilot HR study, reduced hopelessness was linked with increased drive for this same connection post-ketamine. Hopelessness is a possible proxy for suicide risk. Electrophysiological targets for hopelessness include widespread reductions in salience network activity, particularly in the ACC and AI.

Magnetoencephalography biomarkers of suicide attempt history and antidepressant response to ketamine in treatment-resistant major depression.

BACKGROUND: This study examined magnetoencephalographic (MEG) correlates of suicidal ideation (SI) and suicide attempt history in patients with treatment-resistant major depression (TRD) at baseline and following subanesthetic-dose ketamine infusion. METHODS: Twenty-nine drug-free TRD patients (12 suicide attempters/17 non-attempters) participated in a crossover randomized trial of ketamine. MEG data were collected during an attentional dot probe task with emotional face stimuli at baseline and several hours post-ketamine infusion. Synthetic aperture magnetometry was used to project source power in the theta, alpha, beta, and gamma frequencies for angry-neutral, happy-neutral, and neutral-neutral face pairings during a one-second peristimulus period. Mixed models were used to test for clinical, behavioral, and electrophysiological effects of group, emotion, session, and SI score. RESULTS: Ketamine significantly reduced SI and depression across the sample. Post-ketamine, attempters had improved accuracy and non-attempters had reduced accuracy on the task. SI was positively associated with gamma power in regions of the frontal and parietal cortices across groups. In an extended amygdala-hippocampal region, attempters differed significantly in their emotional reactivity to angry versus happy faces as indexed by theta power differences, irrespective of drug. Ketamine significantly reduced the association between alpha power and SI for angry compared with happy faces in a fronto-insular/anterior cingulate region important for regulating sensory attentiveness. LIMITATIONS: Limitations include a small sample size of attempters. CONCLUSIONS: The findings highlight key differences in band-limited power between attempters and non-attempters and reinforce previous findings that ketamine has distinct response properties in patients with a suicide history.

Reduced white matter microstructure in bipolar disorder with and without psychosis.

OBJECTIVES: Affective and psychotic features overlap considerably in bipolar I disorder, complicating efforts to determine its etiology and develop targeted treatments. In order to clarify whether mechanisms are similar or divergent for bipolar disorder with psychosis (BDP) and bipolar disorder with no psychosis (BDNP), neurobiological profiles for both the groups must first be established. This study examines white matter structure in the BDP and BDNP groups, in an effort to identify portions of white matter that may differ between the bipolar and healthy groups or between the bipolar subgroups themselves. METHODS: Diffusion-weighted imaging data were acquired from participants with BDP (n = 45), BDNP (n = 40), and healthy comparisons (HC) (n = 66). Fractional anisotropy (FA), radial diffusivity (RD), and spin distribution function (SDF) values indexing white matter diffusivity or spin density were calculated and compared between the groups. RESULTS: In comparisons between both the bipolar groups and HC, FA (FDR < 0.00001) and RD (FDR = 0.0037) differed minimally, in localized portions of the left cingulum and corpus callosum, while reductions in SDF (FDR = 0.0002) were more widespread. The bipolar subgroups did not differ from each other on FA, RD, or SDF metrics. CONCLUSIONS: Together, these results demonstrate a novel profile of white matter differences in bipolar disorder and suggest that this white matter pathology is associated with the affective disturbance common to those with bipolar disorder rather than the psychotic features unique to some. The white matter alterations identified in this study may provide substrates for future studies examining specific mechanisms that target affective domains of illness.

Microstructural differences in visual white matter tracts in people with aniridia.

Aniridia is a panocular disorder characterized chiefly by iris hypoplasia. Most cases result from mutations of the PAX6 gene, which is important in both eye and brain development. In addition to ocular alterations, differences in global brain volume and functional connectivity have been reported in humans with aniridia. Understanding neural alterations in aniridia may require examination of possible differences in white matter structure, as few studies have assessed white matter in this population. The current study utilized diffusion-weighted imaging to assess white matter structure in 11 people with aniridia and 11 healthy comparison participants, matched for sex and age. A map of the local connectome was calculated to compare quantitative anisotropy (QA), an index of white matter tract density, in all white matter voxels, revealing subcomponents of white matter tracts with differing QA between people with aniridia and healthy comparisons. The analysis indicated that QA was lower for people with aniridia in portions of bilateral optic tract [t(20)=-4.23, P=0.001, d=-1.80], bilateral optic radiation [t(20)=-4.06, P=0.001, d=-1.73], forceps major [t(20)=-3.65, P=0.002, d=-1.55], bilateral superior longitudinal fasciculus [left: t(20)=-3.15, P=0.005, d=-1.34; right, t(20)=-4.28, P<0.001, d=-1.83], and right posterior corona radiata [t(20)=-3.19, P=0.006, d=-1.36]. These differences demonstrate that white matter structure is altered in people with aniridia in both visual tracts and associated posterior visual pathways.

White matter fiber integrity of the saccadic eye movement network differs between schizophrenia and healthy groups.

Recent diffusion tensor imaging (DTI) studies suggest that altered white matter fiber integrity is a pathophysiological feature of schizophrenia. Lower white matter integrity is associated with poor cognitive control, a characteristic of schizophrenia that can be measured using antisaccade tasks. Although the functional neural correlates of poor antisaccade performance have been well documented, fewer studies have investigated the extent to which white matter fibers connecting the functional nodes of this network contribute to antisaccade performance. The aim of the present study was to assess the white matter structural integrity of fibers connecting two functional nodes (putamen and medial frontal eye fields) of the saccadic eye movement network implicated in poor antisaccade performance in schizophrenia. To evaluate white matter integrity, DTI was acquired on subjects with schizophrenia and two comparison groups: (a) behaviorally matched healthy comparison subjects with low levels of cognitive control (LCC group), and (b) healthy subjects with high levels of cognitive control (HCC group). White matter fibers were tracked between functional regions of interest generated from antisaccade fMRI activation maps, and measures of diffusivity were quantified. The results demonstrated lower white matter integrity in the schizophrenia group than in the HCC group, but not the LCC group who showed similarly poor cognitive control performance. Overall, the results suggest that these alterations are not specific to the disease process of schizophrenia, but may rather be a function of uncontrolled cognitive factors that are concomitant with the disease but also observed in some healthy people.

White matter structural integrity differs between people with schizophrenia and healthy groups as a function of cognitive control.

A behavioral hallmark of schizophrenia is poor cognitive control. Recent evidence suggests that problems with cognitive control in schizophrenia are related to disconnectivity along major white matter fibers. Although deficits of cognitive control are common in schizophrenia, a proportion of otherwise healthy subjects show poor cognitive control performance. The present study sought to address this potential confound by comparing white matter integrity between a group with schizophrenia and otherwise healthy individuals with either high or low levels of cognitive control (based on working memory span performance). Diffusion tensor imaging was used to evaluate white matter integrity in 24 participants with schizophrenia, 24 healthy participants with high cognitive control (HCC), and 25 healthy participants with low cognitive control (LCC). To test for differences in fractional anisotropy (FA) across major white matter fiber tracts, a voxelwise region of interest analysis was conducted in standardized brain space. In a separate analysis, regions of interest were manually drawn in native brain space to isolate superior longitudinal fasciculus (SLF), a tract implicated in cognitive control performance. The voxelwise analysis demonstrated widespread lower FA in the schizophrenia group compared to the HCC group. With a high degree of concordance, the manual ROI analysis revealed lower FA in the schizophrenia group compared to the HCC group. Taken together, these results provide evidence to suggest that structural differences identified between healthy groups and schizophrenia may not be entirely specific to the disease process and can vary as a function of cognitive control capacity in the comparison group.