Cognitive Aging and the Primate Basal Forebrain Revisited: Disproportionate GABAergic Vulnerability Revealed.

Basal forebrain (BF) projections to the hippocampus and cortex are anatomically positioned to influence a broad range of cognitive capacities that are known to decline in normal aging, including executive function and memory. Although a long history of research on neurocognitive aging has focused on the role of the cholinergic basal forebrain system, intermingled GABAergic cells are numerically as prominent and well positioned to regulate the activity of their cortical projection targets, including the hippocampus and prefrontal cortex. The effects of aging on noncholinergic BF neurons in primates, however, are largely unknown. In this study, we conducted quantitative morphometric analyses in brains from young adult (6 females, 2 males) and aged (11 females, 5 males) rhesus monkeys (Macaca mulatta) that displayed significant impairment on standard tests that require the prefrontal cortex and hippocampus. Cholinergic (ChAT+) and GABAergic (GAD67+) neurons were quantified through the full rostrocaudal extent of the BF. Total BF immunopositive neuron number (ChAT+ plus GAD67+) was significantly lower in aged monkeys compared with young, largely because of fewer GAD67+ cells. Additionally, GAD67+ neuron volume was greater selectively in aged monkeys without cognitive impairment compared with young monkeys. These findings indicate that the GABAergic component of the primate BF is disproportionally vulnerable to aging, implying a loss of inhibitory drive to cortical circuitry. Moreover, adaptive reorganization of the GABAergic circuitry may contribute to successful neurocognitive outcomes.SIGNIFICANCE STATEMENT A long history of research has confirmed the role of the basal forebrain in cognitive aging. The majority of that work has focused on BF cholinergic neurons that innervate the cortical mantle. Codistributed BF GABAergic populations are also well positioned to influence cognitive function, yet little is known about this prominent neuronal population in the aged brain. In this unprecedented quantitative comparison of both cholinergic and GABAergic BF neurons in young and aged rhesus macaques, we found that neuron number is significantly reduced in the aged BF compared with young, and that this reduction is disproportionately because of a loss of GABAergic neurons. Together, our findings encourage a new perspective on the functional organization of the primate BF in neurocognitive aging.

Psychometric properties of the Distress Tolerance Scale in a clinical sample.

The factor structure, reliability, and concurrent validity of the Distress Tolerance Scale were evaluated in a large outpatient sample (N = 775). Prior research demonstrates mixed findings regarding the most appropriate factor structure, finding evidence for the presence of four subfactors as well as a potential second-order (hierarchical) General Distress Tolerance factor. Competing factor structures were compared using confirmatory factor analyses. A second-order hierarchical model with correlated residuals fit the data well, though results suggested poor factor discrimination. A bifactor hierarchical model also demonstrated acceptable fit. However, all subfactors except for Regulation demonstrated small or nonsignificant loadings and/or variances. The model was respecified with all items loading onto a General Distress Tolerance factor and three items loading onto the Regulation factor, which also demonstrated acceptable fit. In support of its concurrent validity, General Distress Tolerance was more strongly associated with neuroticism and a measure of difficulties with emotion regulation than with symptoms of anxiety and depression. The present study extends the literature by demonstrating support for a hierarchical bifactor structure and the favorable psychometric properties of the Distress Tolerance Scale in a large clinical sample. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Direct and Interactive Effects of Personality and Experiencing Changes in Relationships on Symptoms of Internalizing Psychopathology During the COVID-19 Pandemic.

Purpose: The present study examined the prospective direct and interactive effects of personality (neuroticism, extraversion) and experiencing changes in friendships during the pandemic on symptoms of stress, anxiety, and depression. Methods: A sample of patients (N = 77) at an outpatient treatment clinic who had received a diagnostic assessment in the 6 months prior to the COVID-19 lockdown was re-contacted during the pandemic (May-June 2020) and completed a survey assessing stressors and symptoms of internalizing psychopathology. Results: Neuroticism had main effects on anxiety, whereas experiencing changes in friendships had main effects on stress and depression. Extraversion did not have main effects on stress, depression, or anxiety. The relationship between experiencing changes in friendships and stress and anxiety was moderated by extraversion, such that the strength of the relationship between changes in friendships and stress and anxiety waned as the level of extraversion increased. Neuroticism was not a moderator of the association between changes in friendships and emotional disorder symptoms. Conclusion: These results suggest that higher levels of extraversion may protect against symptoms of stress reactivity and anxiety that are associated with COVID-related changes in friendships, while neuroticism may have limited prospective associations with symptoms during the pandemic. Supplementary Information: The online version of this article contains supplementary material available 10.1007/s10608-023-10364-x.

Developing Transdiagnostic Internalizing Disorder Prognostic Indices for Outpatient Cognitive Behavioral Therapy.

A growing literature is devoted to understanding and predicting heterogeneity in response to cognitive behavioral therapy (CBT), including using supervised machine learning to develop prognostic models that could be used to inform treatment planning. The current study developed CBT prognostic models using data from a broad dimensionally oriented pretreatment assessment (324 predictors) of 1,210 outpatients with internalizing psychopathology. Super learning was implemented to develop prognostic indices for three outcomes assessed at 12-month follow-up: principal diagnosis improvement (attained by 65.8% of patients), principal diagnosis remission (56.8%), and transdiagnostic full remission (14.3%). The models for principal diagnosis remission and transdiagnostic remission performed best (AUROCs = 0.71-0.73). Calibration was modest for all three models. Three-quarters (77.3%) of patients in the top tertile of the predicted probability distribution achieved principal diagnosis remission, compared to 35.0% in the bottom tertile. One-third (35.3%) of patients in the top two deciles of predicted probabilities for transdiagnostic complete remission achieved this outcome, compared to 2.7% in the bottom tertile. Key predictors included principal diagnosis severity, social anxiety diagnosis/severity, hopelessness, temperament, and global impairment. While additional work is needed to improve performance, integration of CBT prognostic models ultimately could lead to more effective and efficient treatment of patients with internalizing psychopathology.

Ketamine and Attentional Bias Toward Emotional Faces: Dynamic Causal Modeling of Magnetoencephalographic Connectivity in Treatment-Resistant Depression.

The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (TRD) and bipolar disorder. While its underlying mechanism of antidepressant action is not fully understood, modulating glutamatergically-mediated connectivity appears to be a critical component moderating antidepressant response. This double-blind, crossover, placebo-controlled study analyzed data from 19 drug-free individuals with TRD and 15 healthy volunteers who received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) as well as an intravenous infusion of saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6-9 h after both drug and placebo infusions. During scanning, participants completed an attentional dot probe task that included emotional faces. Antidepressant response was measured across time points using the Montgomery-Asberg Depression Rating Scale (MADRS). Dynamic causal modeling (DCM) was used to measure changes in parameter estimates of connectivity via a biophysical model that included realistic local neuronal architecture and receptor channel signaling, modeling connectivity between the early visual cortex, fusiform cortex, amygdala, and inferior frontal gyrus. Clinically, ketamine administration significantly reduced depressive symptoms in TRD participants. Within the model, ketamine administration led to faster gamma aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) transmission in the early visual cortex, faster NMDA transmission in the fusiform cortex, and slower NMDA transmission in the amygdala. Ketamine administration also led to direct and indirect changes in local inhibition in the early visual cortex and inferior frontal gyrus and to indirect increases in cortical excitability within the amygdala. Finally, reductions in depressive symptoms in TRD participants post-ketamine were associated with faster α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) transmission and increases in gain control of spiny stellate cells in the early visual cortex. These findings provide additional support for the GABA and NMDA inhibition and disinhibition hypotheses of depression and support the role of AMPA throughput in ketamine's antidepressant effects. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00088699?term=NCT00088699&draw=2&rank=1, identifier NCT00088699.

Magnetoencephalographic Correlates of Suicidal Ideation in Major Depression.

BACKGROUND: Defining the neurobiological underpinnings of suicidal ideation (SI) is crucial to improving our understanding of suicide. This study used magnetoencephalographic gamma power as a surrogate marker for population-level excitation-inhibition balance to explore the underlying neurobiology of SI and depression. In addition, effects of pharmacological intervention with ketamine, which has been shown to rapidly reduce SI and depression, were assessed. METHODS: Data were obtained from 29 drug-free patients with major depressive disorder who participated in an experiment comparing subanesthetic ketamine (0.5 mg/kg) with a placebo saline infusion. Magnetoencephalographic recordings were collected at baseline and after ketamine and placebo infusions. During scanning, patients rested with their eyes closed. SI and depression were assessed, and a linear mixed-effects model was used to identify brain regions where gamma power and both SI and depression were associated. Two regions of the salience network (anterior insula, anterior cingulate) were then probed using dynamic causal modeling to test for ketamine effects. RESULTS: Clinically, patients showed significantly reduced SI and depression after ketamine administration. In addition, distinct regions in the anterior insula were found to be associated with SI compared with depression. In modeling of insula-anterior cingulate connectivity, ketamine lowered the membrane capacitance for superficial pyramidal cells. Finally, connectivity between the insula and anterior cingulate was associated with improvements in depression symptoms. CONCLUSIONS: These findings suggest that the anterior insula plays a key role in SI, perhaps via its role in salience detection. In addition, transient changes in superficial pyramidal cell membrane capacitance and subsequent increases in cortical excitability might be a mechanism through which ketamine improves SI.