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Mesial temporal lobe epilepsy (mTLE) is a neurological disorder in which patients suffer from frequent consciousness-impairing seizures, broad neurocognitive deficits, and diminished quality of life. Although seizures in mTLE originate focally in the hippocampus or amygdala, mTLE patients demonstrate cognitive deficits that extend beyond temporal lobe function-such as decline in executive function, cognitive processing speed, and attention-as well as diffuse decreases in neocortical metabolism and functional connectivity. Given prior observations that mTLE patients exhibit impairments in vigilance, and that seizures may disrupt the activity and long-range connectivity of subcortical brain structures involved in vigilance regulation, we propose that subcortical activating networks underlying vigilance play a critical role in mediating the widespread neural and cognitive effects of focal mTLE. Here, we review evidence for impaired vigilance in mTLE, examine clinical implications and potential network underpinnings, and suggest neuroimaging strategies for determining the relationship between vigilance, brain connectivity, and neurocognition in patients and healthy controls.
Wiley Periodicals, Inc. © 2020 International League Against Epilepsy.
Rapid and accurate detection of threat is adaptive. Yet, threat-related attentional biases, including hypervigilance, avoidance, and attentional disengagement delays, may contribute to the etiology and maintenance of anxiety disorders. Behavioral measures of attentional bias generally indicate that threat demands more attentional resources; however, indices exploring differential allocation of attention using reaction time fail to clarify the time course by which attention is deployed under threatening circumstances in healthy and anxious populations. In this review, we conduct an interpretive synthesis of 28 attentional bias studies focusing on event-related potentials (ERPs) as a primary outcome to inform an ERP model of the neural chronometry of attentional bias in healthy and anxious populations. The model posits that both healthy and anxious populations display modulations of early ERP components, including the P1, N170, P2, and N2pc, in response to threatening and emotional stimuli, suggesting that both typical and abnormal patterns of attentional bias are characterized by enhanced allocation of attention to threat and emotion at earlier stages of processing. Compared to anxious populations, healthy populations more clearly demonstrate modulations of later components, such as the P3, indexing conscious and evaluative processing of threat and emotion and disengagement difficulties at later stages of processing. Findings from the interpretive synthesis, existing bias models, and extant neural literature on attentional systems are then integrated to inform a conceptual model of the processes and substrates underlying threat appraisal and resource allocation in healthy and anxious populations. To conclude, we discuss therapeutic interventions for attentional bias and future directions.
Copyright © 2019 Elsevier B.V. All rights reserved.
Complex circuit interactions within the nucleus accumbens (NAc) facilitate goal-directed behavior. Medium spiny neurons (MSNs) mediate NAc output by projecting to functionally divergent brain regions, a property conferred, in part, by the differential projection patterns of D1- and D2 dopamine receptor-expressing MSNs. Glutamatergic afferents to the NAc direct MSN output by recruiting feedforward inhibitory microcircuits comprised of parvalbumin (PV)-expressing interneurons (INs). Furthermore, the GABA heteroreceptor (GABAR), a G-coupled G-protein-coupled receptor, is expressed at glutamatergic synapses throughout the mesolimbic network, yet its physiological context and synaptic mechanism within the NAc remains unknown. Here, we explored GABAR function at glutamatergic synapses within PV-IN-embedded microcircuits in the NAc core of male mice. We found that GABAR is expressed presynaptically and recruits a noncanonical signaling mechanism to reduce glutamatergic synaptic efficacy at D1(+) and D1(-) (putative D2) MSN subtypes. Furthermore, PV-INs, a robust source of neuronal GABA in the NAc, heterosynaptically target GABAR to selectively modulate glutamatergic transmission onto D1(+) MSNs. These findings elucidate a new mechanism of feedforward inhibition and refine mechanisms by which GABA heteroreceptors modulate mesolimbic circuit function. Glutamatergic transmission in the nucleus accumbens (NAc) critically contributes to goal-directed behaviors. However, intrinsic microcircuit mechanisms governing the integration of these synapses remain largely unknown. Here, we show that parvalbumin-expressing interneurons within feedforward microcircuits heterosynaptically target GABA heteroreceptors (GABAR) on glutamate terminals. Activation of presynaptically-expressed GABAR decreases glutamatergic synaptic strength by engaging a non-canonical signaling pathway that interferes with vesicular exocytotic release machinery. These findings offer mechanistic insight into the role of GABA heteroreceptors within reward circuitry, elucidate a novel arm to feedforward inhibitory networks, and inform the growing use of GABAR-selective pharmacotherapy for various motivational disorders, including addiction, major depressive disorder, and autism (Cousins et al., 2002; Kahn et al., 2009; Jacobson et al., 2018; Stoppel et al., 2018; Pisansky et al., 2019).
Copyright © 2019 the authors.
BACKGROUND - The striatum is abnormal in schizophrenia and possibly represents a common neurobiological mechanism underlying psychotic disorders. Resting-state functional magnetic resonance imaging studies have not reached a consensus regarding striatal dysconnectivity in schizophrenia, although these studies generally find impaired frontoparietal and salience network connectivity. The goal of the current study was to clarify the pattern of corticostriatal connectivity, including whether corticostriatal dysconnectivity is transdiagnostic and extends into psychotic bipolar disorder.
METHODS - We examined corticostriatal functional connectivity in 60 healthy subjects and 117 individuals with psychosis, including 77 with a schizophrenia spectrum illness and 40 with psychotic bipolar disorder. We conducted a cortical seed-based region-of-interest analysis with follow-up voxelwise analysis for any significant results. Further, a striatum seed-based analysis was conducted to examine group differences in connectivity between the striatum and the whole cortex.
RESULTS - Cortical region-of-interest analysis indicated that overall connectivity of the salience network with the striatum was reduced in psychotic disorders, which follow-up voxelwise analysis localized to the left putamen. Striatum seed-based analyses showed reduced ventral rostral putamen connectivity with the salience network portion of the medial prefrontal cortex in both schizophrenia and psychotic bipolar disorder.
CONCLUSIONS - The current study found evidence of transdiagnostic corticostriatal dysconnectivity in both schizophrenia and psychotic bipolar disorder, including reduced salience network connectivity, as well as reduced connectivity between the putamen and the medial prefrontal cortex. Overall, the current study points to the relative importance of salience network hypoconnectivity in psychotic disorders.
Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Catatonia is a psychomotor syndrome associated with several psychiatric and medical conditions. Psychomotor signs range from stupor to agitation, and include pathognomonic features such as verbigeration and waxy flexibility. Disturbances of volition led to the classification of catatonia as a subtype of schizophrenia, but changes in nosology now recognise the high prevalence in mood disorders, overlap with delirium, and comorbidity with medical conditions. Initial psychometric studies have revealed three behavioural factors, but the structure of catatonia is still unknown. Evidence from brain imaging studies of patients with psychotic disorders indicates increased neural activity in premotor areas in patients with hypokinetic catatonia. However, whether this localised hyperactivity is due to corticocortical inhibition or excess activity of inhibitory corticobasal ganglia loops is unclear. Current treatment of catatonia relies on benzodiazepines and electroconvulsive therapy-both effective, yet unspecific in their modes of action. Longitudinal research and treatment studies, with neuroimaging and brain stimulation techniques, are needed to advance our understanding of catatonia.
Copyright © 2019 Elsevier Ltd. All rights reserved.
BACKGROUND - Focal seizures in temporal lobe epilepsy (TLE) are associated with widespread brain network perturbations and neurocognitive problems.
OBJECTIVE - To determine whether brainstem connectivity disturbances improve with successful epilepsy surgery, as recent work has demonstrated decreased brainstem connectivity in TLE that is related to disease severity and neurocognitive profile.
METHODS - We evaluated 15 adult TLE patients before and after (>1 yr; mean, 3.4 yr) surgery, and 15 matched control subjects using magnetic resonance imaging to measure functional and structural connectivity of ascending reticular activating system (ARAS) structures, including cuneiform/subcuneiform nuclei (CSC), pedunculopontine nucleus (PPN), and ventral tegmental area (VTA).
RESULTS - TLE patients who achieved long-term postoperative seizure freedom (10 of 15) demonstrated increases in functional connectivity between ARAS structures and fronto-parietal-insular neocortex compared to preoperative baseline (P = .01, Kruskal-Wallis), with postoperative connectivity patterns resembling controls' connectivity. No functional connectivity changes were detected in 5 patients with persistent seizures after surgery (P = .9, Kruskal-Wallis). Among seizure-free postoperative patients, larger increases in CSC, PPN, and VTA functional connectivity were observed in individuals with more frequent seizures before surgery (P < .05 for each, Spearman's rho). Larger postoperative increases in PPN functional connectivity were seen in patients with lower baseline verbal IQ (P = .03, Spearman's rho) or verbal memory (P = .04, Mann-Whitney U). No changes in ARAS structural connectivity were detected after successful surgery.
CONCLUSION - ARAS functional connectivity disturbances are present in TLE but may recover after successful epilepsy surgery. Larger increases in postoperative connectivity may be seen in individuals with more severe disease at baseline.
Copyright © 2019 by the Congress of Neurological Surgeons.
Early life stress (ELS) is a risk factor for the development of depression in adolescence; the mediating neurobiological mechanisms, however, are unknown. In this study, we examined in early pubertal youth the associations among ELS, cortisol stress responsivity, and white matter microstructure of the uncinate fasciculus and the fornix, two key frontolimbic tracts; we also tested whether and how these variables predicted depressive symptoms in later puberty. A total of 208 participants (117 females; M age = 11.37 years; M Tanner stage = 2.03) provided data across two or more assessment modalities: ELS; salivary cortisol levels during a psychosocial stress task; diffusion magnetic resonance imaging; and depressive symptoms. In early puberty there were significant associations between higher ELS and decreased cortisol production, and between decreased cortisol production and increased fractional anisotropy in the uncinate fasciculus. Further, increased fractional anisotropy in the uncinate fasciculus predicted higher depressive symptoms in later puberty, above and beyond earlier symptoms. In post hoc analyses, we found that sex moderated several additional associations. We discuss these findings within a broader conceptual model linking ELS, emotion dysregulation, and depression across the transition through puberty, and contend that brain circuits implicated in the control of hypothalamic-pituitary-adrenal axis function should be a focus of continued research.
Accurate estimates of the BOLD hemodynamic response function (HRF) are crucial for the interpretation and analysis of event-related functional MRI data. To date, however, there have been no comprehensive measurements of the HRF in white matter (WM) despite increasing evidence that BOLD signals in WM change after a stimulus. We performed an event-related cognitive task (Stroop color-word interference) to measure the HRF in selected human WM pathways. The task was chosen in order to produce robust, distributed centers of activity throughout the cortex. To measure the HRF in WM, fiber tracts were reconstructed between each pair of activated cortical areas. We observed clear task-specific HRFs with reduced magnitudes, delayed onsets and prolonged initial dips in WM tracts compared with activated grey matter, thus calling for significant changes to current standard models for accurately characterizing the HRFs in WM and for modifications of standard methods of analysis of functional imaging data.
This article reviews the interactions of estrogen changes and psychosocial stress in contributing to vulnerability to major depressive disorder (MDD) in women. Estrogen modulates brain networks and processes related to changes in stress response, cognition, and emotional dysregulation that are core characteristics of MDD. Synergistic effects of estrogen on cognitive and emotional function, particularly during psychosocial stress, may underlie the association of ovarian hormone fluctuation and depression in women. We propose a model of estrogen effects on multiple brain systems that interface with stress-related emotional and cognitive processes implicated in MDD and discuss possible mechanisms through which reproductive events and changes in estrogen may contribute to MDD risk in women with other concurrent risk factors.
BACKGROUND - Across networks, connectivity within the frontoparietal network (FPN) and cingulo-opercular network (CON) exhibits reductions earliest during healthy aging, contributing to cognitive impairment. Individuals with psychotic disorders demonstrate evidence of accelerated aging across multiple biological systems. By leveraging a large sample of patients with psychosis from early to chronic illness stages, this study sought to determine whether the CON and FPN exhibit evidence of accelerated aging in psychotic disorders, confirm associations between network efficiency and cognition, and determine whether reduced network efficiency is observed in early-stage psychosis.
METHODS - Resting-state functional magnetic resonance imaging and cognitive data were obtained on 240 patients with psychotic disorder and 178 healthy control participants (HCs). Global efficiency, a measure of functional integration, was calculated for the CON, FPN, subcortical network, and visual network. Associations with age and cognition were assessed and compared between groups.
RESULTS - Consistent with accelerated aging, significant group by age interactions reflected significantly stronger relationships between efficiency and age in patients with psychosis than in HCs for both the CON (psychosis: r = -.37; HC: r = -.16) and FPN (psychosis: r = -.31; HC: r = -.05). Accelerated aging was not observed in either the subcortical or visual network, suggesting specificity for cognitive networks that decline earliest in healthy aging. Replicating prior findings, efficiency of both the CON and FPN correlated with cognitive function across all participants (rs > .11, ps < .031). Furthermore, patients with chronic psychosis (p = .004), but not patients with early psychosis (p = .553), exhibited significantly lower FPN efficiency compared with HCs.
CONCLUSIONS - Functional integration of higher-order cognitive networks is intact in early psychosis but exhibits evidence of accelerated aging, suggesting the potential for intervention targeting cognition within the early psychosis period.
Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.