Ventral tegmental area integrity measured with high-resolution 7-Tesla MRI relates to motivation across depression and anxiety diagnoses.

The ventral tegmental area (VTA) is one of the major sources of dopamine in the brain and has been associated with reward prediction, error-based reward learning, volitional drive and anhedonia. However, precise anatomical investigations of the VTA have been prevented by the use of standard-resolution MRI, reliance on subjective manual tracings, and lack of quantitative measures of dopamine-related signal. Here, we combine ultra-high field 400 µm3 quantitative MRI with dopamine-related signal mapping, and a mixture of machine learning and supervised computational techniques to delineate the VTA in a transdiagnostic sample of subjects with and without depression and anxiety disorders. Subjects also underwent cognitive testing to measure intrinsic and extrinsic motivational tone. Fifty-one subjects were scanned in total, including healthy control (HC) and mood/anxiety (MA) disorder subjects. MA subjects had significantly larger VTA volumes compared to HC but significantly lower signal intensity within VTA compared to HC, indicating reduced structural integrity of the dopaminergic VTA. Interestingly, while VTA integrity did not significantly correlate with self-reported depression or anxiety symptoms, it was correlated with an objective cognitive measure of extrinsic motivation, whereby lower VTA integrity was associated with lower motivation. This is the first study to demonstrate a computational pipeline for detecting and delineating the VTA in human subjects with 400 µm3 resolution. We highlight the use of objective transdiagnostic measures of cognitive function that link neural integrity to behavior across clinical and non-clinical groups.

On what motivates us: a detailed review of intrinsic v. extrinsic motivation.

Motivational processes underlie behaviors that enrich the human experience, and impairments in motivation are commonly observed in psychiatric illness. While motivated behavior is often examined with respect to extrinsic reinforcers, not all actions are driven by reactions to external stimuli; some are driven by 'intrinsic' motivation. Intrinsically motivated behaviors are computationally similar to extrinsically motivated behaviors, in that they strive to maximize reward value and minimize punishment. However, our understanding of the neurocognitive mechanisms that underlie intrinsically motivated behavior remains limited. Dysfunction in intrinsic motivation represents an important trans-diagnostic facet of psychiatric symptomology, but due to a lack of clear consensus, the contribution of intrinsic motivation to psychopathology remains poorly understood. This review aims to provide an overview of the conceptualization, measurement, and neurobiology of intrinsic motivation, providing a framework for understanding its potential contributions to psychopathology and its treatment. Distinctions between intrinsic and extrinsic motivation are discussed, including divergence in the types of associated rewards or outcomes that drive behavioral action and choice. A useful framework for understanding intrinsic motivation, and thus separating it from extrinsic motivation, is developed and suggestions for optimization of paradigms to measure intrinsic motivation are proposed.

Exaggerated amygdala response to threat and association with immune hyperactivity in depression.

BACKGROUND: Depression is characterized by altered neurobiological responses to threat and inflammation may be involved in the development and maintenance of symptoms. However, the mechanistic pathways underlying the relationship between the neural underpinnings of threat, inflammation and depressive symptoms remain unknown. METHODS: Twenty participants with major depressive disorder (MDD) and 17 healthy controls (HCs) completed this study. Peripheral blood mononuclear cells (PBMCs) were collected and stimulated ex vivo with lipopolysaccharide (LPS). We then measured a broad array of secreted proteins and performed principal component analysis to compute an aggregated immune reactivity score. Subjects completed a well-validated emotional face processing task during functional magnetic resonance imaging (fMRI). Amygdala activation was measured during perception of threat for the main contrast of interest: fear > happy face. Participants completed the Mood and Anxiety Symptom Questionnaire (MASQ) and the Perceived Stress Scale (PSS). Correlation analyses between amygdala activation, the aggregate immune score, and symptom were computed across groups. A mediation analysis was also performed across groups to further explore the relationship between these three variables. RESULTS: In line with our hypotheses and with prior work, the MDD group showed greater amygdala activation in response to threat compared to the HC group [t35 = -2.038, p = 0.049]. Internal consistency of amygdala activation to threat was found to be moderate. Response to an ex vivo immune challenge was greater in MDD than HC based on the computed immune reactivity score (PC1; t35 = 2.674, p = 0.011). Amygdala activation was positively correlated with the immune score (r = 0.331, p = 0.045). Moreover, higher amygdala activation was associated with greater anxious arousal measured by the MASQ (r = 0.390, p = 0.017). Exploring the role of stress, we found that higher perceived stress was positively associated with both inflammatory response (r = 0.367, p = 0.026) and amygdala response to threat (r = 0.325, p = 0.050). Mediation analyses showed that perceived stress predicted anxious arousal, but neither inflammation nor amygdala activation fully accounted for the effect of perceived stress on anxious arousal. CONCLUSION: These data highlight the potential importance of threat circuitry hyperactivation in MDD, consistent with prior reports. We found that higher levels of inflammatory biomarkers were associated with higher amygdala activation, which in turn was associated with anxious arousal. Future research utilizing larger sample sizes are needed to replicate these preliminary results.

Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder.

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target-the KCNQ-type potassium channel-for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of 10 weeks. Resting-state functional magnetic resonance imaging data were collected at baseline and posttreatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery-Asberg Depression Rating Scale score change: -13.7 ± 9.7, p < 0.001, d = 2.08) and anhedonic symptoms (Snaith-Hamilton Pleasure Scale score change: -6.1 ± 5.3, p < 0.001, d = 1.00), which remained significant even after controlling for overall depression severity. Improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex (n = 14, voxel-wise p < 0.005). In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.

Stress, Motivation, and the Gut-Brain Axis: A Focus on the Ghrelin System and Alcohol Use Disorder.

Since its discovery, the gut hormone, ghrelin, has been implicated in diverse functional roles in the central nervous system. Central and peripheral interactions between ghrelin and other hormones, including the stress-response hormone cortisol, govern complex behavioral responses to external cues and internal states. By acting at ventral tegmental area dopaminergic projections and other areas involved in reward processing, ghrelin can induce both general and directed motivation for rewards, including craving for alcohol and other alcohol-seeking behaviors. Stress-induced increases in cortisol seem to increase ghrelin in the periphery, suggesting a pathway by which ghrelin influences how stressful life events trigger motivation for rewards. However, in some states, ghrelin may be protective against the anxiogenic effects of stressors. This critical review brings together a dynamic and growing literature, that is, at times inconsistent, on the relationships between ghrelin, central reward-motivation pathways, and central and peripheral stress responses, with a special focus on its emerging role in the context of alcohol use disorder.

Binge drinking differentially affects cortical and subcortical microstructure.

Young adult binge drinkers represent a model for endophenotypic risk factors for alcohol misuse and early exposure to repeated binge cycles. Chronic or harmful alcohol use leads to neurochemical, structural and morphological neuroplastic changes, particularly in regions associated with reward processing and motivation. We investigated neural microstructure in 28 binge drinkers compared with 38 matched healthy controls. We used a recently developed diffusion magnetic resonance imaging acquisition and analysis, which uses three-compartment modelling (of intracellular, extracellular and cerebrospinal fluid) to determine brain tissue microstructure features including neurite density and orientation dispersion index (ODI). Binge drinkers had reduced ODI, a proxy of neurite complexity, in frontal cortical grey matter and increased ODI in parietal grey matter. Neurite density was higher in cortical white matter in adjacent regions of lower ODI in binge drinkers. Furthermore, binge drinkers had higher ventral striatal grey matter ODI that was positively correlated with binge score. Healthy volunteers showed no such relationships. We demonstrate disturbed dendritic complexity of higher-order prefrontal and parietal regions, along with higher dendritic complexity of a subcortical region known to mediate reward-related motivation. The findings illustrate novel microstructural abnormalities that may reflect an infnce of alcohol bingeing on critical neurodevelopmental processes in an at-risk young adult group.

Naltrexone ameliorates functional network abnormalities in alcohol-dependent individuals.

Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50-mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly-drug-dependent individuals compared with 36 healthy volunteers. Graph theoretic and network-based statistical analysis of resting-state functional magnetic resonance imaging (MRI) data revealed that alcohol-dependent subjects had reduced functional connectivity of a dispersed network compared with both poly-drug-dependent and healthy subjects. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol-dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly-substance-dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology.

Compulsive sexual behavior: Prefrontal and limbic volume and interactions.

BACKGROUND: Compulsive sexual behaviors (CSB) are relatively common and associated with significant personal and social dysfunction. The underlying neurobiology is still poorly understood. The present study examines brain volumes and resting state functional connectivity in CSB compared with matched healthy volunteers (HV). METHODS: Structural MRI (MPRAGE) data were collected in 92 subjects (23 CSB males and 69 age-matched male HV) and analyzed using voxel-based morphometry. Resting state functional MRI data using multi-echo planar sequence and independent components analysis (ME-ICA) were collected in 68 subjects (23 CSB subjects and 45 age-matched HV). RESULTS: CSB subjects showed greater left amygdala gray matter volumes (small volume corrected, Bonferroni adjusted P < 0.01) and reduced resting state functional connectivity between the left amygdala seed and bilateral dorsolateral prefrontal cortex (whole brain, cluster corrected FWE P < 0.05) compared with HV. CONCLUSIONS: CSB is associated with elevated volumes in limbic regions relevant to motivational salience and emotion processing, and impaired functional connectivity between prefrontal control regulatory and limbic regions. Future studies should aim to assess longitudinal measures to investigate whether these findings are risk factors that predate the onset of the behaviors or are consequences of the behaviors. Hum Brain Mapp 38:1182-1190, 2017. © 2016 Wiley Periodicals, Inc.

Waiting Impulsivity: The Influence of Acute Methylphenidate and Feedback.

BACKGROUND: The ability to wait and to weigh evidence is critical to behavioral regulation. These behaviors are known as waiting and reflection impulsivity. In Study 1, we examined the effects of methylphenidate, a dopamine and norepinephrine reuptake inhibitor, on waiting and reflection impulsivity in healthy young individuals. In study 2, we assessed the role of learning from feedback in disorders of addiction. METHODS: We used the recently developed 4-Choice Serial Reaction Time task and the Beads task. Twenty-eight healthy volunteers were tested twice in a randomized, double-blind, placebo-controlled cross-over trial with 20mg methylphenidate. In the second study, we analyzed premature responses as a function of prior feedback in disorders of addiction. RESULTS: Study 1: Methylphenidate was associated with greater waiting impulsivity to a cue predicting reward along with faster responding to target onset without a generalized effect on reaction time or attention. Methylphenidate influenced reflection impulsivity based on baseline impulsivity. Study 2: More premature responses occurred after premature responses in stimulant-dependent subjects. CONCLUSIONS: We show that methylphenidate has dissociable effects on waiting and reflection impulsivity. Chronic stimulant exposure impairs learning from prior premature responses, suggesting a failure to learn that premature responding is suboptimal. These findings provide a greater mechanistic understanding of waiting impulsivity.

Longitudinal tracking of alcohol expectancies and their associations with impulsivity in alcohol naïve youth in the adolescent brain cognitive development (ABCD) study.

Background: Positive and negative alcohol expectancies (PAEs and NAEs, respectively) and impulsivity are key risk factors for the onset of alcohol use. While both factors independently contribute to alcohol initiation, the developmental aspects of AEs and their nuanced relationship with impulsivity are not adequately understood. Understanding these relationships is imperative for developing targeted interventions to prevent or delay alcohol use onset in youth. Methods: This study utilized the Adolescent Brain Cognitive Development cohort to examine how PAEs and NAEs develop over time and relate to each other. We also explored how self-reported and behavioral impulsivity at baseline (~10 years old) are associated with the longitudinal development of PAEs and NAEs in youth Ages 11, 12, and 13 (n = 7493; 7500; and 6981, respectively), as well as their time-specific relationships. Results: Findings revealed while PAEs increased steadily over all three years, NAEs increased from ages 11-12 and then remained unchanged between 12 and 13. Overall, PAEs and NAEs were inversely related. Moreover, PAEs positively correlated with sensation seeking and lack of premeditation, while NAEs negatively correlated with positive urgency. Interestingly, a time-specific association was observed with PAEs and lack of perseverance, with a stronger correlation to PAEs at Age 11 compared to Age 12. Conclusions: Overall, this study provides valuable insights into the divergent developmental trajectory of PAEs and NAEs, and their overall and time-specific associations with impulsivity. These findings may guide focused and time-sensitive prevention and intervention initiatives, aiming to modify AEs and reduce underage drinking.

Reward-related self-agency is disturbed in depression and anxiety.

BACKGROUND: The sense of agency, or the belief in action causality, is an elusive construct that impacts day-to-day experience and decision-making. Despite its relevance in a range of neuropsychiatric disorders, it is widely under-studied and remains difficult to measure objectively in patient populations. We developed and tested a novel cognitive measure of reward-dependent agency perception in an in-person and online cohort. METHODS: The in-person cohort consisted of 52 healthy control subjects and 20 subjects with depression and anxiety disorders (DA), including major depressive disorder and generalized anxiety disorder. The online sample consisted of 254 participants. The task consisted of an effort implementation for monetary rewards with computerized visual feedback interference and trial-by-trial ratings of self versus other agency. RESULTS: All subjects across both cohorts demonstrated higher self-agency after receiving positive-win feedback, compared to negative-loss feedback when the level of computer inference was kept constant. Patients with DA showed reduced positive feedback-dependent agency compared to healthy controls. Finally, in our online sample, we found that higher self-agency following negative-loss feedback was associated with worse anhedonia symptoms. CONCLUSION: Together this work suggests how positive and negative environmental information impacts the sense of self-agency in healthy subjects, and how it is perturbed in patients with depression and anxiety.

Altered hippocampus and amygdala subregion connectome hierarchy in major depressive disorder.

The hippocampus and amygdala limbic structures are critical to the etiology of major depressive disorder (MDD). However, there are no high-resolution characterizations of the role of their subregions in the whole brain network (connectome). Connectomic examination of these subregions can uncover disorder-related patterns that are otherwise missed when treated as single structures. 38 MDD patients and 40 healthy controls (HC) underwent anatomical and diffusion imaging using 7-Tesla MRI. Whole-brain segmentation was performed along with hippocampus and amygdala subregion segmentation, each representing a node in the connectome. Graph theory analysis was applied to examine the importance of the limbic subregions within the brain network using centrality features measured by node strength (sum of weights of the node's connections), Betweenness (number of shortest paths that traverse the node), and clustering coefficient (how connected the node's neighbors are to one another and forming a cluster). Compared to HC, MDD patients showed decreased node strength of the right hippocampus cornu ammonis (CA) 3/4, indicating decreased connectivity to the rest of the brain, and decreased clustering coefficient of the right dentate gyrus, implying it is less embedded in a cluster. Additionally, within the MDD group, the greater the embedding of the right amygdala central nucleus (CeA) in a cluster, the greater the severity of depressive symptoms. The altered role of these limbic subregions in the whole-brain connectome is related to diagnosis and depression severity, contributing to our understanding of the limbic system involvement in MDD and may elucidate the underlying mechanisms of depression.

Quantification of brain age using high-resolution 7 tesla MR imaging and implications for patients with epilepsy.

Purpose: Epilepsy patients exhibit morphological differences on neuroimaging compared to age-matched healthy controls, including cortical and sub-cortical volume loss and altered gray-white matter ratios. The objective was to develop a model of normal aging using the 7T MRIs of healthy controls. This model can then be used to determine if the changes in epilepsy patients resemble the changes seen in aging, and potentially give a marker for the severity of those changes. Methods: Sixty-nine healthy controls (24F/45M, mean age 36.5 ± 10.5 years) and forty-four epilepsy patients (24F/20M, 33.2 ± 9.9 years) non-lesional at 3T were scanned with volumetric T1-MPRAGE at 7T. These images were segmented and quantified using FreeSurfer. A linear regression-based model trained on healthy controls was developed to predict ages using derived imaging features among the epilepsy patient cohort. The model used 114 features with significant linear correlation with age. Results: The regression-based model estimated brain age with mean absolute error (MAE) of 6.6 years among controls. Comparable prediction accuracy of 6.9 years MAE was seen epilepsy patients. T-test of mean absolute error showed no difference in the prediction accuracy with controls and epilepsy patients (p = 0.68). However, average signed error showed elevated (+5.0 years, p = 0.0007) predicted age differences (PAD; brain-PAD=, predicted minus biological age) among epilepsy patients. Morphological metrics in the medial temporal lobe were major contributors to PAD. Additionally, patients with seizure frequency greater than once a week showed significantly elevated brain-PAD (+8.2 ± 5.3 years, n = 13) compared to patients with lower seizure frequency (3.7 ± 6.5 years, n = 31, p = 0.033). Major conclusions: Morphological patterns suggestive of premature aging were observed in non-lesional epilepsy patients vs. controls and in high seizure frequency patients vs. low frequency patients. Modeling brain age with 7T MRI may provide a sensitive imaging marker to assess the differential effects of the aging process in diseases such as epilepsy.

Perivascular spaces as a marker of psychological trauma in depression: A 7-Tesla MRI study.

INTRODUCTION: Emerging evidence in depression suggests that blood-brain barrier (BBB) breakdown and elevated inflammatory cytokines in states of persistent stress or trauma may contribute to the development of symptoms. Signal-to-noise ratio afforded by ultra-high field MRI may aid in the detection of maladaptations of the glymphatic system related to BBB integrity that may not be visualized at lower field strengths. METHODS: We investigated the link between glymphatic neuroanatomy via perivascular spaces (PVS) and trauma experience in patients with major depressive disorder (MDD) and in healthy controls using 7-Tesla MRI and a semi-automated segmentation algorithm. RESULTS: After controlling for age and gender, the number of traumatic events was correlated with total PVS volume in MDD patients (r = 0.50, p = .028) and the overall population (r = 0.34, p = .024). The number of traumatic events eliciting horror was positively correlated with total PVS volume in MDD patients (r = 0.50, p = .030) and the overall population (r = 0.32, p = .023). Age correlated positively with PVS count, PVS total volume, and PVS density in all participants (r > 0.35, p < .01). CONCLUSIONS: These results suggest a relationship between glymphatic dysfunction related to BBB integrity and psychological trauma, and that glymphatic impairment may play a role in trauma-related symptomatology.

Semi-automated Segmentation and Quantification of Perivascular Spaces at 7 Tesla in COVID-19.

While COVID-19 is primarily considered a respiratory disease, it has been shown to affect the central nervous system. Mounting evidence shows that COVID-19 is associated with neurological complications as well as effects thought to be related to neuroinflammatory processes. Due to the novelty of COVID-19, there is a need to better understand the possible long-term effects it may have on patients, particularly linkage to neuroinflammatory processes. Perivascular spaces (PVS) are small fluid-filled spaces in the brain that appear on MRI scans near blood vessels and are believed to play a role in modulation of the immune response, leukocyte trafficking, and glymphatic drainage. Some studies have suggested that increased number or presence of PVS could be considered a marker of increased blood-brain barrier permeability or dysfunction and may be involved in or precede cascades leading to neuroinflammatory processes. Due to their size, PVS are better detected on MRI at ultrahigh magnetic field strengths such as 7 Tesla, with improved sensitivity and resolution to quantify both concentration and size. As such, the objective of this prospective study was to leverage a semi-automated detection tool to identify and quantify differences in perivascular spaces between a group of 10 COVID-19 patients and a similar subset of controls to determine whether PVS might be biomarkers of COVID-19-mediated neuroinflammation. Results demonstrate a detectable difference in neuroinflammatory measures in the patient group compared to controls. PVS count and white matter volume were significantly different in the patient group compared to controls, yet there was no significant association between PVS count and symptom measures. Our findings suggest that the PVS count may be a viable marker for neuroinflammation in COVID-19, and other diseases which may be linked to neuroinflammatory processes.

Intrasubject functional connectivity related to self-generated thoughts.

INTRODUCTION: In psychiatric research, functional connectivity (FC) derived from resting-state functional MRI (rsfMRI) is often used to investigate brain abnormalities in psychiatric disorders. This approach assumes implicitly that FC can recover reliable maps of the functional architecture of the brain and that these profiles of connectivity reflect trait differences underlying pathology. However, evidence of FC related to self-generated thoughts (mind-wandering) stands in contrast with these assumptions, as FC may reflect thought patterns rather than functional architecture. METHODS: Multi-factor analysis (MFA) was used to investigate the reported content of self-generated thoughts during high-field (7T) rsfMRI in a repeated sample of 22 healthy individuals. To investigate the relationship between these experiences and FC, individual scores for each of these dimensions were compared with whole-brain connectivity using the network-based statistic (NBS) method. RESULTS: This analysis revealed three dimensions of thought content: self-referential thought, negative thoughts about one's surroundings, and thoughts in the form of imagery. A network of connections within the sensorimotor cortices negatively correlated with self-generated thoughts concerning the self was observed (p = .0081, .0486 FDR). CONCLUSION: These results suggest a potentially confounding relationship between self-generated thoughts and FC, and contribute to the body of research concerning the functional representation of mind-wandering.

Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia.

Increased levels of peripheral cytokines have been previously associated with depression in preclinical and clinical research. Although the precise nature of peripheral immune dysfunction in depression remains unclear, evidence from animal studies points towards a dysregulated response of peripheral leukocytes as a risk factor for stress susceptibility. This study examined dynamic release of inflammatory blood factors from peripheral blood mononuclear cells (PBMC) in depressed patients and associations with neural and behavioral measures of reward processing. Thirty unmedicated patients meeting criteria for unipolar depressive disorder and 21 healthy control volunteers were enrolled. PBMCs were isolated from whole blood and stimulated ex vivo with lipopolysaccharide (LPS). Olink multiplex assay was used to analyze a large panel of inflammatory proteins. Participants completed functional magnetic resonance imaging with an incentive flanker task to probe neural responses to reward anticipation, as well as clinical measures of anhedonia and pleasure including the Temporal Experience of Pleasure Scale (TEPS) and the Snaith-Hamilton Pleasure Scale (SHAPS). LPS stimulation revealed larger increases in immune factors in depressed compared to healthy subjects using an aggregate immune score (t49 = 2.83, p = 0.007). Higher peripheral immune score was associated with reduced neural responses to reward anticipation within the ventral striatum (VS) (r = -0.39, p = 0.01), and with reduced anticipation of pleasure as measured with the TEPS anticipatory sub-score (r = -0.318, p = 0.023). Our study provides new evidence suggesting that dynamic hyper-reactivity of peripheral leukocytes in depressed patients is associated with blunted activation of the brain reward system and lower subjective anticipation of pleasure.

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial.

OBJECTIVE: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. METHODS: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. RESULTS: The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. CONCLUSIONS: The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.

The role of the locus coeruleus in the generation of pathological anxiety.

This review aims to synthesise a large pre-clinical and clinical literature related to a hypothesised role of the locus coeruleus norepinephrine system in responses to acute and chronic threat, as well as the emergence of pathological anxiety. The locus coeruleus has widespread norepinephrine projections throughout the central nervous system, which act to globally modulate arousal states and adaptive behavior, crucially positioned to play a significant role in modulating both ascending visceral and descending cortical neurocognitive information. In response to threat or a stressor, the locus coeruleus-norepinephrine system globally modulates arousal, alerting and orienting functions and can have a powerful effect on the regulation of multiple memory systems. Chronic stress leads to amplification of locus coeruleus reactivity to subsequent stressors, which is coupled with the emergence of pathological anxiety-like behaviors in rodents. While direct in vivo evidence for locus coeruleus dysfunction in humans with pathological anxiety remains limited, recent advances in high-resolution 7-T magnetic resonance imaging and computational modeling approaches are starting to provide new insights into locus coeruleus characteristics.

Ketamine normalizes subgenual cingulate cortex hyper-activity in depression.

Mounting evidence supports the rapid antidepressant efficacy of the N-methyl-D-aspartate receptor antagonist, ketamine, for treating major depressive disorder (MDD); however, its neural mechanism of action remains poorly understood. Subgenual anterior cingulate cortex (sgACC) hyper-activity during rest has been consistently implicated in the pathophysiology of MDD, potentially driven in part by excessive hippocampal gluatmatergic efferents to sgACC. Reduction of sgACC activity has been associated with successful antidepressant treatment. This study aimed to examine whether task-based sgACC activity was higher in patients with MDD compared to controls and to determine whether this activity was altered by single-dose ketamine. In Study 1, patients with MDD (N = 28) and healthy controls (N = 20) completed task-based functional magnetic resonance imaging using an established incentive-processing task. In Study 2, a second cohort of patients with MDD (N = 14) completed the same scanning protocol at baseline and following a 40 min infusion of ketamine (0.5 mg/kg). Task-based activation of sgACC was examined with a seed-driven analysis assessing group differences and changes from pre to post treatment. Patients with MDD showed higher sgACC activation to positive and negative monetary incentives compared to controls, associated with anhedonia and anxiety, respectively. In addition, patients with MDD had higher resting-state functional connectivity between hippocampus and sgACC, associated with sgACC hyper-activation to positive incentives, but not negative incentives. Finally, ketamine reduced sgACC hyper-activation to positive incentives, but not negative incentives. These findings suggest a neural mechanism by which ketamine exerts its antidepressant efficacy, via rapid blunting of aberrant sgACC hyper-reactivity to positive incentives.