Frontostriatal Systems Research Articles

Learning to select actions shapes recurrent dynamics in the corticostriatal system

Learning to select appropriate actions based on their values is fundamental to adaptive behavior. This form of learning is supported by fronto-striatal systems. The dorsal-lateral prefrontal cortex (dlPFC) and the dorsal striatum (dSTR), which are strongly interconnected, are key nodes in this circuitry. Substantial experimental evidence, including neurophysiological recordings, have shown that neurons in these structures represent key aspects of learning. The computational mechanisms that shape the neurophysiological responses, however, are not clear. To examine this, we developed a recurrent neural network (RNN) model of the dlPFC-dSTR circuit and trained it on an oculomotor sequence learning task. We compared the activity generated by the model to activity recorded from monkey dlPFC and dSTR in the same task. This network consisted of a striatal component which encoded action values, and a prefrontal component which selected appropriate actions. After training, this system was able to autonomously represent and update action values and select actions, thus being able to closely approximate the representational structure in corticostriatal recordings. We found that learning to select the correct actions drove action-sequence representations further apart in activity space, both in the model and in the neural data. The model revealed that learning proceeds by increasing the distance between sequence-specific representations. This makes it more likely that the model will select the appropriate action sequence as learning develops. Our model thus supports the hypothesis that learning in networks drives the neural representations of actions further apart, increasing the probability that the network generates correct actions as learning proceeds. Altogether, this study advances our understanding of how neural circuit dynamics are involved in neural computation, revealing how dynamics in the corticostriatal system support task learning.

Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals

Ketamine improves motivation-related symptoms in depression but simultaneously elicits similar symptoms in healthy individuals, suggesting that it might have different effects in health and disease. This study examined whether ketamine affects the brain’s fronto-striatal system, which is known to drive motivational behavior. The study also assessed whether inflammatory mechanisms—which are known to influence neural and behavioral motivational processes—might underlie some of these changes. These questions were explored in the context of a double-blind, placebo-controlled, crossover trial of ketamine in 33 individuals with treatment-resistant major depressive disorder (TRD) and 25 healthy volunteers (HVs). Resting-state functional magnetic resonance imaging (rsfMRI) was acquired 2 days post-ketamine (final sample: TRD n = 27, HV n = 19) and post-placebo (final sample: TRD n = 25, HV n = 18) infusions and was used to probe fronto-striatal circuitry with striatal seed-based functional connectivity. Ketamine increased fronto-striatal functional connectivity in TRD participants toward levels observed in HVs while shifting the connectivity profile in HVs toward a state similar to TRD participants under placebo. Preliminary findings suggest that these effects were largely observed in the absence of inflammatory (C-reactive protein) changes and were associated with both acute and sustained improvements in symptoms in the TRD group. Ketamine thus normalized fronto-striatal connectivity in TRD participants but disrupted it in HVs independently of inflammatory processes. These findings highlight the potential importance of reward circuitry in ketamine’s mechanism of action, which may be particularly relevant for understanding ketamine-induced shifts in motivational symptoms.

Cognitive and behavioural impairment in amyotrophic lateral sclerosis.

The current review provides an up to date overview of the nature and progression of the cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS). Understanding these symptoms has implications for the management of the disease and the design of clinical trials, in addition to the support of patient and caregiver regarding mental capacity and end of life decision-making. Cognitive and behavioural change in ALS are best characterized as the consequence of extensive network dysfunction. 35-45% of ALS patients present with mild-moderate cognitive impairment and comorbid dementia occurs in approximately 14% of patients, the majority of these meeting diagnostic criteria for frontotemporal dementia (FTD). Cognitive change in ALS manifests most commonly as executive dysfunction and language impairment. Behavioural change in the form of apathy, disinhibition, loss of sympathy and empathy, stereotyped behaviours and dietary changes occur. Cognitive and behavioural impairment is an important feature of ALS, and reflects broad network dysfunction of frontostriatal and frontotemporal systems. Cognition and behaviour should be assessed early in the diagnostic process, and data driven approaches should be developed to enable reliable quantitative outcome assessment suitable for clinical trials.

A multimodal imaging study of brain structural correlates of schizotypy dimensions using the MSS

Schizotypy is a multidimensional construct of subclinical schizophrenia-like behavioural traits and cognition. The recently developed multidimensional schizotypy scale (MSS) provides an improved psychometric assessment of the three main dimensions (positive, negative, and disorganised). We tested the hypothesis that the three dimensions are related to brain structural variation in the precuneus and fronto-thalamo-striatal system in a new non-clinical healthy cohort to support a dimensional model of the psychosis spectrum. We analysed data from 104 subjects with Multidimensional Schizotypy Scale (MSS) phenotyping and 3 Tesla magnetic resonance images using voxel-based morphometry (VBM) applying CAT12 software, and diffusion-tensor imaging (DTI) with TBSS in FSL to test for correlations with MSS scores. MSS subscales and total score were negatively associated with GMV in brain areas including the medial prefrontal cortex, anterior cingulate cortex, and lateral prefrontal and orbital cortex. MSS schizotypy was associated with white matter integrity in anterior thalamic radiation, uncinate fasciculus, and superior longitudinal fasciculus. Our findings provide first direct evidence for an association of schizotypy (as a psychosis risk phenotype) and the fronto-thalamo-striatal system, in both grey and white matter with regionally diverging effects across single dimensions. This provides new evidence arguing for the fronto-striatal system (rather than precuneus) in schizotypy.

S166. EFFECTIVE CONNECTIVITY OF FRONTOSTRIATAL SYSTEMS IN FIRST-EPISODE PSYCHOSIS

BackgroundNeuroimaging studies have found dysconnectivity of frontostriatal circuits across a broad spectrum of psychotic symptoms. However, it is unknown whether dysconnectivity within frontostriatal circuits originates from disrupted bottom-up or top-down control signaling within these systems. Here, we used dynamic causal modelling (DCM) to examine the effective connectivity of frontostriatal systems in first-episode psychosis (FEP).MethodsA total of 55 FEP patients (26 males; mean [SD] age = 19.24 [2.89]) and 24 healthy controls (15 males; mean [SD] age = 21.83 [1.93]) underwent a resting-state functional magnetic resonance imaging protocol. Biologically plausible connections between eight left hemisphere regions encompassing the dorsal and ventral frontostriatal systems were modelled using spectral DCM. The regions comprise dorsolateral prefrontal cortex, ventromedial prefrontal cortex, anterior hippocampus, amygdala, dorsal caudate, nucleus accumbens, thalamus, and the midbrain. Effective connectivity between groups were assessed using a parametric Bayesian model. Associations between effective connectivity parameters and positive symptoms, measured by the Brief Psychiatric Rating Scale positive subscale, was assessed in the patient group in a separate Bayesian general linear model.ResultsDCM shows evidence for differences in effective connectivity between patients and healthy controls, namely in the bottom-down connections distributed in the frontostriatal system encompassing the hippocampus, amygdala, striatum, and midbrain. Compared to healthy controls, patients also demonstrated increased disinhibition of the midbrain. In patients, positive symptoms are associated with increased top-down connections to the midbrain. Outgoing connection from the midbrain to the nucleus accumbens is also increased in association with positive symptoms.DiscussionAberrant top-down connectivity in the frontostriatal system in patients is consistent with top-down dysregulation of dopamine function in FEP, as dopaminergic activity in the midbrain is proposed to be under the control of higher brain areas. In patients, increased self-inhibition of the midbrain, as well as symptom associations in both ingoing and outgoing connections of this region, are congruous with hyperactivity of the midbrain as proposed by the dopamine dysregulation hypothesis. Here, we demonstrate that mathematical models of brain imaging signals can be used to identify the key disruptions driving brain circuit dysfunction, identifying new targets for treatment.

T136. NEURAL CORRELATES OF ALTERED COGNITIVE FLEXIBILITY AND STABILITY FOR MOTOR CONTROL IN SCHIZOPHRENIA – JUST TWO SIDES OF THE SAME COIN?

BackgroundIt has been suggested that patients with schizophrenia are impaired in the use of prediction error signals resulting in disturbances of motor control. Alterations in fronto-striatal dopamine transmitter systems are regarded to contribute to these deficits. It is unclear whether the use of predictive strategies for motor control may be systematically related to impaired cognitive functions in patients. In healthy subjects, cognitive flexibility has been related to medial prefrontal cortex (PFC) function, while cognitive stability was related to lateral PFC integrity with both brain regions being modulated by striatal activity. Despite these findings, the interplay of cognitive flexibility and stability needed for motor control and its associations to alterations on the brain system level have not been investigated systematically in this patient group.MethodsWe assessed patients with schizophrenia (N=22) and healthy controls (N=22) on first, detection of relevant unexpected events (cognitive flexibility) and second, distractor resistance to irrelevant prediction errors (cognitive stability) using a serial prediction task including the digits 1-2-3-4. We applied an event-related design in a functional magnetic resonance imaging (fMRI) environment (3T) to explore brain networks underlying cognitive flexibility and stability, respectively. In analyses, the minimum cluster extent was set to k > 20 and corrected using the false discovery rate (FDR) with p < 0.05. Since we were specifically interested in the role of the striatum, we applied small volume correction at p < 0.05 with the minimum cluster extent set to k > 5 in a region of interest analyses. Participants were also assessed on general cognitive function using the Brief Assessment of Cognition in Schizophrenia (BACS) battery and on motor symptoms using the Heidelberg Scale for Neurological Soft Signs (NSS).ResultsPatients detected less behaviorally relevant events (M(Pat) = 0.57 vs. M(HC) = 0.78, F(41,1) = 16.32, p < 0.001) and ignored less irrelevant events (M(Pat) = 0.87 vs. M(HC) = 0.93, F(41,1) = 11.78, p < 0.001) implying impairments of both cognitive flexibility and stability in patients. Motor symptoms (NSS) and cognitive deficits (BACS) in patients were exclusively related to cognitive flexibility, but not stability. Brain correlates of reduced flexibility in patients were found in a fronto-striato-thalamo network. More specifically, reduced striatal activation in patients was related to weaker event discrimination and reduced detection of unexpected relevant events. Additionally, exploratory follow-up analyses revealed reduced fronto-striato-temporal activation in patients associated with weaker distractor resistance during the stability task. Note, chlorpromazine equivalents as an indicator of antipsychotic dosage as well as positive and negative symptoms were unrelated to measures of cognitive flexibility and stability.DiscussionTogether, our findings provide evidence for distinctive neurobiological alterations underlying reduced cognitive flexibility and stability in schizophrenia with reduced flexibility being associated with general cognitive and motor impairments. Our main imaging results show reduced activation in a fronto-striato-thalamo network in response to relevant prediction errors in patients, while impaired cognitive stability may be rather related to alterations in a fronto-striato-temporal network. Reduced caudate activation during behavioral relevant events, which was associated with weaker event discrimination and detection of relevant prediction errors in patients, supports a model of striatal gating being essentially impaired in patients.

Chronic Tinnitus Exhibits Bidirectional Functional Dysconnectivity in Frontostriatal Circuit.

PurposeThe phantom sound of tinnitus is considered to be associated with abnormal functional coupling between the nucleus accumbens (NAc) and the prefrontal cortex, which may form a frontostriatal top-down gating system to evaluate and modulate sensory signals. Resting-state functional magnetic resonance imaging (fMRI) was used to recognize the aberrant directional connectivity of the NAc in chronic tinnitus and to ascertain the relationship between this connectivity and tinnitus characteristics.MethodsParticipants included chronic tinnitus patients (n = 50) and healthy controls (n = 55), matched for age, sex, education, and hearing thresholds. The hearing status of both groups was comparable. On the basis of the NAc as a seed region, a Granger causality analysis (GCA) study was conducted to investigate the directional connectivity and the relationship with tinnitus duration or distress.ResultsCompared with healthy controls, tinnitus patients exhibited abnormal directional connectivity between the NAc and the prefrontal cortex, principally the middle frontal gyrus (MFG), orbitofrontal cortex (OFC), and inferior frontal gyrus (IFG). Additionally, positive correlations between tinnitus handicap questionnaire (THQ) scores and increased directional connectivity from the right NAc to the left MFG (r = 0.357, p = 0.015) and from the right MFG to the left NAc (r = 0.626, p < 0.001) were observed. Furthermore, the enhanced directional connectivity from the right NAc to the right OFC was positively associated with the duration of tinnitus (r = 0.599, p < 0.001).ConclusionIn concurrence with expectations, tinnitus distress was correlated with enhanced directional connectivity between the NAc and the prefrontal cortex. The current study not only helps illuminate the neural basis of the frontostriatal gating control of tinnitus sensation but also contributes to deciphering the neuropathological features of tinnitus.

Gated spiking neural network using Iterative Free-Energy Optimization and rank-order coding for structure learning in memory sequences (INFERNO GATE)

We present a framework based on iterative free-energy optimization with spiking neural networks for modeling the fronto-striatal system (PFC-BG) for the generation and recall of audio memory sequences. In line with neuroimaging studies carried out in the PFC, we propose a genuine coding strategy using the gain-modulation mechanism to represent abstract sequences based solely on the rank and location of items within them. Based on this mechanism, we show that we can construct a repertoire of neurons sensitive to the temporal structure in sequences from which we can represent any novel sequences. Free-energy optimization is then used to explore and to retrieve the missing indices of the items in the correct order for executive control and compositionality. We show that the gain-modulation mechanism permits the network to be robust to variabilities and to have long-term dependencies as it implements a gated recurrent neural network. This model, called Inferno Gate, is an extension of the neural architecture Inferno standing for Iterative Free-Energy Optimization of Recurrent Neural Networks with Gating or Gain-modulation. In experiments performed with an audio database of ten thousand MFCC vectors, Inferno Gate is capable of encoding efficiently and retrieving chunks of fifty items length. We then discuss the potential of our network to model the features of working memory in the PFC-BG loop for structural learning, goal-direction and hierarchical reinforcement learning.

Common and Distinct Functional Brain Networks for Intuitive and Deliberate Decision Making.

Reinforcement learning studies in rodents and primates demonstrate that goal-directed and habitual choice behaviors are mediated through different fronto-striatal systems, but the evidence is less clear in humans. In this study, functional magnetic resonance imaging (fMRI) data were collected whilst participants (n = 20) performed a conditional associative learning task in which blocks of novel conditional stimuli (CS) required a deliberate choice, and blocks of familiar CS required an intuitive choice. Using standard subtraction analysis for fMRI event-related designs, activation shifted from the dorso-fronto-parietal network, which involves dorsolateral prefrontal cortex (DLPFC) for deliberate choice of novel CS, to ventro-medial frontal (VMPFC) and anterior cingulate cortex for intuitive choice of familiar CS. Supporting this finding, psycho-physiological interaction (PPI) analysis, using the peak active areas within the PFC for novel and familiar CS as seed regions, showed functional coupling between caudate and DLPFC when processing novel CS and VMPFC when processing familiar CS. These findings demonstrate separable systems for deliberate and intuitive processing, which is in keeping with rodent and primate reinforcement learning studies, although in humans they operate in a dynamic, possibly synergistic, manner particularly at the level of the striatum.

Structural, functional, and neurochemical neuroimaging of methamphetamine-associated psychosis: A systematic review

Methamphetamine is a highly addictive psychostimulant. A subset of methamphetamine users develops methamphetamine-associated psychosis (MAP), which causes poorer prognoses and cognitive function than those with no psychosis (MNP). Comprehensive and integrative summaries of studies utilizing various neuroimaging modalities (structural, functional, and neurochemical) are limited. We conducted a systematic review of literature regarding clinical neuroimaging research published between January 1988 and July 2018 using the PubMed, Web of Science, Scopus, and ScienceDirect databases. Studies comparing the neuroimaging of patients with MAP with healthy controls or patients with MNP or schizophrenia were included to understand the distinct profiles associated with MAP. A total of six structural, three functional, and three neurochemical studies were reviewed. A general trend was identified that showed MAP-related brain alterations were mainly in the frontal lobe (especially the orbitofrontal cortex), striatum, and limbic systems (amygdala and hippocampus). Furthermore, some clinical manifestations, such as the severity of psychotic symptoms and cognitive performance, were correlated with neuroimaging abnormalities. In summary, distinct structural, functional, and neurochemical changes, especially in the frontostriatal circuit and network dynamic systems, play critical roles in the pathophysiology of MAP. Future studies using longitudinal study designs and including individuals with MNP and schizophrenia as controls are warranted.

Executive control deficits correlate with reduced frontal white matter volume in multiple sclerosis

ABSTRACTIntroduction: Executive control deficits are frequently reported in patients with multiple sclerosis (MS). We have previously proposed that in the context of competing automatic and volitional processes, such deficits may in part reflect poor resolution of response conflict. This study aimed to investigate the neuropathological underpinnings of executive control deficits in MS, focusing on the frontostriatal system proposed to mediate executive control.Method: Forty-one MS patients and 25 healthy controls completed measures of executive control that have previously been used to characterize deficit in MS: antisaccade and endogenously cued saccade paradigms, and the Stroop color and word test. Relationships between task performance and volumetric measures of frontal white matter, frontal gray matter, striatum, and pallidum were investigated.Results: MS participants performed significantly more poorly on the Stroop and antisaccade tasks than controls. For MS patients, higher erroneous responding on the antisaccade task was related to reduced frontal white matter volume.Conclusion: These findings suggest that loss of frontal white matter may underlie executive control deficits in MS, and provides information that may inform the development of targeted cognitive training strategies in MS.

Daytime Central Thalamic Deep Brain Stimulation Modulates Sleep Dynamics in the Severely Injured Brain: Mechanistic Insights and a Novel Framework for Alpha-Delta Sleep Generation.

Loss of organized sleep electrophysiology is a characteristic finding following severe brain injury. The return of structured elements of sleep architecture has been associated with positive prognosis across injury etiologies, suggesting a role for sleep dynamics as biomarkers of wakeful neuronal circuit function. In a continuing study of one minimally conscious state patient studied over the course of ~8½ years, we sought to investigate whether changes in daytime brain activation induced by central thalamic deep brain stimulation (CT-DBS) influenced sleep electrophysiology. In this patient subject, we previously reported significant improvements in sleep electrophysiology during 5½ years of CT-DBS treatment, including increased sleep spindle frequency and SWS delta power. We now present novel findings that many of these improvements in sleep electrophysiology regress following CT-DBS discontinuation; these regressions in sleep features correlate with a significant decrease in behavioral responsiveness. We also observe the re-emergence of alpha-delta sleep, which had been previously suppressed by daytime CT-DBS in this patient subject. Importantly, CT-DBS was only active during the daytime and has been proposed to mediate recovery of consciousness by driving synaptic activity across frontostriatal systems through the enhancement of thalamocortical output. Accordingly, the improvement of sleep dynamics during daytime CT-DBS and their subsequent regression following CT-DBS discontinuation implicates wakeful synaptic activity as a robust modulator of sleep electrophysiology. We interpret these findings in the context of the “synaptic homeostasis hypothesis,” whereby we propose that daytime upregulation of thalamocortical output in the severely injured brain may facilitate organized frontocortical circuit activation and yield net synaptic potentiation during wakefulness, providing a homeostatic drive that reconstitutes sleep dynamics over time. Furthermore, we consider common large-scale network dynamics across several neuropsychiatric disorders in which alpha-delta sleep has been documented, allowing us to formulate a novel mechanistic framework for alpha-delta sleep generation. We conclude that the bi-directional modulation of sleep electrophysiology by daytime thalamocortical activity in the severely injured brain: (1) emphasizes the cyclical carry-over effects of state-dependent circuit activation on large-scale brain dynamics, and (2) further implicates sleep electrophysiology as a sensitive indicator of wakeful brain activation and covert functional recovery in the severely injured brain.

Effects of familial risk and stimulant drug use on the anticipation of monetary reward: an fMRI study

The association between stimulant drug use and aberrant reward processing is well-documented in the literature, but the nature of these abnormalities remains elusive. The present study aims to disentangle the separate and interacting effects of stimulant drug use and pre-existing familial risk on abnormal reward processing associated with stimulant drug addiction. We used the Monetary Incentive Delay task, a well-validated measure of reward processing, during fMRI scanning in four distinct groups: individuals with familial risk who were either stimulant drug-dependent (N = 41) or had never used stimulant drugs (N = 46); and individuals without familial risk who were either using stimulant drugs (N = 25) or not (N = 48). We first examined task-related whole-brain activation followed by a psychophysiological interaction analysis to further explore brain functional connectivity. For analyses, we used a univariate model with two fixed factors (familial risk and stimulant drug use). Our results showed increased task-related activation in the putamen and motor cortex of stimulant-using participants. We also found altered task-related functional connectivity between the putamen and frontal regions in participants with a familial risk (irrespective of whether they were using stimulant drugs or not). Additionally, we identified an interaction between stimulant drug use and familial risk in task-related functional connectivity between the putamen and motor-related cortical regions in potentially at-risk individuals. Our findings suggest that abnormal task-related activation in motor brain systems is associated with regular stimulant drug use, whereas abnormal task-related functional connectivity in frontostriatal brain systems, in individuals with familial risk, may indicate pre-existing neural vulnerability for developing addiction.

Reward network connectivity "at rest" is associated with reward sensitivity in healthy adults: A resting-state fMRI study.

The behavioral approach system (BAS), based on reinforcement sensitivity theory (RST), is a neurobehavioral system responsible for detecting and promoting motivated behaviors towards appetitive stimuli. Anatomically, the frontostriatal system has been proposed as the core of the BAS, mainly the ventral tegmental area and the ventral striatum and their dopaminergic connections with medial prefrontal structures. The RST also proposes the personality trait of reward sensitivity as a measurable construct of stable individual differences in BAS activity. However, the relationship between this trait and brain connectivity "at rest" has been poorly studied, mainly because previous investigations have focused on studying brain activity under reward-related contingency paradigms. Here, we analyzed the influence of reward sensitivity on the resting-state functional connectivity (rs-FC) between BAS-related areas by correlating the BOLD time series with the scores on the Sensitivity to Reward (SR) scale in a sample of 89 healthy young adults. Rs-FC between regions of interest were all significant. Results also revealed a positive association between SR scores and the rs-FC between the VTA and the ventromedial prefrontal cortex, and between the latter structure and the anterior cingulate cortex. These results suggest that reward sensitivity could be associated with different resting-state activity in the mesocortical pathway.

The Role of Frontostriatal Systems in Instructed Reinforcement Learning: Evidence From Genetic and Experimentally-Induced Variation.

Instructions have a powerful effect on learning and decision-making, biasing choice even in the face of disconfirming feedback. Detrimental biasing effects have been reported in a number of studies in which instruction was given prior to trial-and-error learning. Previous work has attributed individual differences in instructional bias to variations in prefrontal and striatal dopaminergic genes, suggesting a role for prefrontally-mediated cognitive control processes in biasing learning. The current study replicates and extends these findings. Human subjects performed a probabilistic reinforcement learning task after receiving inaccurate instructions about the quality of one of the options. In order to establish a causal relationship between prefrontal cortical mechanisms and instructional bias, we applied transcranial direct current stimulation over dorsolateral prefrontal cortex (anodal, cathodal, or sham) while subjects performed the task. We additionally genotyped subjects for the COMT Val158Met genetic polymorphism, which influences the breakdown of prefrontal dopamine, and for the DAT1/SLC6A3 variable number tandem repeat, which affects expression of striatal dopamine transporter. We replicated the finding that the COMT Met allele is associated with increased instructional bias and further demonstrated that variation in DAT1 has similar effects to variation in COMT, with 9-repeat carriers demonstrating increased bias relative to 10-repeat homozygotes. Consistent with increased top-down regulation of reinforcement learning, anodal subjects demonstrated greater bias relative to sham, though this effect was present only early in training. In contrast, there was no effect of cathodal stimulation. Finally, we fit computational models to subjects' data to better characterize the mechanisms underlying instruction bias. A novel choice bias model, in which instructions influence decision-making rather than learning, was found to best account for subjects' behavior. Overall, these data provide further evidence for the role of frontostriatal interactions in biasing instructed reinforcement learning, which adds to the growing literature documenting both costs and benefits of cognitive control.

Reward systems and cognitions in Major Depressive Disorder.

A lack of motivation and anhedonia represent frequent and pervasive symptoms in depression, although with poor specificity. Historically described as a response bias, reward-related impairments in depression may account for the important aspects of the cognitive impairments associated with diagnosis of major depressive disorder. Reward processing is a broad psychological construct that can be parsed into 3 distinct components known as "reinforcement learning" (learning), "reward responsiveness" (liking), and "motivation to obtain a reward" (wanting). Depressed patients respond hyposensitively to reward and maladaptively to punishment: this pattern is related to a dysfunction in the frontostriatal systems modulated by the monoamine systems; seems to be observed in medicated and unmedicated patients with depression and in healthy individuals with high levels of anhedonia; and could be observed in patients with a history of depression, even when in full remission. Considered to be cognitive impairments, reward-related-impairments may also constitute part of an underlying neurobiological vulnerability to major depressive disorder (MDD). For example, the reward-related impairment is state dependent and, more or less, correlated with symptom severity in some studies but has also been proposed as being trait like, with endophenotype characteristics, possibly contributing to the persistence of the disease or treatment resistance. The 3 core aspects of reward processing have specific neurobiological correlates that involve the ventral and dorsal striatum, lateral habenula, ventral tegmental area, orbitofrontal cortex, anterior cingulate cortex, and ventromedial and dorsolateral prefrontal cortex. These structures underline the important role of the dopaminergic mesolimbic pathway, but glutamate and serotonin could also have an important role, at least in some aspects of reward-related impairments.

The Role of Habits in Anorexia Nervosa: Where We Are and Where to Go From Here?

The persistent maladaptive eating behavior characteristic of anorexia nervosa (AN) can be understood as a learned habit. This review describes the cognitive neuroscience background and the existing data from research in AN. Behavior is habitual after it is frequently repeated and becomes nearly automatic, relatively insensitive to outcome, and mediated by dorsal frontostriatal neural systems. There is evidence for such behavior in AN, in which restrictive intake has been related to dorsal frontostriatal systems. Other neural and neurocognitive data provide mixed findings, some of which suggest disturbances in habit systems in AN. There are compelling behavioral and neural data to suggest that habit systems may underlie the persistence of AN. The habit model needs further research, via more direct behavioral hypothesis testing and probes of the development of habitual behavior. Investigation of the habit-centered model of AN may open avenues for the development of novel treatments.

Dissociations of cognitive inhibition, response inhibition, and emotional interference: Voxelwise ALE meta-analyses of fMRI studies.

Inhibitory control is the stopping of a mental process with or without intention, conceptualized as mental suppression of competing information because of limited cognitive capacity. Inhibitory control dysfunction is a core characteristic of many major psychiatric disorders. Inhibition is generally thought to involve the prefrontal cortex; however, a single inhibitory mechanism is insufficient for interpreting the heterogeneous nature of human cognition. It remains unclear whether different dimensions of inhibitory processes-specifically cognitive inhibition, response inhibition, and emotional interference-rely on dissociated neural systems. We conducted systematic meta-analyses of fMRI studies in the BrainMap database supplemented by PubMed using whole-brain activation likelihood estimation. A total of 66 study experiments including 1,447 participants and 987 foci revealed that while the left anterior insula was concordant in all inhibitory dimensions, cognitive inhibition reliably activated specific dorsal frontal inhibitory system, engaging dorsal anterior cingulate, dorsolateral prefrontal cortex, and parietal areas, whereas emotional interference reliably implicated a ventral inhibitory system, involving the ventral surface of the inferior frontal gyrus and the amygdala. Response inhibition showed concordant clusters in the fronto-striatal system, including the dorsal anterior cingulate region and extended supplementary motor areas, the dorsal and ventral lateral prefrontal cortex, basal ganglia, midbrain regions, and parietal regions. We provide an empirically derived dimensional model of inhibition characterizing neural systems underlying different aspects of inhibitory mechanisms. This study offers a fundamental framework to advance current understanding of inhibition and provides new insights for future clinical research into disorders with different types of inhibition-related dysfunctions.

Reward processing dysfunction in ventral striatum and orbitofrontal cortex in Parkinson's disease

BackgroundParkinson's disease is a growing concern as the longevity of the world's population steadily increases. Both ageing and Parkinson's disease have an impact on dopamine neurotransmission. It is therefore important to investigate their relative impact on the fronto-striatal reward system. There has been little investigation of reward processing in terms of anticipation and reward outcome in Parkinson's disease. Abnormal responses during reward processing have previously been demonstrated in whole-brain analysis of Parkinson's patients with mild lateralized disease, but the exact impact in regions specific to reward processing is still unknown. ObjectiveHere we aim to investigate the impact of Parkinson's disease on the orbitofrontal ventral striatal reward system in patients with moderate to severe clinical symptoms. MethodsWe utilized a monetary incentive delay (MID) task in 17 Parkinson's patients who were compared to two control groups stratified by age. The MID paradigm reliably activates the ventral striatum during reward anticipation and the orbitofrontal cortex during reward outcome processing. ResultsRelative to the two control groups, Parkinson's disease patients had abnormal task related activity during both reward anticipation in the ventral striatum and reward outcome in the orbitofrontal cortex. There were no effects of ageing. ConclusionThese findings demonstrate abnormalities in anticipatory as well as reward outcome processing while treated primarily with levodopa. The orbitofrontal dysfunction during reward outcome processing may have specificity in Parkinson's disease, as it has been shown to be relatively unaffected by normal ageing.

Childhood sexual abuse predicts methylation of the glucocorticoid receptor gene (NR3C1) in borderline personality disorder patients and controls

Impulsivity often develops from disturbed inhibitory control, a function mainly regulated by γ-Aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) and the fronto-striatal system. In this study, we combined MRS GABA measurements and fMRI to investigate neurochemical and neurofunctional correlates of interference inhibition, further emphasizing the direct relationship between those two systems, as well as their relations to impulsivity in patients with BPD. In addition to BOLD activation, task-dependent functional connectivity was assessed by a generalized psychophysiological interactions approach. Full factorial analyses were performed via SPM to examine the main effect (within-group associations) as well as the interaction term (group differences in the association slope). The UPPS scales were used to evaluate impulsivity traits. Compared to healthy controls (HCs), BPD patients exhibited significantly less ACC-caudate functional connectivity during interference inhibition. ACC GABA levels in BPD patients but not in HCs were positively related to the magnitude of activation in several fronto-striatal regions (e.g. ACC, frontal regions, putamen, caudate,) and the strength of ACC-caudate functional connectivity during interference inhibition. The strength of the correlations of GABA with connectivity significantly differs between the two groups. Moreover, among all the UPPS impulsivity subscales, UPPS sensation seeking in the BPD group was related to GABA and was also negatively related to the task-dependent BOLD activation and functional connectivity in the fronto-striatal network. Finally, mediation analyses revealed that the magnitude of activation in the caudate and the strength of ACC-caudate functional connectivity mediated the relationship between ACC GABA levels and UPPS sensation seeking in patients with BPD. Our findings suggest a disconnectivity of the fronto-striatal network in BPD patients during interference inhibition, particularly for patients with higher impulsivity. The ACC GABAergic system seems to play a crucial role in regulating regional BOLD activations and functional connectivity in this network, which are further associated with impulsive sensation seeking in BPD.