Frontostriatal Systems Research Articles

Failing to learn from negative prediction errors: Obesity is associated with alterations in a fundamental neural learning mechanism

Prediction errors (PEs) encode the difference between expected and actual action outcomes in the brain via dopaminergic modulation. Integration of these learning signals ensures efficient behavioral adaptation. Obesity has recently been linked to altered dopaminergic fronto-striatal circuits, thus implying impairments in cognitive domains that rely on its integrity.28 obese and 30 lean human participants performed an implicit stimulus-response learning paradigm inside an fMRI scanner. Computational modeling and psycho-physiological interaction (PPI) analysis was utilized for assessing PE-related learning and associated functional connectivity. We show that human obesity is associated with insufficient incorporation of negative PEs into behavioral adaptation even in a non-food context, suggesting differences in a fundamental neural learning mechanism. Obese subjects were less efficient in using negative PEs to improve implicit learning performance, despite proper coding of PEs in striatum. We further observed lower functional coupling between ventral striatum and supplementary motor area in obese subjects subsequent to negative PEs. Importantly, strength of functional coupling predicted task performance and negative PE utilization.These findings show that obesity is linked to insufficient behavioral adaptation specifically in response to negative PEs, and to associated alterations in function and connectivity within the fronto-striatal system. Recognition of neural differences as a central characteristic of obesity hopefully paves the way to rethink established intervention strategies: Differential behavioral sensitivity to negative and positive PEs should be considered when designing intervention programs. Measures relying on penalization of unwanted behavior may prove less effective in obese subjects than alternative approaches.

Post-conventional moral reasoning is associated with increased ventral striatal activity at rest and during task

People vary considerably in moral reasoning. According to Kohlberg’s theory, individuals who reach the highest level of post-conventional moral reasoning judge moral issues based on deeper principles and shared ideals rather than self-interest or adherence to laws and rules. Recent research has suggested the involvement of the brain’s frontostriatal reward system in moral judgments and prosocial behaviors. However, it remains unknown whether moral reasoning level is associated with differences in reward system function. Here, we combined arterial spin labeling perfusion and blood oxygen level-dependent functional magnetic resonance imaging and measured frontostriatal reward system activity both at rest and during a sequential risky decision making task in a sample of 64 participants at different levels of moral reasoning. Compared to individuals at the pre-conventional and conventional level of moral reasoning, post-conventional individuals showed increased resting cerebral blood flow in the ventral striatum and ventromedial prefrontal cortex. Cerebral blood flow in these brain regions correlated with the degree of post-conventional thinking across groups. Post-conventional individuals also showed greater task-induced activation in the ventral striatum during risky decision making. These findings suggest that high-level post-conventional moral reasoning is associated with increased activity in the brain’s frontostriatal system, regardless of task-dependent or task-independent states.

ACC GABA levels are associated with functional activation and connectivity in the fronto-striatal network during interference inhibition in patients with borderline personality disorder

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.

Le cervelet comme acteur majeur dans les troubles moteurs des syndromes autistiques

Scientific backgroundAutism spectrum disorders (ASD) are neurodevelopmental disorders associated with disturbances in communication, social interactions, cognition and affect. ASD are also accompanied by complex movement disorders, including ataxia. A special focus of recent research in this area is made on the striatum and the cerebellum, two structures known not only to control movement but also to be involved in cognitive functions such as memory and language. Dysfunction within the motor system may be associated with abnormal movements in ASD that are translated into ataxia, abnormal pattern of righting, gait sequencing, development of walking, and hand positioning. This line of study may generate new knowledge and understanding of motor symptoms associated with ASD and aims to deliver fresh perspectives for early diagnosis and therapeutic strategies against ASD. Aims of the reviewDespite the relative paucity of research in this area (compared to the social, linguistic, and behavioural disturbances in ASD), there is evidence that the frontostriatal motor system and/or the cerebellar motor systems may be the site of dysfunction in ASD. Indeed, the cerebellum seems to be essential in the development of basic social capabilities, communication, repetitive/restrictive behaviors, and motor and cognitive behaviors that are all impaired in ASD. Cerebellar neuropathology including cerebellar hypoplasia and reduced cerebellar Purkinje cell numbers are the most consistent neuropathologies linked to ASD. The functional state of the cerebellum and its impact on brain function in ASD is the focus of this review. This review starts by recapitulating historical findings pointing towards an implication of the cerebellum, and to a lesser extent the basal ganglia structures, in TSA. We then detail the structure/function of the cerebellum at the regional and cellular levels before describing human and animal findings indicating a role of the cerebellum and basal ganglia in ASD. Human and animal findingsSeveral studies have attempted to identify the nature of the motor system dysfunction in ASD, and it became apparent that the motor fronto-striatal and cerebellar systems are major sites of dysfunction in this psychiatric illness. Anomalies in these structures have been revealed both at the anatomical and functional levels in human patients as well as in animal models. These models are obtained by manipulation of genes that are often implicated in glutamate transmission, by lesions of brain structures among which the cerebellum, by pharmacological treatment with drugs such as the Valproate or by maternal infections with bacterial membrane extracts of double stranded RNA mimicking a viral infection. ConclusionThe “cognitive approach” has dominated ASD research for three decades and led to the design of interventional strategies, which have yielded satisfactory results. Nevertheless, new approaches and alternative hypotheses on the aetiology and diagnosis of ASD are needed. Research focused on motor rather than psychiatric symptoms may have a greater potential to elucidate the neurobiological basis of ASD.

Is it Worth the Effort? Novel Insights into Obesity-Associated Alterations in Cost-Benefit Decision-Making.

Cost-benefit decision-making entails the process of evaluating potential actions according to the trade-off between the expected reward (benefit) and the anticipated effort (costs). Recent research revealed that dopaminergic transmission within the fronto-striatal circuitry strongly modulates cost-benefit decision-making. Alterations within the dopaminergic fronto-striatal system have been associated with obesity, but little is known about cost-benefit decision-making differences in obese compared with lean individuals. With a newly developed experimental task we investigate obesity-associated alterations in cost-benefit decision-making, utilizing physical effort by handgrip-force exertion and both food and non-food rewards. We relate our behavioral findings to alterations in local gray matter volume assessed by structural MRI. Obese compared with lean subjects were less willing to engage in physical effort in particular for high-caloric sweet snack food. Further, self-reported body dissatisfaction negatively correlated with the willingness to invest effort for sweet snacks in obese men. On a structural level, obesity was associated with reductions in gray matter volume in bilateral prefrontal cortex. Nucleus accumbens volume positively correlated with task induced implicit food craving. Our results challenge the common notion that obese individuals are willing to work harder to obtain high-caloric food and emphasize the need for further exploration of the underlying neural mechanisms regarding cost-benefit decision-making differences in obesity.

Integrated analysis of gray and white matter alterations in attention-deficit/hyperactivity disorder.

BackgroundMagnetic resonance imaging (MRI) is able to provide detailed insights into the structural organization of the brain, e.g., by means of mapping brain anatomy and white matter microstructure. Understanding interrelations between MRI modalities, rather than mapping modalities in isolation, will contribute to unraveling the complex neural mechanisms associated with neuropsychiatric disorders as deficits detected across modalities suggest common underlying mechanisms. Here, we conduct a multimodal analysis of structural MRI modalities in the context of attention-deficit/hyperactivity disorder (ADHD).MethodsGray matter volume, cortical thickness, surface areal expansion estimates, and white matter diffusion indices of 129 participants with ADHD and 204 participants without ADHD were entered into a linked independent component analysis. This data-driven analysis decomposes the data into multimodal independent components reflecting common inter-subject variation across imaging modalities.ResultsADHD severity was related to two multimodal components. The first component revealed smaller prefrontal volumes in participants with more symptoms, co-occurring with abnormal white matter indices in prefrontal cortex. The second component demonstrated decreased orbitofrontal volume as well as abnormalities in insula, occipital, and somato-sensory areas in participants with more ADHD symptoms.ConclusionsOur results replicate and extend previous unimodal structural MRI findings by demonstrating that prefrontal, parietal, and occipital areas, as well as fronto-striatal and fronto-limbic systems are implicated in ADHD. By including multiple modalities, sensitivity for between-participant effects is increased, as shared variance across modalities is modeled. The convergence of modality-specific findings in our results suggests that different aspects of brain structure share underlying pathophysiology and brings us closer to a biological characterization of ADHD.

Reinforcement Learning Performance and Risk for Psychosis in Youth.

Early identification efforts for psychosis have thus far yielded many more individuals "at risk" than actually develop psychotic illness. Here, we test whether measures of reinforcement learning (RL), known to be impaired in chronic schizophrenia, are related to the severity of clinical risk symptoms. Because of the reliance of RL on dopamine-rich frontostriatal systems and evidence of dopamine system dysfunction in the psychosis prodrome, RL measures are of specific interest in this clinical population. The current study examines relationships between psychosis risk symptoms and RL task performance in a sample of adolescents and young adults (n = 70) receiving mental health services. We observed significant correlations between multiple measures of RL performance and measures of both positive and negative symptoms. These results suggest that RL measures may provide a psychosis risk signal in treatment-seeking youth. Further research is necessary to understand the potential predictive role of RL measures for conversion to psychosis.

Structural MRI Correlates of Episodic Memory Processes in Parkinson's Disease Without Mild Cognitive Impairment.

Background:Changes in episodic memory are common early in Parkinson’s disease (PD) and may be a risk factor for future cognitive decline. Although medial temporal lobe (MTL) memory and frontostriatal (FS) executive systems are thought to play different roles in distinct components of episodic memory impairment in PD, no study has investigated whether different aspects of memory functioning are differentially associated with MTL and FS volumes in nondemented patients without mild cognitive impairment (PD-woMCI).Objectives:The present study investigated MRI markers of different facets of memory functioning in 48 PD-woMCI patients and 42 controls.Methods:Regional volumes were measured in structures comprising the MTL and FS systems and then correlated with key indices of memory from the California Verbal Learning Test.Results:In PD-woMCI patients, memory was impaired only for verbal learning, which was not associated with executive, attention/working memory, or visuospatial functioning. Despite an absence of cortical atrophy, smaller right MTL volumes in patients were associated with poorer verbal learning, long delayed free recall, long delayed cued recall, and recognition memory hits and false positives. Smaller right pars triangularis (inferior frontal) volumes were also associated with poorer long delayed cued recall and recognition memory hits. These relationships were not found in controls.Conclusions:The findings indicate that MTL volumes are sensitive to subtle changes in almost all facets of memory in PD-woMCI, whereas FS volumes are sensitive only to memory performances in cued-testing formats.

Abnormal asymmetry in frontostriatal white matter in children with attention deficit hyperactivity disorder.

A growing body of work utilizing structural and functional brain imaging and neurocognitive measures of executive and attentional function indicates anomalous asymmetry in ADHD. This study examined the white-matter volume and diffusion properties of frontostriatal tracts, as a function of hemisphere, in ADHD and healthy controls. Forty-three young males (21 ADHD-Combined Type and 22 controls) aged 10-18years underwent structural and diffusion weighted MRI. Tractography applying constrained spherical deconvolution (CSD) was used to construct frontostriatal tracts between each of caudate and putamen and each of dorsolateral prefrontal, ventrolateral prefrontal and orbitofrontal cortices (DLPFC, VLPFC and OFC) in each hemisphere, to examine both volumetric and diffusion microstructure properties. Young people with ADHD did not show the right hemisphere lateralization of volume in the Caudate-VLPFC and Caudate-DLPFC tracts that was evident in controls, however the ADHD group displayed a pronounced lateralization to the left for fractional anisotropy in the Putamen-VLPFC tracts. The degree of volume asymmetry did not correlate with symptom severity; however fractional anisotropy (FA) values that were more strongly lateralized to the left in the Putamen-VLPFC white matter were associated with greater symptom severity. ADHD was associated with anomalous hemispheric asymmetries in both tract volume and underlying white-matter microstructure in major fibre tracts of the frontostriatal system. Our observations of both weaker lateralization to the right in terms of tract volume and stronger lateralization to the left in terms of FA values for the ADHD group, suggests that previous inconsistencies in the literature may reflect the influence of such asymmetries.

HIV Infection Is Associated with Impaired Striatal Function during Inhibition with Normal Cortical Functioning on Functional MRI

The aim of the present study was to investigate the effect of HIV infection on cortical and subcortical regions of the frontal-striatal system involved in the inhibition of voluntary movement. Functional MRI (fMRI) studies suggest that human immunodeficiency virus (HIV) infection is associated with frontostriatal dysfunction. While frontostriatal systems play a key role in behavioral inhibition, there are to our knowledge no fMRI studies investigating the potential impact of HIV on systems involved during the inhibition of voluntary movement. A total of 17 combined antiretroviral therapy (cART) naïve HIV+ participants as well as 18 age, gender, ethnic, education matched healthy controls performed a modified version of the stop-signal paradigm. This paradigm assessed behavior as well as functional brain activity associated with motor execution, reactive inhibition (outright stopping) and proactive inhibition (anticipatory response slowing before stopping). HIV+ participants showed significantly slower responses during motor execution compared to healthy controls, whereas they had normal proactive response slowing. Putamen hypoactivation was evident in the HIV+ participants based on successful stopping, indicating subcortical dysfunction during reactive inhibition. HIV+ participants showed normal cortical functioning during proactive inhibition. Our data provide evidence that HIV infection is associated with subcortical dysfunction during reactive inhibition, accompanied by relatively normal higher cortical functioning during proactive inhibition. This suggests that HIV infection may primarily involve basic striatal-mediated control processes in cART naïve participants.

Biological substrates of migraine

Migraine episodes are probably originated by central mechanisms in brain areas able to cause the classical neurological symptoms of prodromes and aura. Conversely, the headache phase begins with the activation of meningeal nociceptors at the origin of the trigeminovascular system. Recent information has postulated that the occurrence of aura can activate nociceptors in the meninges. Conversely, the mechanisms by which common prodromes initiate the headache phase or what sequence of events triggers activation of the meningeal nociceptors is not yet understood. However, a mechanistic analysis for a common factor in migraine clinical features strongly suggests a genetic predisposition to generalized neuronal hyperexcitability. Hypothalamic neurons are sensitive to changes in physiological and emotional homeostasis and they might activate meningeal nociceptors by altering the balance between parasympathetic and sympathetic influence in the meninges. Accordingly, hypothalamic neurons that contain dopamine, histamine, and orexin, and brainstem neurons that contain noradrenaline and serotonin send inputs to trigemino-thalamic neurons in sensory thalamic nuclei. These neurotransmitters can shift the activity of thalamic neurons. Clinical and preclinical studies suggest that migraine aura is caused by cortical spreading depression (CSD), a slowly propagating wave of depolarization/excitation followed by inhibition in cortical neurons and glia. In the cortex, the initial membrane depolarization is associated with a large efflux of potassium, influx of sodium and calcium and release of glutamate. Interestingly, endogenous CGRP is released in the cortical tissue during CSD, and CGRP receptor antagonists have an inhibitory effect on CSD, suggesting a critical role of CGRP in this phenomenon. The demonstration that CGRP antagonism reduces CSD supports the possible use of drugs targeting central CGRP receptors as antimigraine agents. Finally, among the various pathophysiological conditions controlling the expression and the features of headache in migraine, medication-overuse headache (MOH) plays a central role. MOH is a clinically important entity and it is now well documented that the regular use of acute symptomatic medication by people with migraine increases the risk of aggravation of the primary headache. MOH is one of the most common causes of chronic migraine-like syndrome. We have analyzed the possible mechanisms underlying sensitization in MOH by comparing these mechanisms with those reported for other forms of drug addiction. Recent data support the evidence for cognitive impulsivity in drug overuse in headache and in other forms of addiction associated with dysfunction of the frontostriatal system and an integrative hypothesis for compulsive reward-seeking in MOH.

HIV infection results in ventral-striatal reward system hypo-activation during cue processing.

Functional MRI has thus far demonstrated that HIV has an impact on frontal-striatal systems involved in executive functioning. The potential impact of HIV on frontal-striatal systems involved in reward processing has yet to be examined by functional MRI. This study therefore aims to investigate the effects of HIV infection on reward processing by examining the function of the ventral-striatal reward system during a monetary incentive delay task. This is a cross-sectional case-control study. Eighteen combined antiretroviral therapy-naive HIV-positive (HIV+) participants, as well as 16 matched healthy controls, performed a monetary incentive delay task. This paradigm assesses behaviour as well as functional brain activity-associated reward anticipation and reward outcome. HIV+ participants showed a general decrease in activation associated with both neutral as well as potentially rewarding cues in their ventral striatum. We found normal activity related to reward outcome in the orbito-frontal cortex. Despite HIV+ participants' reaction times being significantly slower when independently measured from the reward paradigm, this performance deficit normalized during the performance of the reward task. HIV caused a decrease in activity during cue processing in the ventral striatum, with normal cortical functioning during reward outcome processing. Our results therefore suggest that HIV not only has an impact on fronto-striatal systems involved in executive functioning, but also has a direct impact on the function of the ventral-striatal reward system.

Recognition memory span in autopsy-confirmed Dementia with Lewy Bodies and Alzheimer's Disease

Evidence from patients with amnesia suggests that recognition memory span tasks engage both long-term memory (i.e., secondary memory) processes mediated by the diencephalic-medial temporal lobe memory system and working memory processes mediated by fronto-striatal systems. Thus, the recognition memory span task may be particularly effective for detecting memory deficits in disorders that disrupt both memory systems. The presence of unique pathology in fronto-striatal circuits in Dementia with Lewy Bodies (DLB) compared to AD suggests that performance on the recognition memory span task might be differentially affected in the two disorders even though they have quantitatively similar deficits in secondary memory. In the present study, patients with autopsy-confirmed DLB or AD, and Normal Control (NC) participants, were tested on separate recognition memory span tasks that required them to retain increasing amounts of verbal, spatial, or visual object (i.e., faces) information across trials. Results showed that recognition memory spans for verbal and spatial stimuli, but not face stimuli, were lower in patients with DLB than in those with AD, and more impaired relative to NC performance. This was despite similar deficits in the two patient groups on independent measures of secondary memory such as the total number of words recalled from long-term storage on the Buschke Selective Reminding Test. The disproportionate vulnerability of recognition memory span task performance in DLB compared to AD may be due to greater fronto-striatal involvement in DLB and a corresponding decrement in cooperative interaction between working memory and secondary memory processes. Assessment of recognition memory span may contribute to the ability to distinguish between DLB and AD relatively early in the course of disease.

Epistatic interaction of BDNF and COMT on the frontostriatal system

The frontostriatal system plays a critical role in emotional and cognitive control. Brain-derived neurotrophic factor (BDNF) influences the release of dopamine (DA) in the ventral striatum (VST), while catechol-O-methyltransferase (COMT) impacts DA availability in the prefrontal cortex (PFC). Behavioral studies have already shown a genetic interaction of BDNF Val66Met and COMT Val158Met, but the interaction on the DA-related neural circuit has not been previously studied. Here we show, using functional magnetic resonance imaging in a sample of healthy human subjects, that BDNF and COMT epistatically interacted on the functional connectivity between the bilateral VST and the anterior cingulate cortex. Specifically, BDNF Val66Met impacted the VST-PFC functional connectivity in an inverted U-shaped in COMT Met carriers, while COMT Val homozygotes displayed a U-shaped. These data may be helpful elucidating the mechanism of the interaction between BDNF and COMT on the cognitive functions that are based in the frontostriatal system.

Predisposition to and effects of methamphetamine use on the adolescent brain.

Adolescence is a period of heightened vulnerability both to addictive behaviors and drug-induced brain damage. Yet, only limited information exists on the brain mechanisms underlying these adolescent-specific characteristics. Moreover, distinctions in brain correlates between predisposition to drug use and effects of drugs in adolescents are unclear. Using cortical thickness and diffusion tensor image analyses, we found greater and more widespread gray and white matter alterations, particularly affecting the frontostriatal system, in adolescent methamphetamine (MA) users compared with adult users. Among adolescent-specific gray matter alterations related to MA use, smaller cortical thickness in the orbitofrontal cortex was associated with family history of drug use. Our findings highlight that the adolescent brain, which undergoes active myelination and maturation, is more vulnerable to MA-related alterations than the adult brain. Furthermore, MA-use-related executive dysfunction was greater in adolescent MA users than in adult users. These findings may provide explanation for the severe behavioral complications and relapses that are common in adolescent-onset drug addiction. Additionally, these results may provide insights into distinguishing the neural mechanisms that underlie the predisposition to drug addiction from effects of drugs in adolescents.

The prefrontal cortex achieves inhibitory control by facilitating subcortical motor pathway connectivity.

Communication between the prefrontal cortex and subcortical nuclei underpins the control and inhibition of behavior. However, the interactions in such pathways remain controversial. Using a stop-signal response inhibition task and functional imaging with analysis of effective connectivity, we show that the lateral prefrontal cortex influences the strength of communication between regions in the frontostriatal motor system. We compared 20 generative models that represented alternative interactions between the inferior frontal gyrus, presupplementary motor area (preSMA), subthalamic nucleus (STN), and primary motor cortex during response inhibition. Bayesian model selection revealed that during successful response inhibition, the inferior frontal gyrus modulates an excitatory influence of the preSMA on the STN, thereby amplifying the downstream polysynaptic inhibition from the STN to the motor cortex. Critically, the strength of the interaction between preSMA and STN, and the degree of modulation by the inferior frontal gyrus, predicted individual differences in participants' stopping performance (stop-signal reaction time). We then used diffusion-weighted imaging with tractography to assess white matter structure in the pathways connecting these three regions. The mean diffusivity in tracts between preSMA and the STN, and between the inferior frontal gyrus and STN, also predicted individual differences in stopping efficiency. Finally, we found that white matter structure in the tract between preSMA and STN correlated with effective connectivity of the same pathway, providing important cross-modal validation of the effective connectivity measures. Together, the results demonstrate the network dynamics and modulatory role of the prefrontal cortex that underpin individual differences in inhibitory control.

Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain.

Author SummaryDoes cognitive self-regulation influence pain experience by affecting the primary representations of painful (nociceptive) stimuli in the brain? Or does it regulate reported pain via a neural pathway that is distinct from the one that mediates nociceptive pain? The present study demonstrates that nociceptive and cognitive manipulations of pain influence two distinct, separable neural systems, which operate together to construct the pain experience. The neurologic pain signature (NPS) mediates the effects of noxious input, whereas a fronto-striatal pathway connecting nucleus accumbens and ventromedial prefrontal cortex mediates the effects of cognitive self-regulation of pain. These findings help move the field beyond the “one system” view of pain as a primarily nociceptive process, and provide a foundation for new approaches to multidimensional pain assessment and treatment.

Damage to left frontal regulatory circuits produces greater positive emotional reactivity in frontotemporal dementia

Positive emotions foster social relationships and motivate thought and action. Dysregulation of positive emotion may give rise to debilitating clinical symptomatology such as mania, risk-taking, and disinhibition. Neuroanatomically, there is extensive evidence that the left hemisphere of the brain, and the left frontal lobe in particular, plays an important role in positive emotion generation. Although prior studies have found that left frontal injury decreases positive emotion, it is not clear whether selective damage to left frontal emotion regulatory systems can actually increase positive emotion. We measured happiness reactivity in 96 patients with frontotemporal dementia (FTD), a neurodegenerative disease that targets emotion-relevant neural systems and causes alterations in positive emotion (i.e., euphoria and jocularity), and in 34 healthy controls. Participants watched a film clip designed to elicit happiness and a comparison film clip designed to elicit sadness while their facial behavior, physiological reactivity, and self-reported emotional experience were monitored. Whole-brain voxel-based morphometry (VBM) analyses revealed that atrophy in predominantly left hemisphere fronto-striatal emotion regulation systems including left ventrolateral prefrontal cortex, orbitofrontal cortex, anterior insula, and striatum was associated with greater happiness facial behavior during the film (pFWE < .05). Atrophy in left anterior insula and bilateral frontopolar cortex was also associated with higher cardiovascular reactivity (i.e., heart rate and blood pressure) but not self-reported positive emotional experience during the happy film (p < .005, uncorrected). No regions emerged as being associated with greater sadness reactivity, which suggests that left-lateralized fronto-striatal atrophy is selectively associated with happiness dysregulation. Whereas previous models have proposed that left frontal injury decreases positive emotional responding, we argue that selective disruption of left hemisphere emotion regulating systems can impair the ability to suppress positive emotions such as happiness.

Frontostriatal systems comprising connections between ventral medial prefrontal cortex and nucleus accumbens subregions differentially regulate motor impulse control in rats.

Deficits in impulse control are prevalent in several neuropsychiatric disorders that are based on impaired frontostriatal communication. The ventral medial prefrontal cortex (vmPFC) and the nucleus accumbens (NAc) are key substrates of impulse control in rats. The NAc core and shell are considered to be differentially involved suggesting a functional distinction between the connections of the vmPFC and particular NAc subregions concerning impulse control. In the present study, simultaneous inactivation of the rats' vmPFC and NAc core or shell by contralateral microinfusion of the GABAA receptor agonist muscimol was used to investigate their relevance for impulse control in the five-choice serial reaction time task (5-CSRTT). Disconnection of the vmPFC and NAc shell produced specific impairments in inhibitory control, indicated by significantly increased premature responding and an enhanced number of time-out responses, closely resembling the effects of bilateral inactivation of either the vmPFC or NAc shell previously reported using the same task. In contrast, disconnection of the vmPFC and NAc core only slightly increased the rate of omissions and latency of reward collection indicating attentional and motivational deficits. Our results extend previous findings indicating the functional specialisation of frontostriatal networks and show a differential contribution of specific vmPFC-NAc connections to behavioural control depending on the NAc subregion. We conclude that the regulation of impulse control in rats requires an intact connection between the vmPFC and the NAc shell, while the vmPFC-NAc core projection seems to be of minor importance.

Regressing to Prior Response Preference After Set Switching Implicates Striatal Dysfunction Across Psychotic Disorders: Findings From the B-SNIP Study.

Difficulty switching behavioral response sets is established in psychotic disorders. In rodent models, prefrontal lesions cause difficulty initially switching to new response sets (perseverative errors) while striatal lesions cause difficulty suppressing responses to previous choice preferences (regressive errors). Studies of psychotic disorders have not previously assessed these 2 error types. Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) participants included probands with schizophrenia (N = 212), psychotic bipolar (N = 192), and schizoaffective disorder (N = 131), their first-degree relatives (N = 267,226,165 respectively), and healthy controls (N = 258). Participants completed the Penn Conditional Exclusion Test (PCET) to assess cognitive set switching and the Brief Assessment of Cognition in Schizophrenia (BACS) to assess generalized neuropsychological dysfunction. All proband groups displayed elevated rates of perseverative and regressive errors compared to controls. After correcting for generalized cognitive deficits to identify specific deficits in set shifting and maintenance, there were no significant group differences for perseverative errors, while the increased rate of regressive errors remained significant. Level of regressive errors was similar across proband groups with minimal correlations with antipsychotic medication dose, clinical ratings, and demographic characteristics. Relatives of schizophrenia patients showed increased rates of regressive errors, but familiality of this trait was significant only in bipolar pedigrees. Regressive errors were partially independent of generalized cognitive deficits, suggesting a potentially informative and specific cognitive deficit across psychotic disorders. Preclinical data indicate that this deficit could be related to altered function in a neural system that may include the dorsal striatum or other elements of frontostriatal systems.