Corticostriatal Circuits Research Articles

Disrupted Prefrontal Regulation of Striatal Subjective Value Signals in Psychopathy

Psychopathy is a personality disorder with strong links to criminal behavior. While research on psychopathy has focused largely on socio-affective dysfunction, recent data suggest that aberrant decision making may also play an important role. Yet, thecircuit-level mechanisms underlying maladaptivedecision making in psychopathy remain unclear. Here, we used a multi-modality functional imaging approach to identify these mechanisms in a population of adult male incarcerated offenders. Psychopathy was associated with stronger subjective value-related activity within the nucleus accumbens(NAcc) during inter-temporal choice and with weakerintrinsic functional connectivity between NAcc and ventromedial prefrontal cortex (vmPFC). NAcc-vmPFC connectivity strength was negatively correlated with NAcc subjective value-related activity; however, this putative regulatory pattern was abolished as psychopathy severity increased. Finally, weaker cortico-striatal regulation predicted more frequent criminal convictions. These data suggest that cortico-striatal circuit dysregulation drives maladaptive decision making in psychopathy, supporting the notion that reward system dysfunction comprises an important neurobiological risk factor.

Calretinin interneuron density in the caudate nucleus is lower in autism spectrum disorder.

Autism spectrum disorder is a debilitating condition with possible neurodevelopmental origins but unknown neuroanatomical correlates. Whereas investigators have paid much attention to the cerebral cortex, few studies have detailed the basal ganglia in autism. The caudate nucleus may be involved in the repetitive movements and limbic changes of autism. We used immunohistochemistry for calretinin and neuropeptide Y in 24 age- and gender-matched patients with autism spectrum disorder and control subjects ranging in age from 13 to 69 years. Patients with autism had a 35% lower density of calretinin+ interneurons in the caudate that was driven by loss of small calretinin+ neurons. This was not caused by altered size of the caudate, as its cross-sectional surface areas were similar between diagnostic groups. Controls exhibited an age-dependent increase in the density of medium and large calretinin+ neurons, whereas subjects with autism did not. Diagnostic groups did not differ regarding ionized calcium-binding adapter molecule 1+ immunoreactivity for microglia, suggesting chronic inflammation did not cause the decreased calretinin+ density. There was no statistically significant difference in the density of neuropeptide Y+ neurons between subjects with autism and controls. The decreased calretinin+ density may disrupt the excitation/inhibition balance in the caudate leading to dysfunctional corticostriatal circuits. The description of such changes in autism spectrum disorder may clarify pathomechanisms and thereby help identify targets for drug intervention and novel therapeutic strategies.

Effects of levodopa on corticostriatal circuits supporting working memory in Parkinson's disease

Working memory dysfunction is common in Parkinson's disease, even in its early stages, but its neural basis is debated. Working memory performance likely reflects a balance between corticostriatal dysfunction and compensatory mechanisms. We tested this hypothesis by examining working memory performance with a letter n-back task in 19 patients with mild-moderate Parkinson's disease and 20 demographically matched healthy controls. Parkinson's disease patients were tested after an overnight washout of their usual dopamine replacement therapy, and again after a standard dose of levodopa. FMRI was used to assess task-related activation and resting state functional connectivity; changes in BOLD signal were related to performance to disentangle pathological and compensatory processes. Parkinson's disease patients off dopamine replacement therapy displayed significantly reduced spatial extent of task-related activation in left prefrontal and bilateral parietal cortex, and poorer working memory performance, compared to controls. Amongst the Parkinson's disease patients off dopamine replacement therapy, relatively better performance was associated with greater activation of right dorsolateral prefrontal cortex compared to controls, consistent with compensatory right hemisphere recruitment. Administration of levodopa remediated the working memory deficit in the Parkinson's disease group, and resulted in a different pattern of performance-correlated activity, with a shift to greater left ventrolateral prefrontal cortex activation in patients on, compared to off dopamine replacement therapy. Levodopa also significantly increased resting-state functional connectivity between caudate and right parietal cortex (within the right fronto-parietal attentional network). The strength of this connectivity contributed to better performance in patients and controls, suggesting a general compensatory mechanism. These findings argue that Parkinson's disease patients can recruit additional neural resources, here, the right fronto-parietal network, to optimize working memory performance despite impaired corticostriatal function. Levodopa seems to both boost engagement of a task-specific prefrontal region, and strengthen a putative compensatory caudate-cortical network to support this executive function.

The Sensory Striatum Is Permanently Impaired by Transient Developmental Deprivation

Corticostriatal circuits play a fundamental role in regulating many behaviors, and their dysfunction isassociated with many neurological disorders. In contrast, sensory disorders, like hearing loss (HL), are commonly linked with processing deficits at or below the level of the auditory cortex (ACx). However, HL can be accompanied by non-sensory deficits, such as learning delays, suggesting the involvement of regions downstream of ACx. Here, we show that transient developmental HL differentially affected the ACx and its downstream target, the sensory striatum. Following HL, both juvenile ACx layer 5 and striatal neurons displayed an excitatory-inhibitory imbalance and lower firing rates. After hearing was restored, adult ACx neurons recovered balanced excitatory-inhibitory synaptic gain and control-like firing rates, but striatal neuron synapses and firing properties did not recover. Thus, a brief period of abnormal cortical activity may induce cellular impairments that persist into adulthood and contribute to neurological disorders that are striatal in origin.

Corticostriatal Regulation of Acute Pain.

The mechanisms for acute pain regulation in the brain are not well understood. The prefrontal cortex (PFC) provides top-down control of emotional processes, and it projects to the nucleus accumbens (NAc). This corticostriatal projection forms an important regulatory pathway within the brain’s reward system. Recently, this projection has been suggested to control both sensory and affective phenotypes specifically associated with chronic pain. As this projection is also known to play a role in the transition from acute to chronic pain, we hypothesized that this corticostriatal circuit can also exert a modulatory function in the acute pain state. Here, we used optogenetics to specifically target the projection from the PFC to the NAc. We tested sensory pain behaviors with Hargreaves’ test and mechanical allodynia, and aversive pain behaviors with conditioned place preference (CPP) test. We found that the activation of this corticostriatal circuit gave rise to bilateral relief from peripheral nociceptive inputs. Activation of this circuit also provided important control for the aversive response to transient noxious stimulations. Hence, our results support a novel role for corticostriatal circuitry in acute pain regulation.

Dissociable corticostriatal circuits underlie goal-directed vs. cue-elicited habitual food seeking after satiation: evidence from a multimodal MRI study.

The present multimodal MRI study advances our understanding of the corticostriatal circuits underlying goal-directed vs. cue-driven, habitual food seeking. To this end, we employed a computerized Pavlovian-instrumental transfer paradigm. During the test phase, participants were free to perform learned instrumental responses (left and right key presses) for popcorn and Smarties outcomes. Importantly, prior to this test half of the participants had been sated on popcorn and the other half on Smarties - resulting in a reduced desirability of those outcomes. Furthermore, during a proportion of the test trials, food-associated Pavlovian cues were presented in the background. In line with previous studies, we found that participants were able to perform in a goal-directed manner in the absence of Pavlovian cues, meaning that specific satiation selectively reduced responding for that food. However, presentation of Pavlovian cues biased choice toward the associated food reward regardless of satiation. Functional MRI analyses revealed that, in the absence of Pavlovian cues, posterior ventromedial prefrontal cortex tracked outcome value. In contrast, during cued trials, the BOLD signal in the posterior putamen differentiated between responses compatible and incompatible with the cue-associated outcome. Furthermore, we identified a region in ventral amygdala showing relatively strong functional connectivity with posterior putamen during the cued trials. Structural MRI analyses provided converging evidence for the involvement of corticostriatal circuits: diffusion tensor imaging data revealed that connectivity of caudate-seeded white-matter tracts to the ventromedial prefrontal cortex predicted responding for still-valuable outcomes; and gray matter integrity in the premotor cortex predicted individual Pavlovian cueing effects.

Alcohol induces input-specific aberrant synaptic plasticity in the rat dorsomedial striatum

Accumulated evidence suggests that the dorsomedial striatum (DMS) of the basal ganglia plays an essential role in pathological excessive alcohol consumption. The DMS receives multiple glutamatergic inputs. However, whether and how alcohol consumption distinctly affects these excitatory afferents to the DMS remains unknown. Here, we used optogenetics to selectively activate the rat medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) inputs in DMS slices, and measured the effects of alcohol consumption on glutamatergic transmission in these corticostriatal and amygdalostriatal circuits. We found that excessive alcohol consumption increased AMPA receptor- and NMDA receptor (NMDAR)-mediated neurotransmission, as well as the GluN2B/NMDAR ratio, at the corticostriatal input to the DMS. The probability of glutamate release was increased selectively at the amygdalostriatal input. Interestingly, we discovered that paired activation of the mPFC and BLA inputs using dual-channel optogenetics induced robust long-term potentiation (LTP) of the corticostriatal input to the DMS. Taken together, these results indicate that excessive alcohol consumption potentiates glutamatergic transmission via a postsynaptic mechanism for the corticostriatal input and via a presynaptic mechanism for the amygdalostriatal input. These changes may in turn contribute to pathological alcohol consumption.

Cortico-Striatal-Thalamic Loop Circuits of the Orbitofrontal Cortex: Promising Therapeutic Targets in Psychiatric Illness.

Corticostriatal circuits through the orbitofrontal cortex (OFC) play key roles in complex human behaviors such as evaluation, affect regulation and reward-based decision-making. Importantly, the medial and lateral OFC (mOFC and lOFC) circuits have functionally and anatomically distinct connectivity profiles which differentially contribute to the various aspects of goal-directed behavior. OFC corticostriatal circuits have been consistently implicated across a wide range of psychiatric disorders, including major depressive disorder (MDD), obsessive compulsive disorder (OCD), and substance use disorders (SUDs). Furthermore, psychiatric disorders related to OFC corticostriatal dysfunction can be addressed via conventional and novel neurostimulatory techniques, including deep brain stimulation (DBS), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). Such techniques elicit changes in OFC corticostriatal activity, resulting in changes in clinical symptomatology. Here we review the available literature regarding how disturbances in mOFC and lOFC corticostriatal functioning may lead to psychiatric symptomatology in the aforementioned disorders, and how psychiatric treatments may exert their therapeutic effect by rectifying abnormal OFC corticostriatal activity. First, we review the role of OFC corticostriatal circuits in reward-guided learning, decision-making, affect regulation and reappraisal. Second, we discuss the role of OFC corticostriatal circuit dysfunction across a wide range of psychiatric disorders. Third, we review available evidence that the therapeutic mechanisms of various neuromodulation techniques may directly involve rectifying abnormal activity in mOFC and lOFC corticostriatal circuits. Finally, we examine the potential of future applications of therapeutic brain stimulation targeted at OFC circuitry; specifically, the role of OFC brain stimulation in the growing field of individually-tailored therapies and personalized medicine in psychiatry.

Reminiscing about positive memories buffers acute stress responses.

Recalling happy memories elicits positive feelings and enhances one's wellbeing, suggesting a potential adaptive function in using this strategy for coping with stress. In two studies, we explored whether recalling autobiographical memories that have a positive content - i.e., remembering the good times - can dampen the hypothalamic-pituitary-adrenal (HPA) axis stress response. Participants underwent an acute stressor or control task followed by autobiographical memory recollection (of only positive or neutral valence). Across both studies, recalling positive, but not neutral, memories resulted in a dampened cortisol rise and reduced negative affect. Further, individuals with greater self-reported resiliency showed enhanced mood, despite stress exposure. During positive reminiscence, we observed engagement of corticostriatal circuits previously implicated in reward-processing and emotion regulation, and stronger connectivity between ventrolateral and dorsolateral prefrontal cortex as a function of positivity. These findings highlight the restorative and protective function of self-generated positive emotions via memory recall in the face of stress.

Motor deficits and beta oscillations are dissociable in an alpha‐synuclein model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterised by progressive motor symptoms resulting from chronic loss of dopaminergic neurons in the nigrostriatal pathway. The over expression of the protein alpha-synuclein in the substantia nigra has been used to induce progressive dopaminergic neuronal loss and to reproduce key histopathological and temporal features of PD in animal models. However, the neurophysiological aspects of the alpha-synuclein PD model have been poorly characterised. Hereby, we performed chronic invivo electrophysiological recordings in the corticostriatal circuit of rats injected with viral vector to over express alpha-synuclein in the right substantia nigra. Our model, previously shown to exhibit mild motor deficits, presented moderate dopaminergic cell loss but did not present prominent local field potential oscillations in the beta frequency range (11-30Hz), considered a hallmark of PD, during the 9weeks after onset of alpha-synuclein over expression. Spinal cord stimulation, a potential PD symptomatic therapy, was applied regularly from sixth to ninth week after alpha-synuclein over expression onset and had an inhibitory effect on the firing rate of corticostriatal neurons in both control and alpha-synuclein hemispheres. Dopamine synthesis inhibition at the end of the experiment resulted in severe parkinsonian symptoms such as akinesia and increased beta and high-frequency (>90Hz) oscillations. These results suggest that the alpha-synuclein PD model with moderate level of dopaminergic depletion does not reproduce the prominent corticostriatal beta oscillatory activity associated to parkinsonian conditions.

Subthalamic Nucleus Deep Brain Stimulation Alters Prefrontal Correlates of Emotion Induction

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor symptoms in advanced Parkinson's disease. STN DBS may also affect emotion, possibly by impacting a parallel limbic cortico-striatal circuit. The objective of this study was to investigate changes in prefrontal cortical activity related to DBS during an emotion induction task. We used near infrared spectroscopy to monitor prefrontal cortex hemodynamic changes during an emotion induction task. Seven DBS patients were tested sequentially in the stimulation-on and stimulation-off states while on dopaminergic medication. Patients watched a series of positive, negative, and neutral videos. The general linear model was used to compare prefrontal oxygenated hemoglobin concentration between DBS states. Deep brain stimulation was correlated with prefrontal oxygenated hemoglobin changes relative to the stimulation off state in response to both positive and negative videos. These changes were specific to emotional stimuli and were not seen during neutral stimuli. These results suggest that STN stimulation influences the prefrontal cortical representation of positive and negative emotion induction.

Impaired dual tasking in Parkinson's disease is associated with reduced focusing of cortico-striatal activity.

See Bell et al. (doi:10.1093/awx063) for a scientific commentary on this article. Impaired dual tasking, namely the inability to concurrently perform a cognitive and a motor task (e.g. 'stops walking while talking'), is a largely unexplained and frequent symptom of Parkinson's disease. Here we consider two circuit-level accounts of how striatal dopamine depletion might lead to impaired dual tasking in patients with Parkinson's disease. First, the loss of segregation between striatal territories induced by dopamine depletion may lead to dysfunctional overlaps between the motor and cognitive processes usually implemented in parallel cortico-striatal circuits. Second, the known dorso-posterior to ventro-anterior gradient of dopamine depletion in patients with Parkinson's disease may cause a funnelling of motor and cognitive processes into the relatively spared ventro-anterior putamen, causing a neural bottleneck. Using functional magnetic resonance imaging, we measured brain activity in 19 patients with Parkinson's disease and 26 control subjects during performance of a motor task (auditory-cued ankle movements), a cognitive task (implementing a switch-stay rule), and both tasks simultaneously (dual task). The distribution of task-related activity respected the known segregation between motor and cognitive territories of the putamen in both groups, with motor-related responses in the dorso-posterior putamen and task switch-related responses in the ventro-anterior putamen. During dual task performance, patients made more motor and cognitive errors than control subjects. They recruited a striatal territory (ventro-posterior putamen) not engaged during either the cognitive or the motor task, nor used by controls. Relatively higher ventro-posterior putamen activity in controls was associated with worse dual task performance. These observations suggest that dual task impairments in Parkinson's disease are related to reduced spatial focusing of striatal activity. This pattern of striatal activity may be explained by a loss of functional segregation between neighbouring striatal territories that occurs specifically in a dual task context.

The Impact of Short and Long-Term Exercise on the Expression of Arc and AMPARs During Evolution of the 6-Hydroxy-Dopamine Animal Model of Parkinson's Disease.

The loss of nigral dopaminergic neurons typical in Parkinson's disease (PD) is responsible for hyperexcitability of medium spiny neurons resulting in abnormal corticostriatal glutamatergic synaptic drive. Considering the neuroprotective effect of exercise, the changes promoted by exercise on AMPA-type glutamate receptors (AMPARs), and the role of activity-regulated cytoskeleton-associated protein (Arc) in the AMPARs trafficking, we studied the impact of short and long-term treadmill exercise during evolution of the unilateral 6-hydroxy-dopamine (6-OHDA) animal model of PD. Wistar rats were divided into sedentary and exercised groups, with and without lesion by 6-OHDA and followed up to 4months. The exercised groups were subjected to a moderate treadmill exercise 3×/week. We measured the proteins tyrosine hydroxylase (TH), Arc, GluA1, and GluA2/3 in the striatum, substantia nigra, and motor cortex. Our results showed a higher reduction of TH expression in all sedentary groups when compared to all exercised groups in striatum and substantia nigra. In general, larger changes occurred in the striatum in the first and third months after training. After 1month of exercise, there was significant increase of GluA2/3 with concomitant reduction of GluA1 and Arc. As a balanced system, these changes were reversed in the third month, showing an increase of Arc and GluA1 and decrease of GluA2/3. Similar results for GluAs and Arc were observed in the motor cortex of the exercised animals. These modifications may be relevant for corticostriatal circuits in PD, since the exercise-dependent plasticity can modulate GluAs expression and maybe neuronal excitability.

Elevated nucleus accumbens structural connectivity associated with proneness to hypomania: a reward hypersensitivity perspective.

The Reward Hypersensitivity Model of bipolar disorder argues that hypersensitivity to reward-relevant cues characterizes risk for hypo/mania. This hypersensitivity leads to increased goal-directed motivation during reward-relevant life events that, in the extreme, is reflected in hypo/manic symptoms. In line with this perspective, individuals with bipolar disorder display elevated activation in a cortico-striatal reward circuit including the nucleus accumbens (NAcc) and medial orbitofrontal cortex (mOFC). To date, however, research on reward-related neural circuitry underlying bipolar symptoms focuses on syndromal bipolar disorder (bipolar I, bipolar II), and typically examines neural regions in isolation of each other. Accordingly, this study examines the relationship between subsyndromal hypo/mania proneness and structural connectivity between the NAcc and both the mOFC and amygdala in a medication-free sample. Fifty-four community participants completed diffusion-weighted imaging and a self-report measure of bipolar risk (hypo/mania proneness). As predicted, elevated structural connectivity between the NAcc and both the mOFC and amygdala were associated with elevated hypo/mania proneness. This relationship was specific to NAcc-centered reward connectivity, as there was no relationship between hypo/mania proneness and either whole-brain or cortico-amygdala connectivity. Results suggest that reward-relevant tractography from cortical (mOFC) and subcortical (amygdala) regions amplify NAcc-centered reward processing in bipolar risk.

Connectivity-based parcellation reveals distinct cortico-striatal connectivity fingerprints in Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) has been associated with abnormal synaptic development causing a breakdown in functional connectivity. However, when measured at the macro scale using resting state fMRI, these alterations are subtle and often difficult to detect due to the large heterogeneity of the pathology. Recently, we outlined a novel approach for generating robust biomarkers of resting state functional magnetic resonance imaging (RS-fMRI) using connectivity based parcellation of gross morphological structures to improve single-subject reproducibility and generate more robust connectivity fingerprints. Here we apply this novel approach to investigating the organization and connectivity strength of the cortico-striatal system in a large sample of ASD individuals and typically developed (TD) controls (N=130 per group). Our results showed differences in the parcellation of the striatum in ASD. Specifically, the putamen was found to be one single structure in ASD, whereas this was split into anterior and posterior segments in an age, IQ, and head movement matched TD group. An analysis of the connectivity fingerprints revealed that the group differences in clustering were driven by differential connectivity between striatum and the supplementary motor area, posterior cingulate cortex, and posterior insula. Our approach for analysing RS-fMRI in clinical populations has provided clear evidence that cortico-striatal circuits are organized differently in ASD. Based on previous task-based segmentations of the striatum, we believe that the anterior putamen cluster present in TD, but not in ASD, likely contributes to social and language processes.

OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency

Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.

Presynaptic Ethanol Actions: Potential Roles in Ethanol Seeking.

Ethanol produces intoxication through actions on numerous molecular and cellular targets. Adaptations involving these and other targets contribute to chronic drug actions that underlie continued and problematic drinking. Among the mechanisms involved in these ethanol actions are alterations in presynaptic mechanisms of synaptic transmission, including presynaptic protein function and excitation-secretion coupling. At synapses in the central nervous system (CNS), excitation-secretion coupling involves ion channel activation followed by vesicle fusion and neurotransmitter release. These mechanisms are altered by presynaptic neurotransmitter receptors and prominently by G protein-coupled receptors (GPCRs). Studies over the last 20-25years have revealed that acute ethanol exposure alters neurotransmitter secretion, with especially robust effects on synapses that use the neurotransmitter gamma-aminobutyric acid (GABA). Intracellular signaling pathways involving second messengers such as cyclic AMP and calcium are implicated in these acute ethanol actions. Ethanol-induced release of neuropeptides and small molecule neurotransmitters that act on presynaptic GPCRs also contribute to presynaptic potentiation at synapses in the amygdala and hippocampus and inhibition of GABA release in the striatum. Prolonged exposure to ethanol alters neurotransmitter release at many CNS GABAergic and glutamatergic synapses, and changes in GPCR function are implicated in many of these neuroadaptations. These presynaptic neuroadaptations appear to involve compensation for acute drug effects at some synapses, but "allostatic" effects that result in long-term resetting of synaptic efficacy occur at others. Current investigations are determining how presynaptic neuroadaptations contribute to behavioral changes at different stages of alcohol drinking, with increasing focus on circuit adaptations underlying these behaviors. This chapter will discuss the acute and chronic presynaptic effects of ethanol in the CNS, as well as some of the consequences of these effects in amygdala and corticostriatal circuits that are related to excessive seeking/drinking and ethanol abuse.

Pathophysiology of refractory obsessive-compulsive disorder: A study of visual search combined with overactive performance monitoring.

Based on both functional and structural studies of excessive activity, fronto-striatal-thalamic-cortical and cortico-striatal circuits have been hypothesized to underlie the pathophysiology of obsessive-compulsive disorder (OCD). However, the neurobiological underpinnings of OCD refractory to medication and therapy remain controversial. This study aimed to evaluate neuroanatomical abnormalities of the whole brain and to evaluate visual processing in patients with refractory OCD.This study was comprised of 2 experiments. The neuroanatomical abnormalities of the whole brain were evaluated using a visual search in combination with overactive performance monitoring (Experiment I), and visual processing was evaluated using event-related potentials recorded from subjects during performance of a visual search task. We also examined the amplitudes and latency of the error-related negativity (ERN) using a modified flanker task (Experiment II). Standard low-resolution electromagnetic tomography analysis was applied to determine the special areas.Patients with refractory OCD had a significantly greater number of saccades and prolonged latencies relative to the healthy controls. Scalp map topography confirmed that visual cognitive and executive dysfunction was localized to the fusiform gyrus. Furthermore, we found that during a modified flanker task, ERNs had a greater amplitude and a prolonged latency relative to those of the healthy controls. Further data analysis suggested that cognitive dysfunction and compulsive behavior in OCD patients were linked to abnormalities within the dorsolateral prefrontal cortex (DLPFC).We identified abnormal activities within the fusiform gyrus and DLPFC that likely play important roles in the pathophysiology of OCD.

Changes in functional organization and white matter integrity in the connectome in Parkinson's disease.

Parkinson's disease (PD) leads to dysfunction in multiple cortico-striatal circuits. The neurodegeneration has also been associated with impaired white matter integrity. This structural and functional “disconnection” in PD needs further characterization.We investigated the structural and functional organization of the PD whole brain connectome consisting of 200 nodes using diffusion tensor imaging and resting-state functional MRI, respectively. Data from 20 non-demented PD patients on dopaminergic medication and 20 matched controls were analyzed using graph theory-based methods. We focused on node strength, clustering coefficient, and local efficiency as measures of local network properties; and network modularity as a measure of information flow.PD patients showed reduced white matter connectivity in frontoparietal-striatal nodes compared to controls, but no change in modular organization of the white matter tracts. PD group also showed reduction in functional local network metrics in many nodes distributed across the connectome. There was also decreased functional modularity in the core cognitive networks including the default mode and dorsal attention networks, and sensorimotor network, as well as a lack of modular distinction in the orbitofrontal and basal ganglia nodes in the PD group compared to controls.Our results suggest that despite subtle white matter connectivity changes, the overall structural organization of the PD connectome remains robust at relatively early disease stages. However, there is a breakdown in the functional modular organization of the PD connectome.

Dysregulation of Corticostriatal Connectivity in Huntington's Disease: ARole for Dopamine Modulation.

Aberrant communication between striatum, the main information processing unit of the basal ganglia, and cerebral cortex plays a critical role in the emergence of Huntington’s disease (HD), a fatal monogenetic condition that typically strikes in the prime of life. Although both striatum and cortex undergo substantial cell loss over the course of HD, corticostriatal circuits become dysfunctional long before neurons die. Understanding the dysfunction is key to developing effective strategies for treating a progressively worsening triad of motor, cognitive, and psychiatric symptoms. Cortical output neurons drive striatal activity through the release of glutamate, an excitatory amino acid. Striatal outputs, in turn, release γ-amino butyric acid (GABA) and exert inhibitory control over downstream basal ganglia targets. Ample evidence from transgenic rodent models points to dysregulation of corticostriatal glutamate transmission along with corresponding changes in striatal GABA release as underlying factors in the HD behavioral phenotype. Another contributor is dysregulation of dopamine (DA), a modulator of both glutamate and GABA transmission. In fact, pharmacological manipulation of DA is the only currently available treatment for HD symptoms. Here, we review data from animal models and human patients to evaluate the role of DA in HD, including DA interactions with glutamate and GABA within the context of dysfunctional corticostriatal circuitry.