Basal Ganglia-thalamocortical Circuitry Research Articles

Increased functional connectivity of thalamic subdivisions in patients with Parkinson's disease.

Parkinson’s disease (PD) affects 2–3% of the population over the age of 65 with loss of dopaminergic neurons in the substantia nigra impacting the functioning of basal ganglia-thalamocortical circuits. The precise role played by the thalamus is unknown, despite its critical role in the functioning of the cerebral cortex, and the abnormal neuronal activity of the structure in PD. Our objective was to more clearly elucidate how functional connectivity and morphology of the thalamus are impacted in PD (n = 32) compared to Controls (n = 20). To investigate functional connectivity of the thalamus we subdivided the structure into two important regions-of-interest, the first with putative connections to the motor cortices and the second with putative connections to prefrontal cortices. We then investigated potential differences in the size and shape of the thalamus in PD, and how morphology and functional connectivity relate to clinical variables. Our data demonstrate that PD is associated with increases in functional connectivity between motor subdivisions of the thalamus and the supplementary motor area, and between prefrontal thalamic subdivisions and nuclei of the basal ganglia, anterior and dorsolateral prefrontal cortices, as well as the anterior and paracingulate gyri. These results suggest that PD is associated with increased functional connectivity of subdivisions of the thalamus which may be indicative alterations to basal ganglia-thalamocortical circuitry.

Dynamics of human subthalamic neuron phase-locking to motor and sensory cortical oscillations during movement.

Coupled oscillatory activity recorded between sensorimotor regions of the basal ganglia-thalamocortical loop is thought to reflect information transfer relevant to movement. A neuronal firing-rate model of basal ganglia-thalamocortical circuitry, however, has dominated thinking about basal ganglia function for the past three decades, without knowledge of the relationship between basal ganglia single neuron firing and cortical population activity during movement itself. We recorded activity from 34 subthalamic nucleus (STN) neurons, simultaneously with cortical local field potentials and motor output, in 11 subjects with Parkinson's disease (PD) undergoing awake deep brain stimulator lead placement. STN firing demonstrated phase synchronization to both low- and high-beta-frequency cortical oscillations, and to the amplitude envelope of gamma oscillations, in motor cortex. We found that during movement, the magnitude of this synchronization was dynamically modulated in a phase-frequency-specific manner. Importantly, we found that phase synchronization was not correlated with changes in neuronal firing rate. Furthermore, we found that these relationships were not exclusive to motor cortex, because STN firing also demonstrated phase synchronization to both premotor and sensory cortex. The data indicate that models of basal ganglia function ultimately will need to account for the activity of populations of STN neurons that are bound in distinct functional networks with both motor and sensory cortices and code for movement parameters independent of changes in firing rate.NEW & NOTEWORTHY Current models of basal ganglia-thalamocortical networks do not adequately explain simple motor functions, let alone dysfunction in movement disorders. Our findings provide data that inform models of human basal ganglia function by demonstrating how movement is encoded by networks of subthalamic nucleus (STN) neurons via dynamic phase synchronization with cortex. The data also demonstrate, for the first time in humans, a mechanism through which the premotor and sensory cortices are functionally connected to the STN.

Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys.

Conventional anti-Parkinsonian dopamine replacement therapy is often complicated by side effects that limit the use of these medications. There is a continuing need to develop nondopaminergic approaches to treat Parkinsonism. One such approach is to use medications that normalize dopamine depletion-related firing abnormalities in the basal ganglia-thalamocortical circuitry. In this study, we assessed the potential of a specific T-type calcium channel blocker (ML218) to eliminate pathologic burst patterns of firing in the basal ganglia-receiving territory of the motor thalamus in Parkinsonian monkeys. We also carried out an anatomical study, demonstrating that the immunoreactivity for T-type calcium channels is strongly expressed in the motor thalamus in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. At the electron microscopic level, dendrites accounted for >90% of all tissue elements that were immunoreactive for voltage-gated calcium channel, type 3.2-containing T-type calcium channels in normal and Parkinsonian monkeys. Subsequent in vivo electrophysiologic studies in awake MPTP-treated Parkinsonian monkeys demonstrated that intrathalamic microinjections of ML218 (0.5 μl of a 2.5-mM solution, injected at 0.1-0.2 μl/min) partially normalized the thalamic activity by reducing the proportion of rebound bursts and increasing the proportion of spikes in non-rebound bursts. The drug also attenuated oscillatory activity in the 3-13-Hz frequency range and increased gamma frequency oscillations. However, ML218 did not normalize Parkinsonism-related changes in firing rates and oscillatory activity in the beta frequency range. Whereas the described changes are promising, a more complete assessment of the cellular and behavioral effects of ML218 (or similar drugs) is needed for a full appraisal of their anti-Parkinsonian potential.

Abnormal Striatal Dopaminergic Neurotransmission during Rest and Task Production in Spasmodic Dysphonia

Spasmodic dysphonia is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The pathophysiology of spasmodic dysphonia is thought to involve structural and functional abnormalities in the basal ganglia-thalamo-cortical circuitry; however, neurochemical correlates underpinning these abnormalities as well as their relations to spasmodic dysphonia symptoms remain unknown. We used positron emission tomography with the radioligand [(11)C]raclopride (RAC) to study striatal dopaminergic neurotransmission at the resting state and during production of symptomatic sentences and asymptomatic finger tapping in spasmodic dysphonia patients. We found that patients, compared to healthy controls, had bilaterally decreased RAC binding potential (BP) to striatal dopamine D2/D3 receptors on average by 29.2%, which was associated with decreased RAC displacement (RAC ΔBP) in the left striatum during symptomatic speaking (group average difference 10.2%), but increased RAC ΔBP in the bilateral striatum during asymptomatic tapping (group average difference 10.1%). Patients with more severe voice symptoms and subclinically longer reaction time to initiate the tapping sequence had greater RAC ΔBP measures, while longer duration of spasmodic dysphonia was associated with a decrease in task-induced RAC ΔBP. Decreased dopaminergic transmission during symptomatic speech production may represent a disorder-specific pathophysiological trait involved in symptom generation, whereas increased dopaminergic function during unaffected task performance may be explained by a compensatory adaptation of the nigrostriatal dopaminergic system possibly due to decreased striatal D2/D3 receptor availability. These changes can be linked to the clinical and subclinical features of spasmodic dysphonia and may represent the neurochemical basis of basal ganglia alterations in this disorder.

Enhanced reward-facilitating effects of d-amphetamine in rats in the quinpirole model of obsessive–compulsive disorder

The underlying neurobiology of addictive or repetitive behaviours, such as obsessive-compulsive disorder (OCD), involves dopaminergic dysregulation. While addictive behaviour depends strongly on mesolimbocortical dopaminergic responses, repetitive behaviours have been associated with dopaminergic dysregulation in the basal ganglia-thalamo-cortical circuitry. The present study investigates differences in brain stimulation reward in rats with quinpirole-induced compulsive checking behaviour, in order to examine if deficits in reward processing are also relevant for OCD. Rats were tested in the intracranial self-stimulation (ICSS) paradigm, which targets reward-related responses. After phenotype induction, animals were implanted with a monopolar stimulation electrode in the left medial forebrain bundle and trained to press a lever to self-administer electric stimulation of varying frequency. The curve-shift method was used to assess the reward-facilitating effects of d-amphetamine and the reward-attenuating effects of haloperidol (a D(2) antagonist). Thresholds for ICSS were estimated before and after drug/saline injection. The reward-facilitating effects of d-amphetamine were enhanced in quinpirole-treated rats in comparison to controls. This finding suggests that chronic quinpirole-treatment induces changes within the reward circuitry relevant for compulsive behaviour in the rat.

Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors

The basal ganglia-thalamocortical circuitry plays a central role in selecting actions that achieve reward-seeking outcomes and avoid aversive ones. Inputs of the nucleus accumbens (NAc) in this circuitry are transmitted through two parallel pathways: the striatonigral direct pathway and the striatopallidal indirect pathway. In the NAc, dopaminergic (DA) modulation of the direct and the indirect pathways is critical in reward-based and aversive learning and cocaine addiction. To explore how DA modulation regulates the associative learning behavior, we developed an asymmetric reversible neurotransmission-blocking technique in which transmission of each pathway was unilaterally blocked by transmission-blocking tetanus toxin and the transmission on the intact side was pharmacologically manipulated by local infusion of a receptor-specific agonist or antagonist. This approach revealed that the activation of D1 receptors and the inactivation of D2 receptors postsynaptically control reward learning/cocaine addiction and aversive learning in a direct pathway-specific and indirect pathway-specific manner, respectively. Furthermore, this study demonstrated that aversive learning is elicited by elaborate actions of NMDA receptors, adenosine A2a receptors, and endocannabinoid CB1 receptors, which serve as key neurotransmitter receptors in inducing long-term potentiation in the indirect pathway. Thus, reward and aversive learning is regulated by pathway-specific neural plasticity via selective transmitter receptors in the NAc circuit.

An adult patient with mucolipidosis III alpha/beta presenting with parkinsonism

A 36-year-old man with mucolipidosis type III alpha/beta presented with hypoactivity, mutism, muscle rigidity, and involuntary movement. The involuntary movement was interpreted to be tremor at rest on physical examination and surface electromyography, which revealed mostly asynchronous contractions at 3–4Hz of the biceps and triceps brachii muscles. All these symptoms were consistent with abnormalities of parkinsonism, which is caused by an insult to the basal ganglia that permeates the entire basal ganglia-thalamocortical circuitry. This report is the first to present a case of mucolipidosis type III alpha/beta in association with parkinsonism.

Somatomotor mu rhythm amplitude correlates with rigidity during deep brain stimulation in Parkinsonian patients

ObjectiveParkinsonian patients have abnormal oscillatory activity within the basal ganglia-thalamocortical circuitry. Particularly, excessive beta band oscillations are thought to be associated with akinesia. We studied whether cortical spontaneous activity is modified by deep brain stimulation (DBS) in advanced Parkinson’s disease and if the modifications are related to the clinical symptoms. MethodsWe studied the effects of bilateral electrical stimulation of subthalamic nucleus (STN) on cortical spontaneous activity by magnetoencephalography (MEG) in 11 Parkinsonian patients. The artifacts produced by DBS were suppressed by tSSS algorithm. ResultsDuring DBS, UPDRS (Unified Parkinson’s Disease Rating Scale) rigidity scores correlated with 6–10Hz and 12–20Hz somatomotor source strengths when eyes were open. When DBS was off UPDRS action tremor scores correlated with pericentral 6–10Hz and 21–30Hz and occipital alpha source strengths when eyes open.Occipital alpha strength decreased during DBS when eyes closed. The peak frequency of occipital alpha rhythm correlated negatively with total UPDRS motor scores and with rigidity subscores, when eyes closed. ConclusionSTN DBS modulates brain oscillations both in alpha and beta bands and these oscillations reflect the clinical condition during DBS. SignificanceMEG combined with an appropriate artifact rejection method enables studies of DBS effects in Parkinson’s disease and presumably also in the other emerging DBS indications.

The influence of dopaminergic dysregulations on brain stimulation reward

Addictive as well as repetitive behaviours like in obsessive compulsive disorder (OCD) were identified to involve dopaminergic dysregulations as major neuropathologic underpinnings. While addictive behaviour depends on dopaminergic responses in the forebrain, repetitive behaviours were associated with dopaminergic dysregulations in the basal ganglia–thalamo–cortical circuitry. The present study investigates differences in brain stimulation reward in rats with genetically or pharmacologically induced dopaminergic dysregulations. DAT-overexpressing animals and rats with quinpirole induced checking behaviour were tested in an intracranial self-stimulation (ICSS) paradigm targeting reward-related forebrain responses. The experimental animals were implanted with a monopolar electrode in the left medial forebrain bundle and trained to press a lever to self-deliver electric stimulation of varying frequency. The curve-shift method was used to asses reward facilitating effects of D-amphetamine and effects of haloperidol (a D2 antagonist). After ICSS thresholds stabilized, rats received i.p. injections of vehicle, 0.5 mg/kg (high dose), 0.1 mg/kg (low dose) D-amphetamine and 0.05 mg/kg (high dose), 0.01 mg/kg (low dose) haloperidol. Thresholds for ICSS were measured before and after injection. We present the successful application of an ICSS paradigm which indicates dysregulations within different dopaminergic circuitries to be relevant for reward-related and repetitive behaviour.

External Globus Pallidus Stimulation Modulates Brain Connectivity in Huntington's Disease

Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntington's disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model.

Update on models of basal ganglia function and dysfunction

Circuit models of basal ganglia function and dysfunction have undergone significant changes over time. The previous view that the basal ganglia are centers in which massive convergence of cortical information occurred has now been replaced by a view in which these structures process information in a highly specific manner, participating in anatomical and functional modules that also involve cortex and thalamus. In addition, much has been learned about the intrinsic connections of the basal ganglia. While the basal ganglia-thalamocortical circuitry was originally seen almost exclusively in its relationship to the control of movement, these structures are now viewed as essential for higher level behavioral control, for instance in the regulation of habit learning or action selection. Probably the greatest benefit of these models has been that they have motivated a wealth of studies of the pathophysiology of movement disorders of basal ganglia origin, such as Parkinson's disease. Such studies, in turn, have helped to reshape the existing circuit models. In this paper we review these fascinating changes of our appreciation of the basal ganglia circuitry, and comment on the current state of our knowledge in this field.

Parkinsonism: evolving pathophysiologic concepts

The link between the hallmark pathology in Parkinson's disease, i.e., dopamine loss in the basal ganglia, and the behavioral signs of parkinsonism, remains mysterious. This presentation will review our knowledge of system-level changes in brain activity in parkinsonism. The most commonly discussed models of the changes in brain activity that lead to parkinsonism were developed twenty years ago, and were strongly based on anatomical considerations and changes in the firing rates of basal ganglia neurons in dopamine-depleted animals. The most important change noted was an increase in the activity of neurons in the basal ganglia output nuclei. A simple anatomic argument was used to link these changes to the striatal loss of dopamine. Since that time, a plethora of new findings has emerged, indicating that the changes in firing rate may be less important than changes in other aspects of basal ganglia activity. Changes in oscillatory activity in the beta- and gamma-bands of frequencies have been observed to be important, as have changes in non-linear firing characteristics such as increases in the bursting activity of individual basal ganglia neurons. Studies in animals and humans have also shown that the ensemble activity of basal ganglia neurons appears to be altered in parkinsonism, with the emergence of pathological levels of synchronization between neighboring neurons. Perhaps most importantly, parkinsonism has emerged as a circuit disorder in which the focal loss of dopamine in the basal ganglia has significant down-stream effects on the activity of other areas of the brain, specifically the thalamus, portions of the cortex, and the brainstem. Many questions in this field remain unanswered. The links between dopamine loss and the changes in firing patterns have not been identified, and the relationship between the electrical changes in the basal ganglia-thalamocortical circuitry and parkinsonian motor signs remains unclear. The significance of anatomical changes that are secondary to long-term dopamine loss, such as loss of the dendritic spines of striatal medium spiny neurons, and the role of non-dopaminergic or extra-basal ganglia pathology in parkinsonism also need to be elucidated. Addressing these questions will be essential for the development of more effective pharmacological and surgical strategies to treat parkinsonian patients.

Deep Brain Stimulation Improves Performance of Complex Instrumental Paradigms

Patients with Parkinson’s disease (PD) show deficits of motion behaviour and cognitive function, which were assessed with various instrumental paradigms. Objectives of the present trial were to investigate the effects of bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) on the performance of complex and simple movement series, on the execution of simple reaction time (SRT) paradigms following an acoustic or a visual stimulus, on scored motor symptoms and the interrelation of the various study parameters in PD patients. Motor symptoms, operation of complex movements, and the execution of SRT tasks significantly improved when the stimulator was switched on. Execution of simple movement series did not differ between the on and off conditions of the stimulator. Instrumental test results significantly correlated with scored motor symptoms in particular during the off condition. During the on state, significant correlations were found between the performance of complex motion sequences and the SRT outcomes. PD patients treated with DBS of the STN show better results for more complex instrumental paradigms with a higher need for cognitive effort during the on situation due to improvements in motor performance, function of the basal ganglia-thalamocortical circuitry and cognitive function.

Basal Ganglia-Thalamocortical Circuitry Disruptions in Schizophrenia During Delayed Response Tasks

Schizophrenia is characterized by executive functioning deficits, presumably mediated by prefrontal cortex dysfunction. For example, schizophrenia participants show performance deficits on ocular motor delayed response (ODR) tasks, which require both inhibition and spatial working memory for correct performance. The present functional magnetic resonance imaging (fMRI) study compared neural activity of 14 schizophrenia and 14 normal participants while they performed ODR tasks. Schizophrenia participants generated: 1) more trials with anticipatory saccades (saccades made during the delay period), 2) memory saccades with longer latencies, and 3) memory saccades of decreased accuracy. Increased blood oxygenation level-dependent (BOLD) signal changes were observed in both groups in ocular motor circuitry (e.g., supplementary eye fields [SEF], lateral frontal eye fields [FEF], inferior parietal lobule [IPL], cuneus, and precuneus). The normal, but not the schizophrenia, group demonstrated BOLD signal changes in dorsolateral prefrontal regions (right Brodmann area [BA] 9 and bilateral BA 10), medial FEF, insula, thalamus, and basal ganglia. Correlations between percentage of anticipatory saccade trials and BOLD signal changes were more similar between groups for subcortical regions and less similar for cortical regions. These results suggest that executive functioning deficits in schizophrenia may be associated with dysfunction of the basal ganglia-thalamocortical circuitry, evidenced by decreased prefrontal cortex, basal ganglia, and thalamus activity in the schizophrenia group during ODR task performance.

The Role of Ventral Frontostriatal Circuitry in Reward-Based Learning in Humans

This study examined changes in behavior and neural activity with reward learning. Using an event-related functional magnetic resonance imaging paradigm, we show that the nucleus accumbens, thalamus, and orbital frontal cortex are each sensitive to reward magnitude, with the accumbens showing the greatest discrimination between reward values. Mean reaction times were significantly faster to cues predicting the greatest reward and slower to cues predicting the smallest reward. This behavioral change over the course of the experiment was paralleled by a shift in peak in accumbens activity from anticipation of the reward (immediately after the response), to the cue predicting the reward. The orbitofrontal and thalamic regions peaked in anticipation of the reward throughout the experiment. Our findings suggest discrete functions of regions within basal ganglia thalamocortical circuitry in adjusting behavior to maximize reward.

Firing rates of pallidal neurons are similar in Huntington’s and Parkinson’s disease patients

According to the now classical basal ganglia-thalamocortical circuitry model, the chorea of Huntington's disease (HD) and the hypokinesia in Parkinson's disease (PD) are explained by a decrease in the inhibitory output (reduced firing rates) from the globus pallidus internus (GPi) in HD and increased output in PD. Differences between firing patterns might also be a factor contributing to the different symptoms, however. To test the predictions of the model we examined neuronal firing rates and patterns in two HD patients and 14 PD patients. Single-cell, microelectrode recordings were obtained from awake patients undergoing stereotactic surgery for implantation of deep brain stimulating (DBS) electrodes in the GPi. The mean neuronal firing rate in the GPi of HD patients was 81.8+/-4.3 Hz (mean+/-SEM), which was not significantly different from that in PD patients (89.9+/-3.0 Hz). Firing pattern analyses using measurements of burst index, coefficient of variation, and percentage participation of spikes in bursts revealed, however, that GPi neurons in HD patients fired in a more regular pattern (fewer "bursts") than in PD patients. These results suggest that the rate-based model does not adequately explain the motor abnormalities present in the two HD patients studied. Furthermore, the findings did reveal a difference between firing patterns in the HD and PD groups, thereby supporting the role of altered firing patterns in the pathophysiology of these diseases.

Functional Neuroanatomy of Human Vocalization: An H215O PET Study

Vocalization in lower animals is associated with a well-described visceromotor call system centered on the mesencephalic periacqueductal grey matter (PAG), which is itself regulated by paramedian cortical structures. To determine the role this phylogenetically older system plays in human phonation, we contrasted voiced and unvoiced speech using positron emission tomography and then evaluated functional connectivity of regions that significantly differentiated these conditions. Vocalization was associated with increased and highly correlated activity within the midline structures--PAG and paramedian cortices--described in lower mammalian species. Concurrent activation and connectivity of neocortical and subcortical motor regions--medial and lateral premotor structures and elements of basal ganglia thalamocortical circuitry--suggest a mechanism by which this system may have come under an increasing degree of voluntary control in humans. Additionally, areas in the temporal lobe and cerebellum were selectively activated during voiced but not unvoiced speech. These regions are functionally coupled to both visceromotor and neocortical motor areas during production of voiced speech, suggesting they may play a central role in self-monitoring and feedback regulation of human phonation.

A Review of Rating Scales for Measuring Behavior Change Due to Frontal Systems Damage

To perform a critical review of scales designed to measure frontal behavior change. Changes in cognition due to frontal disease or damage have been well described, but noncognitive changes in behavior are often more deleterious functionally for frontal patients. The review concentrates on five behavior rating scales: the Behavior Rating Inventory of Executive Functions (BRIEF), the Dysexecutive Questionnaire (DEX), the Frontal Behavior Inventory (FBI), the Frontal Systems Behavior Scale (FrSBe), the Iowa Rating Scales of Personality Change (IRSPC), and the Neuropsychiatric Inventory (NPI). Other scales purporting to measure specific aspects of frontal functioning, but having less research support, are described briefly. The BRIEF and FrSBe have good reliability and large-scale norms. No norms are available for the other scales. The FrSBe and IRSPC have been shown to be valid in discriminating frontal from nonfrontal lesioned patients, but this has not been shown in the other scales. The FBI and NPI require trained raters, whereas the FrSBe, IRSPC, and BRIEF are administered to patients and/or family informants directly. The NPI and FBI are sensitive to certain changes in behavior attributed to frontal systems disruption but have been used primarily in dementia.

Impairment of reward-related learning by cholinergic cell ablation in the striatum

The striatum in the basal ganglia-thalamocortical circuitry is a key neural substrate that is implicated in motor balance and procedural learning. The projection neurons in the striatum are dynamically modulated by nigrostriatal dopaminergic input and intrastriatal cholinergic input. The role of intrastriatal acetylcholine (ACh) in learning behaviors, however, remains to be fully clarified. In this investigation, we examine the involvement of intrastriatal ACh in different categories of learning by selectively ablating the striatal cholinergic neurons with use of immunotoxin-mediated cell targeting. We show that selective ablation of cholinergic neurons in the striatum impairs procedural learning in the tone-cued T-maze memory task. Spatial delayed alternation in the T-maze learning test is also impaired by cholinergic cell elimination. In contrast, the deficit in striatal ACh transmission has no effect on motor learning in the rota-rod test or spatial learning in the Morris water-maze test or on contextual- and tone-cued conditioning fear responses. We also report that cholinergic cell elimination adaptively up-regulates nicotinic ACh receptors not only within the striatum but also in the cerebral cortex and substantia nigra. The present investigation indicates that cholinergic modulation in the local striatal circuit plays a pivotal role in regulation of neural circuitry involving reward-related procedural learning and working memory.

Subthalamic nucleus stimulation affects striato-anterior cingulate cortex circuit in a response conflict task: a PET study.

The subthalamic nucleus (STN) has generally been considered as a relay station within frontal-subcortical motor control circuitry. Little is known about the influence of the STN on cognitive networks. Clinical observations and studies in animals suggest that the STN participates in non-motor functions which can now be probed in Parkinson's disease patients with deep brain stimulation of the STN, allowing selective and reversible modulation of this nucleus. Using PET, we studied changes in regional cerebral blood flow (rCBF) associated with a response conflict task (Stroop task) in Parkinson's disease patients ON and OFF bilateral STN stimulation. The Stroop task requires subjects to name the font colour of colour words (e.g. "blue") printed in an incongruent colour ink (e.g. yellow). During STN stimulation, impaired task performance (prolonged reaction times) was associated with decreased activation in both right anterior cingulate cortex (ACC) and right ventral striatum. Concomitant increased activation in left angular gyrus indicative of ongoing word processing during stimulation is consistent with an impairment to inhibit habitual responses. ACC and ventral striatum are part of the ACC circuit associated with response conflict tasks. The decreased activation during STN stimulation in the ACC circuit, while response conflict processing worsened, provides direct evidence of STN modulating non-motor basal ganglia-thalamocortical circuitry. Impairment in ACC circuit function could account for the subtle negative effects on cognition induced by STN stimulation.