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1.  Contrasting roles for dopamine D1- and D2-receptor subtypes in the dorsomedial striatum but not the nucleus accumbens core during behavioral inhibition in the stop-signal task in rats 
Dopamine and dopamine-receptor function are often implicated in behavioral inhibition, and deficiencies within behavioral inhibition processes linked to ADHD, schizophrenia, obsessive-compulsive disorder and drug addiction. In the stop-signal task, which measures the speed of the process of inhibition (stop-signal reaction time, SSRT), psychostimulant-related improvement of SSRT in ADHD is linked with dopamine function. However, the precise nature of dopaminergic control over SSRT remains unclear.
This study examined region- and receptor-specific modulation of SSRT in the rat using direct infusions, into the dorsomedial striatum (DMStr) or nucleus accumbens core (NAcbC), of the dopamine D1-receptor (DRD1) antagonist SCH 23390 or dopamine D2-receptor (DRD2) antagonist sulpiride. DRD1 and DRD2 antagonists had contrasting effects on SSRT that were specific to the DMStr. SCH 23390 decreased SSRT with little effect on the go response. Conversely, sulpiride increased SSRT but also increased go-trial reaction time and reduced trial completion at the highest doses. These results suggest that DRD1 and DRD2 function within the DMStr, but not the NAcbC, may act to balance behavioral inhibition in a manner that is independent of behavioral activation.
PMCID: PMC3173842  PMID: 21593319
stopping; SSRT; caudate; ADHD; schizophrenia; OCD
2.  The subthalamic nucleus keeps you high on emotion: behavioral consequences of its inactivation 
The subthalamic nucleus (STN) belongs to the basal ganglia and is the current target for the surgical treatment of neurological and psychiatric disorders such as Parkinson’s Disease (PD) and obsessive compulsive disorders (OCD), but also a proposed site for the treatment of addiction. It is therefore very important to understand its functions in order to anticipate and prevent possible side-effects in the patients. Although the involvement of the STN is well documented in motor, cognitive and motivational processes, less is known regarding emotional processes. Here we have investigated the direct consequences of STN inactivation by excitotoxic lesions on emotional processing and reinforcement in the rat. We have used various behavioral procedures to assess affect for neutral, positive and negative reinforcers in STN lesioned rats. STN lesions reduced affective responses for positive (sweet solutions) and negative (electric foot shock, Lithium Chloride-induced sickness) reinforcers while they had no effect on responses for a more neutral reinforcer (novelty induced place preference (NIPP)). Furthermore, when given the choice between saccharine, a sweet but non caloric solution, and glucose, a more bland but caloric solution, in contrast to sham animals that preferred saccharine, STN lesioned animals preferred glucose over saccharine. Taken altogether these results reveal that STN plays a critical role in emotional processing. These results, in line with some clinical observations in PD patients subjected to STN surgery, suggest possible emotional side-effects of treatments targeting the STN. They also suggest that the increased motivation for sucrose previously reported cannot be due to increased pleasure, but could be responsible for the decreased motivation for cocaine reported after STN inactivation.
PMCID: PMC4257083  PMID: 25538581
basal ganglia; emotion; taste reactivity; conditioned fear; ultrasonic vocalization; conditioned place avoidance; novelty-induced place preference; glucose vs. saccharine choice
3.  Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption 
eNeuro  2016;3(5):ENEURO.0264-16.2016.
Visual Abstract
The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson’s disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene (Vglut2/Slc17a6) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist, and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system.
PMCID: PMC5041164  PMID: 27699212
dopamine; dynorphin; glutamate; rearing; reward; self-administration
4.  Basal ganglia dysfunction in OCD: subthalamic neuronal activity correlates with symptoms severity and predicts high-frequency stimulation efficacy 
Translational Psychiatry  2011;1(5):e5-.
Functional and connectivity changes in corticostriatal systems have been reported in the brains of patients with obsessive–compulsive disorder (OCD); however, the relationship between basal ganglia activity and OCD severity has never been adequately established. We recently showed that deep brain stimulation of the subthalamic nucleus (STN), a central basal ganglia nucleus, improves OCD. Here, single-unit subthalamic neuronal activity was analysed in 12 OCD patients, in relation to the severity of obsessions and compulsions and response to STN stimulation, and compared with that obtained in 12 patients with Parkinson's disease (PD). STN neurons in OCD patients had lower discharge frequency than those in PD patients, with a similar proportion of burst-type activity (69 vs 67%). Oscillatory activity was present in 46 and 68% of neurons in OCD and PD patients, respectively, predominantly in the low-frequency band (1–8 Hz). In OCD patients, the bursty and oscillatory subthalamic neuronal activity was mainly located in the associative–limbic part. Both OCD severity and clinical improvement following STN stimulation were related to the STN neuronal activity. In patients with the most severe OCD, STN neurons exhibited bursts with shorter duration and interburst interval, but higher intraburst frequency, and more oscillations in the low-frequency bands. In patients with best clinical outcome with STN stimulation, STN neurons displayed higher mean discharge, burst and intraburst frequencies, and lower interburst interval. These findings are consistent with the hypothesis of a dysfunction in the associative–limbic subdivision of the basal ganglia circuitry in OCD's pathophysiology.
PMCID: PMC3309476  PMID: 22832400
subthalamic nucleus; neuronal activity; obsessive–compusive disorders; Parkinson's disease; deep brain stimulation
5.  Stimulation of the Subthalamic Nucleus and Impulsivity 
Annals of neurology  2009;66(6):817-824.
In Parkinson disease (PD) patients, deep brain stimulation (DBS) of the subthalamic nucleus (STN) may contribute to certain impulsive behavior during high-conflict decisions. A neurocomputational model of the basal ganglia has recently been proposed that suggests this behavioral aspect may be related to the role played by the STN in relaying a “hold your horses” signal intended to allow more time to settle on the best option. The aim of the present study was 2-fold: 1) to extend these observations by providing evidence that the STN may influence and prevent the execution of any response even during low-conflict decisions; and 2) to identify the neural correlates of this effect.
We measured regional cerebral blood flow during a Go/NoGo and a control (Go) task to study the motor improvement and response inhibition deficits associated with STN-DBS in patients with PD.
Although it improved Unified Parkinson Disease Rating Scale motor ratings and induced a global decrease in reaction time during task performance, STN-DBS impaired response inhibition, as revealed by an increase in commission errors in NoGo trials. These behavioral effects were accompanied by changes in synaptic activity consisting of a reduced activation in the cortical networks responsible for reactive and proactive response inhibition.
The present results suggest that although it improves motor functions in PD patients, modulation of STN hyperactivity with DBS may tend at the same time to favor the appearance of impulsive behavior by acting on the gating mechanism involved in response initiation.
PMCID: PMC2972250  PMID: 20035509 CAMSID: cams1535
6.  Mechanisms of deep brain stimulation for obsessive compulsive disorder: effects upon cells and circuits 
Deep brain stimulation (DBS) has emerged as a safe, effective, and reversible treatment for a number of movement disorders. This has prompted investigation of its use for other applications including psychiatric disorders. In recent years, DBS has been introduced for the treatment of obsessive compulsive disorder (OCD), which is characterized by recurrent unwanted thoughts or ideas (obsessions) and repetitive behaviors or mental acts performed in order to relieve these obsessions (compulsions). Abnormal activity in cortico-striato-thalamo-cortical (CSTC) circuits including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), ventral striatum, and mediodorsal (MD) thalamus has been implicated in OCD. To this end a number of DBS targets including the anterior limb of the internal capsule (ALIC), ventral capsule/ventral striatum (VC/VS), ventral caudate nucleus, subthalamic nucleus (STN), and nucleus accumbens (NAc) have been investigated for the treatment of OCD. Despite its efficacy and widespread use in movement disorders, the mechanism of DBS is not fully understood, especially as it relates to psychiatric disorders. While initially thought to create a functional lesion akin to ablative procedures, it is increasingly clear that DBS may induce clinical benefit through activation of axonal fibers spanning the CSTC circuits, alteration of oscillatory activity within this network, and/or release of critical neurotransmitters. In this article we review how the use of DBS for OCD informs our understanding of both the mechanisms of DBS and the circuitry of OCD. We review the literature on DBS for OCD and discuss potential mechanisms of action at the neuronal level as well as the broader circuit level.
PMCID: PMC3375018  PMID: 22712007
deep brain stimulation; obsessive compulsive disorder; neuromodulation; cortico-striato-thalamocortical circuit
7.  Striatal development in autism: repetitive behaviors and the reward circuitry 
Biological psychiatry  2014;76(5):358-359.
Autism spectrum disorder (ASD) is defined by two essential features – impaired social communication abilities, including deficits with social reciprocity, nonverbal communication and establishing relationships, and by the presence of restricted and repetitive behaviors and interests (RRBIs). Social deficits get the majority of attention both in science and in the popular media, but RRBIs are equally important in understanding autism. Although RRBIs are also seen in typically developing preschoolers, as well as in other psychiatric disorders such as obsessive-compulsive disorder, their impairing and persisting character is a hallmark of ASD1.
Repetitive behaviors are among the first signs of ASD, with significant elevations by the child's first birthday2. Individuals with ASD of all ages and cognitive ability levels display RRBIs to variable degrees, with males usually being more severely affected than females3. Caregivers of individuals with ASD commonly emphasize that RRBIs are among the most challenging facets of the disorder on an everyday basis1. They negatively impact social, cognitive, family functioning and well-being, often leading to increased levels of parental stress and negative parenting styles. While the clinical description and natural history of RRBIs is becoming clear, an understanding of the biological bases of this set of features has only recently begun to emerge4. Better insight into the ontogenesis of RRBIs and their underlying neurobiology is needed not only to inform models of the etiology of ASD, but also to foster the development of new interventions.
In this issue of Biological Psychiatry, Langen et al.5 examine differences in the rate of basal ganglia growth in ASD relative to typically developing children (TDC). Their volumetric analyses focused on developmental trajectories of the ventral striatum (with nucleus accumbens) and dorsal striatum (with caudate nucleus and putamen). These components of the basal ganglia are the major subcortical targets within the frontostriatal behavior control loops that are recognized as likely subserving RRBIs4. This current study is a follow up of this same group's earlier work showing cross sectional differences in growth trajectory. While several labs have previously reported enlargement of the caudate nucleus in ASD, this current study is the first to make repeat morphology measurements, thus overcoming limitations associated with cross sectional analyses. This study involved 86 seven to seventeen year old cases and controls who had 2 MRI anatomical scans approximately 2 and a half years apart on average, allowing a direct test of differential striatal growth. The rate of basal ganglia growth was correlated with the severity of RRBIs as assessed by parent interview at the time of the first MRI scan, corroborating earlier work on the role of the striatum in repetitive behaviors among children with ASD.
Specifically the caudate nucleus showed a growth rate in ASD that was twice as high as the growth rate in TDC (i.e., 4.6% vs. 2.3%). This was independent of overall brain growth, use of psychotropic medications, or other major confounds. Most importantly, more severe RRBIs early in life, particularly insistence on sameness behaviors, such as avoiding trivial changes in routines and environments as well as adhering to compulsions and rituals, were related to faster striatal growth between average ages of about 9 and 12 year old, with large effect sizes (e.g., caudate nucleus: Cohen's d = 0.86). While Langen et al. discuss several complementary explanations for their findings, they conclude that the divergent trajectory of caudate development in relation to RRBIs most likely results from early, and possibly continuing, patterns of repetitive behaviors that shape striatal development – not the other way around.
This new set of data elegantly adds to the notion that the striatum plays a central role in core ASD phenomenology6. However, one question lingers: what cause RRBIs, like insistence on sameness, compulsions and rituals, to become such a force so as to impact the growth trajectory of an evolutionarily ancient brain structure like the caudate nucleus? This question ties in with a long-standing debate among clinicians and scientists concerning the potential functions that the myriad of RRBIs might serve in individuals with ASD. While several plausible ideas have been advanced7, convincing support for any specific one is lacking.
One hypothesis that is gaining increased research attention, however, involves the effects of alterations of the balance between social and nonsocial motivation in reward circuitry on RRBIs8. This model suggests that ASD is in part a disorder of “behavioral dependency” to RRBIs because of the rewarding effects they induce1. Indeed, insistence on sameness and preoccupying restricted interests are reported to be quite pleasurable by affected individuals1. The dorsal striatum with caudate nucleus, in particular, is believed to mediate reward value for purposeful actions5. Functional imaging studies show that the brain's reward circuitry in ASD, particularly striatum and ventral prefrontal cortices, selectively over-reacts to objects that may comprise an intense special interest, whereas it under-reacts to more typical desires such as social reward and money6. This may indicate that the brain in ASD cares less for conventional rewards. It is not yet known if an initial lack of social reward motivation opens the door for enhanced rewarding effects of certain circumscribed objects, topics, and routines, or whether the reverse is true – that the dominating reward effects of nonsocial objects, topic and routines diminishes the reward value of social engagement.
The rewarding effects of RRBIs are thought to be fueled by the preference of those with ASD for predictability in their environment, where they can exercise more control; social encounters are in many ways the antithesis of this, as these are often rapid, hard to control and offer much more variable reinforcement contingencies. When RRBIs are rewarding, their pursuit may be strengthened through reinforcement mechanisms that progressively turn them into rigid and strongly desired habits that are performed almost automatically with little conscious oversight. With this heuristic model, RRBIs are self-reinforcing, and they begin to hijack the normal developmental trajectory of entire repertoires of behaviors. The dorsal (associative) striatum with caudate nucleus dominates these processes4. Thus, an accelerated growth rate of the caudate related to RRBIs, as reported by Langen et al.5, could reflect atypical brain specialization in individuals with ASD9. From early in life the caudate nucleus mediates habitual processes for a wide range of different stimuli and contexts. Across development, however, the caudate may become co-opted by the most rewarding aspects of the environment. This interactive and self-sustaining biobehavioral process – in concert with other mesocorticolimbic functions4 – may shape the growth trajectory of the caudate nucleus and strengthens the occurrence of RRBIs in ASD (Figure 1). On a day-to-day basis, RRBIs interfere with social development and functioning as they may absorb resources typically dedicated to other learning opportunities, including social ones6.
The observation that RRBIs in ASD involve plasticity of the caudate nucleus – one major hub within the frontostriatal circuits that control behavior – is a fascinating advance for our field. It brings us closer to the neurobiological roots of how and why affected individuals develop and maintain this set of challenging behaviors. Follow-up research will need to address several issues to improve upon the approach of the Langen et al study. One critical issue is that researchers need to use more precise behavioral measurement tools10. This could involve item rating scales with greater item density around key concepts, as it is clear to all the ADI-R is sorely lacking in this regard. Also, quantitative motion capture tools are now widely available; deploying these in natural environments seems to us to be extremely promising adjuncts to standard rating scales. Repeat behavioral measurement across time, in sync with repeat brain measurement is an important next step that will enable better characterization of the interplay between RRBIs and brain dynamics. In this regard, multimodal imaging in the same sample is called for, as structural imaging will surely only capture portions of the story. The findings by Langen et al.5 call attention to the importance of RRBIs in autism. Because RRBIs may be rooted in the powerful reward circuitries that motivate a great deal of behavior, strategically targeting the role of reward mechanisms promises to improve treatment practices for limiting the life interfering aspects of RRBIs among individuals with ASD and their families.
PMCID: PMC4780436  PMID: 25103541
8.  The Striatum and Subthalamic Nucleus as Independent and Collaborative Structures in Motor Control 
The striatum and the subthalamic nucleus (STN) are two separate input structures into the basal ganglia (BG). Accordingly, research to date has primarily focused on the distinct roles of these structures in motor control and cognition, often through investigation of Parkinson’s disease (PD). Both structures are divided into sensorimotor, associative, and limbic subdivisions based on cortical connectivity. The more recent discovery of the STN as an input structure into the BG drives comparison of these two structures and their respective roles in cognition and motor control. This review compares the role of the striatum and STN in motor response inhibition and execution, competing motor programs, feedback based learning, and response planning. Through comparison, it is found that the striatum and STN have highly independent roles in motor control but also collaborate in order to execute desired actions. There is also the possibility that inhibition or activation of one of these structures indirectly contributes to the function of other connected anatomical structures. Both structures contribute to selective motor response inhibition, which forms the basis of many tasks, but the STN additionally contributes to global inhibition through the hyperdirect pathway. Research is warranted on the functional connectivity of the network for inhibition involving the rIFG, preSMA, striatum, and STN.
PMCID: PMC4771745  PMID: 26973474
striatum; subthalamic nucleus; motor control; cognition; basal ganglia
9.  NMDA Receptors Containing the GluN2D Subunit Control Neuronal Function in the Subthalamic Nucleus 
The Journal of Neuroscience  2015;35(48):15971-15983.
The GluN2D subunit of the NMDA receptor is prominently expressed in the basal ganglia and associated brainstem nuclei, including the subthalamic nucleus (STN), globus pallidus, striatum, and substantia nigra. However, little is known about how GluN2D-containing NMDA receptors contribute to synaptic activity in these regions. Using Western blotting of STN tissue punches, we demonstrated that GluN2D is expressed in the rat STN throughout development [age postnatal day 7 (P7)–P60] and in the adult (age P120). Immunoelectron microscopy of the adult rat brain showed that GluN2D is predominantly expressed in dendrites, unmyelinated axons, and axon terminals within the STN. Using subunit-selective allosteric modulators of NMDA receptors (TCN-201, ifenprodil, CIQ, and DQP-1105), we provide evidence that receptors containing the GluN2B and GluN2D subunits mediate responses to exogenously applied NMDA and glycine, as well as synaptic NMDA receptor activation in the STN of rat brain slices. EPSCs in the STN were mediated primarily by AMPA and NMDA receptors and GluN2D-containing NMDA receptors controlled the slow deactivation time course of EPSCs in the STN. In vivo recordings from the STN of anesthetized adult rats demonstrated that the spike firing rate was increased by the GluN2C/D potentiator CIQ and decreased by the GluN2C/D antagonist DQP-1105, suggesting that NMDA receptor activity can influence STN output. These data indicate that the GluN2B and GluN2D NMDA receptor subunits contribute to synaptic activity in the STN and may represent potential therapeutic targets for modulating subthalamic neuron activity in neurological disorders such as Parkinson's disease.
SIGNIFICANCE STATEMENT The subthalamic nucleus (STN) is a key component of the basal ganglia, a group of subcortical nuclei that control movement and are dysregulated in movement disorders such as Parkinson's disease. Subthalamic neurons receive direct excitatory input, but the pharmacology of excitatory synaptic transmission in the STN has been understudied. Here, we show that GluN2B- and GluN2D-containing NMDA receptors mediate the NMDA receptor component of EPSCs in subthalamic neurons. Moreover, our results demonstrate that pharmacologic modulation of GluN2D-containing receptors alters the time course of EPSCs and controls the in vivo spike-firing rate in the STN. This study identifies GluN2D as a potential target for modulating subthalamic neuron activity.
PMCID: PMC4666920  PMID: 26631477
excitatory synapse; GluN2B; GluN2D; glutamate receptor; NMDA; subthalamic nucleus
10.  Imaging Impulsivity in Parkinson's Disease and the Contribution of the Subthalamic Nucleus 
Parkinson's Disease  2011;2011:594860.
Taking risks is a natural human response, but, in some, risk taking is compulsive and may be detrimental. The subthalamic nucleus (STN) is thought to play a large role in our ability to inhibit responses. Differences between individuals' ability to inhibit inappropriate responses may underlie both the normal variation in trait impulsivity in the healthy population, as well as the pathological compulsions experienced by those with impulse control disorders (ICDs). Thus, we review the role of the STN in response inhibition, with a particular focus on studies employing imaging methodology. We also review the latest evidence that disruption of the function of the STN by deep brain stimulation in patients with Parkinson's disease can increase impulsivity.
PMCID: PMC3135010  PMID: 21765999
11.  Neuropsychology Review Submission 
Neuropsychology review  2015;25(4):398-410.
It has been well documented that deep brain stimulation (DBS) of the subthalamic nucleus (STN) to address some of the disabling motor symptoms of Parkinson’s disease (PD) can evoke unintended effects, especially on non-motor behavior. This observation has catalyzed more than a decade of research concentrated on establishing trends and identifying potential mechanisms for these non-motor effects. While many issues remain unresolved, the collective result of many research studies and clinical observations has been a general recognition of the role of the STN in mediating limbic function. In particular, the STN has been implicated in impulse control and the related construct of valence processing. A better understanding of STN involvement in these phenomena could have important implications for treating impulse control disorders (ICDs). ICDs affect up to 40% of PD patients on dopamine agonist therapy and approximately 15% of PD patients overall. ICDs have been reported to be associated with STN DBS. In this paper we will focus on impulse control and review pre-clinical, clinical, behavioral, imaging, and electrophysiological studies pertaining to the limbic function of the STN.
PMCID: PMC4792181  PMID: 26577509
Subthalamic nucleus; deep brain stimulation; impulse control disorder
12.  Electrode Position and Current Amplitude Modulate Impulsivity after Subthalamic Stimulation in Parkinsons Disease—A Computational Study 
Background: Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) is highly effective in alleviating motor symptoms of Parkinson's disease (PD) which are not optimally controlled by dopamine replacement therapy. Clinical studies and reports suggest that STN-DBS may result in increased impulsivity and de novo impulse control disorders (ICD).
Objective/Hypothesis: We aimed to compare performance on a decision making task, the Iowa Gambling Task (IGT), in healthy conditions (HC), untreated and medically-treated PD conditions with and without STN stimulation. We hypothesized that the position of electrode and stimulation current modulate impulsivity after STN-DBS.
Methods: We built a computational spiking network model of basal ganglia (BG) and compared the model's STN output with STN activity in PD. Reinforcement learning methodology was applied to simulate IGT performance under various conditions of dopaminergic and STN stimulation where IGT total and bin scores were compared among various conditions.
Results: The computational model reproduced neural activity observed in normal and PD conditions. Untreated and medically-treated PD conditions had lower total IGT scores (higher impulsivity) compared to HC (P < 0.0001). The electrode position that happens to selectively stimulate the part of the STN corresponding to an advantageous panel on IGT resulted in de-selection of that panel and worsening of performance (P < 0.0001). Supratherapeutic stimulation amplitudes also worsened IGT performance (P < 0.001).
Conclusion(s): In our computational model, STN stimulation led to impulsive decision making in IGT in PD condition. Electrode position and stimulation current influenced impulsivity which may explain the variable effects of STN-DBS reported in patients.
PMCID: PMC5126055  PMID: 27965590
impulsivity; sub thalamic stimulation; Parkinson's disease; Iowa gambling task; reinforcement learning
13.  Parkinsonian Beta Oscillations in the External Globus Pallidus and Their Relationship with Subthalamic Nucleus Activity 
Inappropriately synchronized beta (β) oscillations (15–30 Hz) in the subthalamic nucleus (STN) accompany movement difficulties in idiopathic Parkinson’s disease (PD). The cellular and network substrates underlying these exaggerated β oscillations are unknown but activity in the external globus pallidus (GP), which forms a candidate pacemaker network with STN, might be of particular importance. Using a clinically relevant rat model of PD, we demonstrate that oscillatory activity in GP neuronal networks becomes excessively and selectively synchronized at β frequencies in a spatially widespread and brain state-dependent manner after lesion of dopamine neurons. Although synchronization of GP unit activity increased by almost 100-fold during β oscillations, the mean firing rate of GP neurons decreased compared with controls. Importantly, in parkinsonian animals, two main types of GP neuron were identified according to their distinct and inversely related firing rates and patterns. Moreover, neurons of the same type tended to fire together, with small phase differences, whereas different types of neuron tended not to do so. This functional dichotomy in temporal coupling persisted across extreme brain states, suggesting that maladaptive interactions are dominated by hard wiring. Finally, the precisely timed discharges of GP and STN neurons indicated that rhythmic sequences of recurrent excitation and inhibition in the STN-GP network, and lateral inhibition between GP neurons, could actively support abnormal β oscillations. We propose that GP neurons, by virtue of their spatiotemporal synchronization, widespread axon collaterals and feed-back/feed-forward mechanisms, are well placed to orchestrate and propagate exaggerated β oscillations throughout the entire basal ganglia in PD.
PMCID: PMC4243385  PMID: 19109506
globus pallidus; subthalamic nucleus; basal ganglia; Parkinson’s disease; dopamine; 6-hydroxydopamine
14.  Probing Compulsive and Impulsive Behaviors, from Animal Models to Endophenotypes: A Narrative Review 
Neuropsychopharmacology  2009;35(3):591-604.
Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive–compulsive disorder (OCD), obsessive–compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field.
PMCID: PMC3055606  PMID: 19940844
impulsive; compulsive; endophenotypes; serotonin; dopamine; Cognition; Psychiatry & Behavioral Sciences; Animal models; Biological Psychiatry; OCD; impulsivity; compulsivity; translational
15.  Abnormal corticostriatal-limbic functional connectivity in obsessive–compulsive disorder during reward processing and resting-state☆ 
NeuroImage : Clinical  2013;3:27-38.
Compulsive behaviors in obsessive–compulsive disorder (OCD) may be related to deficits in reward processing mediated by corticostriatal circuitry, a brain network implicated in the pathophysiology of OCD. Performing compulsive actions can be perceived as a reward to OCD patients because it temporarily reduces the anxiety provoked by obsessions. Although most OCD literature provides evidence of altered regional activity in these corticostriatal circuits, very little is known about the connectivity between individual regions of the corticostriatal-limbic circuits, including the cognitive and affective neural circuitry associated with OCD. Thus, this study investigated the differences in functional connectivity (FC) patterns in this network during resting-state and incentive processing. Nineteen patients with OCD and 18 well-matched healthy controls were scanned during resting-state and a monetary incentive delay task (task state). FC was assessed using both voxel-wise and region-of-interest (ROI)-wise analyses. Voxel-wise FC analysis with the nucleus accumbens seed revealed that patients with OCD exhibited increased FC between the nucleus accumbens and the lateral orbitofrontal cortex during resting-state. Additionally, these patients showed decreased FC between the nucleus accumbens and limbic areas such as the amygdala during incentive processing. Exploratory ROI-wise FC analysis revealed that OCD patients demonstrated enhanced FC between the nucleus accumbens and the lateral orbitofrontal cortex and increased total connectivity of the lateral orbitofrontal cortex during resting-state. Additionally, patients showed alterations in FC between resting and task state. This study provides evidence that patients with OCD have altered FC in the corticostriatal-limbic network, particularly in striatal-amygdala and striatal-orbitofrontal circuitry, during incentive processing and resting-state. These findings also emphasize that functional connections in the network are modulated by affective/motivational states and further suggest that OCD patients may have abnormalities of such modulation in this network.
•Corticostriatal-limbic FC analysis of task-based and resting-state fMRI data in OCD•Dysfunctional connectivity in striatal–amygdala during reward task in OCD•Dysfunctional connectivity in striatal–orbitofrontal cortex at rest in OCD•FC levels in corticostriatal-limbic network are modulated by affective state.•OCD patients have deficits in this modulation of the corticostriatal-limbic network.
PMCID: PMC3791288  PMID: 24179846
Corticostriatal circuitry; Functional connectivity; Obsessive–compulsive disorder; Reward; Resting-state
16.  The Prefrontal Cortex Achieves Inhibitory Control by Facilitating Subcortical Motor Pathway Connectivity 
The Journal of Neuroscience  2015;35(2):786-794.
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.
PMCID: PMC4293423  PMID: 25589771
diffusion MRI tractography; dynamic causal modelling; inferior frontal gyrus; presupplementary motor area; response inhibition; stop-signal task
17.  Asymmetric right/left encoding of emotions in the human subthalamic nucleus 
Emotional processing is lateralized to the non-dominant brain hemisphere. However, there is no clear spatial model for lateralization of emotional domains in the basal ganglia. The subthalamic nucleus (STN), an input structure in the basal ganglia network, plays a major role in the pathophysiology of Parkinson's disease (PD). This role is probably not limited only to the motor deficits of PD, but may also span the emotional and cognitive deficits commonly observed in PD patients. Beta oscillations (12–30 Hz), the electrophysiological signature of PD, are restricted to the dorsolateral part of the STN that corresponds to the anatomically defined sensorimotor STN. The more medial, more anterior and more ventral parts of the STN are thought to correspond to the anatomically defined limbic and associative territories of the STN. Surprisingly, little is known about the electrophysiological properties of the non-motor domains of the STN, nor about electrophysiological differences between right and left STNs. In this study, microelectrodes were utilized to record the STN spontaneous spiking activity and responses to vocal non-verbal emotional stimuli during deep brain stimulation (DBS) surgeries in human PD patients. The oscillation properties of the STN neurons were used to map the dorsal oscillatory and the ventral non-oscillatory regions of the STN. Emotive auditory stimulation evoked activity in the ventral non-oscillatory region of the right STN. These responses were not observed in the left ventral STN or in the dorsal regions of either the right or left STN. Therefore, our results suggest that the ventral non-oscillatory regions are asymmetrically associated with non-motor functions, with the right ventral STN associated with emotional processing. These results suggest that DBS of the right ventral STN may be associated with beneficial or adverse emotional effects observed in PD patients and may relieve mental symptoms in other neurological and psychiatric diseases.
PMCID: PMC3810611  PMID: 24194703
Parkinson's disease; deep brain stimulation (DBS); emotions; subthalamic nucleus; spikes
18.  Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits 
The Journal of Clinical Investigation  2014;124(10):4629-4641.
Parkinson’s disease (PD) is the most prevalent hypokinetic movement disorder, and symptomatic PD pathogenesis has been ascribed to imbalances between the direct and indirect pathways in the basal ganglia circuitry. Here, we applied glutamate receptor blockers to the subthalamic nucleus (STN) of parkinsonian rats and evaluated locomotor behaviors via single-unit and local-field recordings. Using this model, we found that inhibition of NMDAergic cortico-subthalamic transmission ameliorates parkinsonian motor deficits without eliciting any vivid turning behavior and abolishes electrophysiological abnormalities, including excessive subthalamic bursts, cortico-subthalamic synchronization, and in situ beta synchronization in both the motor cortex and STN. Premotor cortex stimulation revealed that cortico-subthalamic transmission is deranged in PD and directly responsible for the excessive stimulation-dependent bursts and time-locked spikes in the STN, explaining the genesis of PD-associated pathological bursts and synchronization, respectively. Moreover, application of a dopaminergic agent via a microinfusion cannula localized the therapeutic effect to the STN, without correcting striatal dopamine deficiency. Finally, optogenetic overactivation and synchronization of cortico-subthalamic transmission alone sufficiently and instantaneously induced parkinsonian-associated locomotor dysfunction in normal mice. In addition to the classic theory emphasizing the direct-indirect pathways, our data suggest that deranged cortico-subthalamic transmission via the NMDA receptor also plays a central role in the pathophysiology of parkinsonian motor deficits.
PMCID: PMC4191009  PMID: 25202982
19.  Proliferation of external globus pallidus-subthalamic nucleus synapses following degeneration of midbrain dopamine neurons 
The symptoms of Parkinson’s disease (PD) are related to changes in the frequency and pattern of activity in the reciprocally connected GABAergic external globus pallidus (GPe) and glutamatergic subthalamic nucleus (STN). In idiopathic and experimental PD the GPe and STN exhibit hypo- and hyper-activity, respectively, and abnormal synchronous rhythmic burst firing. Following lesion of midbrain dopamine neurons abnormal STN activity emerges slowly and intensifies gradually until it stabilizes after 2–3 weeks. Alterations in cellular/network properties may therefore underlie the expression of abnormal firing. Because the GPe powerfully regulates the frequency, pattern and synchronization of STN activity, electrophysiological, molecular and anatomical measures of GPe-STN transmission were compared in the STN of control and 6-hydroxydopamine-lesioned rats and mice. Following dopamine depletion: 1) the frequency (but not the amplitude) of mIPSCs increased by ~70%; 2) the amplitude of evoked IPSCs and isoguvacine-evoked current increased by ~60% and ~70%, respectively; 3) mRNA encoding α1, β2 and γ2 GABAA receptor subunits increased by 15–30%; 4) the density of postsynaptic gephyrin and γ2 subunit co-immunoreactive structures increased by ~40%, whereas the density of vesicular GABA transporter and bassoon co-immunoreactive axon terminals was unchanged; 5) the number of ultrastructurally defined synapses per GPe-STN axon terminal doubled with no alteration in terminal/synapse size or target preference. Thus, loss of dopamine leads, through an increase in the number of synaptic connections per GPe-STN axon terminal, to substantial strengthening of the GPe-STN pathway. This adaptation may oppose hyperactivity but could also contribute to abnormal firing patterns in the parkinsonian STN.
PMCID: PMC3475197  PMID: 23035084
20.  Lesions of the Medial Prefrontal Cortex Abolish Conditioned Aversion Associated with Sexual Behavior in Male Rats 
Biological psychiatry  2010;67(12):1199-1204.
An inability to inhibit behaviors once they become maladaptive is a component of several psychiatric illnesses and the medial prefrontal cortex (mPFC) was identified as a potential mediator of behavioral inhibition. The current study tested if the mPFC is involved in inhibition of sexual behavior when associated with aversive outcomes.
Using male rats, effects of lesions of the infralimbic (IL) and prelimbic (PL) areas of the mPFC on expression of sexual behavior and ability to inhibit mating were tested using a paradigm of copulation-contingent aversion.
mPFC lesions did not alter expression of sexual behavior. In contrast, mPFC lesions completely blocked the acquisition of sex-aversion conditioning and lesioned animals continued to mate, in contrast to the robust behavioral inhibition towards copulation in mPFC intact males, resulting in only 22% of intact males continuing to mate. However, rats with mPFC lesions were capable of forming a conditioned place preference to sexual reward and conditioned place aversion for lithium chloride, suggesting that these lesions did not alter associative learning or sensitivity for lithium chloride.
The current study indicates that animals with mPFC lesions are likely capable of forming the associations with aversive outcomes of their behavior, but lack the ability to suppress seeking of sexual reward in the face of aversive consequences. These data may contribute to a better understanding of a common pathology underlying impulse control disorders as compulsive sexual behavior has a high prevalence of comorbidity with psychiatric disorders and Parkinson’s Disease.
PMCID: PMC2908911  PMID: 20346444
Prefrontal Cortex; Inhibition; Mating; Conditioned; Reward; Aversion; Addiction; Sex
21.  Inhibitory control and error monitoring by human subthalamic neurons 
Translational Psychiatry  2014;4(9):e439-.
The subthalamic nucleus (STN) has been shown to be implicated in the control of voluntary action, especially during tasks involving conflicting choice alternatives or rapid response suppression. However, the precise role of the STN during nonmotor functions remains controversial. First, we tested whether functionally distinct neuronal populations support different executive control functions (such as inhibitory control or error monitoring) even within a single subterritory of the STN. We used microelectrode recordings during deep brain stimulation surgery to study extracellular activity of the putative associative-limbic part of the STN while patients with severe obsessive-compulsive disorder performed a stop-signal task. Second, 2–4 days after the surgery, local field potential recordings of STN were used to test the hypothesis that STN oscillations may also reflect executive control signals. Extracellular recordings revealed three functionally distinct neuronal populations: the first one fired selectively before and during motor responses, the second one selectively increased their firing rate during successful inhibitory control, and the last one fired selectively during error monitoring. Furthermore, we found that beta band activity (15–35 Hz) rapidly increased during correct and incorrect behavioral stopping. Taken together, our results provide critical electrophysiological support for the hypothesized role of the STN in the integration of motor and cognitive-executive control functions.
PMCID: PMC4203004  PMID: 25203170
22.  Functional anatomy of subthalamic nucleus stimulation in Parkinson disease 
Annals of neurology  2014;76(2):279-295.
We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3D brain region and to assign statistical significance after stringent Type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS.
Fifty-one PD participants with STN DBS were evaluated off medication, with DBS off and during unilateral STN DBS with clinically optimized settings. Dependent variables included DBS-induced changes in Unified Parkinson Disease Rating Scale (UPDRS) subscores, kinematic measures of bradykinesia and rigidity, working memory, response inhibition, mood, anxiety, and akathisia. Weighted t-tests at each voxel produced p images showing where DBS most significantly affected each dependent variable based on outcomes of participants with nearby DBS. Finally, a permutation test computed the probability that this p image indicated significantly different responses based on stimulation site.
Most motor variables improved with DBS anywhere in the STN region, but several motor, cognitive and affective responses significantly depended on precise location stimulated, with peak p values in superior STN/zona incerta (quantified bradykinesia), dorsal STN (mood, anxiety), and inferior STN/substantia nigra (UPDRS tremor, working memory).
Our method identified DBS-induced behavioral changes that depended significantly on DBS site. These results do not support complete functional segregation within STN, since movement improved with DBS throughout, and mood improved with dorsal STN DBS. Rather, findings support functional convergence of motor, cognitive and limbic information in STN.
PMCID: PMC4172323  PMID: 24953991
23.  No Effect of Subthalamic Deep Brain Stimulation on Intertemporal Decision-Making in Parkinson Patients123 
eNeuro  2016;3(2):ENEURO.0019-16.2016.
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for the motor symptoms of Parkinson’s disease (PD). DBS or pharmacological treatment is believed to modulate the tendency to, or reverse, impulse control disorders. Several brain areas involved in impulsivity and reward valuation, such as the prefrontal cortex and striatum, are linked to the STN, and activity in these areas might be affected by STN-DBS. To investigate the effect of STN-DBS on one type of impulsive decision-making—delay discounting (i.e., the devaluation of reward with increasing delay until its receipt)—we tested 40 human PD patients receiving STN-DBS treatment and medication for at least 3 months. Patients were pseudo-randomly assigned to one of four groups to test the effects of DBS on/off states as well as medication on/off states on delay discounting. The delay-discounting task consisted of a series of choices among a smaller. sooner or a larger, later monetary reward. Despite considerable effects of DBS on motor performance, patients receiving STN-DBS did not choose more or less impulsively compared with those in the off-DBS group, as well as when controlling for risk attitude. Although null results have to be interpreted with caution, our findings are of significance to other researchers studying the effects of PD treatment on impulsive decision-making, and they are of clinical relevance for determining the therapeutic benefits of using STN-DBS.
PMCID: PMC4876489  PMID: 27257622
deep brain stimulation; intertemporal choice; Parkinson’s disease
24.  The influence of bilateral subthalamic nucleus deep brain stimulation on impulsivity and prepulse inhibition in Parkinson’s disease patients 
At least 14% of Parkinson disease (PD) patients develop impulse control disorders (ICDs). The pathophysiology behind these behaviors and the impact of deep brain stimulation in a real-life setting remains unclear.
We prospectively examined the impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on ICDs in PD patients, as well as the relationship between impaired sensorimotor gaiting and impulsivity.
Patients undergoing bilateral STN-DBS were assessed for ICDs preoperatively and 1-year postoperatively using a validated questionnaire (QUIP-RS). A subset of patients completed the Balloon Analog Risk Task (BART) and auditory pre-pulse inhibition (PPI) testing.
Analysis revealed 12 patients had an improvement in score assessing ICDs (“good responders” – GR; p = 0.006) while 4 had a worse or stable score (“poor responders” – PR; p > 0.05). GR further exemplified a significant decrease in hypersexual behavior (p = 0.005) and binge eating (p = 0.01). Impaired PPI responses also significantly correlated with impulsivity in BART (r = −0.72, p = 0.044).
Following bilateral STN-DBS 75% of our cohort had a reduction in ICDs, thus suggesting deep brain stimulation effectively manages ICDs in PD. The role of impaired PPI in predisposition to ICDs in PD warrants further investigation.
PMCID: PMC4540608  PMID: 26066569
Deep brain stimulation; subthalamic nucleus; Parkinson’s disease; impulsivity; prepulse inhibition
25.  An examination of the effects of subthalamic nucleus inhibition or μ-opioid receptor stimulation on food-directed motivation in the non-deprived rat 
Behavioural Brain Research  2012;230(2):365-373.
The subthalamic nucleus (STN) serves important functions in regulating movement, cognition, and motivation and is connected with cortical and basal ganglia circuits that process reward and reinforcement. In order to further examine the role of the STN on motivation toward food in non-deprived rats, these experiments studied the effects of pharmacological inhibition or μ-opioid receptor stimulation of the STN on the 2-hr intake of a sweetened fat diet, the amount of work exerted to earn sucrose on a progressive ratio 2 (PR-2) schedule of reinforcement, and performance on a differential reinforcement of low-rate responding (DRL) schedule for sucrose reward. Separate behavioral groups (N = 6–9) were tested following bilateral inhibition of the STN with the GABAA receptor agonist muscimol (at 0–5 ng/0.5 μl/side) or following μ-opioid receptor stimulation with the agonist D-Ala2, N-MePhe4, Gly-ol-enkephalin (DAMGO; at 0, 0.025 or 0.25 μg/0.5 μl/side). Although STN inhibition increased ambulatory behavior during 2-hr feeding sessions, it did not significantly alter intake of the sweetened fat diet. STN inhibition also did not affect the breakpoint for sucrose pellets during a 1-hr PR-2 reinforcement schedule or impact the number of reinforcers earned on a 1-hr DRL-20 sec reinforcement schedule in non-deprived rats. In contrast, STN μ-opioid receptor stimulation significantly increased feeding on the palatable diet and reduced the reinforcers earned on a DRL-20 schedule, although DAMGO microinfusions had no effect on PR-2 performance. These data suggest that STN inhibition does not enhance incentive motivation for food in the absence of food restriction and that STN μ-opioid receptors play an important and unique role in motivational processes.
PMCID: PMC3322281  PMID: 22391117
Subthalamic nucleus; motivation; opioids; food intake; reward

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