Basal Ganglia-thalamocortical Circuits Research Articles

A positive correlation between fractional white matter volume and the response of Parkinson disease patients to subthalamic stimulation

Since optimal patient selection is essential for the success of subthalamic nucleus (STN) stimulation, the identification of reliable outcome predictors is important. The purpose of this study was to identify new imaging characteristics sufficiently reliable to predict treatment results. Using preoperative magnetic resonance imaging studies of 21 Parkinson disease (PD) patients treated by STN stimulation, we performed whole brain-based analysis of voxel-based morphometry (VBM) data. Intracranial structures segmented into the gray matter fraction (GMF), white matter fraction (WMF), and cerebrospinal fluid fraction (CSFF) were subjected to univariate and multivariate analysis of the correlation between fractional volumes and postoperative improvement rates using the Unified PD Rating Scale (UPDRS). At 3 months after surgery, the WMF was significantly correlated with improvement rated on the total UPDRS (p = 0.006), UPDRS part II (activities of daily living; p = 0.008), UPDRS part III (motor; p = 0.005). In contrast, there was no significant correlation between the effect of STN stimulation and GMF or the effect of stimulation and CSFF. The WMF also showed a significant correlation with postoperative scores in the "on" drug and "on" stimulation state (total UPDRS, p = 0.027; UPDRS part II, p = 0.019; UPDRS part III, p = 0.034). Our data indicate that patients with a larger white matter volume benefited from STN stimulation whereas the volume of other brain structures was not correlated with its effect. We posit that preserved connectivity between components of the basal ganglia-thalamocortical circuit may be required for the effectiveness of electrical stimulation. VBM may represent a powerful tool to predict the response of patients with advanced PD to STN stimulation.

Comparative anatomy of the ventral striatum

Event Abstract Back to Event Comparative anatomy of the ventral striatum Henk J. Groenwegen1* 1 VU University, Department of Anatomy and Neurosciences, Netherlands The ventral striatum, including the nucleus accumbens, is connectionally associated with limbic structures such as the amygdala, hippocampus, midline thalamus and the prefrontal cortex. In addition, the ventral striatum is strongly innervated by dopaminergic fibers from the ventral tegmental area and has a high density of serotonergic inputs. The inclusion of the ventrally located nucleus accumbens in a ‘unified’ striatum has had great impact on the functional-anatomical concept of the basal ganglia. It has become generally accepted that the basal ganglia, based on their involvement in a set of parallel, functionally segregated basal ganglia-thalamocortical circuits, are not only concerned with somatomotor functions, but are also involved in cognitive and ‘limbic’ functions. In particular the ventral striatum is functionally strongly associated with emotional and motivational aspects of behaviour, and structural and functional disturbances of ventral striatal areas have shown to be correlated with various forms of psychopathology. Whereas the basic organizational scheme for the interactions between the cerebral cortex and the basal ganglia may be formed on the basis of parallel basal ganglia-thalamocortical circuits, there are strong indications for functional and anatomical interactions between such circuits. The ventral striatum might play an important in these interactions. Neuroanatomical and electrophysiological experiments have been shown that ventral striatal efferents, in particular stemming from the shell of the accumbens, influence dopaminergic neurons in the substantia nigra that, in turn, project to more dorsal parts of the striatum. In this way, indirect loops are created through which functionally different striatal regions may influence each other. It has been suggested that such interconnections between cortical-subcortical circuits through the dopaminergic system might play a role in the transition over time of unconditioned via conditioned behaviors to habit formation. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Oral Presentation Topic: Neural mechanisms of the basal ganglia and ventrobasal forebrain Citation: Groenwegen HJ (2010). Comparative anatomy of the ventral striatum. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00238 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 05 May 2010; Published Online: 05 May 2010. * Correspondence: Henk J Groenwegen, VU University, Department of Anatomy and Neurosciences, Amsterdam, Netherlands, hj.groenewegen@vumc.nl Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Henk J Groenwegen Google Henk J Groenwegen Google Scholar Henk J Groenwegen PubMed Henk J Groenwegen Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Núcleos intralaminares posteriores del tálamo y procesos cognitivos

The parafascicular nucleus in rats and the centromedian parafascicular complex in primates and other mammals are the so-called posterior intralaminar nuclei (pIL) of the thalamus. Like the ascending reticular activating system and the basal ganglia-thalamocortical circuit, the pIL nuclei are part of the brain arousal systems.To describe and analyze different animal and human studies suggesting that the pIL could also be part of a neuro-physiological subcortical system related to cognitive processes as attention, learning and memory.Both parafascicular nucleus lesion studies in rats and neuropathological and neuroimaging reports in humans, indicate a relationship between the degeneration of pIL neurons and the cognitive deficits observed in learning and memory tasks in animals and also in several human neurological diseases and in consciousness disorders.Considering its neuroanatomical, neurophysiological and functional characteristics, the pIL can be considered excellent candidates for investigating cognitive processes in the field of psychobiology and clinical neurology.

Electrophysiology in Gilles de la Tourette syndrome

Abnormalities in basal ganglia–thalamocortical circuits presumably play an important role in the pathophysiology underlying the chronic motor and vocal tics that define Gilles de la Tourette syndrome (GTS). Electrophysiological techniques, above all, the use of transcranial magnetic stimulation – a noninvasive and painless tool to examine the excitability of several different circuits in the human motor cortex – has advanced our understanding of the pathophysiology. Motor thresholds are similar in GTS and healthy subjects; in the resting state, recruitment of motor-evoked potentials above threshold is more gradual in patients with GTS compared with controls. By contrast, recruitment of motor-evoked potentials during preactivation is similar in both groups, as is the duration of the cortical silent period. This suggests that the distribution of excitability in the corticospinal system in patients at rest is different to that in healthy individuals. Importantly, correlation analysis has demonstrated that reduced levels of excitability at rest relate, in pure GTS patients, to video ratings of complex tics as well as hand and finger tics, with less excitability predicting fewer tics. The correlations disappear for measures made during voluntary activation. This suggests that this is an adaptive response to abnormal basal ganglia motor cortex inputs in an effort to reduce unwanted movements, a notion supported by electroencephalogram-coherence studies that demonstrated increased cortico–cortical coupling. Compared with the healthy control group, short intracortical inhibition thresholds are similar in patients with GTS. However, above threshold short intracortical inhibition recruitment and sensory afferent inhibition, a paradigm to examine sensory motor integration, is reduced in patients with GTS. This is consistent with the suggestion that reduced excitability of cortical inhibition is one factor that contributes to the difficulty that patients have in suppressing involuntary tics. In addition, the reduced sensory afferent inhibition indicates that impaired intracortical inhibition may not be limited to the motor cortex, but also involves circuits linking sensory input and motor output.

The Nature and Time Course of Cortical Activation Following Subthalamic Stimulation in Parkinson's Disease

We studied the time course and nature of interactions between the subthalamic nucleus (STN) and the motor cortex in 8 Parkinson disease (PD) patients with chronically implanted STN deep-brain stimulation (DBS) electrodes. We first identified the cortical evoked potentials following STN stimulation. The most consistent potential was positive wave with peak latency of 22.2 +/- 1.2 ms from stimulation of clinically effective contacts. We then stimulated the motor cortex with transcranial magnetic stimulation (TMS) at 2-15 ms and at the latency of the evoked potential ( approximately 23 ms) following STN DBS. TMS induced currents in 3 directions: lateral-medial (LM) direction activated corticospinal axons directly, posterior-anterior (PA), and anterior-posterior (AP) directions activated corticospinal neurons transynaptically. Motor-evoked potentials (MEP) elicited by AP and PA TMS were facilitated at short (2-4 ms) and medium latencies (21-24 ms). However, MEPs elicited by LM TMS were not modified by STN DBS. Short-latency antidromic stimulation of the corticosubthalamic projections and medium latency transmission likely through the basal ganglia-thalamocortical circuit led to cortical evoked potentials and increased motor cortex excitability at specific intervals following STN stimulation at clinically effective contacts. Cortical activation may be related to the clinical effects of STN DBS in PD.

The Subthalamic Nucleus in Primary Dystonia: Single-Unit Discharge Characteristics

Most models of dystonia pathophysiology predict alterations of activity in the basal ganglia thalamocortical motor circuit. The globus pallidus interna (GPi) shows bursting and oscillatory neuronal discharge in both human dystonia and in animal models, but it is not clear which intrinsic basal ganglia pathways are implicated in this abnormal output. The subthalamic nucleus (STN) receives prominent excitatory input directly from cortical areas implicated in dystonia pathogenesis and inhibitory input from the external globus pallidus. The goal of this study was to elucidate the role of the STN in dystonia by analyzing STN neuronal discharge in patients with idiopathic dystonia. Data were collected in awake patients undergoing microelectrode recording for implantation of STN deep brain stimulation electrodes. We recorded 62 STN neurons in 9 patients with primary dystonia. As a comparison group, we recorded 143 STN neurons in 20 patients with Parkinson's disease (PD). Single-unit activity was discriminated off-line by principal component analysis and evaluated with respect to discharge rate, bursting, and oscillatory activity. The mean STN discharge rate in dystonia patients was 26.3 Hz (SD 13.6), which was lower than that in the PD patients (35.6 Hz, SD 15.2), but higher than published values for subjects without basal ganglia dysfunction. Oscillatory activity was found in both disorders, with a higher proportion of units oscillating in the beta range in PD. Bursting discharge was a prominent feature of both dystonia and PD, whereas sensory receptive fields were expanded in PD compared with dystonia. The STN firing characteristics, in conjunction with those previously published for GPi, suggest that bursting and oscillatory discharge in basal ganglia output may be transmitted via pathways involving the STN and provide a pathophysiologic rationale for STN as a surgical target in dystonia.

Learning Substrates in the Primate Prefrontal Cortex and Striatum: Sustained Activity Related to Successful Actions

Learning from experience requires knowing whether a past action resulted in a desired outcome. The prefrontal cortex and basal ganglia are thought to play key roles in such learning of arbitrary stimulus-response associations. Previous studies have found neural activity in these areas, similar to dopaminergic neurons' signals, that transiently reflect whether a response is correct or incorrect. However, it is unclear how this transient activity, which fades in under a second, influences actions that occur much later. Here, we report that single neurons in both areas show sustained, persistent outcome-related responses. Moreover, single behavioral outcomes influence future neural activity and behavior: behavioral responses are more often correct and single neurons more accurately discriminate between the possible responses when the previous response was correct. These long-lasting signals about trial outcome provide a way to link one action to the next and may allow reward signals to be combined over time to implement successful learning.

Parsing brain activity associated with acupuncture treatment in Parkinson's diseases

Acupuncture, a common treatment modality within complementary and alternative medicine, has been widely used for Parkinson's disease (PD). Using functional magnetic resonance imaging (fMRI), we explored the neural mechanisms underlying the effect of specific and genuine acupuncture treatment on the motor function in patients with PD. Three fMRI scans were performed in random order in a block design, one for verum acupuncture (VA) treatment, another one for a covert placebo (CP), and the third one for an overt placebo (OP) at the motor function implicated acupoint GB34 on the left foot of 10 patients with PD. We calculated the contrast that subtracts the blood-oxygen-level dependent (BOLD) response for the acupuncture effect (VA vs. CP) and the placebo effect (CP vs. OP). We found a significant improvement in the motor function of the affected hand after acupuncture treatment. The putamen and the primary motor cortex were activated when patients with PD received the acupuncture treatment (VA vs. CP) and these activations correlated with individual enhanced motor function. Expectation towards acupuncture modality (CP vs. OP) elicited activation over the anterior cingulate gyrus, the superior frontal gyrus, and the superior temporal gyrus. These findings suggest that acupuncture treatment might facilitate improvement in the motor functioning of patients with PD via the basal ganglia-thalamocortical circuit.

Activity Propagation in an Avian Basal Ganglia-Thalamocortical Circuit Essential for Vocal Learning

In mammalian basal ganglia-thalamocortical circuits, GABAergic pallidal neurons are thought to "gate" or modulate excitation in thalamus with their strong inhibitory inputs and thus signal to cortex by pausing and permitting thalamic neurons to fire in response to excitatory drive. In contrast, in a homologous circuit specialized for vocal learning in songbirds, evidence suggests that pallidal neurons signal by eliciting postinhibitory rebound spikes in thalamus, which could occur even without any excitatory drive to thalamic neurons. To test whether songbird pallidal neurons can also communicate with thalamus by gating excitatory drive, as well as by postinhibitory rebound, we examined the activity of thalamic relay neurons in response to acute inactivation of the basal ganglia structure Area X; Area X contains the pallidal neurons that project to thalamus. Although inactivation of Area X should eliminate rebound-mediated spiking in thalamus, this manipulation tonically increased the firing rate of thalamic relay neurons, providing evidence that songbird pallidal neurons can gate tonic thalamic excitatory drive. We also found that the increased thalamic activity was fed forward to its target in the avian equivalent of cortex, which includes neurons that project to the vocal premotor area. These data raise the possibility that basal ganglia circuits can signal to cortex through thalamus both by generating postinhibitory rebound and by gating excitatory drive and may switch between these modes depending on the statistics of pallidal firing. Moreover, these findings provide insight into the strikingly different disruptive effects of basal ganglia and cortical lesions on songbird vocal learning.

Altered effective connectivity and anomalous anatomy in the basal ganglia-thalamocortical circuit of stuttering speakers

Combining structural equation modeling (SEM) and voxel-based morphometry (VBM), this study investigated the interactions among neural structures in the basal ganglia-thalamocortical circuit (BGTC) in the left hemisphere of stuttering and non-stuttering speakers. Stuttering speakers ( n = 12) and non-stuttering controls ( n = 12) were scanned while performing a picture-naming task and a passive-viewing (baseline) task. Results showed significant differences between stuttering and non-stuttering speakers in both effective connectivity and anatomical structures in the BGTC in the left brain. Specifically, compared to non-stuttering speakers, stuttering speakers showed weaker negative connectivity from the left posterior middle temporal gyrus (PMTG) to the putamen, but stronger positive connectivity from the putamen to the thalamus, from the thalamus to the PMTG and anterior supplementary motor area (preSMA), and from the anterior superior temporal gyrus (ASTG) to the preSMA. Accompanying such altered connectivity were anatomical differences: compared to non-stuttering controls, stuttering speakers showed more grey matter (GM) volume concentration in the left putamen, less GM volume concentration in the left medial frontal gyrus and ASTG, and less white matter volume concentration underlying the left posterior superior temporal gyrus inside the BGTC. These results shed significant light on the neural mechanisms (in terms of both functional connectivity and neural anatomy) of stuttering.

Prior MDMA (Ecstasy) use is associated with increased basal ganglia–thalamocortical circuit activation during motor task performance in humans: An fMRI study

MDMA (3,4-methylenedioxymethamphetamine; Ecstasy) is a popular recreational drug that produces long-lasting serotonin (5-HT) neurotoxicity consisting of reductions in markers for 5-HT axons. 5-HT innervates cortical and subcortical brain regions mediating motor function, predicting that MDMA users will have altered motor system neurophysiology. We used functional magnetic resonance imaging (fMRI) to assay motor task performance-associated brain activation changes in MDMA and non-MDMA users. 24 subjects (14 MDMA users and 10 controls) performed an event-related motor tapping task (1, 2 or 4 taps) during fMRI at 3 T. Motor regions of interest were used to measure percent signal change (PSC) and percent activated voxels (PAV) in bilateral motor cortex, sensory cortex, supplementary motor area (SMA), caudate, putamen, pallidum and thalamus. We used SPM5 to measure brain activation via three methods: T-maps, PSC and PAV. There was no statistically significant difference in reaction time between the two groups. For the Tap 4 condition, MDMA users had more activation than controls in the right SMA for T-score (p=0.02), PSC (p=0.04) and PAV (p=0.03). Lifetime episodes of MDMA use were positively correlated with PSC for the Tap 4 condition on the right for putamen and pallidum; with PAV in the right motor and sensory cortex and bilateral thalamus. In conclusion, we found a group difference in the right SMA and positive dose–response association between lifetime exposure to MDMA and signal magnitude and extent in several brain regions. This evidence is consistent with MDMA-induced alterations in basal ganglia–thalamocortical circuit neurophysiology and is potentially secondary to neurotoxic effects on 5-HT signaling. Further studies examining behavioral correlates and the specific neurophysiological basis of the observed findings are warranted.

Treatment for Late-Onset Obsessive-Compulsive Disorder with Parkinsonism

Treatment for Late-Onset Obsessive-Compulsive Disorder with Parkinsonism

High‐frequency rTMS over the supplementary motor area for treatment of Parkinson's disease

Dysfunction of the basal ganglia-thalamocortical motor circuit is a fundamental model to account for motor symptoms in Parkinson's disease (PD). Using high-frequency repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA), we investigated whether modulation of SMA excitability engenders therapeutic effects on motor symptoms in PD. In this double-blind placebo-controlled study, 99 patients were enrolled and assigned randomly to SMA-stimulation and sham-stimulation groups. For SMA stimulation, 20 trains of 50 transcranial magnetic stimuli at 5 Hz were delivered at an intensity of 110% active motor threshold for leg muscles in one session. The sham stimulation was 20 trains of electric stimuli given through electrodes fixed on the head to mimic the cutaneous sensation during rTMS. Each session of intervention was carried out once a week for the first 8 weeks. The SMA stimulation, in contrast to the sham stimulation, engendered significant improvements in total scores and motor scores of the Unified Parkinson's Disease Rating Scale. Mean improvements in motor scores were 4.5 points in the SMA-stimulation group and -0.1 points in the sham-stimulation group. Results indicate that 5 Hz rTMS over SMA modestly improves motor symptoms in PD patients; SMA is a potential stimulation site for PD treatment.

Roles of μ-Opioid Receptors in GABAergic Synaptic Transmission in the Striosome and Matrix Compartments of the Striatum

The striatum is divided into two compartments, the striosomes and extrastriosomal matrix, which differ in several cytochemical markers, input-output connections, and time of neurogenesis. Since it is thought that limbic, reward-related information and executive aspects of behavioral information may be differentially processed in the striosomes and matrix, respectively, intercompartmental communication should be of critical importance to proper functioning of the basal ganglia-thalamocortical circuits. Cholinergic interneurons are in a suitable position for this communication since they are preferentially located in the striosome-matrix boundaries and are known to elicit a conditioned pause response during sensorimotor learning. Recently, micro-opioid receptor (MOR) activation was found to presynaptically suppress the amplitude of GABAergic inhibitory postsynaptic currents in striosomal cells but not in matrix cells. Disinhibition of cells in the striosomes is further enhanced by inactivation of the protein kinase C cascade. We discuss in this review the possibility that MOR activation in the striosomes affects the activity of cholinergic interneurons and thus leads to changes in synaptic efficacy in the striatum.

The basal ganglia circuits, dopamine, and ambiguous word processing: A neurobiological account of priming studies in Parkinson's disease

Research into the processing of lexical ambiguities has provided a valuable paradigm for investigating the functional architecture of the language processing system in normal and neurologically impaired populations and specifically, how basal ganglia circuits and the neurotransmitter dopamine may act to enhance and/or suppress various meanings relative to the context in which the lexical ambiguity appears. In this review, we develop the hypothesis that an integrated basal ganglia thalamocortical circuit linking the striatum and inferior frontal cortex is involved in the enhancement and suppression of ambiguous word meanings when a lexical ambiguity is presented within a linguistic context. Reference to behavioral, neurophysiological, and neurochemical studies of subcortical function in both healthy populations and people with Parkinson's disease will be used to provide further support for the proposal that the subcortex is integrally involved in ambiguous word processing.

The Anatomy of First-Episode and Chronic Schizophrenia: An Anatomical Likelihood Estimation Meta-Analysis

The authors sought to map gray matter changes in first-episode schizophrenia and to compare these with the changes in chronic schizophrenia. They postulated that the data would show a progression of changes from hippocampal deficits in first-episode schizophrenia to include volume reductions in the amygdala and cortical gray matter in chronic schizophrenia. A systematic search was conducted for voxel-based structural MRI studies of patients with first-episode schizophrenia and chronic schizophrenia in relation to comparison groups. Meta-analyses of the coordinates of gray matter differences were carried out using anatomical likelihood estimation. Maps of gray matter changes were constructed, and subtraction meta-analysis was used to compare them. A total of 27 articles were identified for inclusion in the meta-analyses. A marked correspondence was observed in regions affected by both first-episode schizophrenia and chronic schizophrenia, including gray matter decreases in the thalamus, the left uncus/amygdala region, the insula bilaterally, and the anterior cingulate. In the comparison of first-episode schizophrenia and chronic schizophrenia, decreases in gray matter volume were detected in first-episode schizophrenia but not in chronic schizophrenia in the caudate head bilaterally; decreases were more widespread in cortical regions in chronic schizophrenia. Anatomical changes in first-episode schizophrenia broadly coincide with a basal ganglia-thalamocortical circuit. These changes include bilateral reductions in caudate head gray matter, which are absent in chronic schizophrenia. Comparing first-episode schizophrenia and chronic schizophrenia, the authors did not find evidence for the temporolimbic progression of pathology from hippocampus to amygdala, but there was evidence for progression of cortical changes.

The role of the subthalamic nucleus in ‘compulsive’ behavior in rats

Different lines of evidence point to dysfunction of basal ganglia-thalamocortical circuits in obsessive-compulsive disorder (OCD). It has been hypothesized that the circuits' dysfunction in OCD may be characterized by a relative under-activity of the indirect compared with the direct pathway within these circuits. The present study tested whether lesions of the subthalamic nucleus (STN), a major node of the indirect pathway, would affect compulsive behavior, using the signal attenuation rat model of OCD. In this model, compulsive lever-pressing is induced by the attenuation of an external signal of reward delivery; an attenuation that is hypothesized to simulate the deficient response feedback suggested to underlie obsessions and compulsions in patients with OCD. Rats sustaining lesions to the STN showed a selective increase in compulsive lever-pressing compared with sham-operated rats. A post mortem biochemical analysis revealed a decrease in serotonin content in the prelimbic and infralimbic cortices, caudate-putamen (but not nucleus accumbens), globus pallidus and substantia nigra-ventral tegmental area, as well as a decrease in dopamine content in the caudate-putamen in STN-lesioned compared with sham rats. A comparison to recent findings that lesions to the orbitofrontal cortex, which also result in a selective increase in compulsive lever-pressing, lead to a decrease in serotonin and dopamine content in the caudate-putamen suggests that there may be a final common pathway by which different brain pathologies may lead to a pro-compulsive state.

Deep brain stimulation: how does it work?

Deep brain stimulation has significantly improved the motor symptoms in patients with Parkinson's disease (PD) and other movement disorders. The mechanisms responsible for these improvements continue to be explored. Inhibition at the site of stimulation has been the prevailing explanation for the symptom improvement observed with deep brain stimulation. Research using microelectrode recording during deep brain stimulation in the MPTP monkey model of PD has helped clarify how electrical stimulation of structures within the basal ganglia-thalamocortical circuit improves motor symptoms, and suggests that activation of output and the resultant change in pattern of neuronal activity that permeates throughout the basal ganglia motor circuit is the mechanism responsible for symptom improvement.

Cocaine Seeking Habits Depend upon Dopamine-Dependent Serial Connectivity Linking the Ventral with the Dorsal Striatum

A neuroanatomical principle of striatal organization has been established through which ventral domains, including the nucleus accumbens, exert control over dorsal striatal processes mediated by so-called "spiraling," striato-nigro-striatal, circuitry. We have investigated the functional significance of this circuitry in the control over a cocaine-seeking habit by using an intrastriatal disconnection procedure that combined a selective, unilateral lesion of the nucleus accumbens core and infusion of a dopamine receptor antagonist into the contralateral dorsolateral striatum, thereby disrupting striato-midbrain-striatal serial connectivity bilaterally. We show that this disconnection selectively decreased drug-seeking behavior in rats extensively trained under a second-order schedule of cocaine reinforcement. These data thereby define the importance of interactions between ventral and dorsal domains of the striatum, mediated by dopaminergic transmission, in the neural mechanisms underlying the development and performance of cocaine-seeking habits that are a key characteristic of drug addiction.

Effects of Striatal GABAA-Receptor Blockade on Striatal and Cortical Activity in Monkeys

To elucidate the role of ambient striatal gamma-aminobutyric acid (GABA) in the regulation of neuronal activity in the basal ganglia-thalamocortical circuits, we studied the effects of blocking striatal GABA(A) receptors on the electrical activities of single striatal neurons, on local field potentials (LFPs) in the striatum, and on motor cortical electroencephalograms (EEGs) in two monkeys. Striatal LFPs were recorded with a device that allowed us to simultaneously record field potentials and apply drugs by reverse microdialysis at the same site. Administration of the GABA(A)-receptor antagonist gabazine (SR95531, 10 and 500 microM) induced large-amplitude LFP fluctuations at the infusion site, occurring every 2-5 s for about 2 h after the start of the 20-min drug administration. These events were prevented by cotreatment with a GABA(A)-receptor agonist (muscimol, 100 microM) or a combination of ionotropic glutamate receptor antagonists (CNQX and MK-801, each given at 100 microM). Gabazine (10 microM) also increased the firing of single neurons recorded close to the injection site, but in most cases there was no correlation between single-neuron activity and the concomitantly recorded LFP signals from the same striatal region. In contrast, intrastriatal application of gabazine increased the correlation between striatal LFPs and EEG, and resulted in the appearance of recurrent EEG events that were temporally related to the striatal LFP events. These data provide evidence that a GABAergic "tone" in the monkey striatum controls the spontaneous activity of striatal neurons, as well as the level of striatal and cortical synchrony.