Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex.

Although there is general consensus that deep brain stimulation (DBS) yields substantial clinical benefit in patients with Parkinson's disease (PD), the therapeutic mechanism of DBS remains a matter of debate. Recent studies demonstrate that DBS targeting the globus pallidus internus (GPi-DBS) suppresses pathological oscillations in firing rate and between-cell spike synchrony in the vicinity of the electrode but has negligible effects on population-level firing rate or the prevalence of burst firing. The present investigation examines the downstream consequences of GPi-DBS at the level of the primary motor cortex (M1). Multielectrode, single cell recordings were conducted in the M1 of two parkinsonian nonhuman primates (Macaca fasicularis). GPi-DBS that induced significant reductions in muscular rigidity also reduced the prevalence of both beta (12-30 Hz) oscillations in single unit firing rates and of coherent spiking between pairs of M1 neurons. In individual neurons, GPi-DBS-induced increases in mean firing rate were three times more common than decreases; however, averaged across the population of M1 neurons, GPi-DBS induced no net change in mean firing rate. The population-level prevalence of burst firing was also not affected by GPi-DBS. The results are consistent with the hypothesis that suppression of both pathological, beta oscillations and synchronous activity throughout the cortico-basal ganglia network is a major therapeutic mechanism of GPi-DBS.

Common therapeutic mechanisms of pallidal deep brain stimulation for hypo- and hyperkinetic movement disorders.

Abnormalities in cortico-basal ganglia (CBG) networks can cause a variety of movement disorders ranging from hypokinetic disorders, such as Parkinson's disease (PD), to hyperkinetic conditions, such as Tourette syndrome (TS). Each condition is characterized by distinct patterns of abnormal neural discharge (dysrhythmia) at both the local single-neuron level and the global network level. Despite divergent etiologies, behavioral phenotypes, and neurophysiological profiles, high-frequency deep brain stimulation (HF-DBS) in the basal ganglia has been shown to be effective for both hypo- and hyperkinetic disorders. The aim of this review is to compare and contrast the electrophysiological hallmarks of PD and TS phenotypes in nonhuman primates and discuss why the same treatment (HF-DBS targeted to the globus pallidus internus, GPi-DBS) is capable of ameliorating both symptom profiles. Recent studies have shown that therapeutic GPi-DBS entrains the spiking of neurons located in the vicinity of the stimulating electrode, resulting in strong stimulus-locked modulations in firing probability with minimal changes in the population-scale firing rate. This stimulus effect normalizes/suppresses the pathological firing patterns and dysrhythmia that underlie specific phenotypes in both the PD and TS models. We propose that the elimination of pathological states via stimulus-driven entrainment and suppression, while maintaining thalamocortical network excitability within a normal physiological range, provides a common therapeutic mechanism through which HF-DBS permits information transfer for purposive motor behavior through the CBG while ameliorating conditions with widely different symptom profiles.

Global dysrhythmia of cerebro-basal ganglia-cerebellar networks underlies motor tics following striatal disinhibition.

Motor tics, a cardinal symptom of Tourette syndrome (TS), are hypothesized to arise from abnormalities within cerebro-basal ganglia circuits. Yet noninvasive neuroimaging of TS has previously identified robust activation in the cerebellum. To date, electrophysiological properties of cerebellar activation and its role in basal ganglia-mediated tic expression remain unknown. We performed multisite, multielectrode recordings of single-unit activity and local field potentials from the cerebellum, basal ganglia, and primary motor cortex using a pharmacologic monkey model of motor tics/TS. Following microinjections of bicuculline into the sensorimotor putamen, periodic tics occurred predominantly in the orofacial region, and a sizable number of cerebellar neurons showed phasic changes in activity associated with tic episodes. Specifically, 64% of the recorded cerebellar cortex neurons exhibited increases in activity, and 85% of the dentate nucleus neurons displayed excitatory, inhibitory, or multiphasic responses. Critically, abnormal discharges of cerebellar cortex neurons and excitatory-type dentate neurons mostly preceded behavioral tic onset, indicating their central origins. Latencies of pathological activity in the cerebellum and primary motor cortex substantially overlapped, suggesting that aberrant signals may be traveling along divergent pathways to these structures from the basal ganglia. Furthermore, the occurrence of tic movement was most closely associated with local field potential spikes in the cerebellum and primary motor cortex, implying that these structures may function as a gate to release overt tic movements. These findings indicate that tic-generating networks in basal ganglia mediated tic disorders extend beyond classical cerebro-basal ganglia circuits, leading to global network dysrhythmia including cerebellar circuits.

Deep brain stimulation reduces Tic-related neural activity via temporal locking with stimulus pulses.

A neurosurgical intervention that has shown potential for treating basal ganglia (BG) mediated motor tics involves high-frequency deep brain stimulation (HF-DBS) targeted to the output nucleus of the BG: the globus pallidus internus (GPi). This study used a nonhuman primate (Macaca fuscata) model of BG-meditated motor tics, and investigated the short-term neuronal mechanism that might underlie the beneficial effects of GPi-HF-DBS. In parallel with behavioral tic expressions, phasic alterations of neuronal activity emerged in the pallidum following focal disinhibition of the striatum with bicuculline. We delivered HF-DBS in the GPi in such a way that on-stimulation and off-stimulation conditions alternated every 30 s. Analysis of electromyographic (EMG) records showed that during on-stimulation, there were significant reductions in tic-related EMG amplitude. Analysis of pallidal activity showed that GPi-HF-DBS induced both sustained and transient patterns of excitation and inhibition in both segments of the GP. Population-scale firing rates were initially raised relative to baseline, but were not significantly different by the time stimulation ceased. Modulation of behavior and neuronal firing rates were associated with the reduction of tic-related phasic activity in pallidal cells. Examination of short-latency responses showed that firing rate changes were strongly associated with locking of the cells' activity with the HF-DBS pulse. This temporal locking often induced multiphasic changes of firing rates in individual cells, which dynamically changed across the stimulation period. These results support clinical studies that reported success in treating motor tics with GPi-HF-DBS, and demonstrate that the underlying local mechanism within the GP is suppression of tic-related activity through temporal locking with the stimulation pulse.

Short-term depression of synaptic transmission during stimulation in the globus pallidus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates.

High-frequency stimulation (HFS) in the globus pallidus is used to ameliorate clinical symptoms of Parkinson's disease, dystonia, and other disorders. Previous in vivo studies have shown diverse static effects of stimulation on discharge rates and firing patterns of neurons along the corticobasal ganglia loop. In vitro studies, together with other experimental and theoretical studies, have suggested the involvement of synaptic plasticity in stimulation effects. To explore the effects of HFS on synaptic transmission, we studied the dynamic changes in neuronal activity in vivo, using multielectrode recordings during stimulation in the globus pallidus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates. Stimulation effects evolved over time and were pronounced during the first 10 s of stimulation, where 69% of the 249 recorded neurons changed their firing rate and 61% displayed time-locked firing. The time-locked response faded away in 43% of the responding neurons, and its pattern was altered in the remaining cells: the peak response shifted away in time from the stimulus onset, and its amplitude decreased. Repetition of the stimulation protocol revealed a full resetting of the effect, implying short-term synaptic depression. This evolving response is indicative of the transient plasticity of the corticobasal ganglia network in vivo during HFS. Therefore, short-term depression of synaptic transmission may contribute to the mechanism underlying the effects of stimulation during the resulting steady state, altering the balance of neuronal interactions and interfering with pathological information transmission.

The neurophysiological correlates of motor tics following focal striatal disinhibition.

The cortico-basal ganglia pathway is involved in normal motor control and implicated in multiple movement disorders. Brief repetitive muscle contractions known as motor tics are a common symptom in several basal ganglia related motor disorders. We used focal micro-injections of the GABA-A antagonist bicuculline to the sensorimotor putamen of behaving primates to induce stereotyped tics similar to those observed in human disorders. This focal disruption of GABA transmission in the putamen led to motor tics confined to a single or a few muscles. The temporal and structural properties of the tics were identified using electromyogram and frame-by-frame analysis of multi-camera video recordings. During experimental sessions the tics would wax and wane, but their size and shape remained highly stereotyped within the session. Neuronal spiking activity and local field potentials were recorded simultaneously from multiple locations along the cortico-basal ganglia pathway: motor cortex, putamen and globus pallidus external and internal segments. The local field potentials displayed stereotyped tic-related voltage transients lasting several hundred milliseconds. These 'local field potential spikes', which appeared throughout the cortico-basal ganglia pathway, were consistently observed in close temporal association to the motor tics. During tic expression, neuronal activity was altered in most of the recorded neurons in a temporally focal manner, displaying phasic firing rate modulations time locked to the tics. Consistent with theoretical models of tic generation, transient inhibition of the basal ganglia output nucleus prior to and during tic expression was observed. The phasic reduction of basal ganglia output was correlated with a disinhibition of cortical activity, manifesting as short bursts of activity in motor cortex. The results demonstrate that the basal ganglia provide a finely timed disinhibition in the output nuclei of the basal ganglia. However, a large fraction of the neurons were simultaneously inhibited during tics, although tics were only manifested in a small confined muscle group. This suggests that rather than representing a specific action within the basal ganglia itself, these nuclei provide a temporally exact but spatially distributed release signal. The tics induced by striatal disinhibition bear a striking resemblance to motor tics recognized in human pathologies associated with basal ganglia dysfunction. The neuronal changes observed during tic formation may provide valuable insights into the underlying mechanism of tic disorders, as well as into basic information processing in the cortico-basal ganglia loop.

Behavioral and movement disorders induced by local inhibitory dysfunction in primate striatum.

The current model of basal ganglia organization postulates their functional division into sensorimotor, associative, and limbic territories, implicated, respectively, in motor, cognitive, and motivational aspects of behavior. Based on this model, we previously demonstrated, in the external segment of globus pallidus of monkeys, that the same neuronal dysfunction induced dyskinesia or abnormal behavior depending on the functional territory. To extend these findings, we performed bicuculline microinjections into the different functional territories of the striatum in 6 monkeys. Abnormal movements were observed after microinjections into the posterior putamen, corresponding to the sensorimotor territory, and into the dorsal part of the anterior striatum, corresponding to the associative functional territory. Within the ventral striatum, referred to as the limbic functional territory, we identified 3 subregions corresponding to different types of abnormal behaviors. Simultaneous neuronal recordings performed close to the microinjection sites confirmed that bicuculline produced a focal increase of neuronal activity surrounded by a zone with neuronal hypoactivity. This study provides new evidence for the involvement of specific striatal regions in movement as well as in a large spectrum of behavioral disorders and suggests that local inhibitory dysfunction could be a pathological mechanism of various neurological and psychiatric disorders.

Electrophysiological and imaging evidence of sustained inhibition in limbic and frontal networks following deep brain stimulation for treatment refractory obsessive compulsive disorder.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder that arises from a complex interaction of environmental and genetic factors. Despite numerous pharmacological and behavioral interventions, approximately 10% of patients remain refractory. High-frequency deep brain stimulation (HF-DBS) has shown promising results for treatment-refractory OCD. We report the follow-up result of up to 6 years of 4 treatment-refractory OCD patients treated by HF-DBS. Targets of stimulation were the anterior limb of the internal capsule (ALIC) in two cases, and the nucleus accumbens (NAc) in the remaining cohort. The clinical profiles were quantified by the Yale-Brown obsessive-compulsive scale (Y-BOCS). Highly significant reductions in Y-BOCS scores were obtained from all patients during the follow-up period. A greater that 90% reduction in Y-BOCS, observed in the most successful case, was achieved with NAc HF-DBS. Y-BOCS scores in the other patients consistently achieved over 50% reductions in OCD symptoms. FDG-PET imaging indicated post-surgical reductions in metabolism, in not only targeted limbic networks, but also other frontal cortical and subcortical regions, suggesting that large-scale network modulation and inhibitions are associated with functional recovery in OCD. This study demonstrates that HF-DBS targeted to the ALIC and NAc is a safe and effective method for ameliorating intractable, treatment-refractory OCD symptoms. The NAc appeared to be the superior target for symptom reduction, and local inhibition of NAc activity and reduced frontal metabolism are key therapeutic indications.

Global network modulation during thalamic stimulation for Tourette syndrome.

Background and objectives: Deep brain stimulation (DBS) of the thalamus is a promising therapeutic alternative for treating medically refractory Tourette syndrome (TS). However, few human studies have examined its mechanism of action. Therefore, the networks that mediate the therapeutic effects of thalamic DBS remain poorly understood. Methods: Five participants diagnosed with severe medically refractory TS underwent bilateral thalamic DBS stereotactic surgery. Intraoperative fMRI characterized the blood oxygen level-dependent (BOLD) response evoked by thalamic DBS and determined whether the therapeutic effectiveness of thalamic DBS, as assessed using the Modified Rush Video Rating Scale test, would correlate with evoked BOLD responses in motor and limbic cortical and subcortical regions. Results: Our results reveal that thalamic stimulation in TS participants has wide-ranging effects that impact the frontostriatal, limbic, and motor networks. Thalamic stimulation induced suppression of motor and insula networks correlated with motor tic reduction, while suppression of frontal and parietal networks correlated with vocal tic reduction. These regions mapped closely to major regions of interest (ROI) identified in a nonhuman primate model of TS. Conclusions: Overall, these findings suggest that a critical factor in TS treatment should involve modulation of both frontostriatal and motor networks, rather than be treated as a focal disorder of the brain. Using the novel combination of DBS-evoked tic reduction and fMRI in human subjects, we provide new insights into the basal ganglia-cerebellar-thalamo-cortical network-level mechanisms that influence the effects of thalamic DBS. Future translational research should identify whether these network changes are cause or effect of TS symptoms.

Motor cortex stimulation: mild transient benefit in a primate model of Parkinson disease.

OBJECT: The authors sought to examine the therapeutic efficacy of motor cortex stimulation (MCS) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaques and to characterize therapeutic differences with varying modes, frequencies, and durations of stimulation. METHODS: Motor cortex stimulation was delivered at currents below motor threshold and at frequencies between 5 and 150 Hz through epidural electrodes over the primary motor cortex. The animals were studied during and without MCS using video analysis, activity logging, and food retrieval tasks. Animals were examined using two different stimulation protocols. The first protocol consisted of 1 hour of MCS therapy daily. The second protocol exposed the animal to continuous MCS for more than 24 hours with at least 2 weeks between MCS treatments. CONCLUSIONS: Daily MCS yielded no consistent change in symptoms, but MCS at 2-week intervals resulted in significant increases in activity. Effects of biweekly MCS disappeared, however, within 24 hours of the onset of continuous MCS. In this study, MCS only temporarily reduced the severity of MPTP-induced parkinsonism.

A Primary Role for Nucleus Accumbens and Related Limbic Network in Vocal Tics.

Inappropriate vocal expressions, e.g., vocal tics in Tourette syndrome, severely impact quality of life. Neural mechanisms underlying vocal tics remain unexplored because no established animal model representing the condition exists. We report that unilateral disinhibition of the nucleus accumbens (NAc) generates vocal tics in monkeys. Whole-brain PET imaging identified prominent, bilateral limbic cortico-subcortical activation. Local field potentials (LFPs) developed abnormal spikes in the NAc and the anterior cingulate cortex (ACC). Vocalization could occur without obvious LFP spikes, however, when phase-phase coupling of alpha oscillations were accentuated between the NAc, ACC, and the primary motor cortex. These findings contrasted with myoclonic motor tics induced by disinhibition of the dorsolateral putamen, where PET activity was confined to the ipsilateral sensorimotor system and LFP spikes always preceded motor tics. We propose that vocal tics emerge as a consequence of dysrhythmic alpha coupling between critical nodes in the limbic and motor networks. VIDEO ABSTRACT.

Behavioural disorders induced by external globus pallidus dysfunction in primates: I. Behavioural study.

The current model of basal ganglia organization postulates the existence of a functional partitioning into sensorimotor, associative and limbic territories, implicated in motor, cognitive and emotional aspects of behaviour, respectively. This organization was proposed initially on the basis of the cortico-striatal projections and was extended to the various structures of the basal ganglia. While there is a considerable body of experimental evidence in support of an involvement of the basal ganglia sensorimotor territory in basic control of movements, evidence for the functional relevance of the non-motor territories has had to be based on a growing number of clinical observations due to the paucity of relevant animal studies. Previous studies in monkeys have, however, shown that a reversible and focal dysfunction induced by microinjections of bicuculline in the sensorimotor territory of the external globus pallidus (GPe) can generate abnormal movements. We therefore hypothesized that the same approach applied to the associative and limbic territories of the GPe would induce behavioural disorders rather than abnormal movements. To address this hypothesis, we performed microinjections of bicuculline, using the same concentration in each of the sensorimotor, associative and limbic territories of the GPe, as defined by striato-pallidal projections. Spontaneous behaviour and performance of a simple food-retrieving task during the effects of these microinjections were compared with data obtained in control conditions in the same monkeys. We found that bicuculline microinjections induced stereotypy when performed in the limbic part of the GPe, and attention deficit and/or hyperactivity when performed in the associative part. No movement disorders were observed during these behavioural disturbances. As previously described, abnormal movements were observed when bicuculline was injected into the sensorimotor territory of the GPe. The relationship between the localization of microinjection sites and the type of behavioural effect was similar for the three monkeys. Control microinjections of bicuculline into surrounding structures (striatum and internal globus pallidus) and saline injections into the GPe failed to induce any observable effect. These results support the hypotheses of functional diversity and territorial specificity in the GPe, in agreement with the parallel circuits organizational model of the basal ganglia. Furthermore, the behavioural effects shared similar features with symptoms observed in Tourette's syndrome, attention deficit/hyperactivity and compulsive disorders. Thus, our study provides experimental evidence for the involvement of the associative and limbic parts of the basal ganglia in these pathologies. These results may provide the basis for a primate model of these disorders.

Behavioural disorders induced by external globus pallidus dysfunction in primates II. Anatomical study.

The anatomical organization of the basal ganglia supports their involvement in movement and behavioural disorders. Thus dyskinesia, attention deficit with or without hyperactivity, and stereotyped behaviour can be induced by microinjections of bicuculline, a GABAergic antagonist, into different parts of the external globus pallidus (GPe) in monkeys. The aim of the present study was to determine the anatomo-functional circuits inside the basal ganglia which are specifically related to each of these behavioural changes. For that, axonal tracers were injected in the same pallidal sites where abnormal behaviours have previously been obtained by bicuculline microinjections. The labelling was mapped in the different basal ganglia and matched with the topography of the cortico-striato-pallidal projections already reported in the literature and with the distribution of calbindin immunoreactivity. Our results first show that the pallidal sites related to dyskinesia, attention deficit with or without hyperactivity, and stereotyped behaviour, were respectively in motor, associative and limbic territories, defined as weak, moderate and intensive calbindin immunoreactivity. The same relationship was observed between the distribution of the labelling in the different basal ganglia after tracer injections performed in these different pallidal sites and the anatomo-functional territories. Thus regarding the origin of the circuits within the striatum, tracer injections performed in the dyskinesia site labelled neurons located in the posterior sensorimotor putamen, those performed in the hyperactivity and/or attention deficit labelled neurons in the laterodorsal putamen and caudate nucleus, regions corresponding to associative and anterior motor territories, while those performed in the stereotyped behaviour site labelled neurons in the ventral limbic striatum. Regarding the GPe output on the basal ganglia, the different circuits also appeared underlined by different anatomo-functional territories, even if a partial overlap exists. Each of these anatomical circuits systematically involves both the internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNr) but, whereas movement circuit is mainly related to the GPi, stereotyped behaviour is mainly related to the SNr. Additionally, subregions of the subthalamic nucleus were also systematically involved, depending on the movement or behavioural disorder produced. These results demonstrate that distinct circuits involving different anatomo-functional territories of the basal ganglia, with partial overlap, participate in different behavioural disorders in monkeys. It seems likely that these neuronal circuits are involved in pathologies like Tourette's syndrome, attention deficit/hyperactivity disorders and obsessional compulsive troubles. This study provides the basis for further researches with a therapeutical viewpoint.

Pharmacological animal models of tic disorders.

This review summarizes animal models of Tourette syndrome (TS) and associated tic disorders that have been developed through pharmacological manipulation. These models provide a useful platform to explore the pathophysiology and the therapeutic interventions available for these disorders. The current pharmacological models, primarily using rodents and nonhuman primates, are classified in this review into two major categories depending on the methodology used for administration, that is, systemic and focal (intracerebral) injection protocols. The systemic protocol primarily targets monoamines such as dopamine and serotonin, whereas the focal protocol mainly manipulates local transmission of gamma-aminobutyric acid (GABA). Each category is capable of inducing behavioral abnormalities that are characteristic of TS spectrum disorders, ranging from sensorimotor to cognitive and emotional symptoms to various degrees. Among a variety of pharmacological models, focal microinjection of GABA antagonists into the sensorimotor striatum has helped identify abnormal neural discharge in the global networks which underlie tourettism, including not only the cerebral cortex and basal ganglia but also the cerebellum, consistent with recent neuroimaging studies for TS subjects. This unique model also provides the opportunity to clarify the effect and mechanisms of therapeutic deep brain stimulation. Continuing efforts to incorporate cutting-edge knowledge into the existing models, as well as to combine different model platforms, will allow further refinement of animal models, thereby leading to a greater understanding of TS and associated tic disorders.

High-frequency pallidal stimulation eliminates tic-related neuronal activity in a nonhuman primate model of Tourette syndrome.

High-frequency deep brain stimulation targeting the output nucleus of the basal ganglia, the globus pallidus internus, has been suggested as a treatment modality for intractable Tourette syndrome and basal-ganglia-mediated motor tics. Recent studies on the modeling of motor tics induced by focal injections of bicuculline to the striatum, a putative model of Tourette syndrome, have shown that tics induce a widespread modulation within both segments of the globus pallidus. The purpose of this study was to investigate, using the bicuculline-induced Tourette syndrome model, whether and how high-frequency deep brain stimulation targeted to the globus pallidus internus could modulate tic-related activity in the pallidum. The perievent rate changes coinciding with tic expression under the on-stimulation and off-stimulation conditions were examined to determine the effect of high-frequency stimulation on pallidal activity. The results showed that the stimulation blocked tic-related phasic changes in the firing pattern of pallidal cells in parallel with a reduction of the peak amplitude of tic events in the electromyography record. This finding supports the premise that deep brain stimulation targeted to the globus pallidus internus could be a viable treatment option for Tourette syndrome, and the use of pallidal stimulation for motor tics warrants further study.

Deep brain stimulation of the globus pallidus internus in the parkinsonian primate: local entrainment and suppression of low-frequency oscillations.

Competing theories seek to account for the therapeutic effects of high-frequency deep brain stimulation (DBS) of the internal globus pallidus (GPi) for medically intractable Parkinson's disease. To investigate this question, we studied the spontaneous activity of 102 pallidal neurons during GPiDBS in two macaques rendered parkinsonian by administration of MPTP. Stimulation through macroelectrodes in the GPi (> or =200 microA at 150 Hz for 30 s) reduced rigidity in one animal and increased spontaneous movement in both. Novel artifact subtraction methods allowed uninterrupted single-unit recording during stimulation. GPiDBS induced phasic (78% of cells) or sustained (22%) peristimulus changes in firing in both pallidal segments. A subset of cells responded at short latency (<2 ms) in a manner consistent with antidromic driving. Later phasic increases clustered at 3- to 5-ms latency. Stimulation-induced decreases were either phasic, clustered at 1-3 ms, or sustained, showing no peristimulus modulation. Response latency and magnitude often evolved over 30 s of stimulation, but responses were relatively stable by the end of that time. GPiDBS reduced mean firing rates modestly and only in GPi (-6.9 spikes/s). Surprisingly, GPiDBS had no net effect on the prevalence or structure of burst firing. GPiDBS did reduce the prevalence of synchronized low-frequency oscillations. Some cell pairs became synchronized instead at the frequency of stimulation. Suppression of low-frequency oscillations did not require high-frequency synchronization, however, or even the presence of a significant peristimulus response. In summary, the therapeutic effects of GPiDBS may be mediated by an abolition of low-frequency synchronized oscillations as a result of phasic driving.