Activity In Globus Pallidus Internus Research Articles

Chronic intracranial recordings in the globus pallidus reveal circadian rhythms in Parkinson’s disease

Circadian rhythms have been shown in the subthalamic nucleus (STN) in Parkinson’s disease (PD), but only a few studies have focused on the globus pallidus internus (GPi). This retrospective study investigates GPi circadian rhythms in a large cohort of subjects with PD (130 recordings from 93 subjects) with GPi activity chronically recorded in their home environment. We found a significant change in GPi activity between daytime and nighttime in most subjects (82.4%), with a reduction in GPi activity at nighttime in 56.2% of recordings and an increase in activity in 26.2%. GPi activity in higher frequency bands ( > 20 Hz) was more likely to decrease at night and in patients taking extended-release levodopa medication. Our results suggest that circadian fluctuations in the GPi vary across individuals and that increased power at night might be due to the reemergence of pathological neural activity. These findings should be considered to ensure successful implementation of adaptive neurostimulation paradigms in the real-world.

Correlated activity in globus pallidus and thalamus during voluntary reaching movement in three children with primary dystonia

Classical models of the physiology of dystonia suggest that involuntary muscle contractions are caused by inappropriately low activity in Globus Pallidus internus (GPi) that fails to adequately inhibit thalamic inputs to cortex. We test this prediction in three children with primary dystonia undergoing depth electrode recording in basal ganglia and thalamus during selection of targets for deep brain stimulation (DBS) implantation. We compare muscle activity to the power in the spectrogram of the local field potential, as well as to counts of identified spikes in GPi, subthalamic nucleus (STN), and the Ventral oralis (VoaVop) and Ventral Anterior (VA) subnuclei of the thalamus, while subjects are at rest or attempting to make active voluntary arm or leg reaching movements. In all three subjects, both spectrogram power and spike activity in GPi, STN, VoaVop, and VA are significantly positively correlated with movement. In particular, GPi and STN both increase activity during attempted movement. These results contradict the classical rate model of the physiology of dystonia, and support more recent models that propose abnormalities in the detailed pattern of activity rather than the overall lumped activity of pallidum and thalamus.

Increased movement-related signals in both basal ganglia and cerebellar output pathways in two children with dystonia.

The contribution of different brain regions to movement abnormalities in children with dystonia is unknown. Three awake subjects undergoing depth electrode implantation for assessments of potential deep brain recording targets performed a rhythmic figure-8 drawing task. Two subjects had dystonia, one was undergoing testing for treatment of Tourette Syndrome and had neither dystonia nor abnormal movements during testing. Movement-related signals were evaluated by determining the magnitude of task-related frequency components. Brain signals were recorded in globus pallidus internus (GPi), the ventral oralis anterior/posterior (VoaVop) and the ventral intermediate (Vim) nuclei of the thalamus. In comparison to the subject without dystonia, both children with dystonia showed increased task-related activity in GPi and Vim. This finding is consistent with a role of both basal ganglia and cerebellar outputs in the pathogenesis of dystonia. Our results further suggest that frequency analysis of brain recordings during cyclic movements may be a useful tool for analysis of the presence of movement-related signals in various brain regions.

Globus pallidus internus activity during simultaneous bilateral microelectrode recordings in status dystonicus

Limited data are available regarding the electrophysiology of status dystonicus (SD). We report simultaneous microelectrode recordings (MERs) from the globus pallidus internus (GPi) of a patient with SD who was treated with bilateral deep brain stimulation (DBS). Mean neuronal discharge rate was of 30.1 ± 10.9Hz and 38.5Hz ± 11.1Hz for the right and left GPi, respectively. On the right side, neuronal electrical activity was completely abolished at the target point, whereas the mean burst index values showed a predominance of bursting and irregular activity along trajectories on both sides. Our data are in line with previous findings of pallidal irregular hypoactivity as a potential electrophysiological marker of dystonia and thus SD, but further electrophysiological studies are needed to confirm our results.

Characteristics of oscillatory pallidal neurons in patients with Parkinson's disease

BackgroundExcessive neuronal activity in the globus pallidus internus (GPi) is believed to promote parkinsonian akinesia/bradykinesia, but not tremor. Parkinsonian tremor is thought to result from dysfunction in the basal ganglia and cerebello-thalamo-cortical circuits. Whether the GPi is involved in tremorgenesis has not been fully elucidated. This study was designed to quantify the characteristics of oscillatory GPi neurons in patients with Parkinson's disease. MethodsNine patients undergoing surgery were studied. Microelectrode recordings in the GPi and electromyographic (EMG) activity in the limbs were recorded and the mean spontaneous firing rates (MSFRs) were calculated. Spectral analysis was used to assess neuronal oscillatory patterns. Coherence analysis was applied to explore the relationship between oscillatory neurons and EMG. ResultsOf 79 GPi neurons, 50.6% oscillated at the tremor frequency; 25.3% oscillated at β frequency, and 24.1% did not oscillate. The MSFR of all neurons was 81.5 ± 7.4 spikes/s. Among neurons oscillating at tremor frequency, 40% were coherent with the tremor. In four neurons, the pattern changed from tremor frequency to β frequency or vice versa. It appeared that the tremor began before the GPi fired bursts. ConclusionSome neuronal activity in the GPi correlates with tremor and this correlation might be due to either feedback, maintenance, or initiation. Since there were examples of EMG tremor prior to GPi activity, initiation seems least likely. The data further support the prediction of the classic pathophysiology model of Parkinson's disease.

Inhibiting Basal Ganglia Regions Reduces Syllable Sequencing Errors in Parkinson's Disease: A Computer Simulation Study.

Background: Parkinson's disease affects many motor processes including speech. Besides drug treatment, deep brain stimulation (DBS) in the subthalamic nucleus (STN) and globus pallidus internus (GPi) has developed as an effective therapy.Goal: We present a neural model that simulates a syllable repetition task and evaluate its performance when varying the level of dopamine in the striatum, and the level of activity reduction in the STN or GPi.Method: The Neural Engineering Framework (NEF) is used to build a model of syllable sequencing through a cortico-basal ganglia-thalamus-cortex circuit. The model is able to simulate a failing substantia nigra pars compacta (SNc), as occurs in Parkinson's patients. We simulate syllable sequencing parameterized by (i) the tonic dopamine level in the striatum and (ii) average neural activity in STN or GPi.Results: With decreased dopamine levels, the model produces syllable sequencing errors in the form of skipping and swapping syllables, repeating the same syllable, breaking and restarting in the middle of a sequence, and cessation (“freezing”) of sequences. We also find that reducing (inhibiting) activity in either STN or GPi reduces the occurrence of syllable sequencing errors.Conclusion: The model predicts that inhibiting activity in STN or GPi can reduce syllable sequencing errors in Parkinson's patients. Since DBS also reduces syllable sequencing errors in Parkinson's patients, we therefore suggest that STN or GPi inhibition is one mechanism through which DBS reduces syllable sequencing errors in Parkinson's patients.

Impulsivity in Parkinson’s disease is associated with altered subthalamic but not globus pallidus internus activity

BackgroundA significant subset of patients with Parkinson’s disease (PD) suffer from impulse control disorders (ICDs). A hallmark feature of many ICDs is the pursuit of rewarding behaviours despite negative consequences....

S9-5. Pathophysiology of dystonia based on the findings of microrecording

We analyzed the features of neuronal activities, (a) firing rate, (b) firing pattern, and (c) response to passive joint movement, recorded from the globus pallidus internus (GPi) of patients with dystonia (DT) and Parkinson’s disease (PD). The spontaneous firing rate of GPi neurons in DT tended to be lower than that in PD. The reduced GPi activity resulted in disinhibition of thalamocortical pathways, which could cause DT as a form of hyperkinesia. However, identifying this reduced GPi activity is inconsistent with alleviation of DT in patients with pallidotomy. The pathology of DT, thus, cannot be explained solely by the reduced GPi activity. Quantitative examination of pauses and bursts from interspike intervals showed that pauses and bursts were significantly higher in DT than in PD. These abnormal firing patterns are conjectured to disrupt signaling along cerebello-thalamocortical pathways, impairing motor control and resulting in DT. Thus, abnormal firing patterns may represent temporal dysfunction. Changes in the GPi included enlargement of the receptive fields and an increased number of neurons exhibiting inhibitory reactions. DT symptoms may arise because of dysfunction of the mechanism inhibiting unrequired movements. The abnormal changes in the neurons in DT may underlie spatiotemporal dysfunction.

Basal Ganglia Neurons Dynamically Facilitate Exploration during Associative Learning

The basal ganglia (BG) appear to play a prominent role in associative learning, the process of pairing external stimuli with rewarding responses. Accumulating evidence suggests that the contributions of various BG components may be described within a reinforcement learning model, in which a broad repertoire of possible responses to environmental stimuli are evaluated before the most profitable one is chosen. The striatum receives diverse cortical inputs, providing a rich source of contextual information about environmental cues. It also receives projections from midbrain dopaminergic neurons, whose phasic activity reflects a reward prediction error signal. These coincident information streams are well suited for evaluating responses and biasing future actions toward the most profitable response. Still lacking in this model is a mechanistic description of how initial response variability is generated. To investigate this question, we recorded the activity of single neurons in the globus pallidus internus (GPi), the primary BG output nucleus, in nonhuman primates (Macaca mulatta) performing a motor associative learning task. A subset (29%) of GPi neurons showed learning-related effects, decreasing firing during the early stages of learning, then returning to higher baseline rates as associations were mastered. On a trial-by-trial basis, lower firing rates predicted exploratory behavior, whereas higher rates predicted an exploitive response. These results suggest that, during associative learning, BG output is initially permissive, allowing exploration of a variety of responses. Once a profitable response is identified, increased GPi activity suppresses alternative responses, sharpening the response profile and encouraging exploitation of the profitable learned behavior.

Pallidotomy for tremor.

We studied tremor-related activity in globus pallidus internus (GPi) neurons and the effects of pallidotomy on tremor in patients with Parkinson's disease. By using microelectrode recording, we identified GPi neurons with rhythmic firing at the frequency of contralateral tremor. There was a strong correlation between the tremor-related neuronal activity and limb tremor (r = 0.73). The majority of tremor-related neurons were located in the ventral one half of the caudal GPi, the area that is the target for pallidotomy. We found that pallidotomy produced striking improvements in off-period contralateral tremor. These effects were immediate and were maintained for > or = 2 years. This benefit is obtained despite the progressive nature of the illness and the often reduced dose of medications after surgery.

Pallidal burst activity during therapeutic deep brain stimulation

Theoretical and experimental analyses of deep brain stimulation (DBS) in the subthalamic nucleus (STN) show both excitatory and inhibitory effects on the neural elements surrounding the electrode. Given these observations, the mechanism underlying the therapeutic effect of STN DBS on parkinsonian motor signs remains under debate. One hypothesis suggests that abnormal levels of bursting activity in the pallidum play a key role in the development of parkinsonian motor signs and that STN DBS may exert its beneficial effect by modifying this type of activity. We quantified the changes in bursting activity of globus pallidus internus (GPi) and externus (GPe) neurons before and during ineffective (subtherapeutic) and effective (therapeutic) STN DBS in two monkeys rendered parkinsonian by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Compared to pre-stimulation control values, the population mean firing rate increased during therapeutic stimulation significantly in both GPe (from 41.7 Hz ± 2.8 to 71.4 Hz ± 7.8) and GPi (from 58.8 Hz ± 4.2 to 71.5 Hz ± 6.2). The burst rate, however, increased significantly in GPe (from 80.1 bursts/min ± 10.0 to 103.1 bursts/min ± 11.1) and decreased significantly in GPi (from 104.2 bursts/min ± 8.3 to 75.8 bursts/min ± 10.8). Although both animals showed improvement in parkinsonian motor signs, changes in rate and bursting activity in GPi were significant only in one animal. These data suggest that while changes in rate and bursting activity may contribute to the improvement in PD motor signs during STN DBS, one cannot explain the therapeutic effects of stimulation in all cases solely on changes in these parameters. Other physiological changes that contribute to its therapeutic effect must also occur.

Customization of coherence analysis by relaxing its iso-frequency constraint

Coherence analysis is a tool to probe the functional connectivity of two neural oscillators through studying the two signals recorded from them. A sliding window cuts the two signals into a number of corresponding epochs. The power of any given frequency in the two signals can be expressed as a pair of multidimensional vectors. The number of dimensions is equal to the number of the epochs. Coherence of the two signals at that given frequency is calculated as the squared cosine of the angle between these two multidimensional vectors. This style of calculation of coherence is based on the presumption that the functional connectivity of the two oscillators would be demonstrated as simultaneous, linearly correlated wax and wane in the power of oscillation in identical frequencies; but many connected neural oscillators do not exhibit this behavior. An example is the circuitry of Globus Pallidus internus (GPi), thalamocortical relay nucleus (TC), and thalamic reticular nucleus (RE). In this circuit, a four Hz burst activity in GPi triggers an eight Hz burst in TC under the effect of RE. Therefore, GPi and TC are functionally connected but not in identical frequencies and this aspect of their connectivity can not be demonstrated by the conventional coherence analysis. The present study suggests a customized version of coherence in which the calculation of coherence can be extrapolated to the vectors representing powers of non identical frequencies in the two signals. This extrapolation has been tested on a model of GPi-TC-RE and a peak in the customized coherence between the vector of 4 Hz activity of GPi and the vector of 8 Hz activity of TC has been demonstrated.

Borrowing from models of motor control to translate cognitive processes: Evidence for hypokinetic–hyperkinetic linguistic homologues?

In relation to motor control, the basal ganglia have been implicated in both the scaling and focusing of movement. Hypokinetic and hyperkinetic movement disorders manifest as a consequence of overshooting and undershooting GPi (globus pallidus internus) activity thresholds, respectively. Recently, models of motor control have been borrowed to translate cognitive processes relating to the overshooting and undershooting of GPi activity, including attention and executive function. Linguistic correlates, however, are yet to be extrapolated in sufficient detail. The aims of the present investigation were to: (1) characterise cognitive–linguistic processes within hypokinetic and hyperkinetic neural systems, as defined by motor disturbances; (2) investigate the impact of surgically-induced GPi lesions upon language abilities. Two Parkinsonian cases with opposing motor symptoms (akinetic versus dystonic/dyskinetic) served as experimental subjects in this research. Assessments were conducted both prior to as well as 3 and 12 months following bilateral posteroventral pallidotomy (PVP). Reliable changes in performance (i.e. both improvements and decrements) were typically restricted to tasks demanding complex linguistic operations across subjects. Hyperkinetic motor symptoms were associated with an initial overall improvement in complex language function as a consequence of bilateral PVP, which diminished over time, suggesting a decrescendo effect relative to surgical beneficence. In contrast, hypokinetic symptoms were associated with a more stable longitudinal linguistic profile, albeit defined by higher proportions of reliable decline versus improvement in postoperative assessment scores. The above findings endorsed the integration of the GPi within cognitive mechanisms involved in the arbitration of complex language functions. In relation to models of motor control, ‘focusing’ was postulated to represent the neural processes underpinning lexical-semantic manipulation, and ‘scaling’ the potential allocation of cognitive resources during the mediation of high-level linguistic tasks.

Neuronal activity in the basal ganglia and thalamus in patients with dystonia

Objective: To explore the role of abnormal neuronal activity in the basal ganglia and thalamus in the generation of dystonia. Methods: Microelectrode recording was performed in the globus pallidus internus (GPi), ventral thalamic nuclear group ventral oral posterior/ventral intermediate, Vop/Vim) and subthalamic nucleus (STN) in patients with primary dystonia ( n=11) or secondary dystonia ( n=9) during surgery. Electromyogram (EMG) was simultaneously recorded in selected muscle groups. Single unit analysis and cross-correlations were carried out. Results: Three hundred and sixty-seven neurons were obtained from 29 trajectories (GPi: 13; Vop/Vim: 12; STN: 4), 87% exhibited altered neuronal activity including grouped discharges in GPi ( n=79) and STN ( n=37), long-lasting neuronal activity ( n=70) and rapid neuronal discharge ( n=86) in Vop/Vim. There were neurons in Vop, GPi and STN firing at the same frequency as EMG during dystonia (mean: 0.39 Hz, range 0.12–0.84 Hz). Significant correlations between neuronal activity and EMG at the frequency of dystonia were obtained (GPi: r 2=0.7 ( n=31), Vop/Vim: r 2=0.64 ( n=18) and STN: r 2=0.86 ( n=17)). Conclusions: Consistent with previous findings of abnormalities observed in Vop/VIM and GPi in relation to dystonia, the present data further show that the altered activity in GPi, specifically in dorsal subregions of GPi, Vop/Vim and STN is likely to be directly involved in the production of dystonic movement. Dystonia-related neuronal activity observed in motor thalamus and basal ganglia nuclei of GPi and STN indicates a critical role of their interactions affecting both indirect and direct pathways in the development of either generalized or focal dystonia. Significance: These data support a central role of the basal ganglia in producing dystonic movements.

The effects of reversible inactivation of the subthalamo-pallidal pathway on the behaviour of naive and hemiparkinsonian monkeys

This study was designed to further investigate the role of the subthalamic nucleus (STN) and globus pallidus internus (GPi) in the pathophysiology of Parkinson's disease. The prevailing theory about the pathophysiology of Parkinson's disease (PD) predicts that there is overactivity of the subthalamo-pallidal pathway. In order to inactivate that pathway, naive and hemiparkinsonian monkeys were locally administered either muscimol (to reversibly inactivate the contralateral STN) or kynurenic acid (to reduce glutamatergic activity in the contralateral GPi). Three naive and 2 hemiparkinsonian monkeys were studied. Intra-carotid MPTP was administered to produce 2 hemiparkinsonian monkeys. Injection sites of muscimol and kynurenic acid in the brain were confirmed electrophysiologically and histologically. Injections of muscimol into the STN in naive and hemiparkinsonian monkeys caused reversible contralateral dystonia, but did not alleviate Parkinsonism. Only one kynurenic acid injection into GPi partially alleviated Parkinsonism. On the basis of the results in this study, aspects of the currently accepted hypothesis of the pathophysiology of PD cannot be confirmed. However, this study reports that the STN has an important role in the production of dystonia. This experimental model of dystonia will prove suitable for further study of both the mechanisms causing dystonia as well as for possible therapeutic approaches to its treatment.

WS-31-1 Subthalamic recording of tremor-like activity

In relation to motor control, the basal ganglia have been implicated in both the scaling and focusing of movement. Hypokinetic and hyperkinetic movement disorders manifest as a consequence of overshooting and undershooting GPi (globus pallidus internus) activity thresholds, respectively. Recently, models of motor control have been borrowed to translate cognitive processes relating to the overshooting and undershooting of GPi activity, including attention and executive function. Linguistic correlates, however, are yet to be extrapolated in sufficient detail. The aims of the present investigation were to: (1) characterise cognitive–linguistic processes within hypokinetic and hyperkinetic neural systems, as defined by motor disturbances; (2) investigate the impact of surgically-induced GPi lesions upon language abilities.Two Parkinsonian cases with opposing motor symptoms (akinetic versus dystonic/dyskinetic) served as experimental subjects in this research. Assessments were conducted both prior to as well as 3 and 12 months following bilateral posteroventral pallidotomy (PVP). Reliable changes in performance (i.e. both improvements and decrements) were typically restricted to tasks demanding complex linguistic operations across subjects. Hyperkinetic motor symptoms were associated with an initial overall improvement in complex language function as a consequence of bilateral PVP, which diminished over time, suggesting a decrescendo effect relative to surgical beneficence. In contrast, hypokinetic symptoms were associated with a more stable longitudinal linguistic profile, albeit defined by higher proportions of reliable decline versus improvement in postoperative assessment scores.The above findings endorsed the integration of the GPi within cognitive mechanisms involved in the arbitration of complex language functions. In relation to models of motor control, ‘focusing’ was postulated to represent the neural processes underpinning lexical-semantic manipulation, and ‘scaling’ the potential allocation of cognitive resources during the mediation of high-level linguistic tasks.