Globus Pallidus Internus Neurons Research Articles

Interrogating basal ganglia circuit function in people with Parkinson's disease and dystonia.

The dichotomy between the hypo- versus hyperkinetic nature of Parkinson's disease (PD) and dystonia, respectively, is thought to be reflected in the underlying basal ganglia pathophysiology. In this study, we investigated differences in globus pallidus internus (GPi) neuronal activity, and short- and long-term plasticity of direct pathway projections. Using microelectrode recording data collected from the GPi during deep brain stimulation surgery, we compared neuronal spiketrain features between people with PD and those with dystonia, as well as correlated neuronal features with respective clinical scores. Additionally, we characterized and compared readouts of short- and long-term synaptic plasticity using measures of inhibitory evoked field potentials. GPi neurons were slower, bustier, and less regular in dystonia. In PD, symptom severity positively correlated with the power of low-beta frequency spiketrain oscillations. In dystonia, symptom severity negatively correlated with firing rate and positively correlated with neuronal variability and the power of theta frequency spiketrain oscillations. Dystonia was moreover associated with less long-term plasticity and slower synaptic depression. We substantiated claims of hyper- versus hypofunctional GPi output in PD versus dystonia, and provided cellular-level validation of the pathological nature of theta and low-beta oscillations in respective disorders. Such circuit changes may be underlain by disease-related differences in plasticity of striato-pallidal synapses. This project was made possible with the financial support of Health Canada through the Canada Brain Research Fund, an innovative partnership between the Government of Canada (through Health Canada) and Brain Canada, and of the Azrieli Foundation (LM), as well as a grant from the Banting Research Foundation in partnership with the Dystonia Medical Research Foundation (LM).

Interrogating basal ganglia circuit function in people with Parkinson’s disease and dystonia

Background:The dichotomy between the hypo- versus hyperkinetic nature of Parkinson’s disease (PD) and dystonia, respectively, is thought to be reflected in the underlying basal ganglia pathophysiology. In this study, we investigated differences in globus pallidus internus (GPi) neuronal activity, and short- and long-term plasticity of direct pathway projections.Methods:Using microelectrode recording data collected from the GPi during deep brain stimulation surgery, we compared neuronal spiketrain features between people with PD and those with dystonia, as well as correlated neuronal features with respective clinical scores. Additionally, we characterized and compared readouts of short- and long-term synaptic plasticity using measures of inhibitory evoked field potentials.Results:GPi neurons were slower, bustier, and less regular in dystonia. In PD, symptom severity positively correlated with the power of low-beta frequency spiketrain oscillations. In dystonia, symptom severity negatively correlated with firing rate and positively correlated with neuronal variability and the power of theta frequency spiketrain oscillations. Dystonia was moreover associated with less long-term plasticity and slower synaptic depression.Conclusions:We substantiated claims of hyper- versus hypofunctional GPi output in PD versus dystonia, and provided cellular-level validation of the pathological nature of theta and low-beta oscillations in respective disorders. Such circuit changes may be underlain by disease-related differences in plasticity of striato-pallidal synapses.Funding:This project was made possible with the financial support of Health Canada through the Canada Brain Research Fund, an innovative partnership between the Government of Canada (through Health Canada) and Brain Canada, and of the Azrieli Foundation (LM), as well as a grant from the Banting Research Foundation in partnership with the Dystonia Medical Research Foundation (LM).

Subthalamic and pallidal neurons are modulated during externally cued movements in Parkinson's disease

External sensory cues can reduce freezing of gait in people with Parkinson's disease (PD), yet the role of the basal ganglia in these movements is unclear. We used microelectrode recordings to examine modulations in single unit (SU) and oscillatory local field potentials (LFP) during auditory-cued rhythmic pedaling movements of the feet. We tested five blocks of increasing cue frequencies (1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz, and 3 Hz) in 24 people with PD undergoing deep brain stimulation surgery of the subthalamic nucleus (STN) or globus pallidus internus (GPi). Single unit firing and beta band LFPs (13–30 Hz) in response to movement onsets or cue onsets were examined. We found that the timing accuracy of foot pedaling decreased with faster cue frequencies. Increasing cue frequencies also attenuated firing rates in both STN and GPi neurons. Peak beta power in the GPi and STN showed different responses to the task. GPi beta power showed persistent suppression with fast cues and phasic modulation with slow cues. STN beta power showed enhanced beta synchronization following movement. STN beta power also correlated with rate of pedaling. Overall, we showed task-related responses in the GPi and STN during auditory-cued movements with differential roles in sensory and motor control. The results suggest a role for both input and output basal ganglia nuclei in auditory rhythmic pacing of gait-like movements in PD.

Healthy and pathological pallidal regulation of thalamic burst versus tonic mode firing: a computational simulation.

The mechanisms by which the basal ganglia influence the pallidal-receiving thalamus remain to be adequately defined. Our prior in vivo recordings in fully alert normal and dystonic rats revealed that normally fast tonic discharging entopeduncular [EP, rodent equivalent of the globus pallidus internus (GPi)] neurons are pathologically slow, highly irregular, and bursty under dystonic conditions. This, in turn, induces pallidal-receiving thalamic movement-related neurons to change from a healthy burst predominant to a pathological tonic-predominant resting firing mode. This study aims to understand the pallidal influence on thalamic firing modes using computational simulations. We inputted various combinations of healthy and pathological (dystonic) in vivo neuronal recordings to the Rubin and Terman's computational model of low threshold spiking pallidothalamic neurons. The input sets consist of representative tonic, burst, irregular tonic and irregular burst inputs collected from EP/GPi in our animal lab. Initial test combinations of EP/ GPi input to the model were identical to the neuronal population distributions observed in vivo. The thalamic neuron model outputted similar firing rate and mode as observed in corresponding in-vivo thalamus. Further influence of each individual patterns was also delineated. By simulating the firing properties of encountered neurons, the basal ganglia output is suggested to critically act as firing mode selector for thalamic motor relay neurons. By selecting and determining the timing and extent of opening of thalamic T-type calcium channels via GABAergic hyperpolarizing input, GPi neurons are in position to precisely orchestrate thalamocortical burst motor signaling.

Multiscale co-simulation of deep brain stimulation with brain networks in neurodegenerative disorders

Deep brain stimulation (DBS) has been used successfully as symptomatic treatment in several neurodegenerative disorders, including Parkinson’s disease (PD). However, the mechanisms of its activity inside the brain network are unclear. Many virtual DBS models investigate the dynamics of a subnetwork surrounding the basal ganglia (BG) as a spiking network has been attracting a growing body of research in neuroscience. Connectomic data, on the other hand, show that DBS has a wide range of impacts on many distinct cortical and subcortical sites. Notably, the nonlinear reaction–diffusion multiscale mathematical models demonstrate the effectiveness of capturing crucial disease characteristics and are used to simulate large-scale brain activity. The BG and associated nuclei comprise many subcortical cell groups in the brain, and their couplings commonly revealed MRI-based assessments of the strength of anatomical connections. We have developed a hybrid modeling formalism and a unique co-simulation technique that allows us to compute electrodiffusive ion dynamics for the cortex–BG–thalamus (BGTH) brain network model within a large-scale brain connectome. We collect data from the Human Connectome Project (HCP) and propose a closed-loop DBS approach based on the brain network model. Moreover, we select regions in the parameter space that reflect the healthy and Parkinsonian states as well as the impact of DBS on the subthalamic nucleus (STN) and globus pallidus internus (GPi) neurons. We predicted that if we apply the DBS to the system described by the temporal model, the brain maintains a healthy state until 0.05ms for STN neurons and 0.035ms for GPi neurons. A local regulatory mechanism known as feedback inhibition control (FIC) points to the existence of underlying network dynamics in the white matter of connected brain regions. The model showed unanticipated effects that in the presence of diffusion, the human brain maintained a healthy state for a long time after the DBS had been applied to STN and GPi neurons. This research helps us better understand the changes in brain activity caused by DBS and enhances this clinical therapy, thus shedding new light on the importance of DBS mechanisms in BGTH brain network models of neurodegenerative disorders.

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.

Modulations in Oscillatory Activity of Globus Pallidus Internus Neurons During a Directed Hand Movement Task-A Primary Mechanism for Motor Planning.

Globus pallidus internus (GPi) neurons in the basal ganglia are traditionally thought to play a significant role in the promotion and suppression of movement via a change in firing rates. Here, we hypothesize that a primary mechanism of movement control by GPi neurons is through specific modulations in their oscillatory patterns. We analyzed neuronal spiking activity of 83 GPi neurons recorded from two healthy nonhuman primates executing a radial center-out motor task. We found that, in directionally tuned neurons, the power in the gamma band is significantly (p < 0.05) greater than that in the beta band (a “cross-over” effect), during the planning stages of movements in their preferred direction. This cross-over effect is not observed in the non-directionally tuned neurons. These data suggest that, during movement planning, information encoding by GPi neurons may be governed by a sudden emergence and suppression of oscillatory activities, rather than simply by a change in average firing rates.

Properties of oscillatory neuronal activity in the basal ganglia and thalamus in patients with Parkinson\u2019s disease

BackgroundThe cardinal features of Parkinson’s disease (PD) are bradykinesia, rigidity and rest tremor. Abnormal activity in the basal ganglia is predicted to underlie the mechanism of motor symptoms. This study aims to characterize properties of oscillatory activity in the basal ganglia and motor thalamus in patients with PD.MethodsTwenty-nine patients with PD who underwent bilateral or unilateral electrode implantation for subthalamic nucleus (STN) DBS (n = 11), unilateral pallidotomy (n = 9) and unilateral thalamotomy (n = 9) were studied. Microelectrode recordings in the STN, globus pallidus internus (GPi) and ventral oral posterior/ventral intermediate of thalamus (Vop/Vim) were performed. Electromyography of the contralateral limbs was recorded. Single unit characteristics including interspike intervals were analyzed. Spectral and coherence analyses were assessed. Mean spontaneous firing rate (MSFR) of neurons was calculated. Analysis of variance and X2 test were performed.ResultsOf 76 STN neurons, 39.5% were 4–6 Hz band oscillatory neurons and 28.9% were β frequency band (βFB) oscillatory neurons. The MSFR was 44.2 ± 7.6 Hz. Of 62 GPi neurons, 37.1% were 4–6 Hz band oscillatory neurons and 27.4% were βFB neurons. The MSFR was 80.9 ± 9.6 Hz. Of 44 Vop neurons, 65.9% were 4–6 Hz band oscillatory neurons and 9% were βFB neurons. The MSFR was 24.4 ± 4.2 Hz. Of 30 Vim oscillatory neurons, 70% were 4–6 Hz band oscillatory neurons and 13.3% were βFB neurons. The MSFR was 30.3 ± 3.6 Hz. Further analysis indicated that proportion of βFB oscillatory neurons in STN and GPi was higher than that of similar neurons in the Vop and Vim (P < 0.05). Conversely, the proportion of 4–6 Hz band oscillatory neurons and tremor related neurons in the Vim and Vop was higher than that of STN and GPi (P < 0.05). The highest MSFR was for GPi oscillatory neurons whereas the lowest MSFR was for Vop oscillatory neurons (P < 0.005).ConclusionThe alterations in neuronal activity in basal ganglia play a critical role in generation of parkinsonism. β oscillatory activity is more prominent in basal ganglia than in thalamus suggesting that the activity likely results from dopaminergic depletion. While both basal ganglia and thalamus have tremor activity, the thalamus appears to play a more important role in tremor production, and basal ganglia β oscillatory activity might be the trigger.

Neuronal firing rate and oscillatory patterns in the basal ganglia nuclei differ from those of the ventrolateral thalamus in patients with Parkinson disease

We compared the firing rates and proportion of patterns of oscillatory neurons in the subthalamic nucleus (STN), globus pallidus internus (GPi), and ventrolateral thalamus (VL) in Parkinson disease (PD). Twenty-nine patients with PD who underwent stereotactic neurosurgery were included in the study. Microelectrode recordings in the STN (n = 16), GPi (n = 9), and VL (n = 9) were performed. Power spectral analysis was used to explore neuronal oscillation. Of 76 STN neurons, 39.5% were tremor frequency oscillatory neurons (4–6 Hz, TFB) and 28.9% were β frequency oscillatory neurons (βFB); their mean spontaneous firing rate (MSFR) was 44.2 ± 7.6 Hz (n = 52). Of 62 GPi neurons, 37.1% were TFB oscillatory neurons and 27.4% were βFB oscillatory neurons; the MSFR was 80.9 ± 9.6 Hz. Of 69 V L neurons, 65.2% were TFB oscillatory neurons and 11.6% were βFB oscillatory neurons; the MSFR was 26.7 ± 5.0 Hz. The increased MSFR of GPi and reduced MSFR of VL oscillatory neurons in parkinsonian patients further support prediction of a pathophysiology model of PD. The high proportion of βFB oscillatory neurons in the STN and GPi suggests that dopaminergic deficits result in abnormal β oscillatory synchronization in the basal ganglia in the parkinsonian state. The high proportion of TFB oscillatory neurons in the VL demonstrates that both the basal ganglia and cerebellothalamic circuits are involved in the generation of parkinsonian tremor; the latter circuit might have a more important role in tremor genesis.

Effects of the temporal pattern of subthalamic deep brain stimulation on the neuronal complexity in the globus pallidus.

Deep brain stimulation (DBS) is a surgical treatment for Parkinson's disease (PD) but, despite clinical efficacy, the mechanisms of DBS still require investigation. Recent evidence suggests that the temporal pattern of the electrical pulses may be critical to the therapeutic merit of DBS and carefully-designed, non-regular patterns could ameliorate some of the motor symptoms in PD. It is unclear, though, how different stimulation patterns affect the neural activity in the basal ganglia and whether this is related to the pathophysiology of PD. In this study, a non-human primate was treated with DBS of the subthalamic nucleus while single-unit recordings were collected in the animal's globus pallidus internus (GPi). Three stimulation patterns were applied (one regular, two non-regular) and the stimulation effects on the GPi spike trains were assessed via point process modeling. On a preliminary set of 23 GPi neurons, we show that regular DBS maximized the neuronal complexity, which is a measure of the amount of information that a single neuron can encode, and significantly increased the dependency of the neurons' spike trains on the background ensemble activity through an articulated balance of excitation and inhibition. Overall, regular DBS caused the largest modulation in the neurons' spiking pattern and the largest increment in encoding capabilities. Both results may be relevant to the mechanisms of therapeutic DBS.

Orexin Directly Enhances the Excitability of Globus Pallidus Internus Neurons in Rat by Co-activating OX1 and OX2 Receptors.

Orexin, released from the hypothalamus, has been implicated in various basic non-somatic functions including feeding, the sleep-wakefulness cycle, emotion, and cognition. However, the role of orexin in somatic motor control is still little known. Here, using whole-cell patch clamp recording and immunostaining, we investigated the effect and the underlying receptor mechanism of orexin-A on neurons in the globus pallidus internus (GPi), a critical structure in the basal ganglia and an effective target for deep brain stimulation therapy. Our results showed that orexin-A induced direct postsynaptic excitation of GPi neurons in a concentration-dependent manner. The orexin-A-induced excitation was mediated via co-activation of both OX1 and OX2 receptors. Furthermore, the immunostaining results showed that OX1 and OX2 receptors were co-localized in the same GPi neurons. These results suggest that the central orexinergic system actively modulates the motor functions of the basal ganglia via direct innervation on GPi neurons and presumably participates in somatic-non-somatic integration.

The human subthalamic nucleus and globus pallidus internus differentially encode reward during action control.

The subthalamic nucleus (STN) and globus pallidus internus (GPi) have recently been shown to encode reward, but few studies have been performed in humans. We investigated STN and GPi encoding of reward and loss (i.e., valence) in humans with Parkinson's disease. To test the hypothesis that STN and GPi neurons would change their firing rate in response to reward- and loss-related stimuli, we recorded the activity of individual neurons while participants performed a behavioral task. In the task, action choices were associated with potential rewarding, punitive, or neutral outcomes. We found that STN and GPi neurons encode valence-related information during action control, but the proportion of valence-responsive neurons was greater in the STN compared to the GPi. In the STN, reward-related stimuli mobilized a greater proportion of neurons than loss-related stimuli. We also found surprising limbic overlap with the sensorimotor regions in both the STN and GPi, and this overlap was greater than has been previously reported. These findings may help to explain alterations in limbic function that have been observed following deep brain stimulation therapy of the STN and GPi. Hum Brain Mapp 38:1952-1964, 2017. © 2017 Wiley Periodicals, Inc.

Information in pallidal neurons increases with parkinsonian severity

IntroductionThe motor symptoms of Parkinson's disease (PD) present with pathological neuronal activity in the basal ganglia. Although neuronal firing rate changes in the globus pallidus internus (GPi) and externus (GPe) are reported to underlie the development of PD motor signs, firing rates change inconsistently, vary confoundingly with some therapies, and are poor indicators of symptom severity. MethodsWe explored the relationship between parkinsonian symptom severity and the effectiveness with which pallidal neurons transmit information. We quantify neuronal entropy and information – alternatives to firing rate and correlations respectively – in and between GPe and GPi neurons using a progressive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, non-human primate model of PD. ResultsNeuronal entropy and symptom severity were not linearly correlated: in both pallidal segments, entropy increased from naive to moderate parkinsonism, but decreased with further progression to the severely parkinsonian condition. In contrast, information transmitted from GPe to GPi increased consistently with symptom severity. Furthermore, antidromic information from GPi to GPe increased substantially with symptom severity. Together, these findings suggest that as parkinsonian severity increases, more and more information enters GPe and GPi from common sources, diminishing the relative importance of the orthodromic GPe to GPi connection. ConclusionsWith parkinsonian progression, the direct and indirect pathways lose their independence and start to convey redundant information. We hypothesize that a loss of parallel processing impairs the ability of the network to select and implement motor commands, thus promoting the hypokinetic symptoms of PD.

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.

Frequency-dependent effects of electrical stimulation in the globus pallidus of dystonia patients

Deep brain stimulation (DBS) in the globus pallidus internus (GPi) has been shown to improve dystonia, a movement disorder of repetitive twisting movements and postures. DBS at frequencies above 60 Hz improves dystonia, but the mechanisms underlying this frequency dependence are unclear. In patients undergoing dual-microelectrode mapping of the GPi, microstimulation has been shown to reduce neuronal firing, presumably due to synaptic GABA release. This study examined the effects of different microstimulation frequencies (1-100 Hz) and train length (0.5-20 s), with and without prior high-frequency stimulation (HFS) on neuronal firing and evoked field potentials (fEPs) in 13 dystonia patients. Pre-HFS, the average firing decreased as stimulation frequency increased and was silenced above 50 Hz. The average fEP amplitudes increased up to frequencies of 20-30 Hz but then declined and at 50 Hz, were only at 75% of baseline. In some cases, short latency fiber volleys and antidromic-like spikes were observed and followed high frequencies. Post-HFS, overall firing was reduced compared with pre-HFS, and the fEP amplitudes were enhanced at low frequencies, providing evidence of inhibitory synaptic plasticity in the GPi. In a patient with DBS electrodes already implanted in the GPi, recordings from four neurons in the subthalamic nucleus showed almost complete inhibition of firing with clinically effective but not clinically ineffective stimulation parameters. These data provide additional support for the hypothesis of stimulation-evoked GABA release from afferent synaptic terminals and reduction of neuronal firing during DBS and additionally, implicate excitation of GPi axon fibers and neurons and enhancement of inhibitory synaptic transmission by high-frequency GPi DBS as additional putative mechanisms underlying the clinical benefits of DBS in dystonia.

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.

Neuronal activity in the globus pallidus internus in parkinsonian patients with rigidity and bradykinesia

To investigate the neuronal activities in the globus pallidus internus (GPi) related to parkinsonian rigidity and bradykinesia Twenty-six patients (M: 13 and F: 13) with parkinsonian syndromes of rigidity and bradykinesia, aged (58 +/- 11) with the duration of disease of (5.5 +/- 3.4) years, underwent pallidotomy. Their unified Parkinson's disease rating scale (UPDRS) motor score of rigidity was > or =5 (total score: 8) and the UPDRS score of bradykinesia was > or =9 (total score: 16) at "off" medication state pre-operationally. During operation, microelectrode recording in the GPi and electromyography (EMG) on the contralateral limbs to the surgery were performed. Single unite analysis and coefficient of variation (CV) of the interspike interval (ISI) were performed. The UPDRS motor score was assessed pre- and post-operationally. One-way ANOVA was carried out to study the firing rate as well as the ISI and CV of the ISI among different types of neuronal activity. Bonferroni test was conducted for means comparison. 10.1% (n = 24) of the total 237 GPi neurons (26 trajectories) showed discharge activity related to tremor (4-6 Hz), 57.4% (n = 136) of the neurons discharged tonic activity, and 32.5% (n = 77) neurons discharged irregular activity. Further analysis focused on 136 tonic active neurons and found that 75.7% (n = 103) of the neurons were characterized by a mean firing rate of (124.1 +/- 39.2) Hz with an ISI of (8.7 +/- 6.9) ms, and 24.3% (n = 33) of the neurons were characterized by a relative normal mean firing rate of (69.5 +/- 5.9) Hz with an ISI of (14.4 +/- 13.2) ms. The neurons with irregular neuronal activity had a mean firing rate of (30.2 +/- 9.8) Hz with an ISI of (35.6 +/- 36.8) ms. ANOVA revealed that there were statistically differences in the mean firing rate, ISI, and CV of the ISI for these neurons with relative normal tonic activity, high frequency tonic activity, and irregular activity (P < 0.01). UPDRS showed that the improvement of rigidity and bradykesia were 71.9% and 61.8% respectively. High percent neurons with high frequency tonic activity and irregular neuronal activity observed in GPi suggest that the neuronal activity with altered rate and pattern may play an important role in parkinsonian symptoms such as rigidity and bradykinesia.

Neuronal Responses to Passive Movement in the Globus Pallidus Internus in Primary Dystonia

Abnormal sensory processing has been implicated in the pathophysiology of primary dystonia. In the globus pallidus internus (GPi), the primary output structure of the basal ganglia, many neurons respond to sensory (proprioceptive) stimulation. Here we have characterized GPi neuronal responses to passive movement of the contralateral limbs in 22 patients with primary dystonia undergoing microelectrode recording for placement of deep brain stimulator leads. We plotted coordinates of cells responding to limb movement in a common space. We observed distinct representations of leg and arm movement localized to the dorsal and ventral part of the posterior GPi, respectively. Comparing patients with generalized dystonia versus patients with segmental craniocervical dystonia, there was no difference in the volumes or separations of leg and arm related territories. In contrast to parkinsonism, only a small minority of units were responsive to movement across multiple joints. Abnormally increased directional selectivity was found in units responding to dystonic limbs compared with nondystonic limbs. Some affected GPi neurons therefore appear to have altered proprioceptive tuning for movement direction. There is an apparent preservation of GPi somatotopic organization in dystonia in comparison with prior studies of GPi somatotopic organization in non-human primates and humans with Parkinson's disease.

Neuronal Firing Rates and Patterns in the Globus Pallidus Internus of Patients With Cervical Dystonia Differ From Those With Parkinson's Disease

Cervical dystonia (CD) is a movement disorder that involves involuntary turning and twisting of the neck caused by abnormal muscle contraction. Deep brain stimulation (DBS) in the globus pallidus internus (GPi) is used to treat both CD and the motor symptoms of Parkinson's disease (PD). It has been suggested that the differing motor symptoms in CD and PD may arise from a decreased GPi output in CD and elevation of output in PD. To test this hypothesis, extracellular recordings of GPi neuronal activity were obtained during stereotactic surgery for the implantation of DBS electrodes in seven idiopathic CD and 14 PD patients. The mean GPi neuronal firing rate recorded from CD patients was lower than that in PD patients (P < 0.001; means +/- SE: 71.4 +/- 2.2 and 91.7 +/- 3.0 Hz, respectively). Furthermore, GPi neurons fired in a more irregular pattern consisting of more frequent and longer pauses in CD compared with PD patients. When comparisons were done based on locations of recordings, these differences in firing rates and patterns were limited to the ventral portion of the GPi. In contrast, no difference in firing rate or pattern was observed in the globus pallidus externus between the two groups. These findings suggest that alterations in both firing rate and firing pattern may underlie the differing motor symptoms associated with these two movement disorders.