Jianyu Zhang

Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus

Microelectrode recording was performed in the basal ganglia of 3 patients with generalized dystonia and 1 patient with hemiballismus secondary to a brainstem hemorrhage. Neuronal activity was recorded from the internal and external segments of the globus pallidus and assessed for mean discharge rate and pattern of spontaneous activity. The responses of neurons in the internal segment of the globus pallidus to passive and active movements were also evaluated. Mean discharge rates of neurons in both segments of the pallidum in patients with dystonia and the patient with hemiballismus were considerably lower than those reported for patients with idiopathic Parkinsons disease. In addition, the pattern of spontaneous neuronal activity was highly irregular, occurring in intermittent grouped discharges separated by periods of pauses. Although receptive fields in the dystonia patients were widened and less specific than those reported in normal monkeys, neuronal responses to movement were uncommon in the hemiballismus patient. Before surgery, patients with dystonia experienced abnormal posturing and involuntary movements. Coactivation of agonist–antagonist muscle groups was observed both at rest and during the performance of simple movements. After pallidotomy there was a significant reduction in the involuntary movement associated with these disorders and a more normal pattern of electromyographic activity during rest and movement. Given the improvement in dystonic and hemiballistic movements in these patients after ablation of the sensorimotor portion of the internal segment of the globus pallidus, we suggest that pallidotomy can be an effective treatment for patients with dystonia and also for patients with medically intractable hemiballismus. Based on the finding of decreased neuronal discharge rates in pallidal neurons, we propose that physiologically dystonia most closely resembles a hyperkinetic movement disorder. A model for dystonia is proposed that incorporates the observed changes in the rate and pattern of neuronal activity in the pallidum with data from neuroimaging with positron emission tomography and 2‐deoxyglucose studies. Ann Neurol 1999;46:22–35

Subthalamic Nucleus Stimulation Modulates Thalamic Neuronal Activity

Deep brain stimulation (DBS) in the subthalamic nucleus (STN) is an effective tool for the treatment of advanced Parkinsons disease. The mechanism by which STN DBS elicits its beneficial effect, however, remains unclear. We previously reported STN stimulation increased the rate and produced a more regular and periodic pattern of neuronal activity in the internal segment of the globus pallidus (GPi). Here we extend our observations to neurons in the pallidal [ventralis lateralis pars oralis (VLo) and ventralis anterior (VA)] and cerebellar [ventralis lateralis posterior pars oralis (VPLo)] receiving areas of the motor thalamus during STN DBS. Stimulation parameters that produced improvement in rigidity and bradykinesia resulted in changes in the pattern and power of oscillatory activity of neuronal activity that were similar in both regions of the motor thalamus. Neurons in both VA/VLo and VPLo tended to become more periodic and regular with a shift in oscillatory activity from low to high frequencies. Burst activity was reduced in VA/VLo, but was not significantly changed in VPLo. There was also a significant shift in the population of VA/VLo neurons that were inhibited during STN DBS, whereas VPLo neurons tended to be activated. These data are consistent with the hypothesis that STN DBS increases output from the nucleus and produces a change in the pattern and periodicity of neuronal activity in the basal ganglia thalamic network, and that these changes include cerebellar pathways likely via activation of adjacent cerebello-thalamic fiber bundles.

Stereotactic neurosurgical planning, recording, and visualization for deep brain stimulation in non-human primates

Methodologies for stereotactic neurosurgery and neurophysiological microelectrode recordings (MER) in non-human primate research typically rely on brain atlases that are not customized to the individual animal, and require paper records of MER data. To address these limitations, we developed a software tool (Cicerone) that enables simultaneous interactive 3D visualization of the neuroanatomy, neurophysiology, and neurostimulation data pertinent to deep brain stimulation (DBS) research studies in non-human primates. Cicerone allows for analysis of co-registered magnetic resonance images (MRI), computed tomography (CT) scans, 3D brain atlases, MER data, and DBS electrode(s) with predictions of the volume of tissue activated (VTA) as a function of the stimulation parameters. We used Cicerone to aid the implantation of DBS electrodes in two parkinsonian rhesus macaques, targeting the subthalamic nucleus in one monkey and the globus pallidus in the other. Cicerone correctly predicted the anatomical position of 79% and 73% of neurophysiologically defined MER sites in the two animals, respectively. In contrast, traditional 2D print atlases achieved 61% and 48% accuracy. Our experience suggests that Cicerone can improve anatomical targeting, enhance electrophysiological data visualization, and augment the design of stimulation experiments.

External pallidal stimulation improves parkinsonian motor signs and modulates neuronal activity throughout the basal ganglia thalamic network

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) are effective for the treatment of advanced Parkinsons disease (PD). We have shown previously that DBS of the external segment of the globus pallidus (GPe) is associated with improvements in parkinsonian motor signs; however, the mechanism of this effect is not known. In this study, we extend our findings on the effect of STN and GPi DBS on neuronal activity in the basal ganglia thalamic network to include GPe DBS using the 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) monkey model. Stimulation parameters that improved bradykinesia were associated with changes in the pattern and mean discharge rate of neuronal activity in the GPi, STN, and the pallidal [ventralis lateralis pars oralis (VLo) and ventralis anterior (VA)] and cerebellar [ventralis lateralis posterior pars oralis (VPLo)] receiving areas of the motor thalamus. Population post-stimulation time histograms revealed a complex pattern of stimulation-related inhibition and excitation for the GPi and VA/VLo, with a more consistent pattern of inhibition in STN and excitation in VPLo. Mean discharge rate was reduced in the GPi and STN and increased in the VPLo. Effective GPe DBS also reduced bursting in the STN and GPi. These data support the hypothesis that therapeutic DBS activates output from the stimulated structure and changes the temporal pattern of neuronal activity throughout the basal ganglia thalamic network and provide further support for GPe as a potential therapeutic target for DBS in the treatment of PD.

Chronic implantation of deep brain stimulation leads in animal models of neurological disorders.

Deep brain stimulation (DBS) has routinely been used as a treatment option in Parkinsons disease (PD), tremor disorders and, more recently, dystonia. Here, we describe a method of implantation of DBS leads in the monkey model of PD. By adapting procedures used in human patients, we have devised implantation techniques that can be readily applied to any animal model in which stimulation of subcortical structures is desired. The procedure for implantation consists of microelectrode mapping of the target structure, DBS lead preparation and implantation, and verification of lead placement. The stimulation system described in this paper allows for simultaneous recording of neuronal activity (during stimulation) and observation of animal behavior without restriction of the subjects head or body. In addition, we detail techniques for stimulation and recording from distant structures (utilizing either a one or two chamber system) to facilitate examination of the effects of DBS on neural activity. Thus, the correlation of changes in neuronal activity with behavior during stimulation of subcortical structures can be accomplished. In addition, the use of leads in primates which are analogous in size to human devices allows for close reproduction of the effects of stimulation as observed in humans.

Neural targets for relieving parkinsonian rigidity and bradykinesia with pallidal deep brain stimulation

Clinical evidence has suggested that subtle changes in deep brain stimulation (DBS) settings can have differential effects on bradykinesia and rigidity in patients with Parkinsons disease. In this study, we first investigated the degree of improvement in bradykinesia and rigidity during targeted globus pallidus DBS in three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus macaques. Behavioral outcomes of DBS were then coupled with detailed, subject-specific computational models of neurons in the globus pallidus internus (GPi), globus pallidus externus (GPe), and internal capsule (IC) to determine which neuronal pathways when modulated with high-frequency electrical stimulation best correlate with improvement in motor symptoms. The modeling results support the hypothesis that multiple neuronal pathways can underlie the therapeutic effect of DBS on parkinsonian bradykinesia and rigidity. Across all three subjects, improvements in rigidity correlated most strongly with spread of neuronal activation into IC, driving a small percentage of fibers within this tract (<10% on average). The most robust effect on bradykinesia resulted from stimulating a combination of sensorimotor axonal projections within the GP, specifically at the site of the medial medullary lamina. Thus the beneficial effects of pallidal DBS for parkinsonian symptoms may occur from multiple targets within and near the target nucleus.

Effect of globus pallidus internus stimulation on neuronal activity in the pedunculopontine tegmental nucleus in the primate model of Parkinson's disease.

The pedunculopontine tegmental nucleus (PPN) is being explored as a site for deep brain stimulation (DBS) for the treatment of patients with medically refractory gait and postural abnormalities (MRGPA) associated with Parkinsons disease (PD). The PPN is involved in initiation and modulation of gait and other stereotyped motor behaviors and is inter-connected with the pallido-thalamo-cortical circuit. Internal segment of the globus pallidus (GPi) DBS is effective at treating the motor signs associated with PD, however its impact on MRGPA is limited and its effect on PPN neuronal activity is unknown. The current work characterizes the effect of therapeutically-effective GPi DBS on PPN neuronal activity in a single rhesus monkey made parkinsonian using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A scaled-down, quadripolar DBS lead was implanted into sensorimotor GPi under electrophysiological and stereotactic guidance. Single-neuron activity was recorded from PPN before, during and after DBS. GPi DBS reduced the mean discharge rate of PPN neurons from 16.8 Hz to 12.8 Hz, with 30 (66.7%) neurons showing a decreased mean rate, 3 (6.7%) increased and 12 (26.7%) unchanged. Consistent with known GABAergic projections from GPi to PPN, and with previous observations that stimulation increases output from the stimulated structure, GPi DBS suppressed activity in the PPN. The present observations, together with previous reports of improvement in MRGPA during low frequency stimulation in PPN, suggest that activation of PPN output may be required to improve MRGPA and may account for the lack of improvement in MRGPA typically observed with GPi or subthalamic nucleus (STN) DBS.

Dissociation of motor symptoms during deep brain stimulation of the subthalamic nucleus in the region of the internal capsule.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be an effective treatment for the motor symptoms of Parkinsons disease. The therapeutic benefits are voltage-dependent and, in many cases, limited by the appearance of side effects, including muscle contractions. We have observed a number of clinical cases where improvements in rigidity were accompanied by a worsening of bradykinesia. Considering the anatomic position of STN and current approaches to implantation of the DBS lead, we hypothesized that this dissociation of motor symptoms arises from activation of pyramidal tract fibers in the adjacent internal capsule. The objective of this study was to assess the physiological basis for this dissociation and to test our hypothesis that the underlying etiology of this paradox is activation of fibers of the internal capsule. The effect of STN DBS at 80% of motor threshold for each of the four contacts was evaluated for its effect on rigidity, bradykinesia, and akinesia in a single primate with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Consistent with our observations in humans, this near-threshold stimulation was found to improve rigidity while bradykinesia and akinesia worsened. Worsening bradykinesia in the face of improvement of other motor signs in Parkinsons disease (PD) patients is suggestive of activation of pyramidal tract (PT) fibers during stimulation. This phenomenon may occur without overt muscle contraction and improved rigidity.

Lesions in monkey globus pallidus externus exacerbate parkinsonian symptoms.

To further define the role of the external segment of the globus pallidus (GPe) in the development of parkinsonian motor signs, two rhesus monkeys were made parkinsonian with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioral assessments of bradykinesia and akinesia as well as single neuron recordings in the internal segment of the globus pallidus (GPi) were performed in both monkeys before and after ablating the sensorimotor portion of GPe. The effects of apomorphine on behavior and neuronal activity were also assessed in the parkinsonian monkeys before and after GPe ablation. We found that lesions in GPe exacerbated parkinsonian symptoms, altered neuronal activity in GPi, and reduced the therapeutic effects of apomorphine. These results support the hypothesis that GPe can influence GPi neuronal activity and is directly involved in parkinsonism. In addition, these data suggest that the inclusion of GPe in pallidotomy lesions for the treatment of Parkinsons disease can block the beneficial effects of antiparkinsonian medications and should be avoided.

Modulation of motor cortex neuronal activity and motor behavior during subthalamic nucleus stimulation in the normal primate

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established surgical therapy for advanced Parkinsons disease (PD). An emerging hypothesis is that the therapeutic benefit of DBS is derived from direct modulation of primary motor cortex (M1), yet little is known about the influence of STN DBS on individual neurons in M1. We investigated the effect of STN DBS, delivered at discrete interval intensities (20, 40, 60, 80, and 100%) of corticospinal tract threshold (CSTT), on motor performance and M1 neuronal activity in a naive nonhuman primate. Motor performance during a food reach and retrieval task improved during low-intensity stimulation (20% CSTT) but worsened as intensity approached the threshold for activation of corticospinal fibers (80% and 100% CSTT). To assess cortical effects of STN DBS, spontaneous, extracellular neuronal activity was collected from M1 neurons before, during, and after DBS at the same CSTT stimulus intensities. STN DBS significantly modulated the firing of a majority of M1 neurons; however, the direction of effect varied with stimulus intensity such that, at 20% CSTT, most neurons were suppressed, whereas at the highest stimulus intensities the majority of neurons were activated. At a population level, firing rates increased as stimulus intensity increased. These results show that STN DBS influences both motor performance and M1 neuronal activity systematically according to stimulus intensity. In addition, the unanticipated reduction in reach times suggests that STN DBS, at stimulus intensities lower than typically used for treatment of PD motor signs, can enhance normal motor performance.