The role of pallidum in the neural integrator model of cervical dystonia.

ABSTRACT

Dystonia is the third most common movement disorder affecting three million people worldwide. Cervical dystonia is the most common form of dystonia. Despite common prevalence the pathophysiology of cervical dystonia is unclear. Traditional view is that basal ganglia is involved in pathophysiology of cervical dystonia, while contemporary theories suggested the role of cerebellum and proprioception in the pathophysiology of cervical dystonia. It was recently proposed that the cervical dystonia is due to malfunctioning of the head neural integrator - the neuron network that normally converts head velocity to position. Most importantly the neural integrator model was inclusive of traditional proposal emphasizing the role of basal ganglia while also accommodating the contemporary view suggesting the involvement of cerebellum and proprioception. It was hypothesized that the head neural integrator malfunction is the result of impairment in cerebellar, basal ganglia, or proprioceptive feedback that converge onto the integrator. The concept of converging input from the basal ganglia, cerebellum, and proprioception to the network participating in head neural integrator explains that abnormality originating anywhere in the network can lead to the identical motor deficits - drifts followed by rapid corrective movements - a signature of neural integrator dysfunction. We tested this hypothesis in an experiment examining simultaneously recorded globus pallidal single-unit activity, synchronized neural activity (local field potential), and electromyography (EMG) measured from the neck muscles during the standard-of-care deep brain stimulation surgery in 12 cervical dystonia patients (24 hemispheres). Physiological data were collected spontaneously or during voluntary shoulder shrug activating the contralateral trapezius muscle. The activity of pallidal neurons during shoulder shrug exponentially decayed with time constants that were comparable to one measured from the pretectal neural integrator and the trapezius electromyography. These results show that evidence of abnormal neural integration is also seen in globus pallidum, and that latter is connected with the neural integrator. Pretectal single neuron responses consistently preceded the muscle activity; while the globus pallidum internus response always lagged behind the muscle activity. Globus pallidum externa had equal proportion of lag and lead neurons. These results suggest globus pallidum receive feedback from the muscles or the efference copy from the integrator or the other source of the feedback. There was bi-hemispheric asymmetry in the pallidal single-unit activity and local field potentials. The asymmetry correlated with degree of lateral head turning in cervical dystonia patients. These results suggest that bihemispheric asymmetry in the feedback leads to asymmetric dysfunction in the neural integrator causing head turning.