Reduced pallidal output causes dystonia

Abstract

Dystonia is a neurological disorder characterized by sustained or repetitive involuntary muscle contractions and abnormal postures. In the present article, we will introduce our recent electrophysiological studies in hyperkinetic transgenic mice generated as a model of DYT1 dystonia and in a human cervical dystonia patient, and discuss the pathophysiology of dystonia on the basis of these electrophysiological findings. Recording of neuronal activity in the awake state of DYT1 dystonia model mice revealed reduced spontaneous activity with bursts and pauses in both internal (GPi) and external (GPe) segments of the globus pallidus. Electrical stimulation of the primary motor cortex evoked responses composed of excitation and subsequent long-lasting inhibition, the latter of which was never observed in normal mice. In addition, somatotopic arrangements were disorganized in the GPi and GPe of dystonia model mice. In a human cervical dystonia patient, electrical stimulation of the primary motor cortex evoked similar long-lasting inhibition in the GPi and GPe. Thus, reduced GPi output may cause increased thalamic and cortical activity, resulting in the involuntary movements observed in dystonia.

Keywords: dystonia; extracellular recording; globus pallidus; movement disorders; stereotactic surgery.

Figure 1

Spontaneous activity of neurons in the internal segment of the globus pallidus (GPi) in DYT1 dystonia model mice. (A,C) Spikes are shown as digital signals in normal (A) and dystonia model (C) mice. Bursts and pauses in the digital signals are indicated by horizontal black thick lines and horizontal white thick lines, respectively. (B,D) Autocorrelograms are shown in normal (B) and dystonia model (D) mice. (E) Box plots of firing rates in normal (left) and dystonia model (right) mice. The boxes are constructed with the top line bounding the upper quartile and the bottom line bounding the lower quartile. The median and mean excluding outliers are indicated by a thick horizontal line and an open circle in the box, respectively. The short horizontal lines show the largest and smallest values that are not outliers. Outliers are shown as small closed circles. *, significantly different (p < 0.001, Mann–Whitney U test). Modified from Chiken et al. (2008).

Figure 2

Responses of GPi neurons to cortical stimulation in DYT1 dystonia model mice. (A) Raster and peristimulus time histograms (PSTHs) for normal mice. Cortical stimuli were delivered at time 0 (arrows) for 100 trials. (B) Raster and PSTHs for dystonia model mice. Abnormal responses with long-lasting inhibition were observed. Modified from Chiken et al. (2008).

Figure 3

Somatotopic organization in the GPi of DYT1 dystonia model mice. (A) Proportions of neurons classified on the basis of cortical inputs in normal (top) and dystonia model (bottom) mice. (B) Distribution of recorded GPi neurons indicated by symbols on the basis of cortical inputs. Data from normal (top) and dystonia model (bottom) mice are shown in frontal sections. Figures in the left upper corner represent distance from bregma. GPe, external segment of the globus pallidus; Rt, reticular thalamic nucleus; Ot, optic tract. Modified from Chiken et al. (2008).

Figure 4

Activity of GPi and GPe neurons in a human cervical dystonia patient. (A) Autocorrelograms and slow traces of digitized spikes of GPe neurons recorded from a cervical dystonia (CD) patient. (B,C) PSTHs (bin width of 1 ms) showing the responses of GPi (B) and GPe (C) neurons evoked by stimulation of the upper limb region of the primary motor cortex in a cervical dystonia patient. Cortical stimuli were delivered at time 0 (arrows) for 100 trials. The mean firing rate is indicated by black dotted lines. The statistical levels of p < 0.05 (one-tailed t-test) calculated from the firing rate during 100 ms preceding the onset of stimulation are indicated by black and white solid lines (upper and lower limits of p < 0.05). Modified from Nishibayashi et al. (2011).

Figure 5

Schematic diagrams showing information processing through the basal ganglia in normal (A) and dystonia (B) conditions. In dystonia (B), cortical activation induces strong inhibition over a wide area of the GPi. Reduced GPi output may cause strong excitation in the thalamus (Th) and cortex (Cx) through disinhibitory mechanism, resulting in the involuntary movements. disinh, disinhibition; ex, excitation; inh, inhibition; STN, subthalamic nucleus. Modified from Chiken et al. (2008).