Deep brain stimulation rectifies the noisy cortex and irresponsive subthalamus to improve parkinsonian locomotor activities.

The success of deep brain stimulation (DBS) therapy indicates that Parkinson's disease is a brain rhythm disorder. However, the manifestations of the erroneous rhythms corrected by DBS remain to be established. We found that augmentation of α rhythms and α coherence between the motor cortex (MC) and the subthalamic nucleus (STN) is characteristically prokinetic and is decreased in parkinsonian rats. In multi-unit recordings, movement is normally associated with increased changes in spatiotemporal activities rather than overall spike rates in MC. In parkinsonian rats, MC shows higher spike rates at rest but less spatiotemporal activity changes upon movement, and STN burst discharges are more prevalent, longer lasting, and less responsive to MC inputs. DBS at STN rectifies the foregoing pathological MC-STN oscillations and consequently locomotor deficits, yet overstimulation may cause behavioral restlessness. These results indicate that delicate electrophysiological considerations at both cortical and subcortical levels should be exercised for optimal DBS therapy.

The genesis and functional consequences of cortico-subthalamic beta augmentation and excessive subthalamic burst discharges after dopaminergic deprivation.

The cardinal electrophysiological signs in Parkinson's disease (PD) include augmented beta oscillations in the motor cortex-subthalamic nucleus (MC-STN) axis and excessive burst discharges in STN. We have shown that excessive STN burst discharges have a direct causal relation with the locomotor deficits in PD. To investigate the correlation between the two cardinal signs, we characterized the courses of development of the electrophysiological abnormalities in the hemiparkinsonian rat model. The loss of dopaminergic neurons develops fast, and is histologically completed within 4-7 days of the lesion. The increase in STN burst discharges is limited to the lesioned side, and follows a very similar course. In contrast, beta augmentation has a bilateral presentation, and requires 14-21 days for full development. Behaviorally, the gross locomotor deficits in open field test and limb akinesia in stepping test match the foregoing fast and slow time courses, respectively. A further look into the spike entrainment shows that the oscillations in local field potential (LFP) of the MC effectively entrain the multi-unit (MU) spikes of MC, STN and entopeduncular nucleus (EPN), a rat homolog of human globus pallidus interna (GPi), whereas the LFP of STN or EPN (GPi) cannot entrain the spikes in MC. We conclude that excessive STN burst discharges are a direct consequence, whereas beta augmentation is probably a secondary or adaptive changes in the cortico-subcortical re-entrant loops, to dopaminergic deprivation. Beta augmentation is therefore not so consistently present as excessive STN burst discharges, but could signal more delicate derangements at the level of cortical programming in PD.

An electrophysiological perspective on Parkinson's disease: symptomatic pathogenesis and therapeutic approaches.

Parkinson's disease (PD), or paralysis agitans, is a common neurodegenerative disease characterized by dopaminergic deprivation in the basal ganglia because of neuronal loss in the substantia nigra pars compacta. Clinically, PD apparently involves both hypokinetic (e.g. akinetic rigidity) and hyperkinetic (e.g. tremor/propulsion) symptoms. The symptomatic pathogenesis, however, has remained elusive. The recent success of deep brain stimulation (DBS) therapy applied to the subthalamic nucleus (STN) or the globus pallidus pars internus indicates that there are essential electrophysiological abnormalities in PD. Consistently, dopamine-deprived STN shows excessive burst discharges. This proves to be a central pathophysiological element causally linked to the locomotor deficits in PD, as maneuvers (such as DBS of different polarities) decreasing and increasing STN burst discharges would decrease and increase the locomotor deficits, respectively. STN bursts are not so autonomous but show a "relay" feature, requiring glutamatergic synaptic inputs from the motor cortex (MC) to develop. In PD, there is an increase in overall MC activities and the corticosubthalamic input is enhanced and contributory to excessive burst discharges in STN. The increase in MC activities may be relevant to the enhanced beta power in local field potentials (LFP) as well as the deranged motor programming at the cortical level in PD. Moreover, MC could not only drive erroneous STN bursts, but also be driven by STN discharges at specific LFP frequencies (~ 4 to 6 Hz) to produce coherent tremulous muscle contractions. In essence, PD may be viewed as a disorder with deranged rhythms in the cortico-subcortical re-entrant loops, manifestly including STN, the major component of the oscillating core, and MC, the origin of the final common descending motor pathways. The configurations of the deranged rhythms may play a determinant role in the symptomatic pathogenesis of PD, and provide insight into the mechanism underlying normal motor control. Therapeutic brain stimulation for PD and relevant disorders should be adaptively exercised with in-depth pathophysiological considerations for each individual patient, and aim at a final normalization of cortical discharge patterns for the best ameliorating effect on the locomotor and even non-motor symptoms.