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

Abstract

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.

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

“…The more “fixed” and prolonged STN burst discharges would decrease the delicacy or faithfulness of STN responses to the incoming MC drives. The “built-in” feedback inhibition of premature MC activities via STN and GPi is then spatiotemporally less accurate, which may contribute to more cortical activities (noises) and thus self-sustaining vicious cycles 17 , 18 . This could embody the core of the deranged cortico-subthalamic transmission in PD or some types of parkinsonisms (e.g.…”

“…The switch to burst discharges in SNpc neurons could be modulated by the glutamatergic innervations from the subthalamus and pedunculopontine nuclei 87 , 88 . If the burst discharges of STN would potentially inhibit an action, then the follow-up dopamine release may switch off the burst discharges in STN to release the “brake” for motor execution 18 . This may be the functional explanation why the midbrain dopaminergic neurons should be degenerated by ~80% for PD to become symptomatic 89 , 90 .…”

“…This is presumably ascribable to the weakened surrounding inhibition for ongoing programming (the “center-surrounded” model) 19 , 91 due to deranged lateral inhibition between the medium spiny neurons in the striatopallidal direct and indirect pathways 92 , 93 . The impaired striatal filtering for MC activities, together with the relatively irresponsive STN with prolonged and less variable burst discharges, could lead to difficulties in motor execution (poor initiation) as well as imprecise derivations of consequential programs (bradykinesia) during movement in PD 18 . In this regard, there are many clinical situations which may share part of the behavioral manifestations of PD without specific degeneration of the midbrain dopaminergic neurons (“parkinsonisms”).…”

“…We have recently demonstrated that MC is directly involved in the genesis of excessive STN burst discharges 17 . Moreover, excessive STN burst discharges could in turn trigger highly correlative MC activities and apparent tremulous behaviors in dopamine-depleted animals 17 , 18 . We therefore postulate that the MC-STN axis, a pathway being relatively neglected before 19 – 21 , may play a pivotal role of feedforward modulation in the symptomatic pathogenesis of PD.…”

Chorea: A Sequelae of Canine Distemper

“…A complete and proper history of the affected animal is necessary, because certain different conditions may appear apparently similar (Lee et al, 2021). The foremost approach to ensuring involuntary muscle movement is that the animal should maintain its normal cardinals during the span between one episode of dysfunction and the other.…”