Disruption of information processing in the supplementary motor area of the MPTP-treated monkey: A clue to the pathophysiology of akinesia?

Abstract

It has been suggested that the underactivity of mesial frontal structures induced by dopamine depletion could constitute one of the main substrates underlying akinesia in Parkinson's disease. Functional imaging and movement-related potential recordings indicate an implication of the frontal lobes in this pathological process, but the question has not yet been investigated at a cellular level using single unit recording. We therefore compared neuronal activity in both the presupplementary motor area (pre-SMA) and the supplementary motor area proper (SMAp) of the Macaca mulatta monkey during a delayed motor task, before and after MPTP treatment. In the pre-SMA, which receives strong inputs from the prefrontal cortex, the baseline firing frequency and the percentage of neurons responding to visual instruction cues decreased in lesioned monkeys. In the SMAp, which sends direct outputs to the primary motor cortex, not only was the response to visual cues impaired, but the percentage of SMAp neurons responding to intracortical microstimulation fell and the threshold of response rose. Neuronal activity after the Go signal diminished sharply in both structures in the symptomatic animal and the discharge pattern became more irregular; in the SMAp neuronal activity remained modified longer. Most of these changes could already be observed in the presymptomatic animal presenting no clinical signs of parkinsonism. These data would indicate that, at the moment when dopamine depletion has impaired the ability of cortical neurons to operate the focused selection of incoming information giving instructions for movement, pre-SMA and SMAp neurons are also in a state of severe hypoactivity. The conjunction of these phenomena could play a critical role in the genesis of akinesia.

Initial clinical manifestations of Parkinson's disease: features and pathophysiological mechanisms

“…50 Accordingly, bradykinesia can be seen as a defect of the motor circuit to generate a phasic and time-locked inhibition of GPi neurons and to achieve substantial desynchronisation in the beta band to facilitate recruitment of cortical motoneurons appropriately adjusted for the intended movement. 41,[53][54][55] This activity is not only due to reduced activation of medium spiny neurons in the direct circuit, 56 but also to the combination of functionally hypoactive GPe with hyperactive STN and GPi, which reduces the probability that a cortical signal will be facilitated via the STN-GPe-GPi loop. 56,57 Increased responsiveness of the STN-GPi might also increase movement-related activity through the hyperdirect pathway and contributes to progressive attenuation of repetitive and sequential movements and micrographia.…”

“…These features fi t well with the concept that the basal ganglia have a fundamental role in modulating activity of premotor areas (supplementary motor area, pre-supplementary motor area, and dorsolateral prefrontal cortex) that deal with selection of self-initiated actions. 39,40,55 However, analysis of the main motor manifestations of PD suggests a more complex pathophysiological origin. Thus, key features of hypokinesia such as absence of spontaneous movement or reduced blink rate are unlikely to share mechanisms with bradykinetic manifestations such as reduced amplitude and slowness of the limbs or simultaneous manual movements.…”

Deep Brain Stimulation of the Subthalamic Nucleus, but not Dopaminergic Medication, Improves Proactive Inhibitory Control of Movement Initiation in Parkinson's Disease

“…For instance, impaired activation of the medial frontal areas and putamen accounts for the difficulties PD patients have in initiating movements [69], with concomitant over-activity of primary sensorimotor cortex [70]. SMA is hypoactivated and SMA-putamen connectivity is abnormal during motor behavior in PD patients [71,72], as well as in animal models of PD [14]. Less stimulusinduced deactivation of the PCC/precuneus and impaired connectivity between dorsomedian frontal cortex and striatum are also symptomatic of executive disorders as assessed by response latency [73].…”

“…The loss of dopamine (DA) in PD may cause the direct pathway to become less active and the indirect pathway to become more active, resulting in increased subthalamic nucleus (STN) and internal globus pallidus activities, and consequent excessive thalamic inhibition. Accordingly, it has long been assumed that the resulting dysfunction of the thalamocortical feedback route produces akinesia through its action upon motor cortical regions [13,14].…”

Progressive Motor Cortex Functional Reorganization Following 6-Hydroxydopamine Lesioning in Rats

“…Several studies have attempted to investigate the relationship between motor cortex activity and PD progression, although results have been controversial. Cortical activity has been found to be reduced (Escola et al, 2002(Escola et al, , 2003Buhmann et al, 2003;Lefaucheur, 2005;Parr-Brownlie and Hyland, 2005;Brown et al, 2009), increased (Sabatini et al, 2000;Pelled et al, 2002;Seiss andPraamstra, 2004, Lefaucheur, 2005), or unchanged (Dick et al, 1984;Metz et al, 2004) in parkinsonian animals as well as PD patients. This variability can be attributed to experimental reasons (i.e., methods, time, and region of interest).…”