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Fig. 4 | Journal of Biomedical Science

Fig. 4

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

Fig. 4

A functional view of the basal ganglia circuitry in normal (left column) and parkinsonian (right shaded column) motor control. A The cortico-subcortical re-entrant loops with delicately controlled oscillating activities in the normal state (left) or deranged oscillating activities in PD (right). MC discharges are transmitted to STN via the hyperdirect pathway, and then loop back to MC to have a negative feedback effect via the GABAergic GPi (i.e. MC-STN-GPi-thalamus-MC, green arrows: glutamatergic, crimson arrows: GABAergic). MC activities are also “filtered” by the striatum, and transformed chiefly as an inhibitory input to GPi via the direct pathway to modify the excitatory drive from STN. B The cortical process at rest. In the normal state (left), the original MC activities (black circles) are erased by the foregoing effect via GPi and conclude the electrophysiological negative feedback process (dashed black circles). However, activities of the lower motor neurons and muscle contractions may well be elicited by the downwardly transmitted MC discharges during the looping process. New (compensatory) MC activities (blue circles) therefore must also be generated for counteractions at the muscle level (the “mechanical” negative feedback) presumably via some indirect excitatory pathways from STN to MC. The mechanical negative feedback ensures no discernible “microscopic” movement at rest. These compensatory MC activities subsequently arouse similar responses, including the electrophysiological negative feedback via GPi (dashed blue circles) and the mechanical negative feedback via STN (the “resurgent” black circles). With timely and appropriately modulated STN bursts by phasic dopamine release, the primary and the compensatory MC activities are accurately configured. Meanwhile, the invisible microscopic movement or “microtremors” may constitute a major base for the genesis of muscle tone. The negative electrophysiological feedback is less precise in PD (right), with excessive STN bursts in response to corticosubthalamic input. Together with the presumable derangement in lateral inhibition in the striatum with dopamine deprivation, MC activities are increased. The mechanical feedback then is less precise, resulting in larger-scale alternating muscle contractions and thus cogwheel rigidity. Discernible tremor may develop, especially if there are enough residual dopaminergic neurons that the erroneously modified MC activities could be partly executed. Under such circumstances, 4–6 Hz could be the “best” oscillating frequencies for generation of manifest tremor, considering the potential phase lag between the coherent MC and STN oscillations. Tremor could be delicately modulated by changes in dopamine (or the other neuromodulators) levels and STN discharge patterns. Thus, psychomotor stress or an intention to move could enhance tremor which could then be suddenly abolished by relief of the stress or execution of the movement. C The cortical process on move. If relevant MC activities are continually presented (e.g. with a will of motion) to the striatum, the MC activity patterns would be gradually specified with striatal filtering in the normal state (left). Meanwhile, the STN drive on GPi is gradually weakened by the inhibitory effect via the direct pathway and/or the decreasing burst discharges with locally accumulated dopamine. Once the erasing actions are no longer complete, discernible movement would happen. This defines the “motor threshold”, which denotes the level for a discernible movement rather than a point of no return, as an executed pattern can still be modified any time. Discernible movement may by itself contribute to the making of the next MC activity patterns with rationales similar to the foregoing electrophysiological and mechanical negative feedbacks (e.g. sequential motions or “motor habits”). The sequential or repetitive moves in a movement set thus are easier to proceed once the first one is executed. In this case, the indirect pathway presumably assumes a more prominent role for the follow-up negative feedback to erase the executed MC activities because of weakened role of STN. In PD (right), initiation of a new motor task is difficult as repeated trials can hardly accumulate enough local dopamine and enough specified MC activities (e.g. with defective striatal filtering) for motor execution. However, if discernible motion does happen in this case, the motor threshold must have been surpassed and enough weakening of the electrophysiological and mechanical negative feedbacks achieved. The next move of the similar kind in a sequential set would then be easier. In general, the net movement of each sequential move would be less efficient and thus “bradykinetic” in PD because of the erroneous cortical programming and thus less efficient derivation of an appropriate pattern from the executed actions and counteractions. However, if the errors in programming happen to be in the same direction, cumulative temporal and spatial changes in motor scale may prevail with motor execution. This could be especially discernible with simple repetitive moves (e.g. micrographia or propulsive gait in clinical settings)

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