Fig. 7. Segregated circuits for bradykinesia and resting tremor in PD.

(A) Loss of nigrostriatal DA changes the regulation of direct/indirect pathways and leads to an abnormal firing pattern in the rostral motor STN (SMA-STN), which is connected with the motor cortex through the SMA-STN hyperdirect pathway. This altered neuronal activity is also present in the rostral area of the motor GPi, which, in turn, projects to the VL thalamus and leads to excessive inhibition of the thalamo-cortical excitatory projection to the motor cortex, particularly SMA. (B) Dopaminergic extrastriatal loss modifies the balance of the STN-GPe microcircuitry (i.e., excitation/inhibition), giving rise to abnormal oscillatory activity at 4 to 6 Hz. This resting tremor activity is found within the most caudal area of the motor STN (M1-STN). Tremor activity probably reaches the cortex through the thalamo-cortical projection to the M1. The cerebello-thalamo-cortical network contributes to the maintenance and amplification of resting tremor triggered by peripheral feedback, and possibly the M1-STN hyperdirect pathway reinforces the oscillatory activity within the STN. A putative direct subthalamo-thalamic connection (77), which might facilitate tremor propagation from the STN-GPe pacemaker to the motor cortex through the thalamus, has not been described in humans. DA, dopaminergic; GPe, globus pallidus pars externa; GPi, globus pallidus pars interna; M1, primary motor cortex; Put, putamen; SNc, substantia nigra pars compacta; STN, subthalamic nucleus; Th, thalamus; SMA, supplementary motor area; VL, ventrolateral thalamus; GABA, γ-aminobutyric acid.