A Review of the Pedunculopontine Nucleus in Parkinson's Disease

Abstract

The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients.

Keywords: Parkinson's disease; Pedunculopontine nucleus; basal ganglia; brainstem; deep brain stimulation; mesenphalic locomotor region; substantia nigra.

Figure 1

The connections of The PPN, and the direct and indirect pathway of BG-thalamocortical circuits under normal (A) and PD (B) conditions. Red, green, and yellow lines denote glutamatergic, GABAergic and dopaminergic projections respectively, while blue lines indicate chemically amalgamated projections. Thickening lines show increased activity whereas thinning lines show decreased activity when alterations occur in the average activity rate of specific projection pathways in PD compared with the normal state. Dotted yellow lines indicate loss. The striatum and STN deliver input from incoming cortical information to the BG. The GPi and SNr deliver output information from the BG to the rest of the brain and apply robust inhibitory control on targets in the thalamus and the brainstem. This tonic inhibitory input must be disinhibited to permit normal movements to occur. The striatum applies opposite influences on the GPi and SNr via two distinct classes of efferent neurons, namely the D1-receptor-rich “direct pathway” positively modulated by DA and the D2-receptor-rich “indirect pathway” negatively modulated by DA. The loss of DA in PD's causes disequilibrium in the activity of these two striatofugal pathways and their corresponding cortical inputs.

Figure 2

Behavior selection: Red lines depict glutamatergic pathways, whereas green lines depict GABAergic pathways. Blue lines depict chemically composite pathways. The corresponding colored notations show how each different movement disorder is elicited.

Figure 3

Volitional and automatic control of locomotor movements by the BG-BS system: GABAergic BG output to thalamocortical and brainstem neurons assimilates volitional and automatic movement control processes. Adapted from Villiger and Piersol (1912).

Figure 4

Saccadic control (A) and postural muscle tone/ locomotion control (B) by the direct and indirect pathways.

Figure 5

The involvement of the PPN in the neuropathology of PD.