The pedunculopontine nucleus and Parkinson's disease

Abstract

Akinesia and gait disturbances are particularly incapacitating for patients with Parkinson's disease. The anatomical and physiological substrates for these disturbances are poorly understood. The pedunculopontine nucleus (PPN) is thought to be involved in the initiation and modulation of gait and other stereotyped movements, because electrical stimulation and the application of neuroactive substances in the PPN can elicit locomotor activity in experimental animals. Glutamatergic neurones of the PPNd (pars dissipatus) are thought to be important regulators of the basal ganglia and spinal cord. The other component of the PPN, the cholinergic pars compacta (PPNc), is a principal component in a feedback loop from the spinal cord and limbic system back into the basal ganglia and thalamus. Electrophysiological studies suggest that 'bursting' glutamatergic PPNd neurones are related to the initiation of programmed movements while non-bursting cholinergic PPNc neurones are related to the maintenance of steady-state locomotion. Furthermore, since patients with Parkinson's disease have significant loss of PPN neurones and experimental lesions in the PPN of normal monkeys result in akinesia, the degeneration of PPN neurones or their dysfunction may be important in the pathophysiology of locomotor and postural disturbances of parkinsonism. The goal of this review is (i) to highlight the anatomical connections and physiological attributes of the PPN, (ii) to discuss how the function of these connections may be altered in the parkinsonian state, and (iii) to speculate how present and potential future therapy directed to the PPN might improve akinesia and gait difficulties in parkinsonian patients.

Network modulation by the subthalamic nucleus in the treatment of Parkinson's disease

“…In the current study, we found that the effects of STN DBS on regional metabolism were generally similar to those identified following subthalamotomy (Su et al, 2001;Trošt et al, 2003). Specifically, declines in glucose utilization during STN stimulation were detected in the rostral pons and midbrain in proximity to the upper portion of the pedunculopontine nucleus (PPN, Pahapill and Lozano, 2000). Metabolic reductions in these regions have also been reported following STN lesioning (Su et al, 2001;Trošt et al, 2003), suggesting diminished outflow from the STN target nucleus to the brainstem in both interventions.…”

Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus

“…The PPN has extensive connections with the basal ganglia 5,11 , receiving strong inhibitory inputs from both the globus pallidus internus and substantia nigra 41 . Thus, the reduction in PPN activity may be mediated by inhibitory input from the basal ganglia 41 .…”

“…Whereas the motor symptoms of PD are responsive to dopamine replacement, gait freezing and postural instability respond poorly. The pathophysiology of these gait disturbances is poorly understood, but their late onset and resistance to levodopa has led to the suggestion that they may result from pathology in nondopaminergic structures involved in locomotion 4,5 .…”

“…Whereas the motor symptoms of PD are responsive to dopamine replacement, gait freezing and postural instability respond poorly. The pathophysiology of these gait disturbances is poorly understood, but their late onset and resistance to levodopa has led to the suggestion that they may result from pathology in nondopaminergic structures involved in locomotion 4,5 .Gait is controlled by genetically defined neuronal networks, the central pattern generators (CPGs), in the spinal cord 6,7 , which are in turn activated by supraspinal centres that initiate and control movement [6][7][8] . Among these, the mesencepalic locomotor region (MLR) in the brainstem plays a key role in the control of gait 9,10 .…”

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…Cholinergic cells predominate in PPNc, but PPNc and anteromedial pars dissipata also contain large populations of GABAergic or glutamatergic neurons [77][78][79]. The input and output relationships of the various neuron groups in the PPN have not been precisely determined, but it is known that the nucleus gives rise to projections to the basal ganglia, thalamus, basal forebrain, reticular formation, and spinal cord [69,74,[80][81][82][83][84][85][86][87][88][89][90][91][92][93], thus being, at the same time, part of the extended basal ganglia family of nuclei [74], and a conduit of descending basal ganglia outputs. The function(s) of this nucleus are poorly understood, although portions of the (primate) PPN are implicated in the control of gait and balance because of overlap with the physiologically identified mesencephalic locomotor region and possibly other motor functions (see below).…”