The Role of the Pedunculopontine Tegmental Nucleus in Experimental Parkinsonism in Primates

Abstract

To clarify the role of the pedunculopontine tegmental nucleus (PPN) in motor behavior, we have conducted a series of experiments in primates. In the first part, PPN was damaged locally with kainic acid, which resulted in mild hemiparkinsonism in the contralateral limbs. In the second part, muscimol (a GABA agonist) was locally injected into the PPN area in monkeys who had been trained to perform a lever-pull movement with an arm, resulting in a slowness of movement and a delay of the movement onset. In the third part, a dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was systemically injected in monkeys with prior PPN lesioning. These monkeys developed no, or if any, very mild parkinsonism. PPN lesioning was supposed to have protected the nigral neurons from the MPTP- toxicity. The PPN facilitates the motor system through its nigral projection. The decreased activity of the PPN may underlie the pathophysiology of parkinsonism.

Altered neuronal activity relationships between the pedunculopontine nucleus and motor cortex in a rodent model of Parkinson's disease

“…Low frequency stimulation, generally thought to drive neuronal activity, is found to be most therapeutically effective when stimulating the PPN in PD patients (Mazzone et al, 2005;Plaha and Gill, 2005;Stefani et al, 2007) and studies in non-human primates suggest that the PPN is overinhibited in PD (Kojima et al, 1997;Munro-Davies et al, 1999;Matsumura and Kojima, 2001;Nandi et al, 2002;Jenkinson et al, 2004). Our results also suggest that the PPN is dominated by inhibitory oscillatory input from the SNpr in the parkinsonian brain.…”

“…Non-human primate and patient data suggest that the PPN is overinhibited in PD. While excitotoxic lesions of the PPN in normal primates cause akinesia (Kojima et al, 1997;Munro-Davies et al, 1999;Matsumura and Kojima, 2001), lowfrequency (2.5-10 Hz) stimulation (Jenkinson et al, 2004) or pharmacological disinhibition (Nandi et al, 2002) of the PPN can dramatically improve motor behavior in parkinsonian MPTP-lesioned primates. Stimulation in the 10-25 Hz range, generally thought to drive local neuronal activity, is also effectively used in the PPN to ameliorate motor symptoms in PD patients (Mazzone et al, 2005;Plaha and Gill, 2005;Stefani et al, 2007).…”

Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease

“…These ibo- tenic PPN lesions resulted in subtle cognitive deficits, but failed to induce impairment in spontaneous locomotion (24,25), except for a deficit in baseline activity when the lesion involved the anterior PPN (26). In monkeys, PPN lesion induced typical parkinsonism with akinesia and hypertonia, but the behavioral analysis in the previous studies did not focus on gait and posture (27)(28)(29). In this context, it is intriguing that the PPN lesions we performed in monkeys failed to produce akinesia.…”

Cerebral blood flow changes induced by pedunculopontine nucleus stimulation in patients with advanced Parkinson's disease: A [15O] H2O PET study

“…This has also been confirmed by electrophysiological studies in rats revealing a decreased firing rate of PPN neurons in the Parkinsonian state [Ogura et al, 1997]. In MPTP monkeys, while lesions of the PPN cause akinesia [Matsumura and Kojima, 2001;Munro-Davies et al, 1999], either stimulation [Jenkinson et al, 2004] or disinhibition with the GABA antagonist bicuculline [Nandi et al, 2002] can alleviate akinesia. In keeping with these observations, recent studies have provided evidence that the PPN could be a potential target for deep brain stimulation (DBS) to improve gait and other axial symptoms [Mazzone et al, 2005;Plaha and Gill, 2005;Stefani et al, 2007], and its modulation may be able to induce corresponding regional cerebral blood flow (rCBF) changes [Strafella et al, 2008].…”