A Review of the Pedunculopontine Nucleus in Parkinson's Disease

Archives of Medical Science, 2011

Postural instability and gait difficulty (PIGD) are commonly observed in advanced Parkinson's disease. The neuronal mechanism of PIGD is not fully understood. Dysfunction of the pedunculopontine nucleus (PPN) might be a possible cause of these symptoms. The autopsy studies of subjects with PIGD revealed a neurodegenerative process involving mainly PPN cholinergic neurons. The PPN participates in the locomotion processes by initiation, modulation and execution of stereotyped patterns of movement. The standard neurosurgical treatment of PD is subthalamic deep brain stimulation (STN DBS). Clinical results revealed low efficiency of STN DBS on PIGD. Preliminary results of simultaneous PPN and STN DBS are very promising. Only a few reports have been published until now; a significant improvement of PIGD was observed in both ON and OFF L-dopa states.

Brain, 2007

Gait disturbances and akinesia are extremely disabling in advanced Parkinson's disease. It has been suggested that modulation of the activity of the pedunculopontine nucleus (PPN) may be beneficial in the treatment of these symptoms. We report the clinical affects of deep brain stimulation (DBS) in the PPN and subthalamic nucleus (STN). Six patients with unsatisfactory pharmacological control of axial signs such as gait and postural stability underwent bilateral implantation of DBS electrodes in the STN and PPN. Clinical effects were evaluated 2^6 months after surgery in the OFF-and ON-medication state, with both STN and PPN stimulation ON or OFF, or with only one target being stimulated. Bilateral PPN-DBS at 25 Hz in OFF-medication produced an immediate 45% amelioration of the motor Unified Parkinson's Disease Rating Scale (UPDRS) subscale score, followed by a decline to give a final improvement of 32% in the score after 3^6 months. In contrast, bilateral STN-DBS at 130^185 Hz led to about 54% improvement. PPN-DBS was particularly effective on gait and postural items. In ON-medication state, the association of STN and PPN-DBS provided a significant further improvement when compared to the specific benefit mediated by the activation of either single target. Moreover, the combined DBS of both targets promoted a substantial amelioration in the performance of daily living activities.These findings indicate that, in patients with advanced Parkinson's disease, PPN-DBS associated with standard STN-DBS may be useful in improving gait and in optimizing the dopamine-mediated ON-state, particularly in those whose response to STN only DBS has deteriorated over time. This combination of targets may also prove useful in extra-pyramidal disorders, such as progressive supranuclear palsy, for which treatments are currently elusive.

Brain, 2000

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

Annals of Neurology, 1989

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

The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015

The pedunculopontine tegmental nucleus (PPTg) has been proposed as a target for deep brain stimulation (DBS) in parkinsonian patients, particularly for symptoms such as gait and postural difficulties refractory to dopaminergic treatments. Several patients have had electrodes implanted aimed at the PPTg, but outcomes have been disappointing, with little evidence that gait and posture are improved. The PPTg is a heterogeneous structure. Consequently, exact target sites in PPTg, possible DBS mechanisms, and potential benefits still need systematic investigation in good animal models. We have investigated the role of PPTg in gait, developed a refined model of parkinsonism including partial loss of the PPTg with bilateral destruction of nigrostriatal dopamine neurons that mimics human pathophysiology, and investigated the effect of DBS at different PPTg locations on gait and posture using a wireless device that lets rats move freely while receiving stimulation. Neither partial nor comple...

Journal of Neural Transmission, 2008

Parkinsonism & Related Disorders, 2007

The pedunculopontine nucleus (PPN) is a brainstem locomotive center that also processes sensory and behavioral information. Through its connections with basal ganglia structures and the spinal cord, the PPN may play a role in axial motor symptoms in Parkinson's disease (PD). We review the anatomical features of the PPN, its role in motor control, and its potential role as a target for PD surgery, including the results of recently published clinical studies.

2010

Experimental Neurology, 2008

The pedunculopontine nucleus (PPN) is a new deep brain stimulation (DBS) target for Parkinson's disease (PD), but little is known about PPN firing pattern alterations in PD. The anesthetized rat is a useful model for investigating the effects of dopamine loss on the transmission of oscillatory cortical activity through basal ganglia structures. After dopamine loss, synchronous oscillatory activity emerges in the subthalamic nucleus and substantia nigra pars reticulata in phase with cortical slow oscillations. To investigate the impact of dopamine cell lesion-induced changes in basal ganglia output on activity in the PPN, this study examines PPN spike timing with reference to motor cortex (MCx) local field potential (LFP) activity in urethane-and ketamine-anesthetized rats. Seven-ten days after unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, spectral power in PPN spike trains and coherence between PPN spiking and PPN LFP activity increased in the ∼1 Hz range in urethane-anesthetized rats. PPN spike timing also changed from firing predominantly in-phase with MCx slow oscillations in the intact urethane-anesthetized rat to firing predominantly antiphase to MCx oscillations in the hemi-parkinsonian rat. These changes were not observed in the ketamine-anesthetized preparation. These observations suggest that dopamine loss alters PPN spike timing by increasing inhibitory oscillatory input to the PPN from basal ganglia output nuclei, a phenomenon that may be relevant to motor dysfunction and PPN DBS efficacy in PD patients.

Brain, 2010

Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year followup. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by lowfrequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio.