Oscillatory activity in the pedunculopontine area of patients with Parkinson's disease

doi:10.1016/j.expneurol.2008.01.002

Experimental Neurology

Volume 211, Issue 1, May 2008, Pages 59-66

https://doi.org/10.1016/j.expneurol.2008.01.002 Get rights and content

Abstract

The pedunculopontine nucleus (PPN) has recently been introduced as a new therapeutic target for deep brain stimulation (DBS) in patients suffering from Parkinson's disease (PD). In a recent case report it was demonstrated that alpha frequency oscillations appear in PPN after the administration of levodopa in PD, indicating a possible physiological role of these oscillations. Here we confirm this result and investigate the functional connectivity and reactivity of subcortical alpha activity by recording LFP activity from the PPN area and EEG in six patients with PD while at rest and in four of them while they performed ipsi- and contralateral self-paced joystick movements. Levodopa strongly promoted 7–11 Hz oscillatory synchronization in the region of PPN and coupling of this activity with similar activity in the cortical EEG. Such coupling was bidirectional. Moreover, the 7–11 Hz oscillatory synchronization in the PPN area increased about 3 s prior to self-paced movements, but only following levodopa treatment. These findings suggest that alpha oscillations in the PPN area may represent a physiological pattern of activity. The subcortical oscillations are coupled to cortical alpha activity and possibly allied to motor related attentional processes.

Introduction

The pedunculopontine nucleus (PPN) is a key part of the reticular activating system and mesencephalic locomotor region (Pahapill and Lozano, 2000, Mena-Segovia et al., 2004, Mena-Segovia et al., 2005). It has extensive connections, including with the basal ganglia and thalamus. Recently, it has been introduced as a therapeutic target for deep brain stimulation (DBS) in patients suffering from Parkinson's disease (PD), particularly those with severe gait and postural impairment (Mazzone et al., 2005, Plaha and Gill, 2005, Lim et al., 2007, Stefani et al., 2007). Effective therapeutic stimulation in PPN is delivered at low frequencies, in line with studies in 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine treated primates where 10 Hz stimulation proved most efficient (Jenkinson et al., 2004). This contrasts with other basal ganglia targets, such as the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi), where stimulation must be delivered at frequencies above 100 Hz to be therapeutic.

Just how and why this unique stimulation regime should work in the PPN in PD remains unclear. In a recent case report we showed that treatment with levodopa in a patient with PD implanted in Bristol (U.K.) lead to the appearance of alpha band activity in the local field potential (LFP) recorded from PPN (Androulidakis et al., 2008). This prompted the suggestion that alpha band synchronization is a physiological feature of PPN function and that this activity may be mimicked by low frequency stimulation of the PPN. Here we confirm our earlier result in a series of six more PD patients in whom the PPN area was implanted in Rome, and investigate the functional connectivity and reactivity of the subcortical alpha activity with the aim of deducing the possible role of this activity in behavioural performance in PD.

Section snippets

Patients and surgery

Six patients gave written informed consent to take part in this study which was approved by the local ethics committee. Cases 1 and 2 underwent bilateral implantation of the STN and PPN area, case 3 and 4 unilateral implantation of the STN and PPN area, case 5 unilateral implantation of the GPi and PPN area, and case 6 unilateral implantation of PPN area alone for the treatment of severe Parkinson's disease. Clinical findings in case 6 have been previously reported as case 3 in Stefani et al.

PPN area alpha band power and reactivity

Raw data showed a prominent 7–11 Hz activity in the LFP from the PPN area but only after treatment with levodopa (8 and 7 sides studied ON and OFF, respectively; Fig. 2, Fig. 3A). Power between 7–11 Hz was significantly higher in the ON (median = 0.14 a.u.) than in the OFF state (median = 0.078 a.u.; z = 2.36, p = 0.018, Wilcoxon test; Fig. 3B). For each DBS electrode, alpha power showed a well-defined peak at one contact pair in the ON state. This peak was arbitrarily distributed between contact pairs

Discussion

In this series of patients with Parkinson's disease we found that levodopa promoted 7–11 Hz oscillatory synchronization in the region of PPN, in accordance with our previous case report (Androulidakis et al., 2008). Moreover, we showed that this oscillatory activity in the PPN area was coherent with similar activity in the cortical EEG, but only after treatment with levodopa. Estimation of the directed coherence revealed that this coupling between the PPN area and cortex was bidirectional,

Acknowledgments

Alexandros Androulidakis is supported by the Onassis and Leventis foundations and Peter Brown by the Medical Research Council of Great Britain.

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¹: These authors contributed equally to this work.

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