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

Abstract

Patients with advanced Parkinson's disease (PD) develop disabling axial symptoms, including gait disturbances, freezing and postural instability poorly responsive to levodopa replacement therapy. The pedunculopontine nucleus (PPN) is involved in locomotion, control of posture, and behavioral states [i.e. wakefulness, rapid eye movement sleep]. Recent reports suggested that PPN modulation with deep brain stimulation (DBS) may be beneficial in the treatment of axial symptoms. However, the mechanisms underlying these effects are still unknown. We used [(15)O] H(2)O PET to investigate regional cerebral blood flow in three patients with advanced PD who underwent a new experimental surgical procedure with implantation of unilateral PPN-DBS. Patients were studied Off-medication with stimulator Off and On, both at rest and during a self-paced alternating motor task of the lower limbs. We used SPM2 for imaging data analysis, threshold P < 0.05 corrected at the cluster level. Stimulation induced significant regional cerebral blood flow increment in subcortical regions such as the thalamus (P < 0.006), cerebellum (P < 0.001), and midbrain region (P < 0.001) as well as different cortical areas involving medial sensorimotor cortex extending into caudal supplementary motor area (BA 4/6; P < 0.001). PPN-DBS in advanced PD resulted in blood flow and presumably neuronal activity changes in subcortical and cortical areas involved in balance and motor control, including the mesencephalic locomotor region (e.g. PPN) and closely interconnected structures within the cerebello-(rubro)-thalamo-cortical circuit. Whether these findings are associated with the DBS-PPN clinical effect remains to be proven. However, they suggest that PPN modulation may induce functional changes in neural networks associated with the control of lower limb movements.

Figure 1

Schematic representation of the location of the electrode contact used for stimulation for one patient. PPTgD = PPN pars dissipata; PPTgC = PPN pars compacta; scp = superior cerebellar peduncle (Modified and reprinted with permission from Paxinos G and Huang XF, Atlas of the Human Brainstem, 1995, ©Academic Press).

Figure 2

Statistical parametric maps of brain regions showing the main effect of the PPN stimulation at a statistical threshold of P < 0.001 (uncorrected) at the single voxel level and P < 0.05 (corrected) at the cluster level. Areas of increased rCBF involve mainly the subcortical structures. These areas are superimposed on sagittal, coronal, and transverse sections of a single subject brain MRI from SPM2. rCBF = regional cerebral blood flow; PPN = pedunculopontine nucleus; R = right; L = left.

Figure 3

Areas of rCBF changes with the task compared to the resting condition at a statistical threshold of P < 0.001 (uncorrected) at the single voxel level and P < 0.05 (corrected) at the cluster level. These areas involve the medial sensorimotor cortex and supplementary motor area. In red: areas commonly activated by the task in both PPN stimulation conditions (inclusive masking analysis). In green: areas specifically activated by the task while ON PPN‐DBS (exclusive masking analysis). rCBF = regional cerebral blood flow; PPN = pedunculopontine nucleus.

Figure 4

Areas showing an increase of rCBF correlating with the decrease in movement frequency (A) and with the increase in the area under the curve (AUC) of the rectified EMG signal (B). At a statistical threshold of P < 0.001 (uncorrected) at the single voxel level and P < 0.05 (corrected) at the cluster level, these areas involve for both correlation analyses the medial sensorimotor cortex and supplementary motor area (SMC/SMA). rCBF = regional cerebral blood flow.