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

A durable gain in motor and non-motor symptoms of Parkinson’s Disease following repeated caloric vestibular stimulation: A single-case study

“…We recognize that the inferential power of the present single-case study is limited, however, the improved response profile demonstrated by the participant, perhaps most notably at 5months follow-up, alludes to a practical patient benefit that, in our opinion, justifies larger-scale investigation. Although the biological basis of recovery was not investigated here, we speculate that the nonmotor gains point to activation of non-dopaminergic pathways and may underline the growing therapeutic relevance of the pedunculopontine nucleus given that it both sends and receives dense projections from areas with known vestibular responses and, when directly activated via deep brain stimulation, has been associated with heightened cognition and arousal (Ballanger et al, 2009). …”

Involvement of the human pedunculopontine nucleus region in voluntary movements

“…4,5 The PPN modulates limb movements and locomotion. PPN neue-Pub ahead of print on August 11, 2010, at www.neurology.org.…”

“…5,26,27 The premovement beta excitatory drive from the SMA to the PPNR may be involved with formulation of motor program for movement executions. Thus, the beta rhythm in the human PPNR may be prokinetic rather than antikinetic.…”

Combined pedunculopontine-subthalamic stimulation in Parkinson disease

“…rCBF increases in prefrontal areas have been noted during unilateral PPN stimulation. 16 The discordance between the patterns of rCBF changes following PPN stimulation may reflect the few patients in both studies giving reduced power to detect subtle changes. Alternatively, the lack of prefrontal activation in our patients may represent degeneration in the ascending cholinergic projections from the PPN to the frontal cortex, which has been described in advanced PD, especially in patients with axial symptoms.…”