Tractography patterns of pedunculopontine nucleus deep brain stimulation

Ashley L B Raghu,Amir P Divanbeighi Zand,Alexander L Green,Jesper Andersson,Tariq Parker,John Stein,Stephen Payne,Tipu Z Aziz

doi:10.1007/s00702-021-02327-x

Abstract

Deep brain stimulation of the pedunculopontine nucleus is a promising surgical procedure for the treatment of Parkinsonian gait and balance dysfunction. It has, however, produced mixed clinical results that are poorly understood. We used tractography with the aim to rationalise this heterogeneity. A cohort of eight patients with postural instability and gait disturbance (Parkinson’s disease subtype) underwent pre-operative structural and diffusion MRI, then progressed to deep brain stimulation targeting the pedunculopontine nucleus. Pre-operative and follow-up assessments were carried out using the Gait and Falls Questionnaire, and Freezing of Gait Questionnaire. Probabilistic diffusion tensor tractography was carried out between the stimulating electrodes and both cortical and cerebellar regions of a priori interest. Cortical surface reconstructions were carried out to measure cortical thickness in relevant areas. Structural connectivity between stimulating electrode and precentral gyrus (r = 0.81, p = 0.01), Brodmann areas 1 (r = 0.78, p = 0.02) and 2 (r = 0.76, p = 0.03) were correlated with clinical improvement. A negative correlation was also observed for the superior cerebellar peduncle (r = −0.76, p = 0.03). Lower cortical thickness of the left parietal lobe and bilateral premotor cortices were associated with greater pre-operative severity of symptoms. Both motor and sensory structural connectivity of the stimulated surgical target characterises the clinical benefit, or lack thereof, from surgery. In what is a challenging region of brainstem to effectively target, these results provide insights into how this can be better achieved. The mechanisms of action are likely to have both motor and sensory components, commensurate with the probable nature of the underlying dysfunction.

Highlights

Gait freezing and balance dysfunction leading to falls are symptoms of Parkinson’s disease (PD) that are typically unresponsive to dopamine agonists or deep brain stimulation (DBS) of the subthalamic nucleus
Patient H developed a mild dysarthria associated with deep breathing, which may have been related to stimulation
During motor performance, blood flow to the supplementary motor area (SMA) is increased when PD akinesia is treated with dopamine agonists (Jenkins et al 1992). This describes an opposing valence of precentral gyrus- and SMA-pedunculopontine nucleus (PPN) interaction, that mirrors the motor cortex tractography correlations we found for gait freezing

Summary

Introduction

Gait freezing and balance dysfunction leading to falls are symptoms of Parkinson’s disease (PD) that are typically unresponsive to dopamine agonists or deep brain stimulation (DBS) of the subthalamic nucleus. Neurosurgery centres have reported mixed clinical results from DBS targeting the PPN for postural instability and gait disturbances (PIGD) in PD (Ferraye et al 2010; Thevathasan et al 2011a), it is clear that stimulation of the PPN region (ventrolateral pontine tegmentum) can alter aspects of gait (Thevathasan et al 2012) and balance (Perera et al 2018), at least in some patients. It remains unknown why the PIGD symptoms of some patients improve with treatment, and with others it does not. Current data are limited to PPN tractography in healthy individuals (Muthusamy et al 2007) and single DBS cases (Schweder et al 2010), leaving questions relating to clinical outcomes unaddressed

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Conclusion