Chronic Ankle Instability and Low Back Pain: A Narrative Review With a Conceptual Framework Linking Distal and Proximal Sensorimotor Dysfunction.

Parkinson’s disease (PD) represents a significant and escalating public health challenge, and is marked by dysfunction in dopaminergic circuits. Increasingly recognized as a neurodegenerative spectrum disorder with a diverse phenotypical combination of motor and non-motor features, PD’s motor aspects - such as bradykinesia, rigidity, and tremor - typically respond well to dopaminergic medication and deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) or globus pallidus internus. However, axial motor symptoms, encompassing dysfunctional gait (e.g., freezing of gait) and postural instability, exhibit poor responsiveness and persist as a clinical concern. Occasionally classified as the PIGD subtype (postural instability and gait difficulty), axial phenotypes remain both insufficiently understood and inadequately addressed by current therapeutic interventions. Thus, there is an urgent need for innovative strategies to address treatment-resistant parkinsonian gait and posture disorders. Previous approaches towards improving axial PD symptoms have emphasized the potential involvement of basal ganglia-brainstem interactions (see Supplementary Fig.  for graphical summary). Specifically, neuromodulation strategies for PIGD have motivated trials of DBS targeting brainstem mesencephalic locomotor region (MLR) nuclei - pedunculopontine (PPN) and cuneiform (CnF) - which yielded inconsistent results. This likely reflects the hitherto poorly understood, complex nature of gait and posture (disorders) in PD and the difficulty of targeting specific MLR pro-locomotor populations identified by cell type-specific means with (electrical) DBS. Recognizing the advantages of non-invasive neuromodulation techniques in terms of ease-of-use and lower complication rates, there is a growing interest in exploring these approaches across different (patho-)physiological states, including PD. However, a prerequisite for better PIGD neuromodulation approaches is a better mechanistic understanding of the circuitry underlying predominantly axial phenotypes. Vestibular stimulation (VS) is a non-invasive method that utilizes, for example, noisy (i.e., thresholded), galvanic (nGVS) or caloric means to activate (central) vestibular circuits via peripheral excitation of the vestibular organ. This technique has shown promise in mitigating motor and non-motor symptoms of PD, potentially by integrating vestibular information for movement into a vestibulo-thalamo-basal ganglia loop. Specifically, some data support a positive impact on axial postural deficits in both PD and atypical parkinsonism, yet less so for gait in PD. Furthermore, nGVS has been reported to improve parkinsonian symptoms, specifically locomotion (putatively by enhanced GABA release by the substantia nigra (SN)) in rats. Vestibular circuits likely exhibit glutamatergic predominance, especially with regard to motor targets. Although anatomical studies suggest possible circuit mechanisms involving vestibulo-thalamic inputs to basal ganglia loops, the structural and functional contributions of vestibular circuits for movement, especially in PD, remain insufficiently understood. Our study thus aimed to better understand how the vestibular nucleus complex (VNC) feeds into basal ganglia loops and contributes to motor function, specifically in the context of parkinsonian neuropathology. First, we sought to further define the former through viral tracing and functional mapping. Second, based on the hypothesis that thresholded human nGVS feeds pro-locomotor information into basal ganglia loops, we tested whether optical activation of the VNC produces therapeutic effects.