Neurobiological Insights Into Gait and Balance Control in Parkinson Disease

Nicolaas Bohnen, MD, PhD

Postural instability and freezing of gait are major motor issues in the advanced stages of Parkinson disease (PD), leading to a higher risk of fall and reduced quality of life. Recent research suggests that patients with PD who experience freezing of gait struggle to use vestibular information effectively for posture, possibly because of changes in the cholinergic system integrity observed through vesicular acetylcholine transporter PET.¹ However, there is still a lack comprehension of how sensory information affects postural control in among these patients with PD.

Recently, at the 2023 International Congress of Parkinson’s Disease and Movement Disorders, held August 27-31, in Copenhagen, Denmark, Nicolaas Bohnen, MD, PhD, professor of radiology and neurology at the University of Michigan, in Ann Arbor, presented a part in the MDS keynote lecture. In the lecture, Bohnen and colleagues presented a review of human neuroanatomy and physiology in relation to gait and posture control as well as explained how approaches in neuromodulation of freezing may help with treatment in PD.²

Following the lecture, Bohnen was interviewed by NeurologyLive® to provide further information from the lecture. He talked about how the activation of brain locomotor regions differs between laboratory-based walking studies and cognitive motor imagery in healthy individuals. He also spoke about the neurodegenerative factors that contribute to postural instability and gait difficulties in PD, and the role of peripheral sensory impairments. Additionally, Bohnen shared some of his thoughts on the potential therapeutic interventions suggested to improve balance and gait in PD, considering factors like cholinergic upregulation and avoidance of certain drugs.

NeurologyLive: Could you provide an overview of your keynote presentation?

Nicolaas Bohnen, MD, PhD: Laboratory-based studies in animals have shown evidence for 3 brain locomotor regions (cerebellar, mesencephalic and subthalamic) that in conjunction with descending pathways from the brainstem and spinal cord pattern generators are activated during walking. Similarly, laboratory-based glucose metabolic PET studying in normal older adults during comfortable walking on even surface and constant lighting confirms activation of the cerebellar locomotor region (CLR) and pre-/post-central cortical and other regions but no specific activation of the mesencephalic (MLR) or subthalamic (SLR) locomotor or basal ganglia regions.

In contrast fMRI motor imagery studies of normal persons who are thinking of various gait functions evidence of activation of all three locomotor regions, striatum and the supplemental motor area but not the pericentral cortices. These data suggest that the cognitive process of thinking about gait recruits extra locomotor and brain regions. In contrast, walking in real life with talking while walking, paying attention to uneven surfaces, busy environments, variable lighting is very different from these well-controlled laboratory studies of isolated gait functions. The traditional research emphasis of gait and balance changes in PD and other neurodegenerative parkinsonisms has been on the brain.

Specific cerebellar-thalamic-striatal-cortical circuitry has been identified with a particular emphasis on nigrostriatal proteinopathies and dopaminergic losses. This model has led to life-changing advances in the field, such as dopaminergic pharmacotherapy and deep brain simulation. However, effective management of postural instability and gait difficulties, such as falls and freezing of gait, remains a critical unmet need in clinical practice. This may point to pathophysiological relevance of non-dopaminergic neurotransmissions and a multisystem biology that involve not only the brain but also the body and their navigation within a complex psychophysical environment. Abnormalities in peripheral proprioceptive, visual, vestibular sensory perception and multi-sensory brain integration occur already in early disease stages and affect motor control by impairing balance and gait.

Evidence is emerging that nigrostriatal dopaminergic losses may be compensated by cholinergic neurotransmission in the brain, at least in an early stage of the disease. Subsequent development of imbalance and falls is associated with cholinergic losses in specific brain regions such as the metathalamus (medial and lateral geniculate nuclei). Other factors include cardiac sympathetic denervation that is associated with not only slower gait but also anxiety. Fear of falling is an important emotional factor that may force fallers to a sedentary lifestyle resulting in a downward vicious cycle of frailty. As a matter of fact, sarcopenia results in muscle weakness (as already recognized by James Parkinson’s shaking palsy description of the disease called after him). Sarcopenia itself is another independent risk factor for falls.

Systemic factors, such as vascular, metabolic, and inflammatory functions interplay with neurodegeneration that can be collectively labelled as ‘neurovasculomitis’ and emphasize the importance of proper management of systemic comorbidities to modify the risk of postural instability and gait difficulties in PD and related neurodegenerative disorders. The retina is a site of not only alpha-synucleinopathy but also dopaminergic losses in PD that may explain why cholinergic and extra-striatal dopaminergic losses in the lateral geniculate nucleus plays an important role in falls.

GABA-ergic changes in the cerebellum, the cerebellar peduncles and the brainstem is another non-dopaminergic factor associated with falls in PD. New research has found evidence that the inferior colliculus with novel pathways to the medial geniculate nucleus, striatum, spinal cord and other regions may provide motor rescue pathways that may explain the previous enigmatic paradoxical kinesia phenomenon in PD.

What would you say are the main takeaways from the research for clinicians in this field?

Gait & balance control in real life mobility is a function of CNS-PNS networks that interact with the autonomic nervous system, peripheral sensory, neuromuscular systems and multi-sensory, cognitive & emotional perception of the outside world with ultimate goal of safe mobility. Ultimately the brain’s main challenge is to integrate motor, attentional/cognitive, multisensory and emotional processes to effectuate motor program controlling mobility.

Neurodegenerative pathophysiology of gait & balance control can be predicted by brain and body multi-organ proteinopathies associated with complex bidirectional neurotransmitter changes with evidence of at least in the initial stage of upregulating systems that subsequently will be lost. Balance and gait functions are controlled by multiple systems involving the brain, body and their interactions with the psychophysical environment. Recognition of the importance of peripheral sensory and multisensory processing may provide therapeutic opportunities to improve balance and gait.

What do you think needs to be further explored in this area?

Next steps would be to investigate the neurobiological mechanisms of neurotransmitter upregulation to inform therapeutic interventions that can be administered in early-stage disease to promote disease modification and prevention of debilitating falls and freezing of gait motor disturbances in parkinsonian disorders. There is a need for specific cholinergic muscarinic an/or nicotinic receptor agonist and inverse GABA-A receptor agonist drug development that may improve balance and gait functions in PD.

Strategies that may improve sympathetic and parasympathetic components of heart rate variability, such as vagal nerve stimulation may be another approach to improve gait and fear of falling in PD. New brainstem inferior colliculus pathways to the medial geniculate nucleus, spinal cord, basal ganglia and other brain regions may inform novel interventions to improve or maintain mobility functions in PD.

Is there anything else that clinicians should keep in mind with this research?

Cholinergic upregulation may be an important compensatory factor in maintaining balance and gait functions in early-stage PD. A simple practical advice would be to avoid drugs with anticholinergic properties, such as commonly used antidepressant, urogenital, gastrointestinal drugs starting in early-stage disease. Un-prescribing and avoidance of GABA-ergic drugs, such as benzodiazepines, may help to prevent falls in PD.

Emotional factors, such as fear of falling, should be recognized early to prevent sarcopenia and multi-organ frailty. Early and effective management of systemic vascular, metabolic and inflammatory processes and their effect on the neurodegenerating central, peripheral and autonomic nervous systems so-called ‘neurovasculomitis’ may provide another avenue to manage the risk of postural instability and gait difficulties in PD.

Transcript edited for clarity. Click here for more coverage of MDS 2023.

REFERENCES
1. Roytman S, Paalanen R, Griggs A, et al. Cholinergic system correlates of postural control changes in Parkinson's disease freezers. Brain. 2023;146(8):3243-3257. doi:10.1093/brain/awad134
2. Bohnen N. Functional Neuroanatomy of Posture and Gait: Physiology and Function. Presented at: MDS Annual Meeting; August 27-31, 2023; Copenhagen, Denmark. MDS Keynote Lecture.