Cerebellar Dysfunction in Multiple Sclerosis: Considerations for Research and Rehabilitation Therapy

Abstract

Introduction. Cerebellar pathology is common among persons with multiple sclerosis (PwMS). The cerebellum is well recognized for its role in motor control and motor learning and cerebellar pathology in multiple sclerosis is associated with enhanced motor impairment and disability progression. The Problem. To mitigate motor disability progression, PwMS are commonly prescribed exercise and task-specific rehabilitation training. Yet, whether cerebellar dysfunction differentially affects rehabilitation outcomes in this population remains unknown. Furthermore, we lack rehabilitation interventions targeting cerebellar dysfunction. The Solution. Here, we summarize the current understanding of the impact of cerebellar dysfunction on motor control, motor training, and rehabilitation in persons with multiple sclerosis. Recommendations. Additionally, we highlight critical knowledge gaps and propose that these guide future research studying cerebellar dysfunction in persons with multiple sclerosis.

Multiple sclerosis (MS) is a complex neurodegenerative disease that selectively impacts the central nervous system (CNS) through demyelination of neurons. Demyelination can occur across multiple brain regions and leads to a distortion or total loss of neuronal signaling ¹ that can impact a variety of motor, cognitive, and sensory functions. One brain area frequently affected by MS is the cerebellum. ² MS-related pathology affects the cerebellar cortex, the deep cerebellar nuclei, and the white matter microstructure that comprises the cerebellar peduncles.^3-5 Cerebellar pathology in MS is associated with impairments in both motor and cognitive domains. It indicates a poor prognosis and greater disability. ⁶ To mitigate the progression of motor impairment, persons with MS (PwMS) are commonly prescribed exercise and task-specific rehabilitation training. However, the cerebellum plays a critical role in both motor control and motor learning,^7,8 which may complicate motor rehabilitation for PwMS with cerebellar dysfunction. ⁹ Yet, how cerebellar dysfunction may affect rehabilitation outcomes in this population remains unknown. Here, we summarize the current understanding of the impacts of cerebellar dysfunction on motor control, motor training, and rehabilitation in PwMS. We then highlight critical knowledge gaps and propose that these guide future research studying cerebellar dysfunction in PwMS.

In the motor domain, cerebellar damage causes ataxia—a movement disorder marked by poorly coordinated movement that can manifest in all body effectors. ⁷ Hallmark signs of cerebellar damage are seen in impaired oculomotor control, impaired upper limb control, and impaired balance and gait. Specifically, oculomotor deficits include saccadic dysmetria (an over- or undershooting of saccade endpoints), nystagmus (a beating of the eyes, particularly in lateral gaze), and saccadic intrusions during smooth pursuit eye movements (a jagged movement of the eyes when tracking a moving stimulus). ¹⁰ In the upper limbs, cerebellar signs include impaired multi-joint coordination and dysmetria when making goal-directed movements.^11,12 In the lower limbs, cerebellar dysfunction is associated with gait ataxia—a condition marked by poor balance control, slow walking speed, and a veering path. ⁹

The motor signs of cerebellar pathology in MS may present as ataxia. ¹³ In PwMS, cerebellar lesions are associated oculomotor impairments such as saccadic dysmetria, nystagmus, and deficits in smooth pursuit.^14,15 Lower cerebellar grey and white matter volume has been associated with impaired upper limb coordination. ¹⁶ Lesions in the cerebellar cortex and peduncles have also been associated with dysmetria and intention tremor during goal-directed reaching. ¹⁷ Perhaps the most well-studied motor signs of cerebellar pathology in PwMS are those seen in gait and balance control. Structural neuroimaging studies show that greater postural sway during quiet stance is associated with grey matter atrophy in cerebellar lobules IV, V, VI, and VIII, ⁵ and myelin damage in the inferior, middle, and superior cerebellar peduncles.^18,19 A functional neuroimaging study also showed that reduced resting state cortico-cerebellar connectivity is associated with greater lags in postural corrections to imposed balance perturbations. ²⁰ With regard to gait, lower overall cerebellar volume is linked to poor coordination, as assessed by the ratio of step length to cadence. ²¹ Reductions in both cerebellar volume and diffusivity have been linked to slower walking speed and time to complete the Timed Up and Go test. ²²

The current standard of cerebellar assessment for PwMS is the Cerebellar Functional Systems Scale of the Expanded Disability Status Scale. ²³ Unfortunately, this assessment is limited to observance of ataxia in the limbs or trunk and does not rate quality of movement or include examination of eye movements or cognition. The criterion used for determining cerebellar dysfunction within clinical trials has also been variable (e.g., Tornes et al, ⁶ Liu et al, ¹⁷ and Weier et al ²⁴ ). The subsequent lack of differentiation between PwMS with and without cerebellar dysfunction limits the generalizability and translation of trial findings to clinical rehabilitation. Without a standardized assessment, it is unlikely that potential differences in motor learning and underlying brain pathology unique to PwMS with cerebellar dysfunction will be identified.

The motor signs of cerebellar damage have been linked to impaired predictive control, affecting the feedforward component of movement. ²⁵ Deficient predictive control strongly impairs a type of motor learning called adaptation. ⁸ Adaptation describes the process of learning to alter movement commands in response to predictable perturbations to the body or environment. It involves a recalibration of sensory-motor mapping and represents an important neural mechanism through which people learn to alter their movement. Adaptation impairments have been well characterized in individuals with focal cerebellar damage, but relatively few studies have examined adaptation in PwMS. The existing literature suggests that MS leaves adaptation intact,^20,26 but may impair more subtle aspects of memory and consolidation. ²⁷ However, few studies have attempted to discern any relationship between adaptation and cerebellar dysfunction in PwMS. Fling et al ²⁰ examined the relationship between resting state cortico-cerebellar connectivity and learning in a postural adaptation task. The authors found no relationship between cortico-cerebellar connectivity and learning. However, this result is difficult to interpret as the baseline degree of cerebellar dysfunction (as determined by neuroimaging or clinical motor signs) in their study sample was not reported. Thus, it is unclear whether there was sufficient variance in the data to find a significant relationship between learning and cortico-cerebellar connectivity, if one exists.

Improving our understanding of the precise impacts of cerebellar dysfunction on motor learning in PwMS may elucidate the appropriate type of rehabilitation intervention for this population. Recent work showed that a training protocol aimed at compensating for impaired adaptation improved motor learning in individuals with focal degeneration of the cerebellum.^28,29 The protocol reduced the specific sensory information about movement errors that drives adaptation, and instead, provided binary outcome feedback to bias the motor system toward less cerebellum-dependent learning and control mechanisms. This training intervention is at a very early stage in the translational pipeline from proof-of-principle to clinical practice. Therefore, the time is ripe for researchers to investigate whether a similar approach could be used to tailor rehabilitation interventions to account for cerebellar dysfunction in PwMS. A critical outstanding question concerns whether the widespread nature of neuronal damage in MS introduces additional deficits that confound the advantages of reinforcement training. For example, demyelination along the dorsal column of the spinal cord can impair proprioceptive sense, ³⁰ which may be integral to solve the credit assignment problem that arises with reinforcement signaling in motor learning tasks.^28,31,32 Additionally, cognitive impairments, which are common in MS, ³³ may further interfere with reinforcement-based interventions. ³⁴

Recent work also opens new avenues for future research to clarify the appropriate timing for rehabilitation. PwMS can have lower cerebellar volume than age-matched controls and exhibit lesions in the cerebellum even though they show low-disability and may not exhibit overt cerebellar motor signs. ¹⁸ These “silent lesions” have led to the hypothesis that there may be a critical window, during which targeted behavioral interventions can prevent further degradation and mitigate loss of function. In support of this, Prosperini et al ¹⁹ showed that a 12-week intensive balance training program induced transient structural plasticity along the white matter tracts forming the cerebellar peduncles. The plastic changes occurred alongside improvements in clinical balance performance. However, it should be noted that the gains did not persist when the intervention was removed. This suggests that ongoing task-specific training may be needed to drive lasting plasticity in PwMS. Nonetheless, it is of great interest for future research to study whether training-induced structural improvements are only seen in those individuals not yet exhibiting cerebellar motor signs, or whether similar effects are seen in PwMS with more progressive cerebellar pathology.

Given the role of the cerebellum in motor learning, motor control, and cognition, all of which may impact intervention response, it is clear that specific considerations are needed for rehabilitation of PwMS with cerebellar dysfunction. Here, we have proposed 3 considerations for future research: (1) standardizing assessment for differentiation of PwMS with and without cerebellar dysfunction, (2) understanding the precise motor learning impairments of PwMS and capitalizing on remaining learning mechanisms, and (3) determining if there may be a critical window where interventions targeting cerebellar dysfunction are more successful in PwMS. Advancing knowledge in these areas has potential to inform the appropriate type and timing of rehabilitation interventions. While we have focused on the motor signs of cerebellar pathology in MS, the cerebellum is also highly interconnected with brain regions responsible for aspects of cognition. We also recognize the impact of cognitive dysfunction on motor learning and motor control. The impact of rehabilitation interventions on cognitive function in PwMS with cerebellar pathology remains unclear. Future work should investigate the efficacy of cognitive rehabilitation on cerebellar dysfunction in MS. Lastly, we recognize that there are other factors specific to MS that can impact daily function and response to training interventions (i.e., fatigue and peripheral problems that are not necessarily observed in other cerebellar disorders, such as the spinocerebellar ataxias.). However, a precise understanding of the impact of cerebellar dysfunction on MS disease progression, motor recovery, and rehabilitation responsiveness will be critical for the development of effective therapeutic interventions.