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Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies. Patients with IMCAs develop cerebellar symptoms, characterized mainly by gait ataxia, showing an acute or subacute clinical course. We present a novel concept of latent autoimmune cerebellar ataxia (LACA), analogous to latent autoimmune diabetes in adults (LADA). LADA is a slowly progressive form of autoimmune diabetes where patients are often initially diagnosed with type 2 diabetes. The sole biomarker (serum anti-GAD antibody) is not always present or can fluctuate. However, the disease progresses to pancreatic beta-cell failure and insulin dependency within about 5 years. Due to the unclear autoimmune profile, clinicians often struggle to reach an early diagnosis during the period when insulin production is not severely compromised. LACA is also characterized by a slowly progressive course, lack of obvious autoimmune background, and difficulties in reaching a diagnosis in the absence of clear markers for IMCAs. The authors discuss two aspects of LACA: (1) the not manifestly evident autoimmunity and (2) the prodromal stage of IMCA's characterized by a period of partial neuronal dysfunction where non-specific symptoms may occur. In order to achieve an early intervention and prevent cell death in the cerebellum, identification of the time-window before irreversible neuronal loss is critical. LACA occurs during this time-window when possible preservation of neural plasticity exists. Efforts should be devoted to the early identification of biological, neurophysiological, neuropsychological, morphological (brain morphometry), and multimodal biomarkers allowing early diagnosis and therapeutic intervention and to avoid irreversible neuronal loss., (© 2023. The Author(s).)

Perception of our linear motion - heading - is critical for postural control, gait, and locomotion, and it is impaired in Parkinson's disease (PD). Deep brain stimulation (DBS) has variable effects on vestibular heading perception, depending on the location of the electrodes within the subthalamic nucleus (STN). Here, we aimed to find the anatomical correlates of heading perception in PD. Fourteen PD participants with bilateral STN DBS performed a two-alternative forced-choice discrimination task where a motion platform delivered translational forward movements with a heading angle varying between 0 and 30° to the left or to the right with respect to the straight-ahead direction. Using psychometric curves, we derived the heading discrimination threshold angle of each patient from the response data. We created patient-specific DBS models and calculated the percentages of stimulated axonal pathways that are anatomically adjacent to the STN and known to play a major role in vestibular information processing. We performed correlation analyses to investigate the extent of these white matter tracts' involvement in heading perception. Significant positive correlations were identified between improved heading discrimination for rightward heading and the percentage of activated streamlines of the contralateral hyperdirect, pallido-subthalamic, and subthalamo-pallidal pathways. The hyperdirect pathways are thought to provide top-down control over STN connections to the cerebellum. In addition, STN may also antidromically activate collaterals of hyperdirect pathway that projects to the precerebellar pontine nuclei. In select cases, there was strong activation of the cerebello-thalamic projections, but it was not consistently present in all participants. Large volumetric overlap between the volume of tissue activation and the STN in the left hemisphere positively impacted rightward heading perception. Altogether, the results suggest heavy involvement of basal ganglia cerebellar network in STN-induced modulation of vestibular heading perception in PD., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Clear vision requires accurate gaze shift from one object to the other and steadily maintaining it when eyes are at the target. The rapid gaze shifts are assured by the high-frequency burst in the brainstem neuronal firing, the mechanism relying on the tight cerebellar supervision. The cerebellar oversight is equally essential for maintaining gaze on the object of interest. The cerebellar significance on the motor control of gaze and the consequences of cerebellar illness are known for almost three quarters of the century - since David Cogan published the classic paper titled "Ocular Dysmetria, Flutter Like Oscillations of the Eyes, and Opsoclonus." In this classic series of cases, three disorders of gaze shifting and gaze holding were described in a number of etiologies, ultimately manifesting in a final common pathway involving the cerebellum. Since the 1950s, there had been substantial progress in contemporary neurology, experimental neuroscience literature has expanded, and computational models of ocular motor control have flourished in the field. In this short commentary, I will highlight Cogan's cerebellar classic in the context of contemporary research on motor control of saccades., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The variability in motor dysfunction is not uncommon in autoimmune disorders. Antibody-mediated system-wide malfunction or effects on the neural network shared by two independent pathophysiological processes can cause such heterogeneity. We tested this prediction for motor dysfunction during gaze holding in 11 patients with increased titers of glutamic acid decarboxylase (anti-GAD) antibody. High-resolution oculography measured horizontal and vertical eye positions. The analysis was performed with customized signal processing algorithms. Downbeat and gaze-evoked nystagmus commonly coexisted; one patient had a combination of upbeat and gaze-evoked nystagmus. The nystagmus was associated with saccadic intrusions in 10 patients; all had squarewaves, but five also had saccadic oscillations. The nystagmus and saccadic intrusions, both in the same axis of eye rotations, were not uncommon. Tandem appearance of the episodes of nystagmus and saccadic intrusions suggested a coupling between the two abnormalities. We speculated a unifying framework where the anti-GAD antibody inhibited (GAD mediated) conversion of glutamate to gamma-aminobutyric acid (GABA). Paucity GABA and excess of glutamate cause nystagmus (less GABA) and high-frequency saccadic oscillations (excessive glutamate)., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Perception of our linear motion, heading, relies on convergence from multiple sensory systems utilizing visual and vestibular signals. Multisensory convergence takes place in the visuo-vestibular areas of the cerebral cortex and posterior cerebellar vermis. Latter closely connected with the inferior olive may malfunction in disorders of olivo-cerebellar hypersynchrony, such as the syndrome of oculopalatal tremor (OPT). We had recently shown an impairment in vestibular heading perception in the subjects with OPT. Here we asked whether the hypersynchrony in the inferior-olive cerebellar circuit also affects the visual perception of heading, and the impairment is coupled with the deficits in vestibular heading perception. Three subjects with OPT and 11 healthy controls performed a two-alternative forced-choice task in two separate experiments; one when they were moved en bloc in a straight-ahead forward direction or at multiple heading angles to the right or the left; and second when under virtual reality goggle they experienced the movement of star cloud leading to the percept of heading straight, left or to the right at the heading angles similar to those utilized in the vestibular task. The resultant psychometric function curves, derived from the two-alternative-forced-choice task, revealed abnormal threshold to perceive heading direction, abnormal sensitivity to the change in heading direction compared to straight ahead, and a bias towards one side. Although the impairment was present in both visual and vestibular heading perception, the deficits were not coupled., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

We examined the role of the cerebellum in patients with tremor-dominant cervical dystonia by measuring the adaptive capacity of rapid reflexive eye movements (saccades). We chose the saccade adaptation paradigm because, unlike other motor learning paradigms, the real-time modification of saccades cannot "wait" for the sensory (visual) feedback. Instead, saccades rely primarily on the internal reafference modulated by the cerebellum. The saccade adaptation happens over fast and slow timescales. The fast timescale has poor retention of learned response, while the slow timescale has strong retention. Cerebellar defects resulting in loss of function affect the fast timescale but the slow timescale of saccade adaptation is retained. In contrast, maladaptive cerebellar disorders feature the absence of both fast and slow timescales. We were able to measure both timescales using noninvasive oculography in 6 normal individuals. In contrast, both timescales were absent in 12 patients with tremor-dominant cervical dystonia. These findings are consistent with maladaptive cerebellar outflow as a putative pathophysiological basis for tremor-dominant cervical dystonia., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Multisensory integration is critical for resolving ambiguities in isolated sensory systems assuring accurate perception of one's own linear motion, i.e., heading. The vestibular signal, a critical source of information for heading perception, is transformed in appropriate coordinates suitable for multisensory integration-such transformation takes place under cerebellar supervision. Deficiency in cerebellar function due to Purkinje cell loss results in inaccurate multisensory integration and impaired heading perception. Here, we predict that a classic movement disorder, the syndrome of oculopalatal tremor (OPT), also presents with inaccurate heading direction perception. The characteristic feature of oculopalatal tremor is pseudohypertrophic inferior olive that constantly sends spontaneous, hypersynchronous, abnormal, and meaningless signals to the cerebellum. Such malicious olive signal can impair heading perception. We examined vestibular heading perception in 6 individuals with OPT and 9 age-matched healthy controls (HC). We used a two-alternative forced choice task performed during passive en bloc translation. Compared with age-matched HC, OPT group had significantly higher heading direction perception threshold indicating a less sensitive vestibular system to variations in heading direction. Using computational simulations, we show that the addition of the abnormal noise into the cerebellar system results in decreased spatiotemporal tuning behavior of the cerebellar output. Such impairment in spatiotemporal tuning causes reduced ability to perceive heading direction. Hyperactivity in the inferior-olive cerebellar pathway impairs the heading direction perception. We suggest that this impairment stems from abnormal noise into the cerebellum due to hypersynchronized inferior olive., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Hyperventilation changes the extracellular pH modulating many central pathologies, such as tremor. The questions that remain unanswered are the following: (1) Hyperventilation modulates which aspects of the oscillations? (2) Whether the effects of hyperventilation are instantaneous and the recovery is rapid and complete? Here we study the effects of hyperventilation on eye oscillations in the syndrome of oculopalatal tremor (OPT), a disease model affecting the inferior olive and cerebellar system. These regions are commonly involved in the pathogenesis of many movement disorders. The focus on the ocular motor system also allows access to the well-known physiology and precise measurement techniques. We found that hyperventilation causes modest but insignificant changes in the intensity of oscillation displacement (i.e., how large the eye excursions are) and velocity (i.e., how fast do the eyes move during oscillations). We found the robust increase in the randomness of the oscillatory waveform during hyperventilation and it instantaneously reverts to the baseline after hyperventilation. The subsequent analysis classified the oscillations according to their waveform shape and randomness into different clusters. The hyperventilation substantially changed the cluster type in 60% of the subjects, but it reverted to the pre-hyperventilation cluster at the conclusion of the hyperventilation. In summary, hyperventilation instantaneously affects the randomness of the oscillatory waveforms but there are less substantial effects on the intensity. The deficits reverse immediately at the end of the hyperventilation., (© 2020. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The virtual practice has made major advances in the way that we care for patients in the modern era. The culture of virtual practice, consulting, and telemedicine, which had started several years ago, took an accelerated leap as humankind was challenged by the novel coronavirus pandemic (COVID19). The social distancing measures and lockdowns imposed in many countries left medical care providers with limited options in evaluating ambulatory patients, pushing the rapid transition to assessments via virtual platforms. In this novel arena of medical practice, which may form new norms beyond the current pandemic crisis, we found it critical to define guidelines on the recommended practice in neurotology, including remote methods in examining the vestibular and eye movement function. The proposed remote examination methods aim to reliably diagnose acute and subacute diseases of the inner-ear, brainstem, and the cerebellum. A key aim was to triage patients into those requiring urgent emergency room assessment versus non-urgent but expedited outpatient management. Physicians who had expertise in managing patients with vestibular disorders were invited to participate in the taskforce. The focus was on two topics: (1) an adequate eye movement and vestibular examination strategy using virtual platforms and (2) a decision pathway providing guidance about which patient should seek urgent medical care and which patient should have non-urgent but expedited outpatient management.

The current worldwide severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that causes coronavirus disease 2019 (COVID-19) has brought some medical systems to the brink of collapse. This crisis is also negatively impacting the care of patients with non-COVID-19 conditions, including those with cerebellar ataxia (CA). Older patients with CA and those with immune-mediated ataxias on immunosuppressive medication are potentially at high risk of developing serious complications of the infection, although it is also possible that immunosuppressive agents may provide a defense against cytokine storm. This has implications for even greater attention to preventing contracting the disease through physical distancing and/or isolation. The CA patient population is also at higher risk because of the neurological complexities of their underlying disorder and the comorbid medical illnesses that often accompany the genetic ataxias. As the disruption of social patterns and healthcare delivery in response to the crisis continues, interruption of rehabilitation, speech and language therapy, and face-to-face consultations threatens to have a negative impact on the course and well-being of CA patients. Mental and physical health is also potentially at greater risk because the prevailing uncertainty and anxiety may be superimposed upon cerebellum-specific neuropsychological challenges. We identify and review some of the short- and long-term consequences of this global pandemic for the community of ataxia patients and their families and for the clinical and academic neurologists/ataxiologists caring for these patients. This includes the recognition that telemedicine has emerged as a principle means of caregiver-patient contact and that neurological manifestations of COVID-19 including those specific to cerebellar neurobiology are increasingly recognized and will require close surveillance and monitoring. This COVID-19 Cerebellum Task Force consensus provides some guidance on how we may approach this uncertain time and consider preparing for the new realities we face in CA patient care once this acute crisis has passed.

The relationship between two common movement disorders, dystonia and tremor, is controversial. Both deficits have correlates in the network that includes connections between the cerebellum and the basal ganglia. In order to assess the physiological relationship between tremor and dystonia, we measured the activity of 727 pallidal single-neurons during deep brain stimulation surgery in patients with cervical dystonia without head oscillations, cervical dystonia plus jerky oscillations, and cervical dystonia with sinusoidal oscillations. Cluster analyses of spike-train recordings allowed classification of the pallidal activity into burst, pause, and tonic. Burst neurons were more common, and number of spikes within spike and inter-burst intervals was shorter in pure dystonia and jerky oscillation groups compared to the sinusoidal oscillation group. Pause neurons were more common and irregular in pure tremor group compared to pure dystonia and jerky oscillation groups. There was bihemispheric asymmetry in spontaneous firing discharge in pure dystonia and jerky oscillation groups, but not in sinusoidal oscillation group. These results demonstrate that the physiology of pallidal neurons in patients with pure cervical dystonia is similar to those who have cervical dystonia combined with jerky oscillations, but different from those who have cervical dystonia combined with sinusoidal oscillations. These results imply distinct mechanistic underpinnings for different types of head oscillations in cervical dystonia.

Ataxia-telangiectasia is the second most common autosomal recessive hereditary ataxia, with an estimated incidence of 1 in 100,000 births. Besides ataxia and ocular telangiectasias, eye movement abnormalities have long been associated with this disorder and is frequently present in almost all patients. A handful of studies have described the phenomenology of ocular motor deficits in ataxia-telangiectasia. Contemporary literature linked their physiology to cerebellar dysfunction and secondary abnormalities at the level of brainstem. These studies, while providing a proof of concept of ocular motor physiology in disease, i.e., ataxia-telangiectasia, also advanced our understanding of how the cerebellum works. Here, we will summarize the clinical abnormalities seen with ataxia-telangiectasia in each subtype of eye movements and subsequently describe the underlying pathophysiology. Finally, we will review how these deficits are linked to abnormal cerebellar function and how it allows better understanding of the cerebellar physiology.

An autoimmune disorder of the central nervous system, stiff person syndrome, frequently presents with increased titers of 65KD anti-glutamic acid decarboxylase (anti-GAD) antibodies. The clinical phenomenology of this syndrome includes stiffness, ataxia, vertigo due to horizontal gaze-evoked and downbeat vertical nystagmus, and dysmetria of saccades and reaching movements. Here, we describe a novel phenomenology of syndrome of anti-GAD antibody, non-position-dependent upbeat nystagmus and superimposed horizontal gaze-evoked nystagmus. Lack of gravity dependence of primary position upbeat nystagmus, intense nystagmus on up-gaze, relatively stable gaze on downward orientation, and the exponentially decaying waveform suggests neural integrator dysfunction. The titer of anti-GAD in our patient (30 U/ml) was consistent with a variant called "low-titer anti-GAD syndrome". In addition of presenting as an unusual manifestation of a rare neurological syndrome, this case presents a neurochemical correlate of upbeat nystagmus in GABA-mediated control system involving horizontal and vertical neural integrators. Furthermore, the variant of "low-titer anti-GAD syndrome" suggests that GABAergic system may be affected at lower level or antibodies, and/or the epitopes of antibody in those with full-blown clinical syndrome, but low titers of anti-GAD may be different.

Constant velocity rotations in darkness evoke vestibulo-ocular reflex in form of pre- and post-rotational nystagmus under cerebellar supervision. Reorientation of the head with respect to gravity, stimulating otolith and semicircular canal, during post-rotational phase rapidly suppresses the post-rotational nystagmus. We asked if pure otolith stimulation without semicircular canal signal is sufficient for the suppression of post-rotational nystagmus. The experimental paradigm comprised of on-axis rotations in the horizontal plane when the subject was sitting upright, followed by a novel stimulus that combined off-axis centrifugation in the horizontal plane with amplitude matched, yet out-of-phase, on-axis horizontal rotation-double centrifugation. The resultant effect of double centrifugation was pure otolith stimulation that constantly changed direction, yet completely canceled out angular velocity (no horizontal semicircular canal stimulation). Double centrifugation without pre-existing on-axis rotations evoked mixture of horizontal and vertical eye movements, latter reflected the known uncertainty of the vestibular system to differentiate whether the sensory signal is related to low-frequency translations in horizontal plane or head tilts relative to the gravity. Double centrifugation during post-rotational phase suppressed the peak slow phase eye velocity of the post-rotational nystagmus, hence affecting the vestibular ocular reflex gain (eye velocity/head velocity) matrix. The decay time constant, however, was unchanged. Amount of suppression of the peak slow phase eye velocity of the post-rotational nystagmus during double centrifugation correlated with the peak vertical eye velocity evoked by the pure otolith stimuli in the absence of pre-existing on axis rotations. In post-rotational phase, the pure otolith signal affects vestibular ocular reflex gain matrix but does not affect the time constant.

Contemporary studies speculated that cerebellar network responsible for motion perception projects to the cerebral cortex via vestibulo-thalamus. Here, we sought for the physiological properties of vestibulo-thalamic pathway responsible for the motion perception. Healthy subjects and the patient with focal vestibulo-thalamic lacunar stroke spun a hand-held rheostat to approximate the value of perceived angular velocity during whole-body passive earth-vertical axis rotations in yaw plane. Vestibulo-ocular reflex was simultaneously measured with high-resolution search coils (paradigm 1). In primates, the vestibulo-thalamic projections remain medial and then dorsomedial to the subthalamus. Therefore, the paradigm 2 assessed the effects of high-frequency subthalamic nucleus electrical stimulation through the medial and caudal deep brain stimulation electrode in five subjects with Parkinson's disease. Paradigm 1 discovered directional mismatch of perceived rotation in a patient with vestibulo-thalamic lacune. There was no such mismatch in vestibulo-ocular reflex. Healthy subjects did not have such directional discrepancy of perceived motion. The results confirmed that perceived angular motion is relayed through the thalamus. Stimulation through medial and caudal-most electrode of subthalamic deep brain stimulator in paradigm 2 resulted in perception of rotational motion in the horizontal semicircular canal plane. One patient perceived riding a swing, a complex motion, possibly the combination of vertical canal and otolith-derived signals representing pitch and fore-aft motion, respectively. The results examined physiological properties of the vestibulo-thalamic pathway that passes in proximity to the subthalamic nucleus conducting pure semicircular canal signals and convergent signals from the semicircular canals and the otoliths.

An attractive hypothesis about how the brain learns to keep its motor commands accurate is centered on the idea that the cerebellar cortex associates error signals carried by climbing fibers with simultaneous activity in parallel fibers. Motor learning can be impaired if the error signals are not transmitted, are incorrect, or are misinterpreted by the cerebellar cortex. Learning might also be impaired if the brain is overwhelmed with a sustained barrage of meaningless information unrelated to simultaneously appearing error signals about incorrect performance. We test this concept in subjects with syndrome of oculopalatal tremor (OPT), a rare disease with spontaneous, irregular, roughly pendular oscillations of the eyes thought to reflect an abnormal, synchronous, spontaneous discharge to the cerebellum from the degenerating neurons in the inferior olive. We examined motor learning during a short-term, saccade adaptation paradigm in patients with OPT and found a unique pattern of disturbed adaptation, quite different from the abnormal adaption when the cerebellum is involved directly. Both fast (seconds) and slow (minutes) timescales of learning were impaired. We suggest that the spontaneous, continuous, synchronous output from the inferior olive prevents the cerebellum from receiving the error signals it needs for appropriate motor learning. The important message from this study is that impaired motor adaptation and resultant dysmetria is not the exclusive feature of cerebellar disorders, but it also highlights disorders of the inferior olive and its connections to the cerebellum.

We describe novel deficits of gaze holding and ocular alignment in patients with spinocerebellar ataxia type 3, also known as Machado-Joseph disease (MJD). Twelve MJD patients were studied. Clinical assessments and quantitative ocular alignment measures were performed. Eye movements were quantitatively assessed with corneal curvature tracker and video-oculography. Strabismus was seen in ten MJD patients. Four patients had mild to moderate intermittent exotropia, three had esotropia, one had skew deviation, one had hypotropia, and one patient had moderate exophoria. Three strabismic patients had V-pattern. Near point of convergence was normal in two out of three patients with exotropia. Gaze holding deficits were also common. Eight patients had gaze-evoked nystagmus, and five had micro-opsoclonus. Other ocular motor deficits included saccadic dysmetria in eight patients, whereas all had saccadic interruption of smooth pursuit. Strabismus and micro-opsoclonus are common in MJD. Coexisting ophthalmoplegia or vergence abnormalities in our patients with exotropia that comprised 50 % of the cohort could not explain the type of strabismus in our patients. Therefore, it is possible that involvement of the brainstem, the deep cerebellar nuclei, and the superior cerebellar peduncle are the physiological basis for exotropia in these patients. Micro-opsoclonus was also common in MJD. Brainstem and deep cerebellar nuclei lesion also explains micro-opsoclonus, whereas brainstem deficits can describe slow saccades seen in our patients with MJD.

Vestibular velocity storage enhances the efficacy of the angular vestibulo-ocular reflex (VOR) during relatively low-frequency head rotations. This function is modulated by GABA-mediated inhibitory cerebellar projections. Velocity storage also exists in perceptual pathway and has similar functional principles as VOR. However, it is not known whether the neural substrate for perception and VOR overlap. We propose two possibilities. First, there is the same velocity storage for both VOR and perception; second, there are nonoverlapping neural networks: one might be involved in perception and the other for the VOR. We investigated these possibilities by measuring VOR and perceptual responses in healthy human subjects during whole-body, constant-velocity rotation steps about all three dimensions (yaw, pitch, and roll) before and after 10 mg of 4-aminopyridine (4-AP). 4-AP, a selective blocker of inward rectifier potassium conductance, can lead to increased synchronization and precision of Purkinje neuron discharge and possibly enhance the GABAergic action. Hence 4-AP could reduce the decay time constant of the perceived angular velocity and VOR. We found that 4-AP reduced the decay time constant, but the amount of reduction in the two processes, perception and VOR, was not the same, suggesting the possibility of nonoverlapping or partially overlapping neural substrates for VOR and perception. We also noted that, unlike the VOR, the perceived angular velocity gradually built up and plateau prior to decay. Hence, the perception pathway may have additional mechanism that changes the dynamics of perceived angular velocity beyond the velocity storage. 4-AP had no effects on the duration of build-up of perceived angular velocity, suggesting that the higher order processing of perception, beyond the velocity storage, might not occur under the influence of mechanism that could be influenced by 4-AP.