Neuronal population activity in the olivocerebellum encodes the frequency of essential tremor in mice and patients.

Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2dupE3 mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.

Quantitative evaluation of posture control in rats with inferior olive lesions.

Impairment of inferior olivary neurons (IONs) affects whole-body movements and results in abnormal gait and posture. Because IONs are activated by unpredicted motion rather than regular body movements, the postural dysfunction caused by ION lesions is expected to involve factors other than simple loss of feedback control. In this study, we measured the postural movements of rats with pharmacological ION lesions (IO rats) trained to stand on their hindlimbs. The coordination of body segments as well as the distribution and frequency characteristics of center of mass (COM) motion were analyzed. We determined that the lesion altered the peak properties of the power spectrum density of the COM, whereas changes in coordination and COM distribution were minor. To investigate how the observed properties reflected changes in the control system, we constructed a mathematical model of the standing rats and quantitatively identified the control system. We found an increase in linear proportional control and a decrease in differential and nonlinear control in IO rats compared with intact rats. The dystonia-like changes in body stiffness explain the nature of the linear proportional and differential control, and a disorder in the internal model is one possible cause of the decrease in nonlinear control.

Transient Palatal Tremor and Action Induced Foot and Leg Dystonia due to Hypertrophic Olivary Degeneration: a Case Report.

Hypertrophic olivary degeneration (HOD) is a rare phenomenon that occurs after various insults to the Guillain-mollaret triangle (GMT). HOD is unique because the degeneration of inferior olivary nucleus becomes hypertrophic rather than atrophic. In this study, a 31-year-old woman developed HOD after pontine cavernoma surgery had been performed. The clinical manifestation was involuntary intorsion of right lower extremity during walking, which has not been reported in the literature. The woman also presented with palatal tremor, the most classic symptom of HOD. HOD's imaging trait include olive hypertrophy with increased T2 signal intensity on MRI, which are corresponding to the pathological findings. HOD is a self-limiting disease and excessive treatments are unnecessary.

Palato-pharyngo-laryngeal myoclonus with recurrent retrograde feeding tube migration after cerebellar hemorrhagic stroke: a case report and review of hypertrophic olivary degeneration.

BACKGROUND: Palato-pharyngo-laryngeal myoclonus, a variant of palatal myoclonus, is characterized by involuntary rhythmic movements of palatal, pharyngeal, and laryngeal muscles. Symptomatic palatal myoclonus is classically associated with hypertrophic olivary degeneration on MRI imaging due to a lesion in the triangle of Guillain-Mollaret. CASE PRESENTATION: We report a case of palato-pharyngo-laryngeal myoclonus in a patient post-cerebellar hemorrhagic stroke who presented with recurrent retrograde migration of his gastrojejunostomy feeding tubes. Treatment with either divalproex sodium or gabapentin resulted in a significant decrease in his gastrointestinal symptoms and no further episodes of gastrojejunostomy tube migration. CONCLUSIONS: This case study indicates that the movement disorder associated with hypertrophic olivary degeneration may involve the gastrointestinal system. Anticonvulsants, such as gabapentin and divalproex sodium, may reduce the severity of gastrointestinal symptoms in cases associated with hypertrophic olivary degeneration. The anatomy of the Guillain-Mollaret triangle and the pathophysiology of hypertrophic olivary degeneration are reviewed.

Differential effects of inferior olive lesion on vestibulo-ocular and optokinetic motor learning.

The combined operation of optokinetic reflex (OKR) and vestibular-ocular reflex (VOR) is essential for image stability during self-motion. Retinal slip signals, which provide neural substrate for OKR and VOR plasticity, are delivered to the inferior olive. Although it has been assumed that the neural circuitry and mechanisms underlying OKR and VOR plasticity are shared, differential role of the inferior olive in the plasticity of OKR and VOR has not been clearly established. To investigate the differential effect of inferior olive lesion on OKR and VOR plasticity, we examined the change of OKR and VOR gains after gain-up and gain-down VOR training. The results demonstrated that inferior olive-lesion differentially affected cerebellum-dependent motor learning. In control mice, OKR gain increased after both gain-up and gain-down VOR training, and VOR gain increased after gain-up VOR training and decreased after gain-down VOR training. In inferior olive-lesioned mice, OKR gain decreased after both gain-up and gain-down VOR training, and while VOR gain did not significantly change after gain-up VOR training, VOR gain decreased after gain-down VOR training. We suggest that multiple mechanisms of plasticity are differentially involved in VOR and OKR adaptation, and gain-up and gain-down VOR learning rely on different plasticity mechanisms.

Systematic Audiological Assessment of Auditory Functioning in Patients With Parkinson's Disease.

Purpose Alterations in primary auditory functioning have been reported in patients with Parkinson's disease (PD). Despite the current findings, the pathophysiological mechanisms underlying these alterations remain unclear, and the effect of dopaminergic medication on auditory functioning in PD has been explored insufficiently. Therefore, this study aimed to systematically investigate primary auditory functioning in patients with PD by using both subjective and objective audiological measurements. Method In this case-control study, 25 patients with PD and 25 age-, gender-, and education-matched healthy controls underwent an audiological test battery consisting of tonal audiometry, short increment sensitivity index, otoacoustic emissions (OAEs), and speech audiometry. Patients with PD were tested in the on- and off-medication states. Results Increased OAE amplitudes were found when patients with PD were tested without dopaminergic medication. In addition, speech audiometry in silence and multitalker babble noise demonstrated higher phoneme scores for patients with PD in the off-medication condition. The results showed no differences in auditory functioning between patients with PD in the on-medication condition and healthy controls. No effect of disease stage or motor score was evident. Conclusions This study provides evidence for a top-down involvement in auditory processing in PD at both central and peripheral levels. Most important, the increase in OAE amplitude in the off-medication condition in PD is hypothesized to be linked to a dysfunction of the olivocochlear efferent system, which is known to have an inhibitory effect on outer hair cell functioning. Future studies may clarify whether OAEs may facilitate an early diagnosis of PD.

Effects of type 1 diabetes mellitus on efferent auditory system in children and adolescents.

AIM: To investigate whether type 1 diabetes mellitus (T1DM) could affect the efferent auditory system by analyzing the relationship between the activation of the medial olivocochlear reflex with disease duration, metabolic control and age at time of diagnosis. METHOD: A total of 101 children and adolescents were evaluated. They were divided into two groups: 50 with T1DM and 51 without the disease. The participants answered a structured questionnaire containing questions about auditory complaints and were evaluated for tonal audiometry, tympanometry, acoustic reflex, otoacoustic emission by distortion product to evaluate the inhibitory effect of medial olivocochlear reflex (MOC). RESULTS: The participants with T1DM presented changed AR (increased or absent) at all the frequencies in both ears (p < 0.05) when compared with the group without the disease. No differences were found between the DPOAE amplitudes of the individuals with and without T1DM, in both ears at all the frequencies. There were significant differences in the activation of the MOC reflex between the groups with and without T1DM, the participants with T1DM presented the absence of the inhibitory effect of the DPOAE in the right and left ears, in the frequencies of 4000 Hz (p = 0.035/0.002respectively) and 6000 Hz (p = 0.033/0.031 respectively) and 8000 Hz (p = 0.007/0.001 respectively) when compared to the healthy group. Significant differences were also observed between the groups with and without T1DM (p < 0.05) for self-reported complaints of tinitus, difficulties with the perception of speech when there was noise and distraction with noise. No association was found between the hearing complaints and the audiological measurements obtained and disease time, metabolic control and age at the time of diagnosis. CONCLUSION: The findings suggest the presence of early auditory dysfunction of the efferent pathway in patients with T1DM.

Auditory event-related potentials and function of the medial olivocochlear efferent system in children with auditory processing disorders.

OBJECTIVE: The objectives were to investigate the function of central auditory pathways and of the medial efferent olivocochlear system (MOCS). DESIGN: Event-related potentials (ERP) were recorded following the delivery of the stimulus /da/ in quiet and in ipsilateral, contralateral, and binaural noise conditions and correlated to the results of the auditory processing disorders (APD) diagnostic test battery. MOCS function was investigated by adding ipsilateral, contralateral, and binaural noise to transient evoked otoacoustic emission recordings. Auditory brainstem responses and pure tone audiogram were also evaluated. STUDY SAMPLE: Nineteen children (7 to 12 years old) with APD were compared with 24 age-matched controls. RESULTS: Otoacoustic emissions and ABR characteristics did not differ between groups, whereas ERP latencies were significantly longer and of higher amplitudes in APD children than in controls, in both quiet and noise conditions. The MOCS suppression was higher in APD children. CONCLUSIONS: Findings indicate that children with APD present with neural deficiencies in both challenging and nonchallenging environments with an increase in the timing of several central auditory processes correlated to their behavioural performances. Meanwhile, their modulation of the auditory periphery under noisy conditions differs from control children with higher suppression.

Active caspase-3 upregulation is augmented in at-risk cerebellar Purkinje cells following inferior olive chemoablation in the shaker mutant rat: an immunofluorescence study.

OBJECTIVES: Mechanisms underlying Purkinje cell (PC) death, which leads to many diseases in humans, are still poorly elucidated. Progressive PC degeneration occurs in shaker mutant rat due to an X-linked recessive mutation leading to gait ataxia and total-body tremors. Chemoablation of the inferior olive (IO) and olivocerebellar deafferentation temporally accelerated PC death from the natural 6-8 week time-course to 1-2 weeks in the shaker mutant rat. The present study posits that IO chemoablation leads to the accelerated and augmented upregulation of the executioner active caspase-3 that triggers apoptosis of at-risk PCs throughout the ordinary phenotypic manifestation of the shaker mutation. METHODS: Immunofluorescence and double labeling for calbindin and active caspase-3 were used in vermal cerebellar sections from IO-chemoablated rats to demonstrate the effect of IO chemoablation on active caspase-3 expression in at-risk PCs. RESULTS: Active caspase-3 expression was enhanced in the anterior degeneration (ADC) and posterior degeneration (PDC) compartments to reach a peak in both degeneration compartments at 24 h following the injections for IO chemoablation. DISCUSSION: Consequently, it can be deduced that active caspase-3 expression in shaker mutant rats is modifiable suggesting the possibility of targeting it therapeutically in an attempt to rescue PCs from death. Abbreviation PC: Purkinje cell; IO: inferior olive; ADC: Anterior degeneration compartment; PDC: Posterior degeneration compartment; ISC: Intermediate survival compartment; FNSC: Flocculonodular survival compartment.

Enhancement of the Medial Olivocochlear System Prevents Hidden Hearing Loss.

Cochlear synaptopathy produced by exposure to noise levels that cause only transient auditory threshold elevations is a condition that affects many people and is believed to contribute to poor speech discrimination in noisy environments. These functional deficits in hearing, without changes in sensitivity, have been called hidden hearing loss (HHL). It has been proposed that activity of the medial olivocochlear (MOC) system can ameliorate acoustic trauma effects. Here we explore the role of the MOC system in HHL by comparing the performance of two different mouse models: an α9 nicotinic receptor subunit knock-out (KO; Chrna9 KO), which lacks cholinergic transmission between efferent neurons and hair cells; and a gain-of-function knock-in (KI; Chrna9L9'T KI) carrying an α9 point mutation that leads to enhanced cholinergic activity. Animals of either sex were exposed to sound pressure levels that in wild-type produced transient cochlear threshold shifts and a decrease in neural response amplitudes, together with the loss of ribbon synapses, which is indicative of cochlear synaptopathy. Moreover, a reduction in the number of efferent contacts to outer hair cells was observed. In Chrna9 KO ears, noise exposure produced permanent auditory threshold elevations together with cochlear synaptopathy. In contrast, the Chrna9L9'T KI was completely resistant to the same acoustic exposure protocol. These results show a positive correlation between the degree of HHL prevention and the level of cholinergic activity. Notably, enhancement of the MOC feedback promoted new afferent synapse formation, suggesting that it can trigger cellular and molecular mechanisms to protect and/or repair the inner ear sensory epithelium.SIGNIFICANCE STATEMENT Noise overexposure is a major cause of a variety of perceptual disabilities, including speech-in-noise difficulties, tinnitus, and hyperacusis. Here we show that exposure to noise levels that do not cause permanent threshold elevations or hair cell death can produce a loss of cochlear nerve synapses to inner hair cells as well as degeneration of medial olivocochlear (MOC) terminals contacting the outer hair cells. Enhancement of the MOC reflex can prevent both types of neuropathy, highlighting the potential use of drugs that increase α9α10 nicotinic cholinergic receptor activity as a pharmacotherapeutic strategy to avoid hidden hearing loss.

In Vivo Analysis of the Climbing Fiber-Purkinje Cell Circuit in SCA2-58Q Transgenic Mouse Model.

Cerebellar Purkinje cells (PCs) and cerebellar pathways are primarily affected in many autosomal dominant cerebellar ataxias. PCs generate complex spikes (CS) in vivo when activated by climbing fiber (CF) which rise from the inferior olive. In this study, we investigated the functional state of the CF-PC circuitry in the transgenic mouse model of spinocerebellar ataxia type 2 (SCA2), a polyglutamine neurodegenerative genetic disease. In our experiments, we used an extracellular single-unit recording method to compare the PC activity pattern and the CS shape in age-matched wild-type mice and SCA2-58Q transgenic mice. We discovered no alterations in the CS properties of PCs in aging SCA2 mice. To examine the integrity of the olivocerebellar pathway, we applied harmaline, an alkaloid that acts directly on the inferior olive neurons. The pharmacological stimulation of olivocerebellar circuit by harmaline uncovered disturbances in SCA2-58Q PC activity pattern and in the complex spike shape when compared with age-matched wild-type cells. The abnormalities in the CF-PC circuitry were aggravated with age. We propose that alterations in CF-PC circuitry represent one of potential causes of ataxic symptoms in SCA2 and in other SCAs.

Brain circuits and neurochemical systems in essential tremor: insights into current and future pharmacotherapeutic approaches.

INTRODUCTION: There are few medications that are available for the treatment of essential tremor (ET) and they are only moderately effective. Areas covered: Data were obtained from a PubMed search. Original articles, review articles, and clinical guidelines were included. Two disease models for ET have been proposed: 1) the olivary model, which attributes ET to a pathological pacemaker in the inferior olivary nucleus, and 2) the cerebellar degeneration model, which postulates that ET originates in the cerebellum and could be related to deficient or abnormal Purkinje cell (PC) output. Underlying biochemical dysfunction in T-type calcium channels (T-tCaC) may loosely be linked to the first model and deficiency/abnormality in γ-aminobutyric acid (GABA) neurotransmission, to the second. Expert commentary: Human data points robustly to the role of GABA in ET. Numerous medications that target the GABA system have been tried, with variable success. Given the many different types of GABA-ergic neurons, and the multitude of GABAA receptor subtypes, a given medication could have competing/cancelling effects. It would seem that influencing GABA receptors broadly is not as effective as targeting certain GABAA receptor subtypes. Future research should seek to identify molecular candidates that have a more targeted effect within the GABA system.

The Olivary Hypothesis of Essential Tremor: Time to Lay this Model to Rest?

BACKGROUND: Although essential tremor (ET) is the most common tremor disorder, its pathogenesis is not fully understood. The traditional model of ET, proposed in the early 1970s, posited that the inferior olivary nucleus (ION) was the prime generator of tremor in ET and that ET is a disorder of electrophysiological derangement, much like epilepsy. This article comprehensively reviews the origin and basis of this model, its merits and problems, and discusses whether it is time to lay this model to rest. METHODS: A PubMed search was performed in March 2017 to identify articles for this review. RESULTS: The olivary model gains support from the recognition of neurons with pacemaker property in the ION and the harmaline-induced tremor models (as the ION is the prime target of harmaline). However, the olivary model is problematic, as neurons with pacemaker property are not specific to the ION and the harmaline model does not completely represent the human disease ET. In addition, a large number of neuroimaging studies in ET have not detected structural or functional changes in the ION; rather, abnormalities have been reported in structures related to the cerebello-thalamo-cortical network. Moreover, a post-mortem study of microscopic changes in the ION did not detect any differences between ET cases and controls. DISCUSSION: The olivary model largely remains a physiological construct. Numerous observations have cast considerable doubt as to the validity of this model in ET. Given the limitations of the model, we conclude that it is time now to lay this model to rest.

Strain-specific differences in the development of neuronal excitability in the mouse ventral nucleus of the trapezoid body.

This investigation compared the development of neuronal excitability in the ventral nucleus of the trapezoid body (VNTB) between two strains of mice with differing progression rates for age-related hearing loss. In contrast to CBA/Ca (CBA) mice, the C57BL/6J (C57) strain are subject to hearing loss from a younger age and are more prone to damage from sound over-exposure. Higher firing rates in the medial olivocochlear system (MOC) are associated with protection from loud sounds and these cells are located in the VNTB. We postulated that reduced neuronal firing of the MOC in C57 mice could contribute to hearing loss in this strain by reducing efferent protection. Whole cell patch clamp was used to compare the electrical properties of VNTB neurons from the two strains initially in two age groups: before and after hearing onset at âˆ¼ P9 and ∼P16, respectively. Prior to hearing onset VNTB neurons electrophysiological properties were identical in both strains, but started to diverge after hearing onset. One week after hearing onset VNTB neurons of C57 mice had larger amplitude action potentials but in contrast to CBA mice, their waveform failed to accelerate with increasing age, consistent with the faster inactivation of voltage-gated potassium currents in C57 VNTB neurons. The lower frequency action potential firing of C57 VNTB neurons at P16 was maintained to P28, indicating that this change was not a developmental delay. We conclude that C57 VNTB neurons fire at lower frequencies than in the CBA strain, supporting the hypothesis that reduced MOC firing could contribute to the greater hearing loss of the C57 strain.

Impaired Motor Learning in a Disorder of the Inferior Olive: Is the Cerebellum Confused?

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.

Descending projections from the inferior colliculus to medial olivocochlear efferents: Mice with normal hearing, early onset hearing loss, and congenital deafness.

Auditory efferent neurons reside in the brain and innervate the sensory hair cells of the cochlea to modulate incoming acoustic signals. Two groups of efferents have been described in mouse and this report will focus on the medial olivocochlear (MOC) system. Electrophysiological data suggest the MOC efferents function in selective listening by differentially attenuating auditory nerve fiber activity in quiet and noisy conditions. Because speech understanding in noise is impaired in age-related hearing loss, we asked whether pathologic changes in input to MOC neurons from higher centers could be involved. The present study investigated the anatomical nature of descending projections from the inferior colliculus (IC) to MOCs in 3-month old mice with normal hearing, and in 6-month old mice with normal hearing (CBA/CaH), early onset progressive hearing loss (DBA/2), and congenital deafness (homozygous Shaker-2). Anterograde tracers were injected into the IC and retrograde tracers into the cochlea. Electron microscopic analysis of double-labelled tissue confirmed direct synaptic contact from the IC onto MOCs in all cohorts. These labelled terminals are indicative of excitatory neurotransmission because they contain round synaptic vesicles, exhibit asymmetric membrane specializations, and are co-labelled with antibodies against VGlut2, a glutamate transporter. 3D reconstructions of the terminal fields indicate that in normal hearing mice, descending projections from the IC are arranged tonotopically with low frequencies projecting laterally and progressively higher frequencies projecting more medially. Along the mediolateral axis, the projections of DBA/2 mice with acquired high frequency hearing loss were shifted medially towards expected higher frequency projecting regions. Shaker-2 mice with congenital deafness had a much broader spatial projection, revealing abnormalities in the topography of connections. These data suggest that loss in precision of IC directed MOC activation could contribute to impaired signal detection in noise.

Palatal and Oromandibular Tremor Secondary to Degenerative Olivary Hypertrophy After Ependymoma Surgery.

Palatal tremor (PT) is a rare movement disorder that involves pharynx, tongue, and other facial muscles. Symptomatic PT is due to lesions on the dentate-rubro-olivary pathways. We present an illustrative case of PT due to degenerative olivary hypertrophy after ependymoma surgery.