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.

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.

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.

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.

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.

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.

The inferior olive is essential for long-term maintenance of a simple motor skill.

The inferior olive (IO) is essential for operant down-conditioning of the rat soleus H-reflex, a simple motor skill. To evaluate the role of the IO in long-term maintenance of this skill, the H-reflex was down-conditioned over 50 days, the IO was chemically ablated, and down-conditioning continued for up to 102 more days. H-reflex size just before IO ablation averaged 62(±2 SE)% of its initial value (P < 0.001 vs. initial). After IO ablation, H-reflex size rose to 75-80% over ∼10 days, remained there for ∼30 days, rose over 10 days to above its initial value, and averaged 140(±14)% for the final 10 days of study (P < 0.01 vs. initial). This two-stage loss of down-conditioning maintenance correlated with IO neuronal loss (r = 0.75, P < 0.01) and was similar to the loss of down-conditioning that follows ablation of the cerebellar output nuclei dentate and interpositus. In control (i.e., unconditioned) rats, IO ablation has no long-term effect on H-reflex size. These results indicate that the IO is essential for long-term maintenance of a down-conditioned H-reflex. With previous data, they support the hypothesis that IO and cortical inputs to cerebellum combine to produce cerebellar plasticity that produces sensorimotor cortex plasticity that produces spinal cord plasticity that produces the smaller H-reflex. H-reflex down-conditioning appears to depend on a hierarchy of plasticity that may be guided by the IO and begin in the cerebellum. Similar hierarchies may underlie other motor learning.

Behavioral correlates of complex spike synchrony in cerebellar microzones.

The olivo-cerebellar system is crucial for smooth and well timed execution of movements based on sensory and proprioceptive cues. The inferior olive (IO) plays a pivotal role in this process by synchronizing its activity across neurons internally through connexin36 gap junctions and providing a timing and/or learning signal to the cerebellum. Even though synchrony achieved through electrical coupling in IO cells is generally thought to be important in timing motor output, a direct relation between timing of movement and synchrony of olivary discharges has never been demonstrated within functional microcomplexes using transgenics. Here we combined in vivo, two-photon calcium imaging of complex spikes in microcomplexes of Purkinje cell (PC) dendrites with high-speed filming of tail, trunk, and limb movements in awake wild-type and connexin36-deficient mice. In wild types at rest, functional clusters of PCs were poorly defined with synchrony correlations that were relatively small and spatially limited to mediolateral distances of ∼50 µm, whereas during locomotion synchrony of the same PCs increased in strength and extended over distances spanning multiple microzones that could be correlated to specific components of sharp and well bounded movements. Instead, connexin36-deficient mice exhibited prolonged and desynchronized complex spike activity within PC microcomplexes both at rest and during behavior. Importantly, the mutants also showed concomitant abnormalities in the execution of spinocerebellar reflexes, which were significantly slower and more gradual than in wild-type littermates, particularly following sensory perturbations. Our results highlight the importance of modulation of synchronous activity within and between cerebellar microcomplexes in on-line temporal processing of motor output.

Vim thalamotomy in a patient with Holmes' tremor and palatal tremor - Pathophysiological considerations.

BACKGROUND: We peformed a ventral intermediate nucleus (Vim) thalamotomy in a patient with Holmes' tremor and palatal tremor. The frequencies of these movement disorders were 4 Hz and 3 Hz, respectively. Vim thalamotomy stopped the Holmes' tremor but not the palatal tremor. Our observations suggest different mechanisms for these two involuntary movements. CASE PRESENTATION: A 57-arm 11 months after a pontine hemorrhage. Transoral carotid ultrasonography revealed periodic motion of her posterior pharyngeal wall with a frequency of 3 Hz. Recording of neuronal activities in the thalamus revealed a 4Hz rhythmic discharge time that was associated with her tremor in the contralateral arm. A left Vim thalamotomy was performed. The resting tremor of the upper limb stopped, but the kinetic tremor recurred 6 months after the thalamotomy. No effect was observed on her palatal tremor. CONCLUSIONS: The different effects of Vim thalamotomy on the Holmes' tremor and palatal tremor suggest different oscillation sources for these two involuntary movements.

Retrocochlear function of the peripheral deafness gene Cacna1d.

Hearing impairment represents the most common sensory deficit in humans. Genetic mutations contribute significantly to this disorder. Mostly, only malfunction of the ear is considered. Here, we assessed the role of the peripheral deafness gene Cacna1d, encoding the L-type channel Ca(v)1.3, in downstream processing of acoustic information. To this end, we generated a mouse conditional Cacna1d-eGFP(flex) allele. Upon pairing with Egr2::Cre mice, Ca(v)1.3 was ablated in the auditory brainstem, leaving the inner ear intact. Structural assessment of the superior olivary complex (SOC), an essential auditory brainstem center, revealed a dramatic volume reduction (43-47%) of major nuclei in young adult Egr2::Cre;Cacna1d-eGFP(flex) mice. This volume decline was mainly caused by a reduced cell number (decline by 46-56%). Abnormal formation of the lateral superior olive was already present at P4, demonstrating an essential perinatal role of Ca(v)1.3 in the SOC. Measurements of auditory brainstem responses demonstrated a decreased amplitude in the auditory nerve between 50 and 75 dB stimulation in Egr2::Cre;Cacna1d-eGFP(flex) knockout mice and increased amplitudes in central auditory processing centers. Immunohistochemical studies linked the amplitude changes in the central auditory system to reduced expression of K(v)1.2. No changes were observed for K(v)1.1, KCC2, a determinant of inhibitory neurotransmission, and choline acetyltransferase, a marker of efferent olivocochlear neurons. Together, these analyses identify a crucial retrocochlear role of Ca(v)1.3 and demonstrate that mutations in deafness genes can affect sensory cells and neurons alike. As a corollary, hearing aids have to address central auditory processing deficits as well.

Targeting the red nucleus for cerebellar tremor.

Deep brain stimulation of the thalamus (and especially the ventral intermediate nucleus) does not significantly improve a drug-resistant, disabling cerebellar tremor. The dentato-rubro-olivary tract (Guillain-Mollaret triangle, including the red nucleus) is a subcortical loop that is critically involved in tremor genesis. We report the case of a 48-year-old female patient presenting with generalized cerebellar tremor caused by alcohol-related cerebellar degeneration. Resistance to pharmacological treatment and the severity of the symptoms prompted us to investigate the effects of bilateral deep brain stimulation of the red nucleus. Intra-operative microrecordings of the red nucleus revealed intense, irregular, tonic background activity but no rhythmic components that were synchronous with upper limb tremor. The postural component of the cerebellar tremor disappeared during insertion of the macro-electrodes and for a few minutes after stimulation, with no changes in the intentional (kinetic) component. Stimulation per se did not reduce postural or intentional tremor and was associated with dysautonomic symptoms (the voltage threshold for which was inversed related to the stimulation frequency). Our observations suggest that the red nucleus is (1) an important centre for the genesis of cerebellar tremor and thus (2) a possible target for drug-refractory tremor. Future research must determine how neuromodulation of the red nucleus can best be implemented in patients with cerebellar degeneration.

Assessment of the noise-protective action of the olivocochlear efferents in humans.

It has been demonstrated in different mammals that the medial olivocochlear efferents (MOC) exert a noise-protective effect on the cochlea. In humans such an effect has not unambiguously been shown as of yet. The objective of this study was to assess the relationship between MOC activity and susceptibility of the cochlea to noise-induced hearing loss in humans. In 40 normally hearing human subjects, we measured the following: (1) magnitude of temporary threshold shift (TTS) after exposure to 60 min broadband noise of 94 dB SPL and (2) contralateral suppression (CS) of distortion product otoacoustic emissions (which reflects MOC activity) using two different measurement paradigms. CS was measured in duplicate on 2 measurement days. The relationship between TTS and CS was assessed. Individual TTS in the most affected frequencies (4 > 3 > 8 kHz) ranged from 9 to 28 dB HL, with an average maximum TTS of 18.4 dB HL. The amount of CS ranged between 0.3 and 3 dB. The repeatability of CS, evaluated by Cronbach's α value, ranged from 0.76 (acceptable repeatability) to 0.86 (good repeatability). One of the two different measurement paradigms showed a statistically significant inverse correlation between CS magnitude and amount of TTS, which was hypothesized. This is the first study on the relationship between TTS and CS in humans employing TTS induced under controlled laboratory conditions and two different MOC paradigms. The findings are compatible with the hypothesis that MOC activity is noise protective in humans. Future perspectives include modified CS paradigms, longitudinal cohort studies or efforts to also monitor lateral efferent effects in humans.

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.

Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive.

The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of Ca(V)3.1 T-type Ca(2+) channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4- to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking Ca(V)3.1 gene. Intracellular recordings in brain-stem slices revealed that the Ca(V)3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of Ca(V)3.1 gene in the inferior olive by shRNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate Ca(V)3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, Ca(V)3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor.

Truncal ataxia from infarction involving the inferior olivary nucleus.

Truncal ataxia in medullary infarction may be caused by involvement of the lateral part of the medulla; however, truncal ataxia in infarction involving the inferior olivary nucleus (ION) has received comparatively little attention. We report a patient with truncal ataxia due to medial medullary infarction located in the ION. A lesion in the ION could produce a contralateral truncal ataxia due to increased inhibitory input to the contralesional vestibular nucleus from the contralesional flocculus.

Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity.

The inferior olivary nuclei clearly play a role in creating oculopalatal tremor, but the exact mechanism is unknown. Oculopalatal tremor develops some time after a lesion in the brain that interrupts inhibition of the inferior olive by the deep cerebellar nuclei. Over time the inferior olive gradually becomes hypertrophic and its neurons enlarge developing abnormal soma-somatic gap junctions. However, results from several experimental studies have confounded the issue because they seem inconsistent with a role for the inferior olive in oculopalatal tremor, or because they ascribe the tremor to other brain areas. Here we look at 3D binocular eye movements in 15 oculopalatal tremor patients and compare their behaviour to the output of our recent mathematical model of oculopalatal tremor. This model has two mechanisms that interact to create oculopalatal tremor: an oscillator in the inferior olive and a modulator in the cerebellum. Here we show that this dual mechanism model can reproduce the basic features of oculopalatal tremor and plausibly refute the confounding experimental results. Oscillations in all patients and simulations were aperiodic, with a complicated frequency spectrum showing dominant components from 1 to 3 Hz. The model's synchronized inferior olive output was too small to induce noticeable ocular oscillations, requiring amplification by the cerebellar cortex. Simulations show that reducing the influence of the cerebellar cortex on the oculomotor pathway reduces the amplitude of ocular tremor, makes it more periodic and pulse-like, but leaves its frequency unchanged. Reducing the coupling among cells in the inferior olive decreases the oscillation's amplitude until they stop (at approximately 20% of full coupling strength), but does not change their frequency. The dual-mechanism model accounts for many of the properties of oculopalatal tremor. Simulations suggest that drug therapies designed to reduce electrotonic coupling within the inferior olive or reduce the disinhibition of the cerebellar cortex on the deep cerebellar nuclei could treat oculopalatal tremor. We conclude that oculopalatal tremor oscillations originate in the hypertrophic inferior olive and are amplified by learning in the cerebellum.

Audiological findings in celiac disease.

OBJECTIVE: Celiac disease (CD) is a gluten-triggered immune enteropathy caused by a genetic predisposition. Recent papers suggest that CD is increasingly recognized by extraintestinal findings. The aim of this study was to investigate the effect of CD on hearing pathway including the olivocochlear efferent system in children. METHODS: Forty-one pediatric CD patients and 31 controls were included in the study. Both groups were evaluated with audiometry, tympanometry, transiently evoked otoacoustic emission (TEOAE), distortion product otoacoustic emission (DPOAE), and contralateral suppression of the TEOAE. RESULTS: The threshold at 250 Hz of the patients with CD was significantly higher (p < 0.05 in CD compared to control group, p < 0.0001). The signal to noise ratio (SNR) amplitudes in DPOAE testing and the SNR amplitudes with and without contralateral acoustic stimulus in TEOAE testing were significantly lower at 1,000 Hz in the CD compared to the control group. There was no significant difference between the CD and the control group regarding contralateral suppression amplitudes. CONCLUSION: CD seems to have an important impact on the auditory system, and results in an elevation of the thresholds at 250 Hz on audiometry and a decrease in the amplitudes of DPOAE and linear TEOAE at 1,000 Hz in children.

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.