Bilateral control of interceptive saccades: evidence from the ipsipulsion of vertical saccades after caudal fastigial inactivation.

The caudal fastigial nuclei (cFN) are the output nuclei by which the medio-posterior cerebellum influences the production of saccades toward a visual target. On the basis of the organization of their efferences to the premotor burst neurons and the bilateral control of saccades, the hypothesis was proposed that the same unbalanced activity accounts for the dysmetria of all saccades during cFN unilateral inactivation, regardless of whether the saccade is horizontal, oblique, or vertical. We further tested this hypothesis by studying, in two head-restrained macaques, the effects of unilaterally inactivating the caudal fastigial nucleus on saccades toward a target moving vertically with a constant, increasing or decreasing speed. After local muscimol injection, vertical saccades were deviated horizontally toward the injected side with a magnitude that increased with saccade size. The ipsipulsion indeed depended on the tested target speed but not its instantaneous value because it did not increase (decrease) when the target accelerated (decelerated). By subtracting the effect on contralesional horizontal saccades from the effect on ipsilesional ones, we found that the net bilateral effect on horizontal saccades was strongly correlated with the effect on vertical saccades. We explain how this correlation corroborates the bilateral hypothesis and provide arguments against the suggestion that the instantaneous saccade velocity would somehow be "encoded" by the discharge of Purkinje cells in the oculomotor vermis.NEW & NOTEWORTHY Besides causing dysmetric horizontal saccades, unilateral inactivation of caudal fastigial nucleus causes an ipsipulsion of vertical saccades. This study is the first to quantitatively describe this ipsipulsion during saccades toward a moving target. By subtracting the effects on contralesional (hypometric) and ipsilesional (hypermetric) horizontal saccades, we find that this net bilateral effect is strongly correlated with the ipsipulsion of vertical saccades, corroborating the suggestion that a common disorder affects all saccades.

Disruption of rat deep cerebellar perineuronal net alters eyeblink conditioning and neuronal electrophysiology.

The perineuronal net (PNN) is a specialized type of extracellular matrix found in the central nervous system. The PNN forms on fast spiking neurons during postnatal development but the ontogeny of PNN development has yet to be elucidated. By studying the development and prevalence of the PNN in the juvenile and adult rat brain, we may be able to understand the PNN's role in development and learning and memory. We show that the PNN is fully developed in the deep cerebellar nuclei (DCN) of rats by P18. By using enzymatic digestion of the PNN with chondroitinase ABC (ChABC), we are able to study how digestion of the PNN affects cerebellar-dependent eyeblink conditioning in vivo and perform electrophysiological recordings from DCN neurons in vitro. In vivo degradation of the PNN resulted in significant differences in eyeblink conditioning amplitude and area. Female animals in the vehicle group demonstrated higher levels of conditioning as well as significantly higher post-probe conditioned responses compared to males in that group, differences not present in the ChABC group. In vitro, we found that DCN neurons with a disrupted PNN following exposure to ChABC had altered membrane properties, fewer rebound spikes, and decreased intrinsic excitability. Together, this study further elucidates the role of the PNN in cerebellar learning in the DCN and is the first to demonstrate PNN degradation may erase sex differences in delay conditioning.

Alcohol-Responsive Hyperkinetic Movement Disorders-a Mechanistic Hypothesis.

Patients with essential tremor, vocal tremor, torticollis, myoclonus-dystonia and posthypoxic myoclonus often benefit in a surprisingly rapid and robust manner from ingestion of a modest amount of alcohol (ethanol). Despite considerable investigation, the mechanism of ethanol's ability to produce this effect remains a mystery. In this paper, we review the pharmacology of ethanol and its analogue GHB (or sodium oxybate), summarize the published literature of alcohol-responsive hyperkinetic movement disorders, and demonstrate videos of patients we have treated over the last fifteen years with either an ethanol challenge or with chronic sodium oxybate therapy. We then propose a novel explanation for this phenomenon-namely, that ingestion of modest doses of ethanol (or sodium oxybate) normalizes the aberrant motor networks underling these disorders. We propose that alcohol and its analogues improve clinical symptoms and their physiologic correlate by restoring the normal firing pattern of the major outflow pathways of the cerebellum (the Purkinje cells and deep cerebellar nuclei), We present evidence to support this hypothesis in animal models and in affected patients, and suggest future investigations to test this model.

A FN-MdV pathway and its role in cerebellar multimodular control of sensorimotor behavior.

The cerebellum is crucial for various associative sensorimotor behaviors. Delay eyeblink conditioning (DEC) depends on the simplex lobule-interposed nucleus (IN) pathway, yet it is unclear how other cerebellar modules cooperate during this task. Here, we demonstrate the contribution of the vermis-fastigial nucleus (FN) pathway in controlling DEC. We found that task-related modulations in vermal Purkinje cells and FN neurons predict conditioned responses (CRs). Coactivation of the FN and the IN allows for the generation of proper motor commands for CRs, but only FN output fine-tunes unconditioned responses. The vermis-FN pathway launches its signal via the contralateral ventral medullary reticular nucleus, which converges with the command from the simplex-IN pathway onto facial motor neurons. We propose that the IN pathway specifically drives CRs, whereas the FN pathway modulates the amplitudes of eyelid closure during DEC. Thus, associative sensorimotor task optimization requires synergistic modulation of different olivocerebellar modules each provide unique contributions.

Hyper-Formation of GABA and Glycine Co-Releasing Terminals in the Mouse Cerebellar Nuclei after Deprivation of GABAergic Inputs from Purkinje Cells.

GABA and glycine are inhibitory neurotransmitters. However, the mechanisms underlying the formation of GABAergic and glycinergic synapses remain unclear. The influence of GABAergic input deprivation on inhibitory terminal formation was investigated using Purkinje cell (PC)-specific vesicular GABA transporter (VGAT) knockout (L7-VGAT) mice, in which GABA release from PCs diminishes in an age-dependent manner. We compared the late development of GABAergic and glycinergic terminals in the cerebellar nucleus (CN) between control and L7-VGAT mice. In the control CN, the density of glutamate decarboxylase (GAD)-positive dots remained unchanged between postnatal 2 months (P2M) and 13 months (P13M), whereas glycine transporter 2 (GlyT2)-positive dots increased in density during this time frame. No difference in the density of GlyT2-positive dots was observed between control and L7-VGAT mice at P2M, but the density was significantly higher in the L7-VGAT fastigial nuclei (FN) than the control FN at P13M. When VGAT was absent from PC terminals, GlyT2-positive dots included GAD and VGAT and formed synapses. These results indicated that GABAergic terminals were formed by P2M, glycinergic terminals were actively formed after P2M, and more glycinergic terminals were formed in the L7-VGAT FN than in the control FN, suggesting that the increased glycinergic terminals may derive from interneurons within the FN and may also release GABA. These results suggest that the deprivation of GABAergic inputs from PCs may accelerate the formation of co-releasing terminals derived from interneurons and that the inhibitory terminal numbers and types may be regulated by the quantity of functional GABAergic inputs.

Effect of Long-Term Retention of Gadolinium on Metabolism of Deep Cerebellar Nuclei After Repeated Injections of Gadodiamide in Rats.

OBJECTIVES: The aim of this study was to determine potential metabolism and histological modifications due to gadolinium retention within deep cerebellar nuclei (DCN) after linear gadolinium-based contrast agent injection (gadodiamide) in rats at 1 year after the last injection. MATERIALS AND METHODS: Twenty female rats received 20 doses of gadodiamide (0.6 mmol of gadolinium per kilogram each) over 5 weeks. They were followed at 1 week (M0), 6 weeks (M1), and 54 to 55 weeks (M13) postinjections to evaluate hypersignal on unenhanced T1-weighted magnetic resonance imaging and metabolic alterations by H magnetic resonance spectroscopy (H-MRS). At 1 year postinjections, brains were sampled to determine the localization of gadolinium within cerebellum by laser ablation inductively coupled mass spectroscopy and to evaluate morphological changes by semiquantitative immunofluorescence analysis. RESULTS: There is a significant increase of the ratio DCN/brainstem for the gadodiamide group at M0 (+7.2% vs control group = 0.989 ± 0.01), M1 (+7.6% vs control group = 1.002 ± 0.018), and it lasted up to M13 (+4.7% vs control group = 0.9862 ± 0.008). No variation among metabolic markers (cellular homeostasis [creatine, choline, taurine], excitatory neurotransmitter [glutamate], and metabolites specific to a cellular compartment [N-acetyl aspartate for neurons and myo-inositol for glial cells]) were detected by H-MRS between gadodiamide and saline groups at M0, M1, and M13. At M13, laser ablation inductively coupled mass spectroscopy demonstrated that long-term gadolinium retention occurred preferentially in DCN. No histological abnormalities (including analysis of astrocytes, neurons, and microglial cells) were found in the rostral part of DCN. CONCLUSIONS: Repeated administration of gadodiamide lead to a retention of gadolinium preferentially within DCN at 1 year postinjections. This retention did not lead to any detectable changes of the measured metabolic biomarkers nor histological alterations.

Metronidazole-induced encephalopathy caused by hyperbaric oxygen therapy in a patient with mandibular osteomyelitis.

Metronidazole (MNZ) is prescribed for the treatment of infection caused by anaerobic bacteria and protozoa. Metronidazole-induced encephalopathy (MIE) has been known to be a side-effect, although its onset ratio is unclear. However, to the best of our knowledge, MIE associated with hyperbaric oxygen therapy (HBO) has not been previously reported. Here, we present the case of a 68-year-old man with mandibular osteomyelitis who received metronidazole for 49 days and received five times HBO therapy. He visited our hospital for evaluation and treatment of peripheral neuropathy, speech disturbance, nausea, and disturbance of gait after 47 days of initiating metronidazole treatment. Brain magnetic resonance imaging revealed hyperintense lesions in the cerebellar dentate nuclei, which was consistent with MIE. The patient's ataxic symptoms improved in 15 days after the discontinuation of MNZ. This is the first report demonstrating case of MIE could be related with HBO, as far as we had searched.

Fastigial nucleus electrostimulation promotes axonal regeneration after experimental stroke via cAMP/PKA pathway.

Axon regeneration after cerebral ischemia in mammals is inadequate to restore function, illustrating the need to design better strategies for improving outcomes. Improvement of axon regeneration has been achieved through fastigial nucleus electrostimulation (FNS) in animal researches. However, the mechanisms underlying this neuroprotection remain poorly understood. Increasing the levels of the second messenger cyclic AMP (cAMP) enhances axon regeneration, making it an excellent candidate molecule that has therapeutic potential. In the present study, we examined the expression of cAMP signaling in ischemic brain tissues following focal cerebral ischemia. Adult rats were subjected to ischemia induced by middle cerebral artery occlusion (MCAO). A dipolar electrode was placed into the cerebellum to stimulate the cerebellar fastigial nucleus for 1 h after ischemia. Neurological deficits and the expressions of cAMP, PKA (protein kinase A) and ROCK (Rho-kinase) were determined. Axonal regeneration was measured by upregulation of growth-associated protein 43 (GAP43). The data indicated that FNS significantly enhanced axonal regeneration and motor function recovery after cerebral ischemia. FNS also significantly increased cAMP and PKA levels after ischemic brain injury. All the beneficial effects of FNS were blocked by Rp-cAMP, an antagonist of PKA. Our research suggested that the axonal regeneration conferred by FNS was likely achieved via the regulation of cAMP/PKA pathway.

Beneficial Effects of Olive Oil on the Rats' Cerebellum: Functional and Structural Evidence.

BACKGROUND: Olive oil is a food additive and used in many biological studies as a solvent for other chemicals, including drugs. AIM: The present study aimed to investigate the effects of olive oil on rats' cerebellum structure and motor function. MATERIALS AND METHODS: Male rats were randomly divided into two groups orally receiving distilled water and olive oil (1 ml/kg/day). At the end of week 4, motor function was assessed in the rotarod test. The cerebellum was removed for stereo-logical assessment. Data were analyzed using a two-way repeated measures ANOVA for rotarod test and Kruskal-Wallis and Mann-Whitney U test for quantitative histological parameters. RESULTS: Performance of the olive oil-treated rats in fixed and accelerating speed rotarod was better and their riding time (endurance) was greater compared to the control group (p<0.05). However, no significant difference was found between the two groups regarding the total volume of the cerebellar hemisphere, its cortex, and deep cerebellar nuclei. The total number of the Purkinje, Bergman, and Golgi of the granular layer as well as neurons of the deep cerebellar nuclei was 26 - 36% higher in the olive oil-treated rats than in the distilled water treated group (p<0.03). CONCLUSION: The study findings suggest that olive oil has neuroprotective effects on the cerebellum and induces better performance of the rats in the rotarod.

Pursuit disorder and saccade dysmetria after caudal fastigial inactivation in the monkey.

The caudal fastigial nuclei (cFN) are the output nuclei by which the medio-posterior cerebellum influences the production of saccadic and pursuit eye movements. We investigated the consequences of unilateral inactivation on the pursuit eye movement made immediately after an interceptive saccade toward a centrifugal target. We describe here the effects when the target moved along the horizontal meridian with a 10 or 20°/s speed. After muscimol injection, the monkeys were unable to track the present location of the moving target. During contralesional tracking, the velocity of postsaccadic pursuit was reduced. This slowing was associated with a hypometria of interceptive saccades such that gaze direction always lagged behind the moving target. No correlation was found between the sizes of saccade undershoot and the decreases in pursuit speed. During ipsilesional tracking, the effects on postsaccadic pursuit were variable across the injection sessions, whereas the interceptive saccades were consistently hypermetric. Here also, the ipsilesional pursuit disorder was not correlated with the saccade hypermetria either. The lack of correlation between the sizes of saccade dysmetria and changes of postsaccadic pursuit speed suggests that cFN activity exerts independent influences on the neural processes generating the saccadic and slow eye movements. It also suggests that the cFN is one locus where the synergy between the two motor categories develops in the context of tracking a moving visual target. We explain how the different fastigial output channels can account for these oculomotor tracking disorders. NEW & NOTEWORTHY Inactivation of the caudal fastigial nucleus impairs the ability to track a moving target. The accuracy of interceptive saccades and the velocity of postsaccadic pursuit movements are both altered, but these changes are not correlated. This absence of correlation is not compatible with an impaired common command feeding the circuits producing saccadic and pursuit eye movements. However, it suggests an involvement of caudal fastigial nuclei in their synergy to accurately track a moving target.

Inactivation of the interpositus nucleus blocks the acquisition of conditioned responses and timing changes in conditioning-specific reflex modification of the rabbit eyeblink response.

Conditioning-specific reflex modification (CRM) of the rabbit eyeblink response is an associative phenomenon characterized by increases in the frequency, size, and peak latency of the reflexive unconditioned eyeblink response (UR) when the periorbital shock unconditioned stimulus (US) is presented alone following conditioning, particularly to lower intensity USs that produced minimal responding prior to conditioning. Previous work has shown that CRM shares many commonalities with the conditioned eyeblink response (CR) including a similar response topography, suggesting the two may share similar neural substrates. The following study examined the hypothesis that the interpositus nucleus (IP) of the cerebellum, an essential part of the neural circuitry of eyeblink conditioning, is also required for the acquisition of CRM. Tests for CRM occurred following delay conditioning under muscimol inactivation of the IP and also after additional conditioning without IP inactivation. Results showed that IP inactivation blocked acquisition of CRs and the timing aspect of CRM but did not prevent increases in UR amplitude and area. Following the cessation of inactivation, CRs and CRM latency changes developed similarly to controls with intact IP functioning, but with some indication that CRs may have been facilitated in muscimol rabbits. In conclusion, CRM timing and CRs both likely require the development of plasticity in the IP, but other associative UR changes may involve non-cerebellar structures interacting with the eyeblink conditioning circuitry, a strong candidate being the amygdala, which is also likely involved in the facilitation of conditioning. Other candidates worth consideration include the cerebellar cortex, prefrontal and motor cortices.

Inactivation of the cerebellar fastigial nuclei alters social behavior in the rat.

Research has implicated the deep cerebellar nuclei in autism. This study questioned whether fastigial nuclei abnormalities account for some of the irregular social behaviors seen in autism. Bilateral cannulation surgery was performed on 13 rats. An ABABAB reversal design was implemented. All animals received a microinfusion of saline during the baseline (A) phases. The experimental animal was placed in an open field with an unfamiliar confederate animal, and social interactions between the two animals were measured for 10 min. Seven animals received microinfusions of bupivacaine during the treatment phases (B), which temporarily inactivated the fastigial nuclei. Six control animals received saline again, and social interaction was retested. This sequence was executed 3 times over 6 days to achieve an ABABAB reversal design. Because the cerebellum is involved in motor behavior, the animals' locomotion was analyzed to ensure results were not because of locomotor deficits. A gait analysis and distance traveled in the open field were used to measure locomotion. No differences were found in locomotor behavior. Results of the social interaction analyses indicate animals with inactivated fastigial nuclei engage in less intense social interactions and engage in more behaviors to prevent social interaction. Knowledge that the fastigial nuclei mediate social interaction can further the understanding of pathology in the autistic brain and lead to breakthrough treatments. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

The caudal fastigial nucleus and the steering of saccades toward a moving visual target.

The caudal fastigial nuclei (cFN) are the output nuclei by which the medio-posterior cerebellum influences the production of visual saccades. We investigated in two head-restrained monkeys their contribution to the generation of interceptive saccades toward a target moving centrifugally by analyzing the consequences of a unilateral inactivation (10 injection sessions). We describe here the effects on saccades made toward a centrifugal target that moved along the horizontal meridian with a constant (10, 20, or 40°/s), increasing (from 0 to 40°/s over 600 ms), or decreasing (from 40 to 0°/s over 600 ms) speed. After muscimol injection, the monkeys were unable to foveate the current location of the moving target. The horizontal amplitude of interceptive saccades was reduced during contralesional target motions and hypermetric during ipsilesional ones. For both contralesional and ipsilesional saccades, the magnitude of dysmetria increased with target speed. However, the use of accelerating and decelerating targets revealed that the dependence of dysmetria upon target velocity was not due to the current velocity but to the required amplitude of saccade. We discuss these results in the framework of two hypotheses, the so-called "dual drive" and "bilateral" hypotheses. NEW & NOTEWORTHY Unilateral inactivation of the caudal fastigial nucleus impairs the accuracy of saccades toward a moving target. Like saccades toward a static target, interceptive saccades are hypometric when directed toward the contralesional side and hypermetric when they are ipsilesional. The dysmetria depends on target velocity, but the use of accelerating or decelerating targets reveals that velocity is not the crucial parameter. We extend the bilateral fastigial control of saccades and fixation to the production of interceptive saccades.

High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted MR Images: Comparison between Gadobutrol and Linear Gadolinium-Based Contrast Agents.

BACKGROUND AND PURPOSE: In view of the recent observations that gadolinium deposits in brain tissue after intravenous injection, our aim of this study was to compare signal changes in the globus pallidus and dentate nucleus on unenhanced T1-weighted MR images in patients receiving serial doses of gadobutrol, a macrocyclic gadolinium-based contrast agent, with those seen in patients receiving linear gadolinium-based contrast agents. MATERIALS AND METHODS: This was a retrospective analysis of on-site patients with brain tumors. Fifty-nine patients received only gadobutrol, and 60 patients received only linear gadolinium-based contrast agents. Linear gadolinium-based contrast agents included gadoversetamide, gadobenate dimeglumine, and gadodiamide. T1 signal intensity in the globus pallidus, dentate nucleus, and pons was measured on the precontrast portions of patients' first and seventh brain MRIs. Ratios of signal intensity comparing the globus pallidus with the pons (globus pallidus/pons) and dentate nucleus with the pons (dentate nucleus/pons) were calculated. Changes in the above signal intensity ratios were compared within the gadobutrol and linear agent groups, as well as between groups. RESULTS: The dentate nucleus/pons signal ratio increased in the linear gadolinium-based contrast agent group (t = 4.215, P < .001), while no significant increase was seen in the gadobutrol group (t = -1.422, P = .08). The globus pallidus/pons ratios followed similarly, with an increase in the linear gadolinium-based contrast agent group (t = 2.931, P < .0001) and no significant change in those receiving gadobutrol (t = 0.684, P = .25). CONCLUSIONS: Successive doses of gadobutrol do not result in T1 shortening compared with changes seen in linear gadolinium-based contrast agents.

Development of High Signal Intensity within the Globus Pallidus and Dentate Nucleus following Multiple Administrations of Gadobenate Dimeglumine.

BACKGROUND AND PURPOSE: Previous studies have evaluated various gadolinium based contrast agents and their association with gadolinium retention, however, there is a discrepancy in the literature concerning the linear agent gadobenate dimeglumine. Our aim was to determine whether an association exists between the administration of gadobenate dimeglumine and the development of intrinsic T1-weighted signal in the dentate nucleus and globus pallidus. MATERIALS AND METHODS: In this single-center, retrospective study, the signal intensity of the globus pallidus, dentate nucleus, thalamus, and middle cerebellar peduncle was measured on unenhanced T1-weighted images in 29 adult patients who had undergone multiple contrast MRIs using exclusively gadobenate dimeglumine (mean, 10.1 ± 3.23 doses; range, 6-18 doses). Two neuroradiologists, blinded to the number of prior gadolinium-based contrast agent administrations, separately placed ROIs within the globi pallidi, thalami, dentate nuclei, and middle cerebellar peduncles on the last MR imaging examinations. The correlations between the globus pallidus:thalamus and the dentate nucleus:middle cerebellar peduncle signal intensity ratios with the number of gadolinium-based contrast agent administrations and cumulative dose were tested with either 1-tailed Pearson or Spearman correlations. A priori, P < .05 was considered statistically significant. RESULTS: Both the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncle ratios showed significant correlation with the number of gadolinium-based contrast agent administrations (r = 0.39, P = .017, and r = 0.58, P = .001, respectively). Additionally, the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncle ratios showed significant correlation with the cumulative dose of gadobenate dimeglumine (r = 0.48, P = .004, and r = 0.43, P = .009, respectively). Dentate nucleus hyperintensity was qualitatively present on the last MR imaging in 79.3%-86.2% of patients and in all patients who had received >10 doses. CONCLUSIONS: At high cumulative doses (commonly experienced by patients, for example, with neoplastic disease), gadobenate dimeglumine is associated with an increase in the globus pallidus:thalamus and dentate nucleus:middle cerebellar peduncles signal intensity ratios.

Evaluation of Gadolinium Retention After Serial Administrations of a Macrocyclic Gadolinium-Based Contrast Agent (Gadobutrol): A Single-Institution Experience With 189 Patients.

OBJECTIVE: There has been controversy as to whether gadobutrol, one of the widely used macrocyclic gadolinium-based contrast agents, can lead to gadolinium retention after serial injections. Our aim was to validate whether serial administrations of gadobutrol can cause signal increase in the dentate nucleus (DN) and globus pallidus (GP) on unenhanced T1-weighted magnetic resonance (MR) images due to gadolinium retention. MATERIALS AND METHODS: A total of 189 patients who had undergone at least 2 contrast-enhanced MR scans using only gadobutrol between August 2009 and August 2016 were retrospectively included. The DN-to-pons and GP-to-thalamus signal intensity (SI) ratio differences on unenhanced T1-weighted MR images were calculated by subtracting the SI ratios at the first MR images from those at the last MR images. One-sample t tests were used to evaluate whether the SI ratio differences differed from 0. Linear regression and Pearson correlations were performed to assess correlations between SI ratio differences and various confounding variables, including the number of MR scans, mean time interval between MR scans, age, sex, history of radiation therapy or chemotherapy, and renal and liver functions. RESULTS: Patients underwent a mean of 5.9 ± 6.3 contrast-enhanced MR scans with a mean interval of 42.8 ± 49.5 weeks between the scans. Sixty-three patients underwent 6 or more MR scans, whereas 126 patients underwent fewer than 6 MR scans. Neither the DN-to-pons SI nor the GP-to-thalamus SI ratio differences differed significantly from 0, with mean values of -0.012 ± 0.115 (P = 0.148) and 0.012 ± 0.111 (P = 0.126), respectively. CONCLUSIONS: Serial administrations of gadobutrol did not result in signal increases in the DN or GP on unenhanced T1-weighted MR images due to gadolinium retention.

[Reversible alterations in the dentate nuclei and rapid-onset cerebral atrophy due to neurotoxicity caused by lithium]. / Alteraciones reversibles en los nucleos dentados y atrofia cerebral de rapida instauracion debido a neurotoxicidad por litio.

INTRODUCTION: Treatment with lithium can cause several neurological side effects, even at therapeutic levels. CASE REPORT: We report the case of a 49-year-old woman, with bipolar disorder and depression, undergoing treatment with lithium, antidepressants and antipsychotics, who was admitted to hospital due to a clinical picture of visual hallucinations with an elevated lithaemia of 2.1 mEq/L (therapeutic range: 0.6-1.2 mEq/L). The patient developed a severe encephalopathy that required the use of assisted ventilation in the intensive care unit. Initial magnetic resonance imaging showed a reversible bilateral symmetrical hyperintensity in the dentate nuclei in T2 and T2-FLAIR sequences. Over the following months she gradually developed a pancerebellar syndrome with evidence of a marked loss of bilateral volume in the cerebellum, above all at the expense of the vermis, which was accompanied by a permanent and disabling cerebellar syndrome. CONCLUSIONS: Although treatment with lithium can cause a variety of neurological side effects, they are usually reversible. However, they occasionally give rise to permanent and disabling sequelae, as in the case of the patient reported here, with a marked and progressive cerebellar atrophy, accompanied by permanent sequelae in the form of a disabling cerebellar syndrome. The cerebellar neurotoxicity of lithium must be taken into account in the broad differential diagnosis of cerebellar ataxia in adults.

TITLE: Alteraciones reversibles en los nucleos dentados y atrofia cerebral de rapida instauracion debido a neurotoxicidad por litio.Introduccion. El tratamiento con litio puede ocasionar diversos efectos adversos neurologicos, incluso con niveles terapeuticos. Caso clinico. Mujer de 49 años, con trastorno bipolar y depresion, en tratamiento con litio, antidepresivos y antipsicoticos, que ingreso por un cuadro de alucinaciones visuales con una litemia elevada de 2,1 mEq/L (rango terapeutico: 0,6-1,2 mEq/L). Progreso a una encefalopatia grave que requirio asistencia respiratoria en la unidad de cuidados intensivos. La resonancia magnetica cerebral inicial mostro una hiperintensidad simetrica bilateral reversible en los nucleos dentados en las secuencias T2 y T2-FLAIR. A lo largo de los meses posteriores desarrollo de forma progresiva un sindrome pancerebeloso con evidencia de una marcada perdida de volumen bilateral en el cerebelo, sobre todo a expensas del vermis, que se acompaño clinicamente de un sindrome cerebeloso permanente e invalidante. Conclusiones. Aunque el tratamiento con litio ocasiona efectos adversos neurologicos variados, estos suelen ser reversibles. Puede dar lugar a secuelas permanentes e incapacitantes, como la paciente descrita, con una atrofia cerebelosa marcada y progresiva, acompañada de secuelas permanentes en forma de sindrome cerebeloso invalidante. La neurotoxicidad cerebelosa del litio debe considerarse en el amplio diagnostico diferencial que representa la ataxia cerebelosa del adulto.

A role for NMDAR-dependent cerebellar plasticity in adaptive control of saccades in humans.

BACKGROUND: Saccade pulse amplitude adaptation is mediated by the dorsal cerebellar vermis and fastigial nucleus. Long-term depression at the parallel fibre-Purkinjie cell synapses has been suggested to provide a cellular mechanism for the corresponding learning process. The mechanisms and sites of this plasticity, however, are still debated. OBJECTIVE: To test the role of cerebellar plasticity phenomena on adaptive saccade control. METHODS: We evaluated the effect of continuous theta burst stimulation (cTBS) over the posterior vermis on saccade amplitude adaptation and spontaneous recovery of the initial response. To further identify the substrate of synaptic plasticity responsible for the observed adaptation impairment, subjects were pre-treated with memantine, an N-methyl-d-aspartate receptor (NMDAR) antagonist. RESULTS: Amplitude adaptation was altered by cTBS, suggesting that cTBS interferes with cerebellar plasticity involved in saccade adaptation. Amplitude adaptation and spontaneous recovery were not affected by cTBS when recordings were preceded by memantine administration. CONCLUSION: The effects of cTBS are NMDAR-dependent and are likely to involve long-term potentiation or long-term depression at specific synaptic connections of the granular and molecular layer, which could effectively take part in cerebellar motor learning.

Labeling of neuronal morphology using custom diolistic techniques.

BACKGROUND: Diolistic labeling is increasingly utilized in neuroscience as an efficient, reproducible method for visualization of neuronal morphology. The use of lipophilic carbocyanine dyes, combined with particle-mediated biolistic delivery allows for non-toxic fluorescent labeling of multiple neurons in both living and fixed tissue. Since first described, this labeling method has been modified to fit a variety of research goals and laboratory settings. NEW METHOD: Diolistic labeling has traditionally relied on commercially available devices for the propulsion of coated micro-particles into tissue sections. Recently, laboratory built biolistic devices have been developed which allow for increased availability and customization. Here, we discuss a custom biolistic device and provide a detailed protocol for its use. RESULTS: Using custom diolistic labeling we have characterized alterations in neuronal morphology of the lateral/dentate nucleus of the rat cerebellum. Comparisons were made in developing rat pups exposed to abnormally high levels of 5-methyloxytryptamine (5-MT) pre-and postnatally. Using quantitative software; dendritic morphology, architecture, and synaptic connections, were analyzed. COMPARISON WITH EXISTING METHOD(S): The rapid nature of custom diolistics coupled with passive diffusion of dyes and compatibility with confocal microscopy, provides an unparalleled opportunity to examine features of neuronal cells at high spatial resolution in a three-dimensional tissue environment. CONCLUSIONS: While decreasing the associated costs, the laboratory-built device also overcomes many of the obstacles associated with traditional morphological labeling, to allow for reliable and reproducible neuronal labeling. The versatility of this method allows for its adaptation to a variety of laboratory settings and neuroscience related research goals.