Cerebellar Circuits Research Articles

Emotional Face Expressions Influence the Delay Eye-blink Classical Conditioning

Recent evidence raised the importance of the cerebellum in emotional processes, with specific regard to negative emotions. However, its role in the processing of face emotional expressions is still unknown. This study was aimed at assessing whether face emotional expressions influence the cerebellar learning processes, using the delay eyeblink classical conditioning (EBCC) as a model. Visual stimuli composed of faces expressing happy, sad and neutral emotions were used as conditioning stimulus in forty healthy subjects to modulate the cerebellum-brainstem pathway underlying the EBCC. The same stimuli were used to explore their effects on the blink reflex (BR) and its recovery cycle (BRRC) and on the cerebellar-brain inhibition (CBI). Data analysis revealed that the learning component of the EBCC was significantly reduced following the passive view of sad faces, while the extinction phase was modulated by both sad and happy faces. By contrast, BR, BRRC and CBI were not significantly affected by the view of emotional face expressions. The present study provides first evidence that the passive viewing of faces displaying emotional expressions, are processed by the cerebellum, with no apparent involvement of the brainstem and the cerebello-cortical connection. In particular, the view of sad faces, reduces the excitability of the cerebellar circuit underlying the learning phase of the EBCC. Differently, the extinction phase was shortened by both happy and sad faces, suggesting that different neural bases underlie learning and extinction of emotions expressed by faces.

Altered Posterior Cerebellar Lobule Connectivity With Perigenual Anterior Cingulate Cortex in Women With Primary Dysmenorrhea.

Objectives: This study aimed to investigate the potential connectivity mechanism between the cerebellum and anterior cingulate cortex (ACC) and the cerebellar structure in primary dysmenorrhea (PDM).Methods: We applied the spatially unbiased infratentorial template (SUIT) of the cerebellum to obtain anatomical details of cerebellar lobules, upon which the functional connectivity (FC) between the cerebellar lobules and ACC subregions was analyzed and the gray matter (GM) volume of cerebellar lobules was measured by using voxel-based morphometry (VBM) in 35 PDM females and 38 age-matched healthy females. The potential relationship between the altered FC or GM volume and clinical information was also evaluated in PDM females.Results: PDM females showed higher connectivity between the left perigenual ACC (pACC) and lobule vermis_VI, between the left pACC and left lobule IX, and between right pACC and right cerebellar lobule VIIb than did the healthy controls. Compared with healthy controls, no altered GM volume was found in PDM females. No significant correlation was found between altered cerebellum–ACC FC and the clinical variables in the PDM females.Conclusion: PDM females have abnormal posterior cerebellar connectivity with pACC but no abnormal structural changes. ACC–cerebellar circuit disturbances might be involved in the PDM females.

Modeling the interaction among three cerebellar disorders of eye movements: periodic alternating, gaze-evoked and rebound nystagmus.

A woman, age 44, with a positive anti-YO paraneoplastic cerebellar syndrome and normal imaging developed an ocular motor disorder including periodic alternating nystagmus (PAN), gaze-evoked nystagmus (GEN) and rebound nystagmus (RN). During fixation there was typical PAN but changes in gaze position evoked complex, time-varying oscillations of GEN and RN. To unravel the pathophysiology of this unusual pattern of nystagmus, we developed a mathematical model of normal function of the circuits mediating the vestibular-ocular reflex and gaze-holding including their adaptive mechanisms. Simulations showed that all the findings of our patient could be explained by two, small, isolated changes in cerebellar circuits: reducing the time constant of the gaze-holding integrator, producing GEN and RN, and increasing the gain of the vestibular velocity-storage positive feedback loop, producing PAN. We conclude that the gaze- and time-varying pattern of nystagmus in our patient can be accounted for by superposition of one model that produces typical PAN and another model that produces typical GEN and RN, without requiring a new oscillator in the gaze-holding system or a more complex, nonlinear interaction between the two models. This analysis suggest a strategy for uncovering gaze-evoked and rebound nystagmus in the setting of a time-varying nystagmus such as PAN. Our results are also consistent with current ideas of compartmentalization of cerebellar functions for the control of the vestibular velocity-storage mechanism (nodulus and ventral uvula) and for holding horizontal gaze steady (the flocculus and tonsil).

Involvement of Cerebellar Neural Circuits in Active Avoidance Conditioning in Zebrafish.

When animals repeatedly receive a combination of neutral conditional stimulus (CS) and aversive unconditional stimulus (US), they learn the relationship between CS and US, and show conditioned fear responses after CS. They show passive responses such as freezing or panic movements (classical or Pavlovian fear conditioning), or active behavioral responses to avoid aversive stimuli (active avoidance). Previous studies suggested the roles of the cerebellum in classical fear conditioning but it remains elusive whether the cerebellum is involved in active avoidance conditioning. In this study, we analyzed the roles of cerebellar neural circuits during active avoidance in adult zebrafish. When pairs of CS (light) and US (electric shock) were administered to wild-type zebrafish, about half of them displayed active avoidance. The expression of botulinum toxin, which inhibits the release of neurotransmitters, in cerebellar granule cells (GCs) or Purkinje cells (PCs) did not affect conditioning-independent swimming behaviors, but did inhibit active avoidance conditioning. Nitroreductase (NTR)-mediated ablation of PCs in adult zebrafish also impaired active avoidance. Furthermore, the inhibited transmission of GCs or PCs resulted in reduced fear-conditioned Pavlovian fear responses. Our findings suggest that the zebrafish cerebellum plays an active role in active avoidance conditioning.

Cerebellar Degeneration Signature in Huntington's Disease.

Recent findings suggest a significant effect of the cerebellar circuit deterioration on the clinical manifestation of Huntington's disease, calling for a better understanding of the cerebellar degeneration in this disorder. Recent brain imaging analyses have provided conflicting results regarding the cerebellar changes during the progression of this disease. To help in resolving this controversy, we examined the cerebellar gray matter structural integrity from a cohort of HD patients. Whole brain voxel-based morphometry (VBM) and spatially unbiased atlas template of the human cerebellum (SUIT) analyses were done from T1-weighted brain images. Our results showed a significant cerebellar degeneration without any sign of volume increase. The highest cerebellar degeneration was identified in Crus I right lobule, Crus II bilaterally, and left VIIb, and left VIIIa lobules. The cerebellar degeneration signature, which controls for severity of degeneration, showed a degeneration pattern that included regions I-IV, Crus II, VIIb, VIIIa, VIIIb and X.

Neuromodulation of the cerebellum rescues movement in a mouse model of ataxia

Deep brain stimulation (DBS) relieves motor dysfunction in Parkinson’s disease, and other movement disorders. Here, we demonstrate the potential benefits of DBS in a model of ataxia by targeting the cerebellum, a major motor center in the brain. We use the Car8 mouse model of hereditary ataxia to test the potential of using cerebellar nuclei DBS plus physical activity to restore movement. While low-frequency cerebellar DBS alone improves Car8 mobility and muscle function, adding skilled exercise to the treatment regimen additionally rescues limb coordination and stepping. Importantly, the gains persist in the absence of further stimulation. Because DBS promotes the most dramatic improvements in mice with early-stage ataxia, we postulated that cerebellar circuit function affects stimulation efficacy. Indeed, genetically eliminating Purkinje cell neurotransmission blocked the ability of DBS to reduce ataxia. These findings may be valuable in devising future DBS strategies.

Modulation of the dynamics of cerebellar Purkinje cells through the interaction of excitatory and inhibitory feedforward pathways

The dynamics of cerebellar neuronal networks is controlled by the underlying building blocks of neurons and synapses between them. For which, the computation of Purkinje cells (PCs), the only output cells of the cerebellar cortex, is implemented through various types of neural pathways interactively routing excitation and inhibition converged to PCs. Such tuning of excitation and inhibition, coming from the gating of specific pathways as well as short-term plasticity (STP) of the synapses, plays a dominant role in controlling the PC dynamics in terms of firing rate and spike timing. PCs receive cascade feedforward inputs from two major neural pathways: the first one is the feedforward excitatory pathway from granule cells (GCs) to PCs; the second one is the feedforward inhibition pathway from GCs, via molecular layer interneurons (MLIs), to PCs. The GC-PC pathway, together with short-term dynamics of excitatory synapses, has been a focus over past decades, whereas recent experimental evidence shows that MLIs also greatly contribute to controlling PC activity. Therefore, it is expected that the diversity of excitation gated by STP of GC-PC synapses, modulated by strong inhibition from MLI-PC synapses, can promote the computation performed by PCs. However, it remains unclear how these two neural pathways are interacted to modulate PC dynamics. Here using a computational model of PC network installed with these two neural pathways, we addressed this question to investigate the change of PC firing dynamics at the level of single cell and network. We show that the nonlinear characteristics of excitatory STP dynamics can significantly modulate PC spiking dynamics mediated by inhibition. The changes in PC firing rate, firing phase, and temporal spike pattern, are strongly modulated by these two factors in different ways. MLIs mainly contribute to variable delays in the postsynaptic action potentials of PCs while modulated by excitation STP. Notably, the diversity of synchronization and pause response in the PC network is governed not only by the balance of excitation and inhibition, but also by the synaptic STP, depending on input burst patterns. Especially, the pause response shown in the PC network can only emerge with the interaction of both pathways. Together with other recent findings, our results show that the interaction of feedforward pathways of excitation and inhibition, incorporated with synaptic short-term dynamics, can dramatically regulate the PC activities that consequently change the network dynamics of the cerebellar circuit.

How and Why the Cerebellum Recodes Input Signals: An Alternative to Machine Learning

Mossy fiber input to the cerebellum is received by granule cells where it is thought to be recoded into internal signals received by Purkinje cells, which alone carry the output of the cerebellar cortex. In any neural network, variables are contained in groups of signals as well as signals themselves—which cells are active and how many, for example, and statistical variables coded in rates, such as the mean and range, and which rates are strongly represented, in a defined population. We argue that the primary function of recoding is to confine translation to an effect of some variables and not others—both where input is recoded into internal signals and the translation downstream of internal signals into an effect on Purkinje cells. The cull of variables is harsh. Internal signaling is group coded. This allows coding to exploit statistics for a reliable and precise effect despite needing to work with high-dimensional input which is a highly unpredictably variable. An important effect is to normalize eclectic input signals, so that the basic, repeating cerebellar circuit, preserved across taxa, does not need to specialize (within regional variations). With this model, there is no need to slavishly conserve or compute data coded in single signals. If we are correct, a learning algorithm—for years, a mainstay of cerebellar modeling—would be redundant.

Gating by Functionally Indivisible Cerebellar Circuits: a Hypothesis

The attempt to understand the cerebellum has been dominated for years by supervised learning models. The central idea is that a learning algorithm modifies transmission strength at repeatedly co-active synapses, creating memories stored as finely calibrated synaptic weights. As a result, Purkinje cells, usually the de facto output cells of these models, acquire a modified response to input in a remembered pattern. This paper proposes an alternative model of pattern memory in which the function of a match is permissive, allowing but not driving output, and accordingly controlling the timing of output but not the rate of firing by Purkinje cells. Learning does not result in graded synaptic weights. There is no supervised learning algorithm or memory of individual patterns, which, like graded weights, are unnecessary to explain the evidence. Instead, patterns are classed as simply either known or not, at the level of input to a functional population of 100s of Purkinje cells (a microzone). The standard is strict. If only a handful of Purkinje cells receive a mismatch output of the whole circuit is blocked. Only if there is a full and accurate match are projection neurons in deep nuclei, which carry the output of most circuits, released from default inhibitory restraint. Purkinje cell firing at those times is a linear function of input rates. There is no effect of modification of synaptic transmission except to either allow or block output.

The Understanding of Pediatric Akinetic Mutism.

Pediatric akinetic mutism syndrome is a clinical disease resulting from cerebellar injury and characterized by the absence of speech or reduced speech, emotional lability, there may also be hypotonia, oropharyngeal dysfunction/dysphagia, bladder and intestinal incontinence, or other behavioral disorders and neurological signals. It is described as the most recurrent complication in children, after posterior fossa tumor surgery, mainly related to cerebellar midline injuries. An increasing number of research and prospective reviews have provided valuable information on cerebellar mutism syndrome in recent years. The purpose of this review was to elucidate the pathophysiological basis and the predictive factors for this syndrome. Most cases of mutism are due to injury cerebellar tracts and cerebellar-cerebral circuits, involving particularly distinct points of the dentate-thalamus-cortical and dentato-rubro-thalamus-cortical. Advanced neuroimaging techniques, such as tractography and perfusion studies, have contributed to demonstrating changes in these pathways in patients with pediatric cerebellar mutism.

Cerebellar Activation Deficits in Schizophrenia During an Eyeblink Conditioning Task.

The cognitive dysmetria theory of psychotic disorders posits that cerebellar circuit abnormalities give rise to difficulties coordinating motor and cognitive functions. However, brain activation during cerebellar-mediated tasks is understudied in schizophrenia. Accordingly, this study examined whether individuals with schizophrenia have diminished neural activation compared to controls in key regions of the delay eyeblink conditioning (dEBC) cerebellar circuit (eg, lobule VI) and cerebellar regions associated with cognition (eg, Crus I). Participants with schizophrenia-spectrum disorders (n = 31) and healthy controls (n = 43) underwent dEBC during functional magnetic resonance imaging (fMRI). Images were normalized using the Spatially Unbiased Infratentorial Template (SUIT) of the cerebellum and brainstem. Activation contrasts of interest were “early” and “late” stages of paired tone and air puff trials minus unpaired trials. Preliminary whole brain analyses were conducted, followed by cerebellar-specific SUIT and region of interest (ROI) analyses of lobule VI and Crus I. Correlation analyses were conducted between cerebellar activation, neuropsychological test scores, and psychotic symptom scores. In controls, the largest clusters of cerebellar activation peaked in lobule VI during early dEBC and Crus I during late dEBC. The schizophrenia group showed robust cortical activation to unpaired trials but no significant conditioning-related cerebellar activation. Crus I ROI activation during late dEBC was greater in the control than schizophrenia group. Greater Crus I activation correlated with higher working memory scores in the full sample and lower positive psychotic symptom severity in schizophrenia. Findings indicate functional cerebellar abnormalities in schizophrenia which relate to psychotic symptoms, lending direct support to the cognitive dysmetria framework.

Hyperbaric Oxygen Therapy Effect on "Kinesia Paradoxa" Brain Circuits.

This article aims to determine the effectiveness of hyperbaric oxygen therapy (HBOT) for treating symptoms of Parkinson's disease. We present a brief review of the relevant literature and general information about HBOT. This paper describes evidence that HBOT has crucial effects to the three specific brain circuits possibly involved in "Kinesia Paradoxa" (noradrenergic system, basal ganglia, and the cerebellum circuit). Moreover, we are presenting clues supporting "Norepinephrine Hypothesis" according to which HBOT increases norepinephrine levels and restores motor deficits in Parkinson's disease patients.

Treatment of pseudobulbar affect (PBA) in a patient with a history of traumatic brain injury, partial brain resection, and brainstem stroke: a case report

BackgroundPseudobulbar affect is a very distressing and underdiagnosed neuropsychiatric disorder that causes contextually inappropriate episodes of laughing and crying and general emotional incontinence. Although many proposed etiologies exist, the most widely accepted theory espouses the disruption of a corticopontine–cerebellar circuit that governs the modulation of emotional response. Pseudobulbar affect is commonly diagnosed secondary to primary neurological disorders such as amyotrophic lateral sclerosis, multiple sclerosis, and traumatic brain injury. Traditional pharmacological treatment of pseudobulbar affect is largely comprised of antidepressant therapy, including tricyclic antidepressants such as amitriptyline and selective serotonin reuptake inhibitors such as fluvoxamine. However, neither of these medication classes has been studied for the treatment of pseudobulbar affect in controlled trials, and their utility remains questionable.Case presentationWe describe a case of a 62-year-old Caucasian man with history of traumatic brain injury, ischemic brainstem stroke, and depression who developed intractable pseudobulbar affect. This patient’s intensely distressing symptoms were not alleviated by amitriptyline. However, after being placed on fixed-dose 20 mg/10 mg dextromethorphan/quinidine (Nuedexta), our patient experienced complete resolution of his symptoms. He has experienced no deleterious side effects.ConclusionsThis case provides anecdotal evidence for the efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect with remarkably swift and complete cessation of symptoms. As a secondary point, it is worth noting that our patient had experienced two devastating neurological traumas, both in anatomical areas that have been implicated in the corticopontine–cerebellar circuit thought to be responsible for pseudobulbar affect. However, only the second trauma, an acute left pontine infarction, produced symptoms of emotional disinhibition. The authors hope that reporting this case will provide both context for physicians managing this condition and hope for patients with this socially and psychiatrically damaging disease.

Does Essential Tremor Alter the Axonal Excitability Properties of Lower Motor Neurons?

Automated nerve excitability testing has identified that the altered excitability of lower motor neuron (LMN) axons in central diseases is because of trans-synaptic plasticity. Essential tremor (ET) is considered a central disorder caused by an altered cerebellar circuit. This study aimed to identify alterations in the excitability of distal motor axons in subjects with ET, with the intention of clarifying whether a trans-synaptic mechanism or LMN adaptation for tremor affects the LMNs of subjects with ET. Twenty-one consecutive patients diagnosed with ET underwent a clinical and electrophysiological evaluation. For the enrolled cases and 45 age- and gender-matched healthy controls, automated nerve excitability testing with threshold tracking techniques (QTRACS software with TRONDF multiple-excitability protocol) was used to evaluate multiple nerve excitability indices in distal median nerve motor axons. The automated protocol calculated the strength-duration time constant, parameters of threshold electrotonus and current-threshold relationship, and the recovery cycle of excitability. Comparisons of the automated nerve excitability testing parameters revealed no significant differences between the ET and control groups in any of strength-duration time constant, threshold electrotonus, current-threshold relationship, and recovery cycle, whereas the rheobase was higher in the ET group (3.4 ± 1.1 vs. 2.3 ± 1.1, mean ± standard error mean; P < 0.01). With the exception of an increased rheobase in ET subjects, no significant differences were observed in LMN excitability between the ET subjects and their controls. The extent of plasticity or adaptation in LMNs may be limited to a major change in central processes that exert marked effects on the pool of LMNs.

Pogz deficiency leads to transcription dysregulation and impaired cerebellar activity underlying autism-like behavior in mice

Several genes implicated in autism spectrum disorder (ASD) are chromatin regulators, including POGZ. The cellular and molecular mechanisms leading to ASD impaired social and cognitive behavior are unclear. Animal models are crucial for studying the effects of mutations on brain function and behavior as well as unveiling the underlying mechanisms. Here, we generate a brain specific conditional knockout mouse model deficient for Pogz, an ASD risk gene. We demonstrate that Pogz deficient mice show microcephaly, growth impairment, increased sociability, learning and motor deficits, mimicking several of the human symptoms. At the molecular level, luciferase reporter assay indicates that POGZ is a negative regulator of transcription. In accordance, in Pogz deficient mice we find a significant upregulation of gene expression, most notably in the cerebellum. Gene set enrichment analysis revealed that the transcriptional changes encompass genes and pathways disrupted in ASD, including neurogenesis and synaptic processes, underlying the observed behavioral phenotype in mice. Physiologically, Pogz deficiency is associated with a reduction in the firing frequency of simple and complex spikes and an increase in amplitude of the inhibitory synaptic input in cerebellar Purkinje cells. Our findings support a mechanism linking heterochromatin dysregulation to cerebellar circuit dysfunction and behavioral abnormalities in ASD.

Increased Purkinje Cell Complex Spike and Deep Cerebellar Nucleus Synchrony as a Potential Basis for Syndromic Essential Tremor. A Review and Synthesis of the Literature.

We review advances in understanding Purkinje cell (PC) complex spike (CS) physiology that suggest increased CS synchrony underlies syndromic essential tremor (ET). We searched PubMed for papers describing factors that affect CS synchrony or cerebellar circuits potentially related to tremor. Inferior olivary (IO) neurons are electrically coupled, with the degree of coupling controlled by excitatory and GABAergic inputs. Clusters of coupled IO neurons synchronize CSs within parasagittal bands via climbing fibers (Cfs). When motor cortex is stimulated in rats at varying frequencies, whisker movement occurs at ~10Hz, correlated with synchronous CSs, indicating that the IO/CS oscillatory rhythm gates movement frequency. Intra-IO injection of the GABAA receptor antagonist picrotoxin increases CS synchrony, increases whisker movement amplitude, and induces tremor. Harmaline and 5-HT2a receptor activation also increase IO coupling and CS synchrony and induce tremor. The hotfoot17 mouse displays features found in ET brains, including cerebellar GluRδ2 deficiency and abnormal PC Cf innervation, with IO- and PC-dependent cerebellar oscillations and tremor likely due to enhanced CS synchrony. Heightened coupling within the IO oscillator leads, through its dynamic control of CS synchrony, to increased movement amplitude and, when sufficiently intense, action tremor. Increased CS synchrony secondary to aberrant Cf innervation of multiple PCs likely also underlies hotfoot17 tremor. Deep cerebellar nucleus (DCN) hypersynchrony may occur secondary to increased CS synchrony but might also occur from PC axonal terminal sprouting during partial PC loss. Through these combined mechanisms, increased CS/DCN synchrony may plausibly underlie syndromic ET.

Visual Perception of Heading in the Syndrome of Oculopalatal Tremor.

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.

Basal ganglia and cerebellar circuits have distinct roles in blepharospasm

IntroductionTo identify areas of brain activity associated with involuntary muscle contractions in patients with blepharospasm using functional MRI. Methods15 patients with blepharospasm underwent 8-min resting state scans with spontaneous orbicularis oculi muscle contractions simultaneously recorded using MRI-compatible surface electromyography. Spasm severity and spasm onset/offset were modeled using the amplitude of the electromyography signal (EMG-Amp) and its first temporal derivative (EMG-Onset), respectively, and included in a multiple regression functional MRI analysis using SPM12. Primary outcome was within-group blood-oxygen-level dependent activations that co-varied with EMG-Amp and EMG-Onset following correction for multiple comparisons for an overall cluster corrected p < 0.05. Secondary analyses included testing for correlations between imaging findings and symptom severity, as measured by clinical dystonia rating scales, using an uncorrected voxel-level threshold of p < 0.001. ResultsImaging data from one subject were excluded due to excessive movement. EMG-Amp co-activated within the left sensorimotor cortex and cerebellum, as well as right lingual gyrus and superior temporal gyrus. EMG-Onset co-activated within the left posterior putamen/pallidum and a frontal eye field region in the left superior frontal gyrus. Symptom severity and EMG-Amp significantly co-varied in a small cluster within the left cerebellum. ConclusionOur preliminary findings here suggest that cerebello-cortical circuits in blepharospasm could drive the intensity of eyelid spasms while basal ganglia circuits are associated with the triggering of spasms. This supports the network model for dystonia and identifies specific areas of involvement consistent with known brain regions responsible for control of movement.

Differential effects of two early life stress paradigms on cerebellar-dependent delay eyeblink conditioning

Early life stress paradigms have become prominent in the animal literature to model atypical development. Currently, two models have prevailed within the literature: (1) limited bedding or nesting and (2) maternal separation or deprivation. Both models have produced aberrations spanning behavior and neural circuitry. Surprisingly, these two models have yet to be directly compared. The current study utilized delay eyeblink conditioning, an associative learning task with a well-defined cerebellar circuit, to compare the behavioral effects of standard limited bedding (postnatal day 2–9, n = 15) and maternal separation (60 min per day during postnatal day 2–14, n = 13) early life stress paradigms. Animals in all groups exhibited robust learning curves. Surprisingly, facilitated conditioning was observed in the maternal separation group. Rats that underwent limited bedding did not differ from the control or maternal separation groups on any conditioning measures. This study contributes to a clearer understanding of early life stress paradigms and the claims made about their mechanisms, which if better clarified can be properly leveraged to increase translational value.

Cerebellar Intermittent Theta-Burst Stimulation Combined with Vestibular Rehabilitation Improves Gait and Balance in Patients with Multiple Sclerosis: a Preliminary Double-Blind Randomized Controlled Trial.

Difficulties in gait and balance disorders are among the most common mobility limitations in multiple sclerosis (MS), mainly due to a damage of cerebellar circuits. Moreover, the cerebellum plays a critical role in promoting new motor tasks, which is an essential function for neurorehabilitation. In this study, we investigated the effects of cerebellar intermittent theta burst stimulation (c-iTBS), a high-frequency rTMS protocol able to increase cerebellar activity, on gait and balance in a sample of 20 hospitalized participants with MS, undergoing vestibular rehabilitation (VR), an exercise-based program primarily designed to reduce vertigo and dizziness, gaze instability, and/or imbalance and falls in MS. Patients were assigned to receive either c-iTBS or sham iTBS before being treated with VR during 2weeks. VR consisted of two types of training: gaze stability and postural stability exercises. The primary outcome measure was the change from baseline in the Tinetti Balance and Gait scale (TBG). The secondary outcome measures were changes from baseline in Berg Balance Scale (BBS), Fatigue Severity Scale (FSS), Two Minute Walking Test (2MWT), and Timed 25-ft walk test (T25FW) scales. MS patients treated with c-iTBS-VR showed a significant improvement in the TBG as compared to patients treated with sham iTBS-VR. Moreover, MS patients in the c-iTBS groups showed better performances in the vestibular-ocular reflex exercises. Combined c-iTBS and VR improves gait and balance abilities more than standard VR treatment in MS patients with a high level of disability.