Abnormal Function in Dentate Nuclei Precedes the Onset of Psychosis: A Resting-State fMRI Study in High-Risk Individuals.

OBJECTIVE: The cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into 3 functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN, precede the onset of psychosis in individuals at risk of developing schizophrenia. METHODS: We used the magnetic resonance imaging (MRI) dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N = 144), with longitudinal follow-up to determine which subjects developed a psychotic episode within 1 year of their functional magnetic resonance imaging (fMRI) scan (converters N = 23). Analysis used the 3 functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis. RESULTS: RsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the 3 functional territories of the DN that were evaluated. CONCLUSIONS: We show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention.

Neurostructural changes and declining sensorimotor function due to cerebellar cortical degeneration.

Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of gait, posture, speech, fine motor, and oculomotor function. Yet, little is known how the cerebro-cerebellar network compensates for the loss in cerebellar cortical neurons. To address this knowledge gap, we examined 30 people with cerebellar cortical degeneration and a group of 30 healthy controls. We assessed visuomotor performance during a forearm-pointing task to 10°, 25°, and 50° targets. In addition, using MRI imaging, we determined neurodegenerative-induced changes in gray matter volume (GMV) in the cerebro-cerebellar network and correlated them to markers of motor performance. The main results are as follows: first, the relative joint position error (RJPE) during pointing was significantly greater in the ataxia group for all targets confirming the expected motor control deficit. Second, in the ataxia group, GMV was significantly reduced in cerebellar cortex but increased in the deep cerebellar nuclei. Motor error (RJPE) correlated negatively with decreased cerebellar GMV but positively with increased GMV in supplementary motor area (SMA) and premotor cortex. GMV of the deep cerebellar nuclei did not correlate significantly with markers of motor performance. We discuss whether the GMV changes in the cerebellar output nuclei and the extracerebellar efferent targets in secondary motor cortex can be understood as a central compensatory response to the neurodegeneration of the cerebellar cortex.NEW & NOTEWORTHY Neurodegeneration of the cerebellum progresses over years and primarily affects cerebellar cortex. It leads to a progressive loss of control and coordination of movement. We here show that the neurodegenerative process not only leads to cells loss in cerebellar cortex but also induces neurostructural changes in the form of increased gray matter in the efferent targets of the cerebellar cortex, namely, the cerebellar output nuclei, the SMA, and premotor cortex.

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 ~10 Hz, 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.

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.

Cerebellospinal Neurons Regulate Motor Performance and Motor Learning.

To understand the neural basis of behavior, it is important to reveal how movements are planned, executed, and refined by networks of neurons distributed throughout the nervous system. Here, we report the neuroanatomical organization and behavioral roles of cerebellospinal (CeS) neurons. Using intersectional genetic techniques, we find that CeS neurons constitute a small minority of excitatory neurons in the fastigial and interpositus deep cerebellar nuclei, target pre-motor circuits in the ventral spinal cord and the brain, and control distinct aspects of movement. CeS neurons that project to the ipsilateral cervical cord are required for skilled forelimb performance, while CeS neurons that project to the contralateral cervical cord are involved in skilled locomotor learning. Together, this work establishes CeS neurons as a critical component of the neural circuitry for skilled movements and provides insights into the organizational logic of motor networks.

Cerebellar dentate nucleus functional connectivity with cerebral cortex in Alzheimer's disease and memory: a seed-based approach.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by specific patterns of gray and white matter damage and cognitive/behavioral manifestations. The cerebellum has also been implicated in the pathophysiology of AD. Because the cerebellum is known to have strong functional connectivity (FC) with associative cerebral cortex regions, it is possible to hypothesize that it is incorporated into intrinsic FC networks relevant to cognitive manifestation of AD. In the present study, the cerebellar dentate nucleus, the largest cerebellar nucleus and the major output channel to the cerebral cortex, was chosen as the region of interest to test potential cerebellocerebral FC alterations and correlations with patients' memory impairment in a group of patients with AD. Compared to controls, patients with AD showed an increase in FC between the dentate nucleus and regions of the lateral temporal lobe. This study demonstrates that lower memory performances in AD may be related to altered FC within specific cerebellocortical functional modules, thus suggesting the cerebellar contribution to AD pathophysiology and typical memory dysfunctions.

Functional disconnection of the dentate nucleus in essential tremor.

Despite previous functional MRI studies on alterations within the cerebello-thalamo-cortical circuit in patients with essential tremor (ET), the specific role of disconnection of the dentate nucleus (DN), the main output cerebellar pathway, still needs clarification. In this study, we evaluated DN functional connectivity (FC) changes and their relationship with motor and non-motor symptoms in ET. We studied 25 ET patients and 26 healthy controls. Tremor severity was assessed using the Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) and tremor amplitude and frequency were evaluated using kinematic techniques. Cognitive profile was assessed by montreal cognitive assessment (MoCA) and frontal assessment battery (FAB). All participants underwent a 3 T MRI protocol including resting-state blood oxygenation level dependent and diffusion tensor sequences. We used a seed-based approach to investigate DN FC and to explore the diffusion properties of cerebellar peduncles. There was significantly decreased DN FC with cortical, subcortical, and cerebellar areas in ET patients compared with healthy controls. Correlation analysis showed that: (1) the DN FC with the supplementary motor area, pre and postcentral gyri, and prefrontal cortex negatively correlated with FTM-TRS score and disease duration; (2) DN FC changes in the thalamus and caudate negatively correlated with peak tremor frequency, changes in the cerebellum positively correlated with tremor amplitude, and changes in the bilateral thalamus negatively correlated with tremor amplitude, and (3) DN FC with the associative prefrontal and parietal cortices, basal ganglia, and thalamus positively correlated with the MoCA score. Diffusion abnormalities were found in the three cerebellar peduncles, which did not correlate with clinical scores.

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures.

KEY POINTS: On-demand optogenetic inhibition of glutamatergic neurons in the fastigial nucleus of the cerebellum does not alter hippocampal seizures in a mouse model of temporal lobe epilepsy. In contrast, on-demand optogenetic excitation of glutamatergic neurons in the fastigial nucleus successfully inhibits hippocampal seizures. With this approach, even a single 50 ms pulse of light is able to significantly inhibit seizures. On-demand optogenetic excitation of glutamatergic fastigial neurons either ipsilateral or contralateral to the seizure focus is able to inhibit seizures. Selective excitation of glutamatergic nuclear neurons provides greater seizure inhibition than broadly exciting nuclear neurons without cell-type specificity. ABSTRACT: Temporal lobe epilepsy is the most common form of epilepsy in adults, but current treatment options provide limited efficacy, leaving as many as one-third of patients with uncontrolled seizures. Recently, attention has shifted towards more closed-loop therapies for seizure control, and on-demand optogenetic modulation of the cerebellar cortex was shown to be highly effective at attenuating hippocampal seizures. Intriguingly, both optogenetic excitation and inhibition of cerebellar cortical output neurons, Purkinje cells, attenuated seizures. The mechanisms by which the cerebellum impacts seizures, however, are unknown. In the present study, we targeted the immediate downstream projection of vermal Purkinje cells - the fastigial nucleus - in order to determine whether increases and/or decreases in fastigial output can underlie seizure cessation. Though Purkinje cell input to fastigial neurons is inhibitory, direct optogenetic inhibition of the fastigial nucleus had no effect on seizure duration. Conversely, however, fastigial excitation robustly attenuated hippocampal seizures. Seizure cessation was achieved at multiple stimulation frequencies, regardless of laterality relative to seizure focus, and even with single light pulses. Seizure inhibition was greater when selectively targeting glutamatergic fastigial neurons than when an approach that lacked cell-type specificity was used. Together, these results suggest that stimulating excitatory neurons in the fastigial nucleus may be a promising approach for therapeutic intervention in temporal lobe epilepsy.

Differential involvement of rubral branches in chronic capsular and pontine stroke.

BACKGROUND AND PURPOSE: Early studies have indicated that the cortico-rubro-spinal tracts play important roles in motor dysfunction after stroke. However, the differential involvement of the rubral branches in capsular and pontine stroke, and their associations with the motor impairment are still unknown. METHODS: The present study recruited 144 chronic stroke patients and 91 normal controls (NC) from three hospitals, including 102 cases with capsular stroke (CS) and 42 cases with pontine stroke (PS). The rubral branches, including bilateral corticorubral tracts (CRT), dentatorubral tracts (DRT), and rubrospinal tracts (RST), and the cortico-spinal tract (CST) were reconstructed based on the dataset of the Human Connectome Project. Group differences in diffusion scalars of each rubral branch were compared, and the associations between the diffusion measures of rubral branches and the Fugl-Meyer assessment (FMA) scores were tested. RESULTS: The bilateral CRT of the CS cases showed significantly lower factional anisotropy (FA) than in the NC. The bilateral DRT of the PS cases had lower FA than in the NC. Both CS and PS cases had significantly lower FA of the bilateral RST than the NC. Besides, the stroke patients demonstrated significantly lower FA in bilateral CSTs than the NC. Partial correlation analysis identified significantly positive correlations between the FA of the ipsilesional and CRT and the FMA scores in the CS group, and significantly positive correlations between the FA of the RST bilaterally and the FMA scores in the CS and PS groups. Furthermore, the association between RST integrity and FMA scores still survived after controlling for the effect of the CST. Finally, multiple regression modelling found that rubral tract FA explained 39.2% of the variance in FMA scores for CS patients, and 48.8% of the variance in FMA scores for PS patients. CONCLUSIONS: The bilateral rubral branches were differentially involved in the chronic capsular and pontine stroke, and the impairment severity of each rubral branch was dependent on lesion locations. The integrity of the rubral branches is related to motor impairment in both the chronic capsular and pontine stroke.

Intrinsic Functional Connectivity of Dentate Nuclei in Autism Spectrum Disorder.

Cerebellar abnormalities are commonly reported in autism spectrum disorder (ASD). Dentate nuclei (DNs) are key structures in the anatomical circuits linking the cerebellum to the extracerebellum. Previous resting-state functional connectivity (RsFc) analyses reported DN abnormalities in high-functioning ASD (HF-ASD). This study examined the RsFc of the DN in young adults with HF-ASD compared with healthy controls (HCs) with the aim to expand upon previous findings of DNs in a dataset using advanced, imaging acquisition methods that optimize spatiotemporal resolution and statistical power. Additional seed-to-voxel analyses were carried out using motor and nonmotor DN coordinates reported in previous studies as seeds. We report abnormal dentato-cerebral and dentato-cerebellar functional connectivity in ASD. Our results expand and, in part, replicate previous descriptions of DN RsFc abnormalities in this disorder and reveal correlations between DN-cerebral RsFc and ASD symptom severity.

Role of cerebellar GABAergic dysfunctions in the origins of essential tremor.

Essential tremor (ET) is among the most prevalent movement disorders, but its origins are elusive. The inferior olivary nucleus (ION) has been hypothesized as the prime generator of tremor because of the pacemaker properties of ION neurons, but structural and functional changes in ION are unlikely under ET. Abnormalities have instead been reported in the cerebello-thalamo-cortical network, including dysfunctions of the GABAergic projections from the cerebellar cortex to the dentate nucleus. It remains unclear, though, how tremor would relate to a dysfunction of cerebellar connectivity. To address this question, we built a computational model of the cortico-cerebello-thalamo-cortical loop. We simulated the effects of a progressive loss of GABAA α1-receptor subunits and up-regulation of α2/3-receptor subunits in the dentate nucleus, and correspondingly, we studied the evolution of the firing patterns along the loop. The model closely reproduced experimental evidence for each structure in the loop. It showed that an alteration of amplitudes and decay times of the GABAergic currents to the dentate nucleus can facilitate sustained oscillatory activity at tremor frequency throughout the network as well as a robust bursting activity in the thalamus, which is consistent with observations of thalamic tremor cells in ET patients. Tremor-related oscillations initiated in small neural populations and spread to a larger network as the synaptic dysfunction increased, while thalamic high-frequency stimulation suppressed tremor-related activity in thalamus but increased the oscillation frequency in the olivocerebellar loop. These results suggest a mechanism for tremor generation under cerebellar dysfunction, which may explain the origin of ET.

Altered functional connectivity of dentate nucleus in parkinsonian and cerebellar variants of multiple system atrophy.

The cerebellum is known to influence cerebral cortical activity via cerebello-thalamo-cortical (CTC) circuits and thereby may be implicated in the pathophysiology of multiple system atrophy (MSA). As the aim of this study, we investigated the abnormalities of corticocerebellar functional connectivity (FC) in patients with two variants of MSA. Resting-state functional magnetic resonance imaging (rs-fMRI) studies were obtained from 55 patients with MSA, including Parkinsonian (MSAp, n = 29) and cerebellar (MSAc, n = 26) variants. We also examined a similar number of healthy controls (HC, n = 51). Seed-based connectivity analysis was performed to assess alterations in CTC circuits. Relations between FC and clinical scores were assessed as well. Compared with the HC group, diminished FC was evident from bilateral dentate nucleus (DN) to motor cortex, bilateral basal ganglia, right cerebellum, default mode network (DMN), and limbic system in patients with MSAc. Patients with MSAp (vs HC subjects) showed less FC from left DN to right putamen, DMN, and limbic systems. Reduced FC was also demonstrated from left DN to DMN in patients with MSAc (vs MSAp), as well as from right DN to right cerebellum, DMN, basal ganglia, motor cortex, and limbic systems. In addition, the extent of FC from right DN to right cerebellum negatively correlated with Unified Parkinson's Disease Rating Scale-III scores in patients with MSA, while showing a positive association with Montreal Cognitive Assessment scores. The FC of DN was similarly altered in patients with MSAc and MSAp, although right cerebellar and motor cortical changes were more widespread in the MSAc group. There may be differing mechanisms of cerebellar functional activity responsible for motor and cognitive impairment, which should be further investigated.

Functional and Structural Connectivity of the Cerebellar Nuclei With the Striatum and Cerebral Cortex in First-Episode Psychosis.

OBJECTIVE: Evidence suggests that the cortico-striatal-thalamo-cortical circuitry plays an important role in schizophrenia pathophysiology. Cerebellar contribution from deep cerebellar nuclei to the circuitry has not yet been examined. The authors investigated resting-state functional connectivity (RSFC) of cerebellar output nuclei with striatal-thalamic-cortical regions in relation to white-matter integrity and regional gray-matter volumes in first-episode psychosis (FEP). Methods: Forty FEP patients and 40 age- and gender-matched healthy control subjects (HCs) participated. RSFC between cerebellar nuclei and striatal-thalamic-cortical regions was examined. Diffusion tensor imaging and volumetric scans were examined for possible structural constraints on RSFC. The authors also examined relationships between neuroimaging variables and cognitive and clinical measures. Results: FEP patients, compared with HCs, exhibited decreased RSFC between the left fastigial nucleus and right putamen, which was associated with poor letter fluency performance and lower global assessment of functioning scores. By contrast, patients showed widespread increased accumbens network connectivity in the left nucleus. The authors further observed both hypo- and hyper-RSFC between the cerebellar nuclei and fronto-parietal areas in patients, independent of striatal activity. Finally, the authors found impaired integrity of the left superior cerebellar peduncle and decreased bilateral putamen volume in patients, whereas structural-functional relationships found in HCs were absent in patients. Conclusions: This study provides evidence of disordered RSFC of cerebellar output nuclei to the striatum and neocortex at the early stage of schizophrenia. Furthermore, dysfunctional cerebellar influences on fronto-parietal areas that are independent of striatal dysfunction in patients with FEP were observed. The results suggest that cortico-striatal abnormalities in patients with FEP are produced by abnormal cerebellar influences.

Comparison of tractography-assisted to atlas-based targeting for deep brain stimulation in essential tremor.

BACKGROUND: Direct targeting of the dentato-rubro-thalamic tract is efficacious in DBS for tremor suppression. OBJECTIVES: We sought to compare outcomes and optimal stimulation parameters for tremor control using the technique of directly targeting the dentato-rubro-thalamic tract to those who underwent indirect targeting of the ventral intermediate nucleus thalamus. METHODS: Twenty consecutive essential tremor patients obtained preoperative diffusion MRIs, where the dentato-rubro-thalamic tract was individually drawn and used to directly target the ventral intermediate nucleus of the thalamus during surgery. These patients were compared to an earlier cohort of 20 consecutive patients who underwent surgery using atlas-based coordinates. Baseline and 1-year postsurgery tremor amplitude using The Essential Tremor Rating Assessment Scale was recorded, as were the parameters needed for successful tremor control. RESULTS: The indirectly targeted group had greater baseline and postop tremor severity relative to those directly targeted (baseline, 2.9 vs. 2.6; P = 0.02; postop, 1.1 vs. 0.8; P = 0.03). Mean voltage, pulse width, and frequency for optimal tremor control in the directly targeted group (38 electrodes) = 2.8 V, 80 µs, 153 Hz; the parameters for the indirectly targeted group (38 electrodes) = 2.9 V, 86 µs, 179 Hz (significantly greater, P < 0.001). Both groups had significant improvement in arm tremor amplitude from baseline (P < 0.001) without sustained side effects. CONCLUSION: Direct targeting of the dentato-rubro-thalamic tract provides excellent tremor control, comparable to indirectly targeting the ventral intermediate nucleus of the thalamus. Use of lower stimulation parameters, especially frequency, to control tremor in the directly targeted group suggests that it is a more efficient targeting methodology, which may minimize battery depletion. © 2018 International Parkinson and Movement Disorder Society.

Changes in membrane properties of rat deep cerebellar nuclear projection neurons during acquisition of eyeblink conditioning.

Previous studies have shown changes in membrane properties of neurons in rat deep cerebellar nuclei (DCN) as a function of development, but due to technical difficulties in obtaining viable DCN slices from adult animals, it remains unclear whether there are learning-related alterations in the membrane properties of DCN neurons in adult rats. This study was designed to record from identified DCN cells in cerebellar slices from postnatal day 25-26 (P25-26) rats that had a relatively mature sensory nervous system and were able to acquire learning as a result of tone-shock eyeblink conditioning (EBC) and to document resulting changes in electrophysiological properties. After electromyographic electrode implantation at P21 and inoculation with a fluorescent pseudorabies virus (PRV-152) at P22-23, rats received either four sessions of paired delay EBC or unpaired stimulus presentations with a tone conditioned stimulus and a shock unconditioned stimulus or sat in the training chamber without stimulus presentations. Compared with rats given unpaired stimuli or no stimulus presentations, rats given paired EBC showed an increase in conditioned responses across sessions. Whole-cell recordings of both fluorescent and nonfluorescent DCN projection neurons showed that delay EBC induced significant changes in membrane properties of evoked DCN action potentials including a reduced after-hyperpolarization amplitude and shortened latency. Similar findings were obtained in hyperpolarization-induced rebound spikes of DCN neurons. In sum, delay EBC produced significant changes in the membrane properties of juvenile rat DCN projection neurons. These learning-specific changes in DCN excitability have not previously been reported in any species or task.

Weekly enhanced T1-weighted MRI with Gadobutrol injections in MS patients: Is there a signal intensity increase in the dentate nucleus and the globus pallidus?

BACKGROUND AND PURPOSE: Gadolinium-based contrast agents (GBCAs) administration have drastically improved the accuracy of Multiple Sclerosis (MS) diagnosis by highlighting any damage to the brain blood barrier, thereby differentiating between active and non-active lesions. Following multiple administrations of GBCAs, several MS studies have reported a signal intensity (SI) increase on unenhanced T1-weighted images in certain brain regions such as the dentate nucleus (DN) and the globus pallidus (GP). Our aim was therefore to determine the accumulation of macrocyclic GBCAs on enhanced T1-weighted images SI in the DN and the GP of MS patients injected eight times. MATERIALS AND METHODS: Five MS patients underwent eight weekly consecutive MRI scans. Enhanced 3D T1-weighted images with Gadobutrol as a macrocyclic GBCA, were acquired. A ROI-based approach was applied for the evaluation of SI in the DN to middle cerebellar peduncle (DN-MCP) and GP to semi-oval white matter (GP-SOWM) ratios. An analysis of variance on repeated measures was used for the statistical analysis of each ratio. RESULTS: No DN-MCP and GP-SOWM SI ratio differences were observed over the eight-weeks period using the macrocyclic GBCA. CONCLUSION: Iterative and weekly injections of macrocyclic GBCAs are not associated with T1 signal increase in the DN and GP of MS patients. These results would suggest a no gadolinium accumulation in the brain using macrocyclic GBCA even after several close injections and promote the use of a macrocylcic GBCA rather than linear agents for MS patients.

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).

Lateral Cerebellar Nucleus Stimulation has Selective Effects on Glutamatergic and GABAergic Perilesional Neurogenesis After Cortical Ischemia in the Rodent Model.

BACKGROUND: Chronic deep brain stimulation of the rodent lateral cerebellar nucleus (LCN) has been demonstrated to enhance motor recovery following cortical ischemia. This effect is concurrent with synaptogenesis and expression of long-term potentiation markers in the perilesional cerebral cortex. OBJECTIVE: To further investigate the cellular changes associated with chronic LCN stimulation in the ischemic rodent by examining neurogenesis along the cerebellothalamocortical pathway. METHODS: Rats were trained on the pasta matrix task, followed by induction of cortical ischemia and electrode implantation in the contralesional LCN. Electrical stimulation was initiated 6 wk after stroke induction and continued for 4 wk prior to sacrifice. Neurogenesis was examined using immunohistochemistry. RESULTS: Treated animals showed enhanced performance on the pasta matrix task relative to sham controls. Increased cell proliferation colabeled with 5'-Bromo-2'-deoxyuridine and neurogenic markers (doublecortin) was observed in the perilesional cortex as well as bilateral mediodorsal and ventrolateral thalamic subnuclei in treated vs untreated animals. The neurogenic effect at the level of motor cortex was selective, with stimulation-treated animals showing greater glutamatergic neurogenesis but significantly less GABAergic neurogenesis. CONCLUSION: These findings suggest that LCN deep brain stimulation modulates postinjury neurogenesis, providing a possible mechanistic foundation for the associated enhancement in poststroke motor recovery.

Optogenetic neuronal stimulation of the lateral cerebellar nucleus promotes persistent functional recovery after stroke.

Stroke induces network-wide changes in the brain, affecting the excitability in both nearby and remotely connected regions. Brain stimulation is a promising neurorestorative technique that has been shown to improve stroke recovery by altering neuronal activity of the target area. However, it is unclear whether the beneficial effect of stimulation is a result of neuronal or non-neuronal activation, as existing stimulation techniques nonspecifically activate/inhibit all cell types (neurons, glia, endothelial cells, oligodendrocytes) in the stimulated area. Furthermore, which brain circuit is efficacious for brain stimulation is unknown. Here we use the optogenetics approach to selectively stimulate neurons in the lateral cerebellar nucleus (LCN), a deep cerebellar nucleus that sends major excitatory output to multiple motor and sensory areas in the forebrain. Repeated LCN stimulations resulted in a robust and persistent recovery on the rotating beam test, even after cessation of stimulations for 2 weeks. Furthermore, western blot analysis demonstrated that LCN stimulations significantly increased the axonal growth protein GAP43 in the ipsilesional somatosensory cortex. Our results demonstrate that pan-neuronal stimulations of the LCN is sufficient to promote robust and persistent recovery after stroke, and thus is a promising target for brain stimulation.

Functional disconnection of thalamic and cerebellar dentate nucleus networks in progressive supranuclear palsy and corticobasal syndrome.

AIM: To assess functional rearrangement following neurodegeneration in the thalamus and dentate nucleus in patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). METHODS: We recruited 19 patients with PSP, 11 with CBS and 14 healthy subjects. All the subjects underwent resting-state (rs) fMRI using a 3T system. Whole brain functional connectivity of the thalamus and dentate nucleus were calculated by means of a seed-based approach with FEAT script in FSL toolbox. Thalamic volume was calculated by means of FIRST, and the dentate area by means of Jim software. RESULTS: Both thalamic volume and dentate area were significantly smaller in PSP and CBS patients than in healthy subjects. No significant difference emerged in thalamic volume between PSP and CBS patients, whereas dentate area was significantly smaller in PSP than in CBS. Thalamic functional connectivity was significantly reduced in both patient groups in various cortical, subcortical and cerebellar areas. By contrast, changes in dentate nucleus functional connectivity differed in PSP and CBS: it decreased in subcortical and prefrontal cortical areas in PSP, but increased asymmetrically in the frontal cortex in CBS. CONCLUSIONS: Evaluating the dentate nucleus size and its functional connectivity may help to differentiate patients with PSP from those with CBS.