Littérature scientifique sur le sujet « Cerebellar-thalamo-cortical network »

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.

AbstractTinnitus is the perception of a ‘ringing’ sound without an acoustic source. It is generally accepted that tinnitus develops after peripheral hearing loss and is associated with altered auditory processing. The thalamus is a crucial relay in the underlying pathways that actively shapes processing of auditory signals before the respective information reaches the cerebral cortex. Here, we review animal and human evidence to define thalamic function in tinnitus. Overall increased spontaneous firing patterns and altered coherence between the thalamic medial geniculate body (MGB) and auditory cortices is observed in animal models of tinnitus. It is likely that the functional connectivity between the MGB and primary and secondary auditory cortices is reduced in humans. Conversely, there are indications for increased connectivity between the MGB and several areas in the cingulate cortex and posterior cerebellar regions, as well as variability in connectivity between the MGB and frontal areas regarding laterality and orientation in the inferior, medial and superior frontal gyrus. We suggest that these changes affect adaptive sensory gating of temporal and spectral sound features along the auditory pathway, reflecting dysfunction in an extensive thalamo-cortical network implicated in predictive temporal adaptation to the auditory environment. Modulation of temporal characteristics of input signals might hence factor into a thalamo-cortical dysrhythmia profile of tinnitus, but could ultimately also establish new directions for treatment options for persons with tinnitus.

AbstractObjectives: Essential tremor (ET) is a movement disorder characterized by action tremor which impacts motor execution. Given the disrupted cerebellar-thalamo-cortical networks in ET, we hypothesized that ET could interfere with the control mechanisms involved in regulating motor performance. The ability to inhibit or stop actions is critical for navigating many daily life situations such as driving or social interactions. The current study investigated the speed of action initiation and two forms of action control, response stopping and proactive slowing in ET. Methods: Thirty-three ET patients and 25 healthy controls (HCs) completed a choice reaction task and a stop-signal task, and measures of going speed, proactive slowing and stop latencies were assessed. Results: Going speed was significantly slower in ET patients (649 ms) compared to HCs (526 ms; F(1,56) = 42.37; p <.001; η2 = .43), whereas proactive slowing did not differ between groups. ET patients exhibited slower stop signal reaction times (320 ms) compared to HCs (258 ms, F(1,56) = 15.3; p <.00; η2 = .22) and more severe motor symptoms of ET were associated with longer stopping latencies in a subset of patients (Spearman rho = .48; p <.05). Conclusions: In line with previous studies, ET patients showed slower action initiation. Additionally, inhibitory control was impaired whereas proactive slowing remained intact relative to HCs. More severe motor symptoms of ET were associated with slower stopping speed, and may reflect more progressive changes to the cerebellar-thalamo-cortical network. Future imaging studies should specify which structural and functional changes in ET can explain changes in inhibitory action control. (JINS, 2019, 25, 156–164)

Background and ObjectivesThe main culprit gene for paroxysmal kinesigenic dyskinesia, characterized by brief and recurrent attacks of involuntary movements, is PRRT2. The location of the primary dysfunction associated with paroxysmal dyskinesia remains a matter of debate and may vary depending on the etiology. While striatal dysfunction has often been implicated in these patients, evidence from preclinical models indicates that the cerebellum could also play a role. We aimed to investigate the role of the cerebellum in the pathogenesis of PRRT2-related dyskinesia in humans.MethodsWe enrolled 22 consecutive right-handed patients with paroxysmal kinesigenic dyskinesia with a pathogenic variant of PRRT2 and their matched controls. Participants underwent a multimodal neuroimaging protocol. We recorded anatomic and diffusion-weighted MRI, as well as resting-state fMRI, during which we tested the aftereffects of sham and repetitive transcranial magnetic stimulation applied to the cerebellum on endogenous brain activity. We quantified the structural integrity of gray matter using voxel-based morphometry, the structural integrity of white matter using fixel-based analysis, and the strength and direction of functional cerebellar connections using spectral dynamic causal modeling.ResultsPatients with PRRT2 had decreased gray matter volume in the cerebellar lobule VI and in the medial prefrontal cortex, microstructural alterations of white matter in the cerebellum and along the tracts connecting the cerebellum to the striatum and the cortical motor areas, and dysfunction of cerebellar motor pathways to the striatum and the cortical motor areas, as well as abnormal communication between the associative cerebellum (Crus I) and the medial prefrontal cortex. Cerebellar stimulation modulated communication within the motor and associative cerebellar networks and tended to restore this communication to the level observed in healthy controls.DiscussionPatients with PRRT2-related dyskinesia have converging structural alterations of the motor cerebellum and related pathways with a dysfunction of cerebellar output toward the cerebello-thalamo-striato-cortical network. We hypothesize that abnormal cerebellar output is the primary dysfunction in patients with a PRRT2 pathogenic variant, resulting in striatal dysregulation and paroxysmal dyskinesia. More broadly, striatal dysfunction in paroxysmal dyskinesia might be secondary to aberrant cerebellar output transmitted by thalamic relays in certain disorders.Trial Registration Information:ClinicalTrials.gov identifier: NCT03481491.

OBJECTIVE The tremor circuitry has commonly been hypothesized to be driven by one or multiple pacemakers within the cerebello-thalamo-cortical pathway, including the cerebellum, contralateral motor thalamus, and primary motor cortex. However, previous studies, using multiple methodologies, have advocated that tremor could be influenced by changes within the right extrastriate cortex, at both the structural and functional level. The purpose of this work was to evaluate the role of the extrastriate cortex in tremor generation and further arrest after left unilateral stereotactic radiosurgery thalamotomy (SRS-T). METHODS The authors considered 12 healthy controls (HCs, group 1); 15 patients with essential tremor (ET, right-sided, drug-resistant; group 2) before left unilateral SRS-T; and the same 15 patients (group 3) 1 year after the intervention, to account for delayed effects. Blood oxygenation level–dependent functional MRI during resting state was used to characterize the dynamic interactions of the right extrastriate cortex, comparing HC subjects against patients with ET before and 1 year after SRS-T. In particular, the authors applied coactivation pattern analysis to extract recurring whole-brain spatial patterns of brain activity over time. RESULTS The authors found 3 different sets of coactivating regions within the right extrastriate cortex in HCs and patients with pretherapeutic ET, reminiscent of the “cerebello-visuo-motor,” “thalamo-visuo-motor” (including the targeted thalamus), and “basal ganglia and extrastriate” networks. The occurrence of the first pattern was decreased in pretherapeutic ET compared to HCs, whereas the other two patterns showed increased occurrences. This suggests a misbalance between the more prominent cerebellar circuitry and the thalamo-visuo-motor and basal ganglia networks. Multiple regression analysis showed that pretherapeutic standard tremor scores negatively correlated with the increased occurrence of the thalamo-visuo-motor network, suggesting a compensatory pathophysiological trait. Clinical improvement after SRS-T was related to changes in occurrences of the basal ganglia and extrastriate cortex circuitry, which returned to HC values after the intervention, suggesting that the dynamics of the extrastriate cortex had a role in tremor generation and further arrest after the intervention. CONCLUSIONS The data in this study point to a broader implication of the visual system in tremor generation, and not only through visual feedback, given its connections to the dorsal visual stream pathway and the cerebello-thalamo-cortical circuitry, with which its dynamic balance seems to be a crucial feature for reduced tremor. Furthermore, SRS-T seems to bring abnormal pretherapeutic connectivity of the extrastriate cortex to levels comparable to those of HC subjects.

Background: Maladaptive neuroplasticity-related learned response in substance use disorder (SUD) can be ameliorated using noninvasive brain stimulation (NIBS); however, inter-individual variability needs to be addressed for clinical translation. Objective: Our first objective was to develop a hypothesis for NIBS for learned response in SUD based on a competing neurobehavioral decision systems model. The next objective was to develop the theory by conducting a computational simulation of NIBS of the cortico-cerebello-thalamo-cortical (CCTC) loop in cannabis use disorder (CUD)-related dysfunctional “cue-reactivity”—a construct closely related to “craving”—that is a core symptom. Our third objective was to test the feasibility of a neuroimaging-guided rational NIBS approach in healthy humans. Methods: “Cue-reactivity” can be measured using behavioral paradigms and portable neuroimaging, including functional near-infrared spectroscopy (fNIRS) and electroencephalogram (EEG) metrics of sensorimotor gating. Therefore, we conducted a computational simulation of NIBS, including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) of the cerebellar cortex and deep cerebellar nuclei (DCN) of the CCTC loop for its postulated effects on fNIRS and EEG metrics. We also developed a rational neuroimaging-guided NIBS approach for the cerebellar lobule (VII) and prefrontal cortex based on a healthy human study. Results: Simulation of cerebellar tDCS induced gamma oscillations in the cerebral cortex, while transcranial temporal interference stimulation induced a gamma-to-beta frequency shift. A preliminary healthy human study (N = 10) found that 2 mA cerebellar tDCS evoked similar oxyhemoglobin (HbO) response in the range of 5 × 10−6 M across the cerebellum and PFC brain regions (α = 0.01); however, infra-slow (0.01–0.10 Hz) prefrontal cortex HbO-driven phase–amplitude-coupled (PAC; 4 Hz, ±2 mA (max)) cerebellar tACS evoked HbO levels in the range of 10−7 M that were statistically different (α = 0.01) across these brain regions. Conclusion: Our healthy human study showed the feasibility of fNIRS of cerebellum and PFC and closed-loop fNIRS-driven ctACS at 4 Hz, which may facilitate cerebellar cognitive function via the frontoparietal network. Future work needs to combine fNIRS with EEG for multi-modal imaging for closed-loop NIBS during operant conditioning.

Background: The pathophysiology of multiple sclerosis (MS) tremor is uncertain with limited phenotypical studies available. Objective: To investigate whether dystonia contributes to MS tremor and its severity. Methods: MS patients ( n = 54) with and without disabling uni- or bilateral upper limb tremor were recruited (39 limbs per group). We rated tremor severity, writing and Archimedes spiral drawing; cerebellar dysfunction (SARA score); the Global Dystonia Scale (GDS) for proximal and distal upper limbs, dystonic posturing, mirror movements, geste antagoniste, and writer’s cramp. Results: Geste antagoniste, mirror dystonia, and dystonic posturing were more frequent and severe ( p < 0.001) and dystonia scores were correlated with tremor severity in tremor compared to non-tremor patients. A 1-unit increase in distal dystonia predicted a 0.52-Bain unit (95% confidence interval (CI) 0.08–0.97), p = 0.022) increase in tremor severity and a 1-unit (95% CI 0.48–1.6, p = 0.001) increase in drawing scores. A 1-unit increase in proximal dystonia predicted 0.93-Bain unit increase (95% CI 0.45–1.41, p < 0.001) in tremor severity and 1.5-units (95% CI 0.62–2.41, p = 0.002) increase in the drawing score. Cerebellar function in the tremor limb and tremor severity was correlated ( p < 0.001). Conclusions: Upper limb dystonia is common in MS tremor suggesting that MS tremor pathophysiology involves cerebello-pallido-thalamo-cortical network dysfunction.

Compared to unimanual task execution, simultaneous bimanual tapping tasks are associated with a significantly reduced intertap variability. It has been suggested that this bimanual advantage is based on the integration of timing signals which otherwise control each hand independently. Although its functional and anatomic foundations are poorly understood, functional coupling between cerebellar hemispheres might be behind this process. Because the execution of fast alternating fingertaps increases intertap variability, it is hypothesized that intercerebellar coupling is reduced in such tasks. To shed light on the functional significance of intercerebellar coupling, 14 right-handed subjects performed unimanual right, bimanual simultaneous, and bimanual alternating synchronization tasks with respect to a regular auditory pacing signal. In all conditions, within-hand intertap interval was 500 msec. Continuous neuromagnetic activity, using a 122-channel wholehead neuromagnetometer and surface electromyograms of the first dorsal interosseus muscle of both hands, were recorded. For data analysis, we used the analysis tool Dynamic Imaging of Coherent Sources, which provides a tomographic map of cerebromuscular and cerebrocerebral coherence. Analysis revealed a bilateral cerebello-thalamo-cortical network oscillating at alpha (8–12 Hz) and beta (13–24 Hz) frequencies associated with bimanual synchronization. In line with our hypothesis, coupling between cerebellar hemispheres was restricted to simultaneous task execution. This result implies that intercerebellar coupling is key for the execution of simultaneous bimanual movements. Although the criticality of a specific magneto-encephalography pattern for behavioral changes should be interpreted with caution, data suggest that intercerebellar coupling possibly represents the functional foundation of the bimanual advantage.

Introduction Cognitive difficulties and neuropsychological alterations in Duchenne and Becker muscular dystrophy (DMD, BMD) boys are not yet sufficiently explored, although this topic could have a relevant impact, finding novel biomarkers of disease both at genetics and neuroimaging point of view. The current study aims to: 1) analyze the neuropsychological profile of a group of DMD and BMD boys without cognitive impairment with an assessment of their executive functions; 2) explore the structural connectivity in DMD, BMD, and age-matched controls focusing on cortico-subcortical tracts that connect frontal cortex, basal ganglia, and cerebellum via the thalamus; 3) explore possible correlations between altered structural connectivity and clinical neuropsychological measures. Materials and methods This pilot study included 15 boys (5 DMD subjects, 5 BMD subjects, and 5 age-matched typically developing, TD). They were assessed using a neuropsychological assessment protocol including cognitive and executive functioning assessment and performed a 1.5T MRI brain exam including advance Diffusion Weighted Imaging (DWI) method for tractography. Structural connectivity measurements were extracted along three specific tracts: Cortico-Ponto-Cerebellar Tract (CPCT), Cerebellar-Thalamic Tract (CTT), and Superior Longitudinal Fasciculus (SLF). Cortical-Spinal Tract (CST) was selected for reference, as control tract. Results Regarding intellectual functioning, a major impairment in executive functions compared to the general intellectual functioning was observed both for DMD (mean score = 86.20; SD = 11.54) and for BMD children (mean score = 88; SD = 3.67). Mean FA resulted tendentially always lower in DMD compared to both BMD and TD groups for all the examined tracts. The differences in FA were statistically significant for the right CTT (DMD vs BMD, p = 0.002, and DMD vs TD, p = 0.0015) and the right CPCT (DMD vs TD, p = 0.008). Concerning DMD, significant correlations emerged between FA-R-CTT and intellectual quotients (FIQ, p = 0.044; ρs = 0.821), and executive functions (Denomination Total, p = 0.044, ρs = 0.821; Inhibition Total, p = 0.019, ρs = 0.900). BMD showed a significant correlation between FA-R-CPCT and working memory index (p = 0.007; ρs = 0.949). Discussion and conclusion In this pilot study, despite the limitation of sample size, the findings support the hypothesis of the involvement of a cerebellar-thalamo-cortical loop for the neuropsychological profile of DMD, as the CTT and the CPCT are involved in the network and the related brain structures are known to be implied in executive functions. Our results suggest that altered WM connectivity and reduced fibre organization in cerebellar tracts, probably due to the lack of dystrophin in the brain, may render less efficient some neuropsychological functions in children affected by dystrophinopathies. The wider multicentric study could help to better establish the role of cerebellar connectivity in neuropsychological profile for dystrophinopathies, identifying possible novel diagnostic and prognostic biomarkers.

Several studies have reported cognitive difficulties and neuropsychological alterations in Duchenne muscular dystrophy (DMD) boys, which may be due to the lack of specific dystrophin isoforms in the brain, taking account of the possible involvement of cerebellum and of a complex cerebro-cerebellar network. The PhD project comes from the neuropsychological data collected before the beginning of the PhD in a multicenter setting by a group of Centres from the DMD Italian Network, including IRCCS Stella Maris Foundation, that produced two scientific reports, published during the second year of the PhD (Battini et al., 2018; Vicari et al., 2018). An impairment of multitasking, problem solving, inhibition and working memory (Battini et al., 2018) and an implicit learning deficit (Vicari et al., 2018) emerged in the analyzed DMD patients, supporting the hypothesis of a specific involvement of cerebellum as part of a more general involvement of the cerebellar-thalamo-cortical network. Starting from these results, in the PhD project we aimed to deepen the neuropsychological functioning of DMD boys without intellectual disability during school age, assessing longitudinally the subjects previously evaluated and extending the neuropsychological evaluation in another group of DMD Italian children. We wanted indeed to define the trend of impairments over time and to confirm the neuropsychological profile in a wider cohort of subjects than previously evaluated. Our overall findings confirm the impairment of some neuropsychological functions, in particular executive functions, in DMD boys, even without intellectual disability, and suggest the stability of the neuropsychological profile over time. As the results deriving from a specific questionnaire for DMD boys’parents show that neuropsychological deficits may be not completely recognized in the home environment, we believe that the detection of neuropsychological impairments in DMD boys without intellectual disability may be an important challenge. Actually, misdiagnosed neuropsychological deficits may have a negative impact on the global functioning of these children. We were also interested in analyzing possible correlations between neuropsychological findings and the site of mutations in DMD gene, according to the involvement of Dp140 dystrophin isoform. According to literature, possible genotype-neuropsychological phenotype correlations emerged both from the follow up and the total cohort assessment. Globally, the DMD boys who do not express Dp140 show greater difficulties in cognitive performances, in particular in the manipulation of stored information than children with a certain Dp140 dystrophin expression, while this last subgroup exhibits better performances in cognitive flexibility and in switching the tasks, and are more accurate in tasks requiring planning and problem solving. Since genetic mechanisms other than site of mutation have been widely described to explain variability in DMD clinical phenotype in terms of motor and cardiac outcome but not regarding neuropsychological functioning, as an ancillary genetic study, we wanted to verify the possible modifier effect of specific genetic loci (in LTBP4, SPP1, CD40 genes) for the neuropsychological variability in DMD. In fact, possible distribution of genetic modifiers and their protein products in the brain and their possible involvement in neuroprotection and in the pathogenesis of neurodegenerative disorders have been described in literature. The results suggest that some polymorphisms may play a role also in the modulation of the neuropsychological phenotype in DMD without intellectual disability, in particular regarding executive functioning as switching, planning and problem solving abilities. Eventually, in a functional neuroimaging pilot study, we explored structural connectivity in a small group of DMD boys. Because of the involvement of dystrophin in all dystrophinopathies, also a small cohort of Becker muscular dystrophy (BMD) children was enrolled. We focused in particular on cerebellar tracts and on tracts that have been described to be possibly involved in executive functions. Moreover, we explored possible correlations between altered scalar measures and neuropsychological functions in DMD and BMD groups. The results suggest that altered white matter connectivity and reduced fibre organization in cerebellar tracts, probably due to the lack of dystrophin in the brain, may render less efficient some neuropsychological functions in children affected by dystrophinopathies, identifying possible functional neuroimaging biomarkers for the neuropsychological profile of DMD without intellectual disability. In conclusion, our research confirms the hypothesis of the involvement of the cerebro-cerebellar network in DMD, which connects the neuropsychological, genetic and functional neuroimaging aspects, based on the localisation of dystrophin isoforms in normal brain.