Consensus Paper: Cerebellum and Ageing.

Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.

Infantile status epilepticus disrupts myelin development.

Temporal lobe epilepsy (TLE) is the most prevalent type of epilepsy in adults; it often starts in infancy or early childhood. Although TLE is primarily considered to be a grey matter pathology, a growing body of evidence links this disease with white matter abnormalities. In this study, we explore the impact of TLE onset and progression in the immature brain on white matter integrity and development utilising the rat model of Li-pilocarpine-induced TLE at the 12th postnatal day (P). Diffusion tensor imaging (DTI) and Black-Gold II histology uncovered disruptions in major white matter tracks (corpus callosum, internal and external capsules, and deep cerebral white matter) spreading through the whole brain at P28. These abnormalities were mostly not present any longer at three months after TLE induction, with only limited abnormalities detectable in the external capsule and deep cerebral white matter. Relaxation Along a Fictitious Field in the rotating frame of rank 4 indicated that white matter changes observed at both timepoints, P28 and P72, are consistent with decreased myelin content. The animals affected by TLE-induced white matter abnormalities exhibited increased functional connectivity between the thalamus and medial prefrontal and somatosensory cortex in adulthood. Furthermore, histological analyses of additional animal groups at P15 and P18 showed only mild changes in white matter integrity, suggesting a gradual age-dependent impact of TLE progression. Taken together, TLE progression in the immature brain distorts white matter development with a peak around postnatal day 28, followed by substantial recovery in adulthood. This developmental delay might give rise to cognitive and behavioural comorbidities typical for early-onset TLE.

Individual differences in interoceptive accuracy and prediction error in motor functional neurological disorders: A DTI study.

In motor functional neurological disorders (mFND), relationships between interoception (a construct of high theoretical relevance to its pathophysiology) and neuroanatomy have not been previously investigated. This study characterized white matter in mFND patients compared to healthy controls (HCs), and investigated associations between fiber bundle integrity and cardiac interoception. Voxel-based analysis and tractography quantified fractional anisotropy (FA) in 38 mFND patients compared to 38 HCs. Secondary analyses compared functional seizures (FND-seiz; n = 21) or functional movement disorders (n = 17) to HCs. Network lesion mapping identified gray matter origins of implicated fiber bundles. Within-group mFND analyses investigated relationships between FA, heartbeat tracking accuracy and interoceptive trait prediction error (discrepancies between interoceptive accuracy and self-reported bodily awareness). Results were corrected for multiple comparisons, and all findings were adjusted for depression and trait anxiety. mFND and HCs did not show any between-group interoceptive accuracy or FA differences. However, the FND-seiz subgroup compared to HCs showed decreased integrity in right-lateralized tracts: extreme capsule/inferior fronto-occipital fasciculus, arcuate fasciculus, inferior longitudinal fasciculus, and thalamic/striatum to occipital cortex projections. These alterations originated predominantly from the right temporoparietal junction and inferior temporal gyrus. In mFND patients, individual differences in interoceptive accuracy and interoceptive trait prediction error correlated with fiber bundle integrity originating from the insula, temporoparietal junction, putamen and thalamus among other regions. In this first study investigating brain-interoception relationships in mFND, individual differences in interoceptive accuracy and trait prediction error mapped onto multimodal integration-related fiber bundles. Right-lateralized limbic and associative tract disruptions distinguished FND-seiz from HCs.

Contemporary clinical neurophysiology applications in dystonia.

The complex phenomenological understanding of dystonia has transcended from the clinics to genetics, imaging and neurophysiology. One way in which electrophysiology will impact into the clinics are cases wherein a dystonic clinical presentation may not be typical or a "forme fruste" of the disorder. Indeed, the physiological imprints of dystonia are present regardless of its clinical manifestation. Underpinnings in the understanding of dystonia span from the peripheral, segmental and suprasegmental levels to the cortex, and various electrophysiological tests have been applied in the course of time to elucidate the origin of dystonia pathophysiology. While loss of inhibition remains to be the key finding in this regard, intricacies and variabilities exist, thus leading to a notion that perhaps dystonia should best be gleaned as network disorder. Interestingly, the complex process has now spanned towards the understanding in terms of networks related to the cerebellar circuitry and the neuroplasticity. What is evolving towards a better and cohesive view will be neurophysiology attributes combined with structural dynamic imaging. Such a sound approach will significantly lead to better therapeutic modalities in the future.

Processing of emotionally ambiguous stimuli in eating disorders: an fMRI pilot study.

PURPOSE: People with eating disorders (EDs) have difficulties understanding their own emotions and recognizing the emotions of others, especially in ambiguous settings. We examined the neuronal mechanisms underlying the emotion processing of ambiguous interpersonal stimuli in EDs and healthy controls (HCs). METHODS: The fMRI data were acquired by a blocked experimental design with 28 women (14 EDs) during the visual presentation of a modified Thematic Apperception Test. RESULTS: EDs showed very strong associations between experienced and inferred emotions evoked by the stimuli; no such relationship was found in HCs. HCs displayed elevated left anterior insula activity during the mentalizing condition; EDs showed increased activity in the right supramarginal gyrus and medial prefrontal cortex. CONCLUSION: The two groups seem to apply different strategies for judging emotionally ambiguous stimuli, albeit resulting in equivalent judgments. We assume that activity in the supramarginal gyrus and insula in EDs is linked with suppressing their own perspective while considering emotional states, probably due to alexithymia and the lack of awareness of their own mental states. We hypothesize that the strong correlation between experienced and inferred emotions in EDs could reflect their tendency to use others as a reference point for perceiving themselves and gaining information about their affective state. LEVEL OF EVIDENCE: No level of evidence, this is a basic science study.

Impulsivity in patients with borderline personality disorder: a comprehensive profile compared with healthy people and patients with ADHD.

BACKGROUND: Impulsivity is a core symptom of borderline personality disorder (BPD). Impulsivity is a heterogeneous concept, and a comprehensive evaluation of impulsivity dimensions is lacking in the literature. Moreover, it is unclear whether BPD patients manifest impaired cognitive functioning that might be associated with impulsivity in another patient group, such as ADHD, a frequent comorbidity of BPD. METHODS: We tested 39 patients with BPD without major psychiatric comorbidities and ADHD, 25 patients with ADHD, and 55 healthy controls (HC) using a test battery consisting of a self-report measure of impulsivity (UPPS-P questionnaire), behavioral measures of impulsivity - impulsive action (Go/NoGo task, stop signal task) and impulsive choice (delay discounting task, Iowa gambling task), and standardized measures of attention (d2 test), working memory (digit span), and executive functioning (Tower of London). RESULTS: Patients with BPD and ADHD, as compared with HC, manifested increased self-reported impulsivity except sensation seeking and increased impulsive choice; patients with ADHD but not BPD showed increased impulsive action and deficits in cognitive functioning. Negative urgency was increased in BPD as compared to both HC and ADHD groups and correlated with BPD severity. CONCLUSIONS: Patients with BPD without ADHD comorbidity had increased self-reported impulsivity and impulsive choice, but intact impulsive action and cognitive functioning. Controlling for ADHD comorbidity in BPD samples is necessary. Negative urgency is the most diagnostically specific impulsivity dimension in BPD.

Quantitative but Not Qualitative Performance Changes in Predictive Motor Timing as a Result of Overtraining.

The possibilities of substantial long-term improvement of predictive timing might be sometimes seen as limited, with scanty information of neural substrates underlying the potential learning process. To address this issue, we have investigated the performance of 21 baseball professionals and 21 matched controls in a predictive motor timing task previously shown to engage the cerebellum. Baseball players, hypothesized as a model of overtraining of the prediction of future state of the surroundings, showed significantly higher quantitative performance than nonathletic controls, with a substantial part of the baseball players reaching levels far beyond the range observed in common population. Furthermore, the qualitative performance profile of baseball players under various conditions as target speed and acceleration modes did not differ from the profile of healthy controls. Our results suggest that regular exigent training has the potential to vastly improve predictive motor timing. Moreover, the quantitative but not qualitative difference in the performance profile allows us to hypothesize that the selective honing of the same cerebellar processes and networks as in non-trained individuals is the substrate for the quantitative performance improvement, without substantial engagement of further neural nodes.

Associated factors of REM sleep without atonia in younger (≤ 50 years) hospitalized psychiatric patients.

BACKGROUND: Isolated REM sleep without atonia (RSWA) as a main polysomnograhic feature of REM sleep behaviour disorder (RBD) is thought to be a prodromal or subclinical state of the disease. RSWA/RBD occurence in psychiatric population is much more frequent than in general population but its associated factors are still not known. METHODS: We invited 88 psychiatry in-patients to undervent video-polysomnography. The visual scoring was focused on RSWA in submentales and flexores digitales superficiales muscles. This parametr was subsequently correlated mainly with age/gender, their medication and mental status. RESULTS: The RWSA was mostly still in normal range despite the fact, that selected psychiatry patients (≤ 50 years) were taking several classes of psychoactive medication. 3,6% had convincingly RBD, although 35.7% reported rare lifetime occurence of dream-enacting behaviour and 62.8% sporadic nightmares. We found correlation between RSWA and SNRI medication class (p = 0.015), specifically venlafaxine (p = 0.029) as well as quetiapine (p = 0.030). Another significant associated factors were current anxiety (p < 0.001) and depressive symptoms (p = 0.05), but we found no relation between RSWA and given diagnosis. CONLUCIONS: Isolated RSWA in younger psychiatry patients might be a result of multiple factors, including medication and current mental status but these factors are in most cases not sufficient to manifest RBD.

Neural Scaffolding as the Foundation for Stable Performance of Aging Cerebellum.

Although recently conceptualized as a neural node essential for a vast spectrum of associative and cognitive processes, the cerebellum has largely eluded attention in the research of aging, where it is marginalized mainly to structural analyses. In the current cross-sectional study of 67 healthy subjects of various ages (20 to 76 years), we sought to provide a comprehensive, multimodal account of age-related changes in the cerebellum during predictive motor timing, which was previously shown to engage this structure. We combined behavioral assessments of performance with functional MRI and voxel-based morphometry using an advanced method to avoid cerebellar deformation and registration imprecisions inherent to the standard processing at the whole-brain level. Higher age was surprisingly associated with stable behavioral performance during predictive motor timing, despite the massive decrease of infratentorial gray matter volume of a far higher extent than in the supratentorial region, affecting mainly the posterior cerebellar lobe. Nonetheless, this very area showed extensive hyperactivation directly correlated with age. The same region had decreased connectivity with the left caudate and increased connectivity with the left fusiform gyrus, the right pallidum, the hippocampus, and the lingual gyrus. Hence, we propose to extend the scaffolding theory of aging, previously limited mainly to the frontal cortices, to include also the cerebellum, which is likewise suffering from atrophy to a far greater extent than the rest of the brain and is similarly counteracting it by bilateral hyperactivation.

Consensus paper: Decoding the Contributions of the Cerebellum as a Time Machine. From Neurons to Clinical Applications.

Time perception is an essential element of conscious and subconscious experience, coordinating our perception and interaction with the surrounding environment. In recent years, major technological advances in the field of neuroscience have helped foster new insights into the processing of temporal information, including extending our knowledge of the role of the cerebellum as one of the key nodes in the brain for this function. This consensus paper provides a state-of-the-art picture from the experts in the field of the cerebellar research on a variety of crucial issues related to temporal processing, drawing on recent anatomical, neurophysiological, behavioral, and clinical research.The cerebellar granular layer appears especially well-suited for timing operations required to confer millisecond precision for cerebellar computations. This may be most evident in the manner the cerebellum controls the duration of the timing of agonist-antagonist EMG bursts associated with fast goal-directed voluntary movements. In concert with adaptive processes, interactions within the cerebellar cortex are sufficient to support sub-second timing. However, supra-second timing seems to require cortical and basal ganglia networks, perhaps operating in concert with cerebellum. Additionally, sensory information such as an unexpected stimulus can be forwarded to the cerebellum via the climbing fiber system, providing a temporally constrained mechanism to adjust ongoing behavior and modify future processing. Patients with cerebellar disorders exhibit impairments on a range of tasks that require precise timing, and recent evidence suggest that timing problems observed in other neurological conditions such as Parkinson's disease, essential tremor, and dystonia may reflect disrupted interactions between the basal ganglia and cerebellum.The complex concepts emerging from this consensus paper should provide a foundation for further discussion, helping identify basic research questions required to understand how the brain represents and utilizes time, as well as delineating ways in which this knowledge can help improve the lives of those with neurological conditions that disrupt this most elemental sense. The panel of experts agrees that timing control in the brain is a complex concept in whom cerebellar circuitry is deeply involved. The concept of a timing machine has now expanded to clinical disorders.

Beck Depression Inventory-II: Self-report or interview-based administrations show different results in older persons.

ABSTRACTBeck Depression Inventory-II (BDI-II) is one of the most-used rating scales. It was developed as a tool administered either as a self-rating or interview-based, observer-rating scale. OBJECTIVE: The goal of this study is to compare BDI-II scores obtained with two standard methods of administration in community-based older persons. METHODS: BDI-II was administered at first in the self-rated version to a sample of 60 mentally healthy older persons (age 60-87 years). Afterward, the interview-based administration was performed. ANALYSES: We compared the scores with nonparametric tests - Spearman's correlation coefficient and Wilcoxon Signed Ranks test. We also computed internal consistency. RESULTS: Self-rated BDI-II yielded significantly higher total score than interview (p < 0.001, P = 88%). The correlation between total scores was moderate (rs = 0.46, p < 0.001). Item analysis revealed a larger decrease (lower scores) in the somatic items in the interview-based version. CONCLUSIONS: The two methods of administration result in different total score in healthy older persons. Therefore, interpretation of the scores should reflect the administration, which should be always specified in the studies.

24-Hour Alberta Stroke Program Early CT Score Assessment in Post-Stroke Spasticity Development in Patients with a First Documented Anterior Circulation Ischemic Stroke.

BACKGROUND: Neuroanatomic substrates responsible for development of post-stroke spasticity are still poorly understood. The study is focused on identification of brain regions within the territory of the middle cerebral artery associated with spasticity development. METHODS: This is a single-center prospective cohort study of first documented anterior circulation ischemic strokes with a neurologic deficit lasting >7 days (from March 2014 to September 2016, all patients are involved in a registry). Ischemic cerebral lesions within the territory of middle cerebral artery were evaluated using the Alberta Stroke Program Early CT Score (ASPECTS) on control 24-hour computed tomography or magnetic resonance imaging. Spasticity was assessed with modified Ashworth scale. RESULTS: Seventy-six patients (mean age 72 years, 45% females; 30% treated with IV tissue plasminogen activator, 6.5% mechanical thrombectomy) fulfilled the study inclusion criteria. Forty-nine (64%) developed early elbow or wrist flexor spasticity defined as modified Ashworth scale >1 (at day 7-10), in 44 (58%) the spasticity remained present at 6 months. There were no differences between the patients who developed spasticity and those who did not when comparing admission stroke severity (National Institutes of Health Stroke Scale 5 [interquartile range {IQR} 4-8] versus 6 [IQR 4-10]) and vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, coronary artery disease). Nor was there a difference in 24-hour ASPECTS score (9 [IQR 8-10] versus 9 [IQR 7-10]). No differences were found between the groups with and without the early upper limb flexor spasticity of particular regions (M1, M2, M3, M4, M5, M6, lentiform, insula, caudate, internal capsule) and precentral-postcentral gyrus, premotor cortex, supplementary motor area, posterior limb of internal capsule, and thalamus were compared. CONCLUSIONS: We did not find any middle cerebral artery territory associated with post-stroke spasticity development by detailed evaluation of ASPECTS.

Disruption in cerebellar and basal ganglia networks during a visuospatial task in cervical dystonia.

BACKGROUND: Although dystonia is traditionally conceptualized as a basal ganglia disorder, increasing interest has been directed at a different neural network node, the cerebellum, which may play a significant role in the pathophysiology of dystonia. Abnormal sensorimotor processing and disturbed motor schemes, possibly attributable to cerebellar changes, remain unclear. METHODS: We sought to characterize the extent of cerebellar dysfunction within the motor network using functional MRI activation analysis, connectivity analysis, and voxel-based morphometry in cervical dystonia patients (n = 25, 15 women, mean age 45.8 years) and healthy volunteers (n = 25, 15 women, mean age 44.7 years) in a visuospatial task requiring predictive motor timing. RESULTS: Cervical dystonia patients showed decreased activation in the posterior cerebellar lobules as well as in the premotor areas, the associative parietal cortex, and visual regions. Patients also had decreased cerebellar connectivity with bilateral basal ganglia structures and the dorsolateral prefrontal cortex. CONCLUSIONS: This promotes the view that dystonia results from miscommunication between the basal ganglia and cerebellar loops, thus providing new insights into the brain regions essential for the development of cervical dystonia. © 2017 International Parkinson and Movement Disorder Society.

Social cognition and idiopathic isolated cervical dystonia.

For a long time, cervical dystonia (CD) has been characterised only by disturbances in motor functioning. Despite accumulating evidence for symptomatology in various non-motor domains, to date no study has investigated social cognition in CD. The aim of this study was to compare performance of CD patients and healthy controls in neurocognitive and socio-cognitive domain. Twenty-five non-depressed patients with CD and 26 healthy controls underwent neuropsychological testing. This involved assessment of cognitive status (general intellect, verbal memory, and executive function), and socio-cognitive functions using a Theory of mind task and self-report on empathy and emotion regulation. In comparison to controls, CD patients displayed significantly decreased cognitive abilities, particularly in executive function and verbal memory tasks. Difficulties in inferring mental states on both cognitive and affective levels were also observed. The largest discrepancies were detected in understanding intentionality in others. Poorer performance in cognitive and socio-cognitive tasks was unrelated to severity of the disease. This is the first evidence of compromised socio-cognitive functions in CD patients, highlighting this domain as another facet of non-motor symptoms of this disease. Future studies should advance our understanding of the extent, nature, and time course of these deficits in other aspects of social cognition in this patient population.

Motion and emotion: anxiety-axial connections in Parkinson's disease.

Anxiety is a serious and frequent complication in Parkinson's disease (PD) that significantly affects the quality of life of patients. Multiple neuroanatomical, experimental, and clinical studies suggest its close association with axial disturbances. However, whether this relation applies for PD patients (commonly suffering from axial difficulties, such as balance and gait disturbance) has not been properly tested yet. The purpose of this study was to determine whether PD patients suffering from axial symptoms have higher levels of anxiety than others and to identify other factors associated with anxiety-axial connections. In this questionnaire study, 212 patients with PD were assessed by standardized scales, such as Hamilton Anxiety Scale, Montgomery-Asberg Depression Rating Scale, Montreal Cognitive Assessment, examining their mood and cognitive status. These data were correlated to dominant motor symptoms of these patients, such as tremor, rigidity, bradykinesia, and axial symptoms. Unlike other motor symptoms, only axial symptoms showed to be significantly related to higher levels of anxiety. The patients suffering from anxiety and axial problems have also shown significantly higher depression levels. Axial disturbances are related to higher anxiety levels in PD patients. It is crucial to pay high attention to symptoms of anxiety in patients having postural instability or gait disorder. Further clinical studies are desirable to investigate new, practical implications of anxiety-axial connection to provide complex management options of these serious symptoms.

The Comparison of Effectiveness of Various Potential Predictors of Response to Treatment With SSRIs in Patients With Depressive Disorder.

The substantial non-response rate in depressive patients indicates a continuing need to identify predictors of treatment outcome. The aim of this 6-week, open-label study was (1) to compare the efficacy of a priori defined predictors: ≥20% reduction in MADRS score at week 1, ≥20% reduction in MADRS score at week 2 (RM ≥ 20% W2), decrease of cordance (RC), and increase of serum and plasma level of brain-derived neurotrophic factor at week 1; and (2) to assess whether their combination yields higher efficacy in the prediction of response to selective serotonin re-uptake inhibitors (SSRIs) than when used singly. Twenty-one patients (55%) achieved a response to SSRIs. The RM ≥20% W2 (areas under curve-AUC = 0.83) showed better predictive efficacy compared to all other predictors with the exception of RC. The identified combined model (RM ≥ 20% W2 + RC), which predicted response with an 84% accuracy (AUC = 0.92), may be a useful tool in the prediction of response to SSRIs.

Trial-to-trial Adaptation: Parsing out the Roles of Cerebellum and BG in Predictive Motor Timing.

We previously demonstrated that predictive motor timing (i.e., timing requiring visuomotor coordination in anticipation of a future event, such as catching or batting a ball) is impaired in patients with spinocerebellar ataxia (SCA) types 6 and 8 relative to healthy controls. Specifically, SCA patients had difficulties postponing their motor response while estimating the target kinematics. This behavioral difference relied on the activation of both cerebellum and striatum in healthy controls, but not in cerebellar patients, despite both groups activating certain parts of cerebellum during the task. However, the role of these two key structures in the dynamic adaptation of the motor timing to target kinematic properties remained unexplored. In the current paper, we analyzed these data with the aim of characterizing the trial-by-trial changes in brain activation. We found that in healthy controls alone, and in comparison with SCA patients, the activation in bilateral striatum was exclusively associated with past successes and that in the left putamen, with maintaining a successful performance across successive trials. In healthy controls, relative to SCA patients, a larger network was involved in maintaining a successful trial-by-trial strategy; this included cerebellum and fronto-parieto-temporo-occipital regions that are typically part of attentional network and action monitoring. Cerebellum was also part of a network of regions activated when healthy participants postponed their motor response from one trial to the next; SCA patients showed reduced activation relative to healthy controls in both cerebellum and striatum in the same contrast. These findings support the idea that cerebellum and striatum play complementary roles in the trial-by-trial adaptation in predictive motor timing. In addition to expanding our knowledge of brain structures involved in time processing, our results have implications for the understanding of BG disorders, such as Parkinson disease where feedback processing or reward learning is affected.

Efficacy and safety of abobotulinumtoxinA liquid formulation in cervical dystonia: A randomized-controlled trial.

BACKGROUND: Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA. OBJECTIVES: The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia. METHODS: This was a phase-3, multicenter, prospective, double-blind, randomized, active, and placebo-controlled study (N = 369). Patients with cervical dystonia were randomized (3:3:1) to abobotulinumtoxinA solution for injection 500 U, abobotulinumtoxinA 500 U, or placebo. Following the double-blind phase, patients received abobotulinumtoxinA solution for injection, open-label, for up to 4 cycles. The primary outcome was change from baseline at week 4 of the Toronto Western Spasmodic Torticollis Rating Scale total score. Secondary measures included change from baseline or cycle baseline in Toronto Western Spasmodic Torticollis Rating Scale scores. RESULTS: At week 4, both products were superior to placebo (Toronto Western Spasmodic Torticollis Rating Scale total score least square mean decrease from baseline, abobotulinumtoxinA solution for injection 500 U -12.5, abobotulinumtoxinA 500 U -14.0, placebo -3.9; P < .0001 vs placebo). The noninferiority limit of 3 points in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 was not met for abobotulinumtoxinA solution for injection versus abobotulinumtoxinA. Toronto Western Spasmodic Torticollis Rating Scale total score reductions were maintained for up to 4 cycles of abobotulinumtoxinA solution for injection open-label follow-up treatment. Safety profiles of abobotulinumtoxinA solution for injection and abobotulinumtoxinA were similar, with dysphagia and injection-site pain the most frequent drug-related adverse events. CONCLUSIONS: Although the predefined noninferiority criterion was not met, abobotulinumtoxinA solution for injection was similarly effective to freeze-dried abobotulinumtoxinA in reducing Toronto Western Spasmodic Torticollis Rating Scale total scores with a similar safety profile. AbobotulinumtoxinA solution for injection efficacy was maintained with chronic open-label treatment, and this novel formulation may add convenience as well as dosing accuracy to treatment with abobotulinumtoxinA. © 2016 International Parkinson and Movement Disorder Society.

Linking Essential Tremor to the Cerebellum: Physiological Evidence.

Essential tremor (ET), clinically characterized by postural and kinetic tremors, predominantly in the upper extremities, originates from pathological activity in the dynamic oscillatory network comprising the majority of nodes in the central motor network. Evidence indicates dysfunction in the thalamus, the olivocerebellar loops, and intermittent cortical engagement. Pathology of the cerebellum, a structure with architecture intrinsically predisposed to oscillatory activity, has also been implicated in ET as shown by clinical, neuroimaging, and pathological studies. Despite electrophysiological studies assessing cerebellar impairment in ET being scarce, their impact is tangible, as summarized in this review. The electromyography-magnetoencephalography combination provided the first direct evidence of pathological alteration in cortico-subcortical communication, with a significant emphasis on the cerebellum. Furthermore, complex electromyography studies showed disruptions in the timing of agonist and antagonist muscle activation, a process generally attributed to the cerebellum. Evidence pointing to cerebellar engagement in ET has also been found in electrooculography measurements, cerebellar repetitive transcranial magnetic stimulation studies, and, indirectly, in complex analyses of the activity of the ventral intermediate thalamic nucleus (an area primarily receiving inputs from the cerebellum), which is also used in the advanced treatment of ET. In summary, further progress in therapy will require comprehensive electrophysiological and physiological analyses to elucidate the precise mechanisms leading to disease symptoms. The cerebellum, as a major node of this dynamic oscillatory network, requires further study to aid this endeavor.

The clinical phenomenology and associations of trick maneuvers in cervical dystonia.

Sensory trick is an unusual clinical feature in cervical dystonia that attenuates disease symptoms by slight touch to a specific area of the face or head. Using a semi-quantitative questionnaire-based study of 197 patients with idiopathic cervical dystonia, we sought to determine probable pathophysiologic correlates, with the wider aim of examining its eventual clinical significance. The typical sensory trick, i.e., light touch, not necessitating the use of force leading to simple overpowering of dystonic activity, was present in 83 (42.1 %) patients. The vast majority of the patients required a specific sequence of sensorimotor inputs, including touch sensation on the face or different areas of the head, and also sensory and motor input of the hand itself. Deviations often led to a significant decrease in effectiveness and lack of expected benefit. Moreover, patients able to perform the maneuver reported compellingly higher subjective effect of botulinum toxin treatment (median 7 vs. 5 on a scale of 0-10; p < 0.0001) and lower depression score (median 10 vs. 14 on the Montgomery Åsberg Depression Rating scale; p < 0.001). Overall, the results point to marked disruption of sensorimotor networks in cervical dystonia. The mechanism of the sensory trick action may be associated with balancing the abnormal activation patterns by specific sensorimotor inputs. Its presence may be considered a positive predictive factor for responsiveness to botulinum toxin treatment.