Force dysmetria in spinocerebellar ataxia 6 correlates with functional capacity

Spinocerebellar ataxia type 6 (SCA6) is a genetic disease that causes pure cerebellar degeneration affecting walking, balance, and coordination. One of the main symptoms of SCA6 is dysmetria. The magnitude of dysmetria and its relation to functional capacity in SCA6 has not been studied. Our purpose was to quantify dysmetria and determine the relation between dysmetria and functional capacity in SCA6. Ten individuals diagnosed and genetically confirmed with SCA6 (63.7 ± 7.02yrs) and nine age-matched healthy controls (65.9 ± 8.5yrs) performed goal-directed isometric contractions with the ankle joint. Dysmetria was quantified as the force and time error during goal-directed contractions. SCA6 functional capacity was determined by ICARS and SARA clinical assessments. We found that SCA6 participants exhibited greater force dysmetria than healthy controls (P < 0.05), and reduced time dysmetria than healthy controls (P < 0.05). Only force dysmetria was significantly related to SCA6 functional capacity, as measured with ICARS kinetic score (R2 = 0.63), ICARS total score (R2 = 0.43), and SARA total score (R2 = 0.46). Our findings demonstrate that SCA6 exhibit force dysmetria and that force dysmetria is associated to SCA6 functional capacity. Quantifying force and time dysmetria in individuals with SCA6 could provide a more objective evaluation of the functional capacity and disease state in SCA6

Intention Tremor and Deficits of Sensory Feedback Control in Multiple Sclerosis: a Pilot Study

Background Intention tremor and dysmetria are leading causes of upper extremity disability in Multiple Sclerosis (MS). The development of effective therapies to reduce tremor and dysmetria is hampered by insufficient understanding of how the distributed, multi-focal lesions associated with MS impact sensorimotor control in the brain. Here we describe a systems-level approach to characterizing sensorimotor control and use this approach to examine how sensory and motor processes are differentially impacted by MS. Methods Eight subjects with MS and eight age- and gender-matched healthy control subjects performed visually-guided flexion/extension tasks about the elbow to characterize a sensory feedback control model that includes three sensory feedback pathways (one for vision, another for proprioception and a third providing an internal prediction of the sensory consequences of action). The model allows us to characterize impairments in sensory feedback control that contributed to each MS subject’s tremor. Results Models derived from MS subject performance differed from those obtained for control subjects in two ways. First, subjects with MS exhibited markedly increased visual feedback delays, which were uncompensated by internal adaptive mechanisms; stabilization performance in individuals with the longest delays differed most from control subject performance. Second, subjects with MS exhibited misestimates of arm dynamics in a way that was correlated with tremor power. Subject-specific models accurately predicted kinematic performance in a reach and hold task for neurologically-intact control subjects while simulated performance of MS patients had shorter movement intervals and larger endpoint errors than actual subject responses. This difference between simulated and actual performance is consistent with a strategic compensatory trade-off of movement speed for endpoint accuracy. Conclusions Our results suggest that tremor and dysmetria may be caused by limitations in the brain’s ability to adapt sensory feedback mechanisms to compensate for increases in visual information processing time, as well as by errors in compensatory adaptations of internal estimates of arm dynamics

The cerebellum and motor dysfunction in neuropsychiatric disorders

The cerebellum is densely interconnected with sensory-motor areas of the cerebral cortex, and in man, the great expansion of the association areas of cerebral cortex is also paralleled by an expansion of the lateral cerebellar hemispheres. It is therefore likely that these circuits contribute to non-motor cognitive functions, but this is still a controversial issue. One approach is to examine evidence from neuropsychiatric disorders of cerebellar involvement. In this review, we narrow this search to test whether there is evidence of motor dysfunction associated with neuropsychiatric disorders consistent with disruption of cerebellar motor function. While we do find such evidence, especially in autism, schizophrenia and dyslexia, we caution that the restricted set of motor symptoms does not suggest global cerebellar dysfunction. Moreover, these symptoms may also reflect involvement of other, extra-cerebellar circuits and detailed examination of specific sub groups of individuals within each disorder may help to relate such motor symptoms to cerebellar morphology

Motor deficits in schizophrenia quantified by nonlinear analysis of postural sway.

Motor dysfunction is a consistently reported but understudied aspect of schizophrenia. Postural sway area was examined in individuals with schizophrenia under four conditions with different amounts of visual and proprioceptive feedback: eyes open or closed and feet together or shoulder width apart. The nonlinear complexity of postural sway was assessed by detrended fluctuation analysis (DFA). The schizophrenia group (n = 27) exhibited greater sway area compared to controls (n = 37). Participants with schizophrenia showed increased sway area following the removal of visual input, while this pattern was absent in controls. Examination of DFA revealed decreased complexity of postural sway and abnormal changes in complexity upon removal of visual input in individuals with schizophrenia. Additionally, less complex postural sway was associated with increased symptom severity in participants with schizophrenia. Given the critical involvement of the cerebellum and related circuits in postural stability and sensorimotor integration, these results are consistent with growing evidence of motor, cerebellar, and sensory integration dysfunction in the disorder, and with theoretical models that implicate cerebellar deficits and more general disconnection of function in schizophrenia

Novel pathogenic COX20 variants causing dysarthria, ataxia, and sensory neuropathy.

COX20/FAM36A encodes a mitochondrial complex IV assembly factor important for COX2 activation. Only one homozygous COX20 missense mutation has been previously described in two separate consanguineous families. We report four subjects with features that include childhood hypotonia, areflexia, ataxia, dysarthria, dystonia, and sensory neuropathy. Exome sequencing in all four subjects identified the same novel COX20 variants. One variant affected the splice donor site of intron-one (c.41A&gt;G), while the other variant (c.157+3G&gt;C) affected the splice donor site of intron-two. cDNA and protein analysis indicated that no full-length cDNA or protein was generated. These subjects expand the phenotype associated with COX20 deficiency

Isolated Subtle Neurological Abnormalities in Mild Cognitive Impairment Types

Background: Isolated, subtle neurological abnormalities (ISNA) are commonly seen in aging and have been related to cerebral small vessel disease (SVD) and subcortical atrophy in neurologically and cognitively healthy aging subjects. Objective: To investigate the frequency of ISNA in different mild cognitive impairment (MCI) types and to evaluate for each MCI type, the crosssectional relation between ISNA and white matter hyperintensities (WMH), lacunes, caudate atrophy, and ventricular enlargement. Methods: One thousand two hundred fifty subjects with different MCI types were included in the analysis and underwent brain magnetic resonance imaging. WMHs were assessed through two visual rating scales. Lacunes were also rated. Atrophy of the caudate nuclei and ventricular enlargement were assessed through the bicaudate ratio (BCr) and the lateral ventricles to brain ratio (LVBr), respectively. Apolipoprotein E (APOE) genotypes were also assessed. The routine neurological examination was used to evaluate ISNAs that were clustered as central-based signs, cerebellar-based signs, and primitive reflexes. The items of Part-III of the Unified Parkinson’s Disease Rating Scale were used to evaluate ISNAs that were clustered as mild parkinsonian signs. Associations of ISNAs with imaging findings were determined through logistic regression analysis. Results: The ISNAs increase with the age and are present in all MCI types, particularly in those multiple domains, and carrying the APOE ϵ4 allele, and are associated with WMH, lacunes, BCr, and LVBr. Conclusion: This study demonstrates that cortical and subcortical vascular and atrophic processes contribute to ISNAs. Long prospective population-based studies are needed to disentangle the role of ISNAs in the conversion from MCI to dementia

EVIDENCE FOR "UNER TAN SYNDROME" AS A HUMAN MODEL FOR REVERSE EVOLUTION

“Uner Tan Syndrome” was further studied in a second family. There was no cerebellar atrophy, except a mild vermial atrophy in MRI scans of the affected individuals. This is not, however, the pathogenesis of the “Uner Tan Syndrome”, since in the first and second families there were bipedal men exhibiting very similar MRI scans. The second family may also be considered a live model for reverse evolution in human beings. The present work provided evidence for a reverse evolution: (i) quadrupedality; (ii) primitive mental abilities including language; (iii) curved fingers during wrist-walking of the quadrupedal woman; (iv) arm to leg ratios being close to those of the human-like apes. The quadrupedal individuals were raised in separate places, so that they could not imitate each other, excluding the socio-cultural factors contributing to the habitual quadrupedal gait. The results are consistent with the single gene theory, suggesting a single gene controlling multiple behavioral traits, and the psychomotor theory, and a co-evolution of the human mind, an emergent property of the motor system expressed by human language