Slow Motor Research Articles

Sensorimotor Impairment of Speech and Hand Movement Timing Processing in Parkinson’s Disease

Models of motor control have highlighted the role of temporal predictive mechanisms in sensorimotor processing of speech and limb movement timing. We investigated how these mechanisms are affected in Parkinson’s disease (PD) while patients performed speech and hand motor reaction time tasks in response to sensory stimuli with predictable and unpredictable temporal dynamics. Results showed slower motor reaction times in PD vs. control in response to temporally predictable, but not unpredictable stimuli. This effect was driven by faster motor responses to predictable stimuli in control subjects; however, no such effect was observed in the PD group. These findings indicated the relationship between PD pathology and sensorimotor deficits in temporal predictive mechanisms of timing processing during speech production and hand movement.

Cognitive predictors of parent-rated inattention in very preterm children: The role of working memory and processing speed

ABSTRACTInattention is one of the most common neurobehavioral problems following very preterm birth. Attention problems can persist into adulthood and are associated with negative socio-emotional and educational outcomes. This study aimed to determine whether the cognitive processes associated with inattention differ between term-born and very preterm children. Sixty-five children born very preterm (<33+0 weeks’ gestation) aged 8–11 years were recruited alongside 48 term-born controls (?37 20 +0 weeks’ gestation). Both groups included children with a wide spectrum of parent-rated inattention (above average attention to severe inattention) measured as a continuous dimension using the Strengths and Weaknesses of ADHD and Normal-Behavior (SWAN) scale. The children completed tests to assess basic cognitive processes and executive function. A hierarchical multiple regression analysis was implemented to assess which neurocognitive processes explained variance in parent-rated inattention and whether these differed between preterm and term-born children. In both groups, poorer verbal and visuospatial short-term memory and poorer visuospatial working memory independently explained variance in parent-rated inattention. Slower motor processing speed explained variance in inattention among very preterm children only. The cognitive mechanisms associated with parent-rated inattention were predominantly overlapping between groups, but relationships between motor processing speed and inattention were unique to very preterm children. These associations may reflect risk factors for inattention in term and very preterm children. Future research should assess the efficacy of these cognitive processes as potential targets for intervention

CONGENITAL MUSCULAR DYSTROPHIES: P.324Clinical characteristics and long-term course of selenoprotein N1 related myopathy in a large multi-centric cohort

Selenoprotein N1 related myopathies (SEPN1-RM), including congenital muscular dystrophy with rigid spine (RSMD1), multiminicore disease (MmD), desmin-related myopathy with Mallory body-like inclusions and congenital fiber-type disproportion, are autosomal-recessive disorders caused by pathogenic variants in the SELENON gene. They are collectively characterized by early onset muscle weakness especially of the axial muscles, respiratory insufficiency often more severe and out of proportion to skeletal weakness, spinal rigidity and scoliosis. Here we present a detailed phenotypic review of 61 patients (2-58 years) with genetically confirmed SEPN1-RM, with long-term follow-up data for 25 of them. Mean age at onset was 2.2 years, with 47/61 patients presenting before age 2 years mostly with hypotonia, poor head/neck control and developmental delay. Over a mean follow up of 4.8 years, a decline from a mean of 33 to 27 on the 40 point Hammersmith ambulant motor scale was noted in 10/19 patients (range 0.7-14.1 years), with an estimated annual change in motor ability scores of -0.55, indicative of a slow motor decline. Ten children of the total cohort (16%) lost ambulation within the first two decades of life. 45/61 patients (74%) developed scoliosis at a mean age of 10.3 years and 18 (29%) patients underwent scoliosis surgery. Weight trends, available for 21 children, showed values below 2nd centile for 10, while nasogastric feeds and/or gastrostomy was needed in 6/61 children (10%). FVC trends, available for 20 children, showed an estimated % change per year of -2.04 (SE 0.46; p value< 0.001). Nocturnal ventilator support was required in 50/61 (82%) at a mean age of 13 years. This study expands our knowledge of the clinical phenotype and long-term course of SEPN1-RM, and highlights the importance of robust and consistent multi-disciplinary assessment and management to improving outcomes in these children.

Neurochemical Aspects of Alzheimer's Disease and Movement Disturbances: A Theory of β-Amyloid and τ-Protein.

The pathologic and molecular substrate of people diagnosed with cognitive deficits and movement disturbance may not occur exclusively in the context of a brain region, but it may be expressed in another part of body such as muscle. A large body of research has demonstrated that slow motor performance is associated with cognitive impairment in elderly people. The interdependence between motor dysfunction and cognition decline is still not fully understood. Although several factors have been suggested to give a plausible explanation, β-amyloid (Aβ) and τ-protein aggregation is a common feature of a number of neurodegenerative disorders which are characterized by both motor and cognitive impairment, and it is assumed that the aggregation process plays a central role in the pathogenesis of cognitive impairment and motor dysfunction in Alzheimer's disease. The purpose of the present review is to provide an overview of the available evidence that can help to better elucidate the pathophysiological mechanisms underlying the relationship between cognitive and movement disturbances by focusing on Aβ and τ-protein.

Developing and validating Parkinson’s disease subtypes and their motor and cognitive progression

ObjectivesTo use a data-driven approach to determine the existence and natural history of subtypes of Parkinson’s disease (PD) using two large independent cohorts of patients newly diagnosed with this condition.Methods1601...

Progressive myoclonus epilepsy without renal failure in a Chinese family with a novel mutation in SCARB2 gene and literature review

PurposeTo describe the clinical and genetic features of a Chinese progressive myoclonus epilepsy (PME) patient related with SCARB2 mutation without renal impairment and review 27 SCARB2-related PME patients from 11 countries. MethodsThe patient was a 27-year-old man with progressive action myoclonus, ataxia, epilepsy, dysarthria and absence of cognitive deterioration. Renal functional test was normal. Electroencephalography (EEG) showed progressively slowed background activity and sporadic generalized spike-and-wave discharges. Electromyography (EMG) showed slowed motor and sensory nerve conduction velocities and distal motor latency delay accompanied by normal compound motor action potential (CMAP) and amplitudes of sensory nerve action potential (SNAP). The amplitude of cortical components of brainstem auditory-evoked potential (BAEP) was normal with slightly prolonged latencies. Generalized atrophy, ventricle enlargement and white matter degeneration was observed in brain magnetic resonance imaging (MRI). Open muscle biopsy and genetic analysis were performed. Two hundred healthy individuals were set for control. Quantitative real time PCR (qPCR), western blotting and immunofluorescence were carried out to evaluate the fate of the SCARB2 mRNA and lysosomal-membrane type 2 (LIMP2) protein level. ResultsOne homozygous mutation in SCARB2 gene (c.1187 + 5G > T) was identified in the patient. Each of his parents carried a heterozygous variant. This mutation was not detected among the healthy controls and predicted to be damaging or disease causing by prediction tools. qPCR revealed a significantly lower level of SCARB2 mRNA in peripheral blood cell of the proband compared with his parents and healthy control individuals. Muscle biopsy showed mild variation in fiber size. Western blotting and immunofluorescence detected an extremely weak signal of LIMP2 protein from skeletal muscle of the proband. ConclusionIn this study, we identified a SCARB2-related PME patient with normal renal function and a novel homozygous splicing mutation. SCARB2 gene should be analyzed in patients with progressive action myoclonus, epilepsy, peripheral neuropathy, without cognitive deterioration or renal failure.

Task-dependent activation of distinct fast and slow(er) motor pathways during motor imagery

BackgroundMotor imagery and actual movements share overlapping activation of brain areas but little is known about task-specific activation of distinct motor pathways during mental simulation of movements. For real contractions, it was demonstrated that the slow(er) motor pathways are activated differently in ballistic compared to tonic contractions but it is unknown if this also holds true for imagined contractions. ObjectiveThe aim of the present study was to assess the activity of fast and slow(er) motor pathways during mentally simulated movements of ballistic and tonic contractions. MethodsH-reflexes were conditioned with transcranial magnetic stimulation at different interstimulus intervals to assess the excitability of fast and slow(er) motor pathways during a) the execution of tonic and ballistic contractions, b) motor imagery of these contraction types, and c) at rest. ResultsIn contrast to the fast motor pathways, the slow(er) pathways displayed a task-specific activation: for imagined ballistic as well as real ballistic contractions, the activation was reduced compared to rest whereas enhanced activation was found for imagined tonic and real tonic contractions. ConclusionsThis study provides evidence that the excitability of fast and slow(er) motor pathways during motor imagery resembles the activation pattern observed during real contractions. The findings indicate that motor imagery results in task- and pathway-specific subliminal activation of distinct subsets of neurons in the primary motor cortex.

Should I Stay or Should I Go? FMRI Study of Response Inhibition in Early Illness Schizophrenia and Risk for Psychosis.

Response inhibition (RI) is a component of the cognitive control systems that support optimal cognition. Cognitive control deficits are well-described in schizophrenia, but are not well characterized in individuals at clinical high risk (CHR) for developing psychosis. Functional magnetic resonance imaging during Go/NoGo task performance was collected from 30 CHR youth, 23 early illness schizophrenia patients (ESZ), and 72 healthy adolescents and young adults (HC). Voxelwise main effects of group were examined (P < .005 height threshold, family-wise error-corrected cluster threshold, P < .05) for correct NoGo-Go contrast values and task-based functional connectivity. CHR and ESZ groups had slower and more variable reaction times (RT) on Go trials compared to HCs. Significant main effects of group in bilateral dorsal anterior cingulate (dACC) and right inferior frontal cortex stemmed from CHR and ESZ groups showing significantly less NoGo-Go activation, relative to HCs. Faster responding HCs had less functional coupling between dACC and medial prefrontal cortex, a default mode network (DMN) region during NoGo vs Go trials. This functional connectivity-performance relationship was not present in ESZ or CHR groups. The pattern of findings suggests CHR and ESZ groups were deficient in developing strong and consistent prepotent responding, based on their slow and variable motor responses and decreased engagement of dACC and right inferior frontal regions implicated in inhibitory control. Furthermore, only the control group showed a functional connectivity relationship consistent with greater response prepotency requiring more decoupling of inhibitory control regions from DMN regions during RI.

Protective effects of long-term lithium administration in a slowly progressive SMA mouse model.

In the present study we evaluated the long-term effects of lithium administration to a knock-out double transgenic mouse model (Smn-/-; SMN1A2G+/-; SMN2+/+) of Spinal Muscle Atrophy type III (SMA-III). This model is characterized by very low levels of the survival motor neuron protein, slow disease progression and motor neuron loss, which enables to detect disease-modifying effects at delayed time intervals. Lithium administration attenuates the decrease in motor activity and provides full protection from motor neuron loss occurring in SMA-III mice, throughout the disease course. In addition, lithium prevents motor neuron enlargement and motor neuron heterotopy and suppresses the occurrence of radial-like glial fibrillary acidic protein immunostaining in the ventral white matter of SMA-III mice. In SMA-III mice long-term lithium administration determines a dramatic increase of survival motor neuron protein levels in the spinal cord. These data demonstrate that long-term lithium administration during a long-lasting motor neuron disorder attenuates behavioural deficit and neuropathology. Since low level of survival motor neuron protein is bound to disease severity in SMA, the robust increase in protein level produced by lithium provides solid evidence which calls for further investigations considering lithium in the long-term treatment of spinal muscle atrophy.

Selective elimination of slow motor neurons in mice progressively induces a kinetic tremor that resembles patients with essential tremor

Selective elimination of slow motor neurons in mice progressively induces a kinetic tremor that resembles patients with essential tremor

PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by duplication of peripheral myelin protein 22 (PMP22) and is the most common hereditary peripheral neuropathy. CMT1A is characterized by demyelination and axonal loss, which underlie slowed motor nerve conduction velocity (MNCV) and reduced compound muscle action potentials (CMAP) in patients. There is currently no known treatment for this disease. Here, we show that antisense oligonucleotides (ASOs) effectively suppress PMP22 mRNA in affected nerves in 2 murine CMT1A models. Notably, initiation of ASO treatment after disease onset restored myelination, MNCV, and CMAP almost to levels seen in WT animals. In addition to disease-associated gene expression networks that were restored with ASO treatment, we also identified potential disease biomarkers through transcriptomic profiling. Furthermore, we demonstrated that reduction of PMP22 mRNA in skin biopsies from ASO-treated rats is a suitable biomarker for evaluating target engagement in response to ASO therapy. These results support the use of ASOs as a potential treatment for CMT1A and elucidate potential disease and target engagement biomarkers for use in future clinical trials.

Motor planning in children with cerebral palsy: A longitudinal perspective

ABSTRACTIntroduction: Motor planning is important for daily functioning. Deficits in motor planning can result in slow, inefficient, and clumsy motor behavior and are linked to disruptions in performance of activities of daily living in children with cerebral palsy (CP). However, the evidence in CP is primarily based on cross-sectional data. Method: Data are presented on the development of motor planning in children with CP using a longitudinal design with three measurement occasions, each separated by 1 year. Twenty-two children with CP (9 boys, 13 girls; age in years;months, M = 7;1, SD = 1;2) and 22 age-matched controls (10 boys, 12 girls, M = 7;1, SD = 1;3) participated. Children performed a bar transport task in which some conditions (“critical angles”) required participants to sacrifice initial posture comfort in order to achieve end-state comfort. Performance on critical trials was analyzed using linear growth curve modeling. Results: In general, children with CP showed poor end-state planning for critical angles. Importantly, unlike in controls, motor planning ability did not improve across the three measurement occasions in children with CP. Conclusion: These longitudinal results show that motor planning issues in CP do not resolve with development over childhood. Strategies to enhance motor planning are suggested for intervention.

Neuropathy genetics

Charcot-Marie-Tooth disease (CMT) is the most frequent form of hereditary neuropathy. Three genes commonly causing CMT encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). PMP22 duplication causes mainly demyelinating phenotype, known as CMT1A, with slowed motor nerve conduction velocity (MCV). Two distinctive phenotypic subgroups are present in patients with MPZ mutations: one shows preserved MCV and exclusively axonal pathological features, while the other is exclusively demyelinating. Patients with Cx32 mutations show intermediate slowing of MCV. Hereditary neuropathy with liability to pressure palsies (HNPP) usually is associated with a deletion of PMP22, which represents a reciprocal product of CMT1A. Focal thickening of the myelin sheath, known as tomacula, is a characteristic pathological feature in HNPP. Motor conduction studies show age-associated deterioration of compound muscle action potentials in nerves vulnerable to repetitive compression (median, ulnar, and peroneal nerves), but not in others such as the tibial nerve, suggesting that irreversible axonal damage occurs at entrapment sites in motor nerves in HNPP patients. Familial amyloid polyneuropathy (FAP) is also an important hereditary neuropathy. Although FAP was originally reported in endemic foci of Portugal, Japan, and Sweden, recent progress in diagnostic techniques has revealed that late-onset form of this disease is widely prevalent beyond these conventional endemic foci. Clinicians should consider the possibility of FAP in patients presenting with neuropathy of undetermined etiology to avoid misdiagnosis.

P 43 A novel deletion in two exons of the SH3TC2 gene with mutation in the DPYD gene in Charcot-Marie-Tooth disease type 4C

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive demyelinating neuropathy associated with SH3TC2 mutations. More than 60 variants including nonsense, frameshift, and splice site variants have been reported in families of different ethnic origins as well as in sporadic patients. CMT4C is clinically characterised by early onset neuropathy, cranial nerve involvement and spine deformities. We present a family from Kuwait with a novel deletion of exons 13 and 14 in the SH3TC2 gene combined with a novel homozygous mutation in the DPYD gene. The 40 year-old male patient had foot deformities in infancy and delayed walking after the age of two. He first required walking aids when ten years old and became wheelchair-bound since the age of 18. He had progressive hearing loss over five years. Walking difficulties and wheelchair-dependency were reported in his father as well as a cousin of his mother while there were no symptoms reported in his own siblings and child. Clinical examination showed hypoacusis requiring the use of hearing aids, marked widespread symmetric muscular atrophies with weakness, and areflexia. He could walk a few steps with bilateral support. He had sensory neuropathy with skin atrophy and loss of hair on the lower legs. Spinal examination and X-ray showed slight hyperkyphosis of the thoracic spine but no signs of kyphoscoliosis. Electrophysiological studies showed severe motor and sensory neuropathy with very low amplitudes, markedly prolonged distal motor latencies and very slow motor nerve conduction velocities in the ulnar nerve. Needle electromyography detected fibrillations, positive sharp waves and complex repetitive discharges. High resolution sonography of the median nerve at the wrist showed a few enlarged fascicles with only moderately raised cross sectional area. Creatin kinase levels were constantly and significantly raised. Genetic testing revealed a homozygous large deletion in the SH3TC2 gene comprising exons 13 and 14 that had not been described before. Furthermore a second homozygous novel mutation (c.680+1G>T;p.?) was found in the DPYD gene. The same combination in heterozygous form was detected in the asymptomatic eight year old daughter. This newly described family with CMT4C broadens the spectrum of genetic causes and underlines the clinical variability of phenotypes as the absence of scoliosis does not exclude mutations in the SH3TC2 gene even in patients with severe disabling Azzedine et al., 2006 , Azzedine et al., 2016 , Varley et al., 2015 , Inherited Peripheral Neuropathies Mutation Database, 2016 .

Heterogeneity in kinesin function.

The kinesin family proteins are often studied as prototypical molecular motors; a deeper understanding of them can illuminate regulation of intracellular transport. It is typically assumed that they function identically. Here we find that this assumption of homogeneous function appears incorrect: variation among motors' velocities in vivo and in vitro is larger than the stochastic variation expected for an ensemble of "identical" motors. When moving on microtubules, slow and fast motors are persistently slow, and fast, respectively. We develop theory that provides quantitative criteria to determine whether the observed single-molecule variation is too large to be generated from an ensemble of identical molecules. To analyze such heterogeneity, we group traces into homogeneous sub-ensembles. Motility studies varying the temperature, pH and glycerol concentration suggest at least 2 distinct functional states that are independently affected by external conditions. We end by investigating the functional ramifications of such heterogeneity through Monte-Carlo multi-motor simulations.

Excitability and firing behavior of single slow motor axons transmitting natural repetitive firing of human motoneurons.

Excitability of motor axons is critically important for realizing their main function, i.e., transmitting motoneuron firing to muscle fibers. The present study was designed to explore excitability recovery and firing behavior in single slow axons transmitting human motoneuron firing during voluntary muscle contractions. The abductor digiti minimi, flexor carpi ulnaris, and tibialis anterior were investigated during threshold stimulation of corresponding motor nerves. Motor unit (MU) firing index in response to testing volleys evoking M-responses was used as a physiological measure of axonal excitability and its changes throughout a target interspike interval (ISI) were explored. It was shown that axons displayed an early irresponsive period (within the first ~2-5 ms of a target ISI) that was followed by a responsive period (for the next 5-17 ms of the ISI), in which MUs fired axonal doublets, and a later irresponsive period. At the beginning of the responsive period, M-responses showed small latency delays. However, since at that ISI moment, MUs displayed excitability recovery with high firing index, slight latency changes may be considered as a functionally insignificant phenomenon. The duration of axonal doublet ISIs did not depend on motoneuron firing frequencies (range 4.3-14.6 imp/s). The question of whether or not traditionally described axonal recovery excitability cycle is realistic in natural motor control is discussed. In conclusion, the present approach, exploring, for the first time, excitability recovery in single slow axons during motoneuron natural activation, can provide further insight into axonal firing behavior in normal states and diseases.NEW & NOTEWORTHY Excitability of single slow axons was estimated by motor unit firing index in response to motor nerve stimulation, and its changes throughout a target interspike interval were explored during transmitting human motoneuron natural firing. It was found that axons exhibited early irresponsive, responsive, and later irresponsive periods. Findings question whether the traditionally described axonal excitability recovery cycle is realistic in natural motor control.

Hereditary neuropathy with liability to pressure palsy in patients under 30 years old: Neurophysiological data and proposed electrodiagnostic criteria.

In young patients with mononeuropathy who lack family history and precipitating factors, hereditary neuropathy with liability to pressure palsy (HNPP) may be a possibility. Our objective is to propose neurophysiological criteria for HNPP in patients <30 years of age. We conducted a national multicenter retrospective clinical and neurophysiological study in patients under 30 with genetically confirmed HNPP. All of the 51 patients included in the study had at least 1 demyelinating pattern in 2 asymptomatic nerves, and 3 abnormalities were found in almost 90%, including slowed motor nerve conduction velocity across the elbow in at least 1 ulnar nerve (97.5%), increased distal motor latency (DML) in at least 1 fibular nerve (95.8%), and increased DML in both median nerves (89%). Age influenced DML slightly only in the fibular nerve. Dissemination of nerve involvement in HNPP incites to perform a complete nerve conduction study. including bilateral ulnar, fibular, and median nerves. Muscle Nerve 57: 217-221, 2018.

Human myosin VIIa is a very slow processive motor protein on various cellular actin structures

Human myosin VIIa (MYO7A) is an actin-linked motor protein associated with human Usher syndrome (USH) type 1B, which causes human congenital hearing and visual loss. Although it has been thought that the role of human myosin VIIa is critical for USH1 protein tethering with actin and transportation along actin bundles in inner-ear hair cells, myosin VIIa's motor function remains unclear. Here, we studied the motor function of the tail-truncated human myosin VIIa dimer (HM7AΔTail/LZ) at the single-molecule level. We found that the HM7AΔTail/LZ moves processively on single actin filaments with a step size of 35 nm. Dwell-time distribution analysis indicated an average waiting time of 3.4 s, yielding ∼0.3 s-1 for the mechanical turnover rate; hence, the velocity of HM7AΔTail/LZ was extremely slow, at 11 nm·s-1 We also examined HM7AΔTail/LZ movement on various actin structures in demembranated cells. HM7AΔTail/LZ showed unidirectional movement on actin structures at cell edges, such as lamellipodia and filopodia. However, HM7AΔTail/LZ frequently missed steps on actin tracks and exhibited bidirectional movement at stress fibers, which was not observed with tail-truncated myosin Va. These results suggest that the movement of the human myosin VIIa motor protein is more efficient on lamellipodial and filopodial actin tracks than on stress fibers, which are composed of actin filaments with different polarity, and that the actin structures influence the characteristics of cargo transportation by human myosin VIIa. In conclusion, myosin VIIa movement appears to be suitable for translocating USH1 proteins on stereocilia actin bundles in inner-ear hair cells.

The somatosensory-evoked potential in reaction time is gated and elicited earlier when the motor response to a somatosensory cue is faster.

The aim of this study was to investigate whether the somatosensory-evoked potential (SEP) is gated and elicited earlier when a motor response to a somatosensory stimulus is faster. In healthy humans, the left index finger and thumb were pinched in response to a somatosensory stimulus administered over the left median nerve. The SEP elicited by this stimulus when producing a fast motor response was compared with that when producing a slow motor response. The amplitudes of N18 and frontal P40 when producing a fast motor response were smaller than those when producing a slow motor response. The latencies of frontal P22 and P40 when producing a fast motor response were shorter than those when producing a slow motor response. These findings indicated that the responses of the primary sensory and frontal areas elicited by a somatosensory stimulus are gated and that the responses of the frontal areas elicited by this stimulus occur earlier when a motor response to this stimulus is faster. The enhanced efficiency or increased speed of the stimulus identification process may be related to the gating and early onset of the SEP components when producing a fast motor response.

Ischemic Sciatic Neuropathy in a Patient with Liposarcoma

Background Various etiologies are the causative agents for sciatic neuropathy. We present here a case of ischemic sciatic neuropathy in a patient with liposarcoma. Case report A 55-year-old woman presented with severe pain and weakness of the left leg. She had a history of recurred retroperitoneal liposarcoma, and was being administered chemotherapy. Examination revealed weakness in ankle dorsiflexion, plantar flexion and hamstring. Complaints also included dysesthesia, and numbness in the sole and dorsum of the foot. Nerve conduction study showed low compound muscle action potentials and slow motor conduction velocity of left peroneal and tibial nerves, with indiscernible sensory nerve action potentials of the left superficial peroneal and sural nerves. Computed tomography angiography revealed occlusion of the left common iliac artery. Commencement of intravenous infusion of heparin resulted in skin color change and progression of the weakness. Hence, the patient underwent an emergency thrombectomy. Conclusions Ischemia should be considered as a cause of sciatic neuropathy in cancer patients, which requires management with timely treatment. Key Words: Sciatic neuropathy; Liposarcoma; Ischemia