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1.
To investigate whether a period of 1 Hz repetitive transcranial magnetic stimulation (rTMS) over M1 preconditioned by tDCS improves bradykinesia of the upper limb in Parkinson’s disease (PD). Fifteen patients with PD performed index finger, hand tapping and horizontal pointing movements as well as reach-to-grasp movements with either hand before (baseline conditions) and after a period of 1 Hz rTMS preconditioned by (1) sham, (2) anodal or (3) cathodal tDCS over the primary motor cortex contralateral to the more affected body side. Movement kinematics was analysed using an ultrasound-based motion analyser at baseline, immediately after and 30 min after each stimulation session. Dopaminergic medication was continued. Compared to baseline, 1 Hz rTMS significantly increased the frequency of index finger and hand tapping as well as horizontal pointing movements performed with the contralateral hand. Movement frequency increased up to 40% over 30 min after cessation of the stimulation. Preconditioning with cathodal tDCS, but not with anodal tDCS, reduced the effectiveness of 1 Hz rTMS to improve tapping and pointing movements. There was no significant increase of movement frequencies of the ipsilateral hand induced by 1 Hz rTMS preconditioned by either tDCS session. Movement kinematics of reach-to-grasp movements were not significantly influenced by either stimulation session. In PD the beneficial effects of 1 Hz rTMS over the primary motor cortex on bradykinesia of simple finger, hand and pointing movements is reduced by preconditioning with cathodal tDCS, but not with anodal tDCS. Preconditioning with tDCS is a powerful tool to modulate the behavioural effect of 1 Hz rTMS over the primary motor cortex in PD.  相似文献   

2.
Sensorimotor integration in movement disorders.   总被引:9,自引:0,他引:9  
Although current knowledge attributes movement disorders to a dysfunction of the basal ganglia-motor cortex circuits, abnormalities in the peripheral afferent inputs or in their central processing may interfere with motor program execution. We review the abnormalities of sensorimotor integration described in the various types of movement disorders. Several observations, including those of parkinsonian patients' excessive reliance on ongoing visual information during movement tasks, suggest that proprioception is defective in Parkinson's disease (PD). The disturbance of proprioceptive regulation, possibly related to the occurrence of abnormal muscle-stretch reflexes, might be important for generating hypometric or bradykinetic movements. Studies with somatosensory evoked potentials (SEPs), prepulse inhibition, and event-related potentials support the hypothesis of central abnormalities of sensorimotor integration in PD. In Huntington's disease (HD), changes in SEPs and long-latency stretch reflexes suggest that a defective gating of peripheral afferent input to the brain might impair sensorimotor integration in cortical motor areas, thus interfering with the processing of motor programs. Defective motor programming might contribute to some features of motor impairment in HD. Sensory symptoms are frequent in focal dystonia and sensory manipulation can modify the dystonic movements. In addition, specific sensory functions (kinaesthesia, spatial-temporal discrimination) can be impaired in patients with focal hand dystonia, thus leading to a "sensory overflow." Sensory input may be abnormal and trigger focal dystonia, or defective "gating" may cause an input-output mismatch in specific motor programs. Altogether, several observations strongly support the idea that sensorimotor integration is impaired in focal dystonia. Although elemental sensation is normal in patients with tics, tics can be associated with sensory phenomena. Some neurophysiological studies suggest that an altered "gating" mechanism also underlies the development of tics. This review underlines the importance of abnormal sensorimotor integration in the pathophysiology of movement disorders. Although the physiological mechanism remains unclear, the defect is of special clinical relevance in determining the development of focal dystonia.  相似文献   

3.
It is well established clinically that rhythmic auditory cues can improve gait and other motor behaviors in Parkinson's disease (PD) and other disorders. However, the neural systems underlying this therapeutic effect are largely unknown. To investigate this question we scanned people with PD and age‐matched healthy controls using functional magnetic resonance imaging (fMRI). All subjects performed a rhythmic motor behavior (right hand finger tapping) with and without simultaneous auditory rhythmic cues at two different speeds (1 and 4 Hz). We used spatial independent component analysis (ICA) and regression to identify task‐related functional connectivity networks and assessed differences between groups in intra‐ and inter‐network connectivity. Overall, the control group showed greater intra‐network connectivity in perceptual and motor related networks during motor tapping both with and without rhythmic cues. The PD group showed greater inter‐network connectivity between the auditory network and the executive control network, and between the executive control network and the motor/cerebellar network associated with the motor task performance. We interpret our results as indicating that the temporal rhythmic auditory information may assist compensatory mechanisms through network‐level effects, reflected in increased interaction between auditory and executive networks that in turn modulate activity in cortico‐cerebellar networks.  相似文献   

4.
Sensory and motor systems interact closely during movement performance. Furthermore, proprioceptive feedback from ongoing movements provides an important input for successful learning of a new motor skill. Here, we show in humans that attention to proprioceptive input during a purely sensory task can influence subsequent learning of a novel motor task. We applied low-amplitude vibration to the abductor pollicis brevis (APB) muscle of eight healthy volunteers for 15 min while they discriminated either a small change in vibration frequency or the presence of a simultaneous weak cutaneous stimulus. Before and after the sensory attention tasks, we evaluated the following in separate experiments: (1) sensorimotor interaction in the motor cortex by testing the efficacy of proprioceptive input to reduce GABA(A)ergic intracortical inhibition using paired-pulse transcranial magnetic stimulation, and (2) how well the same subjects learned a ballistic thumb abduction task using the APB muscle. Performance of the vibration discrimination task increased the interaction of proprioceptive input with motor cortex excitability in the APB muscle, whereas performance in the cutaneous discrimination task had the opposite effect. There was a significant correlation between the integration of proprioceptive input in the motor cortex and the motor learning gain: increasing the integration of proprioceptive input from the APB increased the rate of motor learning and reduced performance variability, while decreasing proprioceptive integration had opposite effects. These findings suggest that the sensory attention tasks transiently change how proprioceptive input is integrated into the motor cortex and that these sensory changes drive subsequent learning behavior in the human motor cortex.  相似文献   

5.
Uncertainty exists on whether Parkinson's disease (PD) and essential tremor (ET) patients have similar degree of impairment during motor tasks. We investigated this problem by analyzing nonlinear dynamics of repetitive movements in 21 control subjects, 33 mild‐moderate PD patients, and 18 ET patients. Accelerometer signals were recorded during finger tapping and unbounded forearm movements between two points, and processed with moving average filtering to generate a new signal consisting of the temporal distance between consecutive cycles. We calculated: mean interpeak interval (slowness), interpeak interval variability (irregularity), and beat decay (BD) of the auto mutual information (AMI) value, which estimates signal predictability by measuring the loss of signal information over a timescale. Both PD and ET had longer interpeak interval (except for finger tapping), higher interpeak interval variability, and higher BD‐AMI values than controls (P ≤ 0.007, all comparisons). ET patients had higher BD‐AMI values than PD (P = 0.003). BD‐AMI was the parameter that discriminated better between subjects (diagnosis accuracies about 80%). No differences existed between PD patients with and without tremor or between PD or ET patients with different disease stages, for any parameter. Evaluation of nonlinear dynamics of oscillatory repetitive movements is a feasible and promising tool for studying movement physiology. Movement performance is more predictable in PD and ET than in controls, even in early disease stages. Slowness and irregularity of movement in PD and ET cannot be fully explained by tremor. Some common pathogenic mechanisms leading to bradykinesia may contribute to this impairment. © 2010 Movement Disorder Society  相似文献   

6.
Fourteen typically developing children from 7.9-11.3 years in age were studied with functional magnetic resonance imaging to identify the cerebral loci involved in performance of paced finger tapping by children. Each child performed two bimanual alternating paced finger-tapping tasks. In the first, paced finger tapping was conducted to external 3-Hz pacing provided by a metronome. In the second, the metronome was turned off and finger tapping continued while each child tried to maintain the 3-Hz rhythm by self pacing. Individual and group data were analyzed with statistical parametric mapping techniques that resulted in activation maps for the two tasks. Metronome tapping produced activation of the posterior regions of both superior temporal gyri, both primary sensorimotor cortices, anterodorsomedial cerebellum and supplementary motor area. Self-tapping resulted in recruitment of pre-supplementary motor area and cerebellum in addition to bilateral supplementary motor area and primary sensorimotor cortical activation. Bimanual alternating paced finger tapping performed by children activates a neural network involving primary motor cortex, supplementary motor area, and cerebellum. Posterior superior temporal gyrus may be important for encoding auditory information, and presupplementary motor area and midline cerebellum play an important role in self-paced finger tapping.  相似文献   

7.
IntroductionVisual and auditory cueing improve functional performance in Parkinson's disease (PD) patients. However, audiovisual processing shares many cognitive resources used for attention-dependent tasks such as communication, spatial orientation, and balance. Conversely, tactile cues (TC) may be processed faster, with minimal attentional demand, and may be more efficient means for modulating motor-cognitive performance. In this study we aimed to investigate the efficacy and limitations of TC for modulating simple (heel tapping) and more complex (walking) motor tasks (1) over a range of cueing intervals, (2) with/without a secondary motor task (holding tray with cups of water).MethodsTen PD patients (71 ± 9 years) and 10 healthy controls (69 ± 7 years) participated in the study. TCs was delivered through a smart phone attached to subjects' dominant arm and were controlled by a custom-developed Android application.ResultsPD patients and healthy controls were able to use TC to modulate heel tapping (F(3.8,1866.1) = 1008.1, p < 0.001), and partially modulate walking (F(3.5,1448.7) = 187.5, p < 0.001) tasks. In the walking task, PD patients modulated performance over a narrower range of cueing intervals (R2 = 0.56) than healthy controls (R2 = 0.84; group difference F(3.5,1448.7) = 8.6, p < 0.001). TC diminished synchronization error associated with performance of secondary motor task during walking in PD patients and healthy controls (main effect of Task (F(1,494) = 0.4; p = 0.527), Task X Group interaction (F(1,494) = 0.5; p = 0.493)).ConclusionThis study expands modalities of TC usage for movement modulation and motor-cognitive integration in PD patients. The smartphone TC application was validated as a user-friendly movement modulation aid.  相似文献   

8.
Moving and interacting with the world requires that the sensory and motor systems share information, but while some information about tactile events is preserved during sensorimotor transfer the spatial specificity of this information is unknown. Afferent inhibition (AI) studies, in which corticospinal excitability (CSE) is inhibited when a single tactile stimulus is presented before a transcranial magnetic stimulation pulse over the motor cortex, offer contradictory results regarding the sensory‐to‐motor transfer of spatial information. Here, we combined the techniques of AI and tactile repetition suppression (the decreased neurophysiological response following double stimulation of the same vs. different fingers) to investigate whether topographic information is preserved in the sensory‐to‐motor transfer in humans. We developed a double AI paradigm to examine both spatial (same vs. different finger) and temporal (short vs. long delay) aspects of sensorimotor interactions. Two consecutive electrocutaneous stimuli (separated by either 30 or 125 ms) were delivered to either the same or different fingers on the left hand (i.e. index finger stimulated twice or middle finger stimulated before index finger). Information about which fingers were stimulated was reflected in the size of the motor responses in a time‐constrained manner: CSE was modulated differently by same and different finger stimulation only when the two stimuli were separated by the short delay (= 0.004). We demonstrate that the well‐known response of the somatosensory cortices following repetitive stimulation is mirrored in the motor cortex and that CSE is modulated as a function of the temporal and spatial relationship between afferent stimuli.  相似文献   

9.
BOLD fMRI signal increases with age in selected brain regions in children   总被引:1,自引:0,他引:1  
To determine whether the BOLD signal used in fMRI is age dependent in childhood, 332 healthy children (age 4.9-18.9 years) performed tasks in a periodic block design during 3 T fMRI: (1) a verb generation task interleaved with a finger tapping task; (2) a word-picture matching task interleaved with an image discrimination task. Significant correlations between percent signal change in BOLD effect and age occurred in left Broca's, middle frontal, Wernicke's, and inferior parietal regions, and anterior cingulate during the verb generation task; in precentral, postcentral, middle frontal, supplementary motor, and precuneus regions during the finger tapping task; and in bilateral lingula gyri during the word-picture matching task. Thus, BOLD effect increases with age in children during sensorimotor and language tasks.  相似文献   

10.
Transcranial alternating current stimulation (tACS) has emerged as a promising tool for modulating cortical oscillations. In previous electroencephalogram (EEG) studies, tACS has been found to modulate brain oscillatory activity in a frequency‐specific manner. However, the spatial distribution and hemodynamic response for this modulation remains poorly understood. Functional magnetic resonance imaging (fMRI) has the advantage of measuring neuronal activity in regions not only below the tACS electrodes but also across the whole brain with high spatial resolution. Here, we measured fMRI signal while applying tACS to modulate rhythmic visual activity. During fMRI acquisition, tACS at different frequencies (4, 8, 16, and 32 Hz) was applied along with visual flicker stimulation at 8 and 16 Hz. We analyzed the blood‐oxygen‐level‐dependent (BOLD) signal difference between tACS‐ON vs tACS‐OFF, and different frequency combinations (e.g., 4 Hz tACS, 8 Hz flicker vs 8 Hz tACS, 8 Hz flicker). We observed significant tACS modulation effects on BOLD responses when the tACS frequency matched the visual flicker frequency or the second harmonic frequency. The main effects were predominantly seen in regions that were activated by the visual task and targeted by the tACS current distribution. These findings bridge different scientific domains of tACS research and demonstrate that fMRI could localize the tACS effect on stimulus‐induced brain rhythms, which could lead to a new approach for understanding the high‐level cognitive process shaped by the ongoing oscillatory signal.  相似文献   

11.
Oscillatory synchronization between somatosensory and motor cortex has previously been reported using field potential recordings, but interpretation of such results can be confounded by volume conduction. We examined coherence between single-unit discharge in somatosensory/parietal areas and local field potential from the same area as the unit, or from the motor cortex, in two macaque monkeys trained to perform a finger movement task. There were clear coherence peaks at approximately 17.5 Hz for cells in the primary somatosensory cortex (both proprioceptive and cutaneous areas) and posterior parietal cortex (area 5). The size of coherence in all areas was comparable to previous reports analysing motor cortical cells and M1 field potentials. Many coherence phases clustered around -pi/2 radians, indicating zero lag synchronization of parietal cells with M1 oscillatory activity. These results indicate that cells in somatosensory and parietal areas have information about the presence of oscillations in the motor system. Such oscillatory coupling across the central sulcus may play an important role in sensorimotor integration of both proprioceptive and cutaneous signals.  相似文献   

12.
OBJECTIVE: Recent transcranial magnetic stimulation (TMS) studies showed that the sensory input can decrease the motor cortex excitability (afferent inhibition). To clarify the effect of attention on sensorimotor integration, we investigated the effect of spatial attention on afferent inhibition. METHODS: Right median nerve electrical stimulation followed, at variable delays (10-300 ms), by TMS over the left motor cortex was applied to 9 subjects, during 3 conditions; spatial attention to the right and left hand, and control (no attention) tasks. RESULTS: Inhibition of the motor evoked potential occurred at inter-stimulus interval of 20 and 100 ms, which was more was marked during spatial attention to the right than to the left hand. CONCLUSIONS: Enhancement of the afferent inhibition induced by spatial attention to the stimulated side is likely to reflect the interaction between attention and sensorimotor integration. SIGNIFICANCE: The spatial attention may modulate the sensorimotor integration studied by afferent inhibition of the MEP.  相似文献   

13.
BackgroundIdiopathic rapid eye movement sleep behaviour (iRBD) is considered as a risk factor for Parkinson's disease (PD) development. Evaluation of repetitive movements with finger tapping, which serves as a principal task to measure the extent of bradykinesia in PD, may undercover potential PD patients. The aim of this study was to explore whether finger tapping abnormalities, evaluated with a 3D motion capture system, are already present in RBD patients.MethodsFinger tapping data was acquired using a contactless 3D motion capture system from 40 RBD subjects and compared to 25 de-novo PD patients and 25 healthy controls. Objective assessment of amplitude decrement, maximum opening velocity and their combination representing finger tapping decrement was performed in the sequence of the first ten tapping movements. The association between instrumental finger tapping data and semi-quantitative clinical evaluation was analyzed.ResultsWhile significant differences between PD and controls were found for all investigated finger tapping measures (p < 0.002), RBD differed from controls in finger tapping amplitude (p = 0.004) and velocity (p = 0.007) decrement but not in maximal opening velocity. A significant relationship between the motor score from the Movement Disorders Society - Unified Parkinson's Disease Rating Scale and finger tapping decrement was shown for both patient groups, ie RBD (r = 0.36, p = 0.02) and PD (r = 0.60, p = 0.002).ConclusionsIn our group of RBD patients we demonstrated amplitude decrement of repetitive movements, which may correspond with prodromal bradykinesia. Our findings suggest instrumental analysis of finger tapping abnormalities as a potential novel clinical marker reflecting subclinical motor disturbances in RBD.  相似文献   

14.
Bimanual movements involve the interactions between both primary motor cortices. These interactions are assumed to involve phase‐locked oscillatory brain activity referred to as inter‐hemispheric functional coupling. So far, inter‐hemispheric functional coupling has been investigated as a function of motor performance. These studies report mostly a negative correlation between the performance in motor tasks and the strength of functional coupling. However, correlation might not reflect a causal relationship. To overcome this limitation, we opted for an alternative approach by manipulating the strength of inter‐hemispheric functional coupling and assessing bimanual motor performance as a dependent variable. We hypothesize that an increase/decrease of functional coupling deteriorates/facilitates motor performance in an out‐of‐phase bimanual finger‐tapping task. Healthy individuals were trained to volitionally regulate functional coupling in an operant conditioning paradigm using real‐time magnetoencephalography neurofeedback. During operant conditioning, two discriminative stimuli were associated with upregulation and downregulation of functional coupling. Effects of training were assessed by comparing motor performance prior to (pre‐test) and after the training (post‐test). Participants receiving contingent feedback learned to upregulate and downregulate functional coupling. Comparing motor performance, as indexed by the ratio of tapping speed for upregulation versus downregulation trials, no change was found in the control group between pre‐ and post‐test. In contrast, the group receiving contingent feedback evidenced a significant decrease of the ratio implicating lower tapping speed with stronger functional coupling. Results point toward a causal role of inter‐hemispheric functional coupling for the performance in bimanual tasks. Hum Brain Mapp 38:4353–4369, 2017. © 2017 Wiley Periodicals, Inc.  相似文献   

15.
Abnormalities of cerebellar function have been implicated in the pathophysiology of schizophrenia. Since the cerebellum has afferent and efferent projections to diverse brain regions, abnormalities in cerebellar lobules could affect functional connectivity with multiple functional systems in the brain. Prior studies, however, have not examined the relationship of individual cerebellar lobules with motor and nonmotor resting‐state functional networks. We evaluated these relationships using resting‐state fMRI in 30 patients with a schizophrenia‐spectrum disorder and 37 healthy comparison participants. For connectivity analyses, the cerebellum was parcellated into 18 lobular and vermal regions, and functional connectivity of each lobule to 10 major functional networks in the cerebrum was evaluated. The relationship between functional connectivity measures and behavioral performance on sensorimotor tasks (i.e., finger‐tapping and postural sway) was also examined. We found cerebellar–cortical hyperconnectivity in schizophrenia, which was predominantly associated with Crus I, Crus II, lobule IX, and lobule X. Specifically, abnormal cerebellar connectivity was found to the cerebral ventral attention, motor, and auditory networks. This cerebellar–cortical connectivity in the resting‐state was differentially associated with sensorimotor task‐based behavioral measures in schizophrenia and healthy comparison participants—that is, dissociation with motor network and association with nonmotor network in schizophrenia. These findings suggest that functional association between individual cerebellar lobules and the ventral attentional, motor, and auditory networks is particularly affected in schizophrenia. They are also consistent with dysconnectivity models of schizophrenia suggesting cerebellar contributions to a broad range of sensorimotor and cognitive operations.  相似文献   

16.
Spinocerebellar ataxia 6 (SCA6) is a hereditary disease characterized by a trinucleotide repeat expansion in the CACNA1A gene and late‐onset bilateral cerebellar atrophy. It is unclear if there is significant pathology outside of the cerebellum. We used transcranial magnetic stimulation to assess sensorimotor cortical circuits and cortical plasticity in 8 SCA6 patients and 8 age‐matched controls. Behavioral performance was assessed using a rhythmic tapping task. Neurophysiological measures of SCA6 patients showed a prolonged cortical silent period (CSP) but normal MEP recruitment curve, short‐latency afferent inhibition, long‐latency afferent inhibition and ipsilateral silent period. Paired‐associative stimulation induction also increased motor‐evoked potentials normally. SCA6 patients had greater variability with cued rhythmic tapping than normals and deteriorated when the cue was removed; in comparison, normal subjects had similar variability between cued and uncued rhythmic tapping. Analysis using a Wing–Kristofferson timing model indicated that both clock variance and motor delay variance were abnormal. Conclusion. In SCA6, the circuits for sensorimotor integration and the mechanisms for LTP‐like plasticity in the sensorimotor cortex are unimpaired. A prolonged CSP in SCA6 just like in other cerebellar atrophies would suggest that this neurophysiological change typifies cerebellar dysfunction. © 2007 Movement Disorder Society  相似文献   

17.
This study examined sensorimotor integration and motor functioning in seven patients with Parkinson's disease (PD) who had mild symptoms, and seven age-matched controls. Neuro-oscillations were recorded by high-density 128-channel electroencephalography (EEG). Participants were required to perform two tasks: simple tapping of the index finger and thumb and a complex Luria finger apposition task. Both tasks were performed unimanually and bimanually. There were no significant group differences in the task-related power (TRPow) within alpha 1 (mu1) or in beta 1 frequencies (beta1). In contrast, there were significant group differences in the alpha 2 (mu2) and beta 2 frequencies (beta2). Patients had less desychronisation than controls at the electrodes covering the central regions of the scalp. Alpha 2 and beta 2 frequencies have been associated with task-specific sensorimotor integration and motor function, respectively. This activity difference in patients with Parkinson's disease may be due to deficits in sensorimotor integration.  相似文献   

18.
Parkinson's disease is associated with pathological oscillatory activity in a wide-range cerebral network of sensory and motor areas. A number of studies identified 5 Hz, 10 Hz and 20 Hz as predominant frequencies of oscillatory activity in this cerebral oscillatory network. Clinical evidence for the importance of the pathological oscillatory activity derives from studies showing modulation of motor deficits and cognitive performance during external stimulation of patients with Parkinson's disease at 5 Hz, 10 Hz and 20 Hz. Furthermore, high-frequency stimulation in the subthalamic nucleus successfully alleviates all cardinal motor deficits in Parkinson's disease probably by suppression of 5 Hz, 10 Hz and 20 Hz activity. However, the specific role of each of these frequencies so far remains unclear. The present commentary summarizes the current pathophysiological concepts of pathological oscillatory activity in Parkinson's disease and highlights the new ideas of modulatory intervention.  相似文献   

19.
Background – Hereditary spastic paraparesis (HSP) is a heterogeneous group of disorders characterized by progressive bilateral lower limb spasticity. Functional imaging studies in patients with corticospinal tract involvement have shown reorganization of motor circuitry. Our study investigates functional changes in sensorimotor brain areas in patients with HSP. Methods – Twelve subjects with HSP and 12 healthy subjects were studied. Functional magnetic resonance imaging (fMRI) was used to measure brain activation during right‐hand finger tapping. Image analysis was performed using general linear model and regions of interest (ROI)‐based approach. Weighted laterality indices (wLI) and anterior/posterior indicies (wAI and wPI) were calculated for predefined ROIs. Results and discussion – Comparing patients and controls at the same finger‐tapping rate (1.8 Hz), there was increased fMRI activation in patients’ bilateral posterior parietal cortex and left primary sensorimotor cortex. No differences were found when comparing patients and controls at 80% of their individual maximum tapping rates. wLI of the primary sensorimotor cortex was significantly lower in patients. Subjects with HSP also showed a relative increase in the activation of the posterior parietal and premotor areas compared with that of the primary sensorimotor cortex. Our findings demonstrate an altered pattern of cortical activation in subjects with HSP during motor task. The increased activation probably reflects reorganization of the cortical motor system.  相似文献   

20.
Autism spectrum disorder (ASD) often involves sensory and motor problems, yet the proprioceptive sense of limb position has not been directly assessed. We used three tasks to assess proprioception in adolescents with ASD who had motor and sensory perceptual abnormalities, and compared them to age- and IQ-matched controls. Results showed no group differences in proprioceptive accuracy or precision during active or passive tasks. Both groups showed (a) biases in elbow angle accuracy that varied with joint position, (b) improved elbow angle precision for active versus passive tasks, and (c) improved precision for a fingertip versus elbow angle estimation task. Thus, a primary proprioceptive deficit may not contribute to sensorimotor deficits in ASD. Abnormalities may arise at later sensory processing stages.  相似文献   

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