Motor-related Areas Research Articles

C-FOS and n-NOS reactive neurons in response to circulating Phoneutria nigriventer spider venom

Drugs and neurotoxins activate specific neural circuits by increasing or decreasing the formation and release of neurotransmitters, such as nitric oxide (NO), and by inducing immediate early genes, such as FOS. We have previously shown that Phoneutria nigriventer spider venom (PNV) impairs the microtubule-dependent transcellular barrier of the blood–brain interface and causes structural alterations in perivascular astrocytic end-feet without producing morphological changes in central neuronal cells. In the present study, we used FOS and neuronal nitric oxide synthase (n-NOS) immunolabeling to investigate the ability of PNV to activate the central nervous system. Three groups of rats were used: the first group received a sublethal dose of PNV (850 μg/kg, via a tail vein), the second received an equal volume of 0.9% saline (sham group) and the third group received no injection. Envenomed rats showed salivation, lachrymation, tremors and flaccidity followed by spastic paralysis of the hind limbs and convulsions. Cryosections (30 μm thick) were serially collected at 600 μm intervals for free-floating immunohistochemical analysis. FOS-like positive neurons predominated in motor-related areas such as dorsolateral (dlPAG) and ventral periaqueductal gray matter (vPAG), frontal (FCM) and parietal motor cortex (PCM), and periventricular thalamic nucleus (PTN) and in acute stress-related areas (rhinal cortex and lateral septal nuclei). The greatest relative increases in FOS-like positive neurons occurred in the vPAG, PCM and PTN motor-related areas. n-NOS-positive neurons predominated in the periventricular thalamic nuclei, followed by the dorsolateral periaqueductal gray matter and parietal cortex motor area. The marked activation of motor areas and, to a lesser extent, of acute stress-related areas suggested the involvement of neuronal pathways in these regions in the response to envenoming by PNV. In addition, the occurrence of n-NOS immunolabeling in some anatomical regions with FOS-like positive neurons suggests that NO may modulate the response to PNV in these regions.

Distinct neural correlates underlying two- and three-dimensional mental rotations using three-dimensional objects

Two strategies–motor and visual–are considered to be used for performing mental rotation. The former involves the functions of the motor-related areas of the brain, whereas the latter does not. It is known that subjects' experiences influence strategy selection during the mental rotation of three-dimensional (3D) shapes. However, it remains questionable as to whether the attributes of 3D objects enhance the motor-related activities. In this regard, using functional magnetic resonance imaging, we compared the brain activities during two types of mental rotations–two-dimensional (2D) and 3D rotations–using 3D objects. 2D rotation using 3D objects requires rotation in a screen plain, whereas 3D rotation requires in-depth rotation. Only 3D rotation implicitly requires subjects to construct and manipulate 3D images with visualizations of the hidden parts; this plays an important role in visuo-motor tasks such as preshaping. As a result, a wide area of the right superior parietal lobule (SPL) was activated in relation to a 2D rotation angle. Conversely, a wide area of the right dorsal premotor cortex (PMd) was activated in relation to a 3D rotation angle. The right PMd activity is related to visualization of the hidden parts of visual stimuli, which is required only for 3D rotation. This implies that task difficulty enhanced by rotation dimensionality is a major factor related to the selection of motor strategy. In addition, it implies that the right SPL and the right PMd play important roles in rotation imagery without visualization and in constructing and manipulating 3D images, respectively.

Gene expression analysis of motor-related areas and prefrontal area of the monkey neocortex

Gene expression analysis of motor-related areas and prefrontal area of the monkey neocortex

Cerebral correlates of the “Kohnstamm phenomenon”: An fMRI study

This paper addresses the issue of the central correlates of the “Kohnstamm phenomenon”, i.e. the long-lasting involuntary muscle contraction which develops after a prolonged isometric voluntary contraction. Although this phenomenon was described as early as 1915, the mechanisms underlying these post-effects are not yet understood. It was therefore proposed to investigate whether specific brain areas may be involved in the motor post-effects induced by either wrist muscle contraction or vibration using the fMRI method. For this purpose, experiments were carried out on the right wrist of 11 healthy subjects. Muscle activity (EMG) and regional cerebral blood flow were recorded during isometric voluntary muscle contraction and muscle vibration, as well as during the subsequent involuntary contractions (the post-effects) which occurred under both conditions. Brain activations were found to occur during the post-contraction and post-vibration periods, which were very similar under both conditions. Brain activation involved motor-related areas usually responsible for voluntary motor command (primary sensory and motor cortices, premotor cortex, anterior and posterior cingulate gyrus) and sensorimotor integration structures such as the posterior parietal cortex. Comparisons between the patterns of brain activation associated with the involuntary post-effects and those accompanying voluntary contraction showed that cerebellar vermis was activated during the post-effect periods whereas the supplementary motor area was activated only during the induction periods. Although post-effects originate from asymmetric proprioceptive inputs, they might also involve a central network where the motor and somatosensory areas and the cerebellum play a key role. In functional terms, they might result from the adaptive recalibration of the postural reference frame altered by the sustained proprioceptive inputs elicited by muscle contraction and vibration.

Heterarchical reinforcement-learning model for integration of multiple cortico-striatal loops: fMRI examination in stimulus-action-reward association learning

The brain's most difficult computation in decision-making learning is searching for essential information related to rewards among vast multimodal inputs and then integrating it into beneficial behaviors. Contextual cues consisting of limbic, cognitive, visual, auditory, somatosensory, and motor signals need to be associated with both rewards and actions by utilizing an internal representation such as reward prediction and reward prediction error. Previous studies have suggested that a suitable brain structure for such integration is the neural circuitry associated with multiple cortico-striatal loops. However, computational exploration still remains into how the information in and around these multiple closed loops can be shared and transferred. Here, we propose a "heterarchical reinforcement learning" model, where reward prediction made by more limbic and cognitive loops is propagated to motor loops by spiral projections between the striatum and substantia nigra, assisted by cortical projections to the pedunculopontine tegmental nucleus, which sends excitatory input to the substantia nigra. The model makes several fMRI-testable predictions of brain activity during stimulus-action-reward association learning. The caudate nucleus and the cognitive cortical areas are correlated with reward prediction error, while the putamen and motor-related areas are correlated with stimulus-action-dependent reward prediction. Furthermore, a heterogeneous activity pattern within the striatum is predicted depending on learning difficulty, i.e., the anterior medial caudate nucleus will be correlated more with reward prediction error when learning becomes difficult, while the posterior putamen will be correlated more with stimulus-action-dependent reward prediction in easy learning. Our fMRI results revealed that different cortico-striatal loops are operating, as suggested by the proposed model.

Pre-movement modulation of tibial nerve SEPs caused by a self-initiated dorsiflexion

Objective To investigate the centrifugal effect on somatosensory evoked potentials (SEPs), we recorded the pre-movement modulation of SEPs following stimulation of the tibial nerve caused by a self-initiated dorsiflexion. Methods SEPs following stimulation of the right tibial nerve at the popliteal fossa were recorded during self-initiated dorsiflexion of the right ankle every 5–7 s. Based on the onset of Bereitschaftspotential and negative slope, the preparatory period before dorsiflexion was divided into four sub-periods (pre-BP, BP1a, BP1b and BP2 sub-period), and SEPs in each sub-period were averaged. SEPs were also recorded in a stationary condition. Results P30, N40, P50 and N70 were identified at Cz in all subjects. The amplitude of P30 was significantly smaller in the BP2 sub-period than in the pre-BP sub-period. The N40 amplitude was significantly attenuated in the BP2 sub-period compared with the stationary condition, the pre-BP sub-period, the BP1a sub-period and the BP1b sub-period. Conclusions These results suggested that the motor-related areas involved in generating negative slope modulated the tibial nerve SEPs preceding a self-initiated contraction of the agonist muscle. Significance The centrifugal gating effect on SEPs extends to the somatosensory information from the antagonistic body part.

Language models based on Hebbian cell assemblies

This paper demonstrates how associative neural networks as standard models for Hebbian cell assemblies can be extended to implement language processes in large-scale brain simulations. To this end the classical auto- and hetero-associative paradigms of attractor nets and synfire chains (SFCs) are combined and complemented by conditioned associations as a third principle which allows for the implementation of complex graph-like transition structures between assemblies. We show example simulations of a multiple area network for object-naming, which categorises objects in a visual hierarchy and generates different specific syntactic motor sequences ("words") in response. The formation of cell assemblies due to ongoing plasticity in a multiple area network for word learning is studied afterwards. Simulations show how assemblies can form by means of percolating activity across auditory and motor-related language areas, a process supported by rhythmic, synchronized propagating waves through the network. Simulations further reproduce differences in own EEG&MEG experiments between responses to word- versus non-word stimuli in human subjects.

Aging is associated with contrasting changes in local and distant cortical connectivity in the human motor system

Pathophysiological changes in neurological and neuropsychiatric diseases are increasingly described in terms of abnormal network connectivity. However, the anatomical integrity and efficacy of connections among multiple brain regions change with aging, even in healthy adults. We combined low-frequency transcranial magnetic stimulation and positron emission tomography to study the age-related changes in regional activation and effective connectivity, associated with voluntary action by healthy adults between 22 and 68 years old. Contrasting effects of aging on the motor network were seen using analyses of regional activation, effective connectivity mediating task-related neuronal activation and effective connectivity in response to transcranial magnetic stimulation. Low-frequency rTMS reduced cerebral blood flow during both movement and resting conditions, at the site of stimulation and neighboring frontal cortex. Aging was associated with increased movement-related activation in premotor cortex, bilaterally. Increasing age also increased the susceptibility of the cortex to the inhibitory effects of rTMS, at the site of stimulation and its contralateral homologue. Moreover, older subjects showed enhanced local effective connectivity, centered on the left premotor cortex, but reduced effective connectivity between distant motor-related cortical areas. We discuss these results in relation to the HAROLD model of aging and propose that there are differential effects of aging on local and distributed neuronal subpopulations in the motor network. This differential effect of aging has important implications for the study of neurodegenerative and cerebrovascular diseases that primarily affect older people, as well as our understanding of the normal aging process.

Shift of activity from attention to motor-related brain areas during visual learning

With practice, we become increasingly efficient at visual object comparisons. This may be due to the formation of a memory template that not only binds individual features together to create an object, but also links the object with an associated response. In a longitudinal fMRI study of object matching, evidence for this link between perception and action was observed as a shift of activation from visual-attentive processing areas along the posterior intraparietal sulcus to hand-sensory and motor-related areas.

Sigma‐1 receptor as regulator of neuronal intracellular Ca2+: clinical and therapeutic relevance

Preserving brain function and cognitive faculties during aging and psychiatric diseases (e.g. psychotic, anxiety and affective disorders, dementia) is essential for the self-reliance and quality of life of patients. Cognitive loss involves not only memory, but also motor function. The decrease of catecholaminergic and excitatory neurotransmissions, as well as of protein phosphorylation, have currently been identified as prominent biological markers of the above-mentioned diseases. Such deleterious biological events are well known to occur downstream of a progressive decline of intracellular Ca2+ signalling. This latter constitutes a key target for the neuronal plasticity that has also been reported during aging and psychiatric disorders. Most of the medicines used in psychiatry are active on the sigma-1 receptor. This membrane bound receptor is widely distributed in memory-associated cortical and motor-related brainstem areas, prompting the hypothesis that it might contribute to the pathophysiology of these behavioural brain diseases. The sigma-1 receptor is characterized by a unique mode of action by regulating both Ca2+ entry at the plasma membrane level (i.e. via potassium channels, voltage-sensitive Ca2+ channels) and Ca2+ mobilization from endoplasmic stores [i.e. via Ins(1,4,5)P3 receptors]. This review presents recent data supporting the notion that drugs acting via the endoplasmic reticulum-coupled sigma-1 receptor might reverse these deleterious events by restoring both extra- and intra-cellular Ca(2+)-dependent neuronal responses.

Ipsilateral premotor activity in ALS

Sirs: We would like to thank the authors for their comments in which they point out that in their experiment they adjusted the motor task to the patient’s impaired abilities. Further, they criticize the fact that we only increased the difficulty of the task in the controls group but not in the ALS group thus preventing statistical separation of the factor “difficulty”. Finally, they believe their approach to adjust the force and the subjective effort in patients and controls to be advantageous compared with ours, in which we adjusted the error rates of the control group to match the patient group. Indeed, the way we quoted the work of Konrad et al. [2] is misleading since their task was adapted in that patients and controls performed at 10 % of their individual maximal force. Having equated the subjective effort feeling and having controlled for the pace of the motor task the authors compared the activations of patients and controls. In this way they found that motor activity in ALS was associated with additional recruitment of ipsilateral sensorimotor areas and increased cluster sizes. These findings were interpreted as a general pattern of reorganization in ALS in which enhanced recruitment of functionally related motor areas involved in initiation and planning occurs. Given the elevated age of the patients, the brisk ongoing neurodegenerative changes and the limited options with respect to the therapy, the question whether the cortex of ALS patients is subject to reorganization has a great importance for the development of treatment strategies. The experimental approaches to this question are related to a series of problems that have not yet been solved. Chief among those is that groups of patients with impaired motor abilities have to be compared with healthy controls. As mentioned above Konrad et al. [2] addressed this problem by having patients and controls performing at 10 % of their maximal force in a simple motor task. Our study [3] employed a different experimental strategy. In a first experiment we compared the hemodynamic activation patterns of patients and controls during exactly the same motor task. This revealed similar results to those reported by Konrad et al. [2] in which premotor areas were activated more in patients than in controls. Importantly, ipsilateral recruitment of premotor areas could only be observed in patients during this experiment. The behavioral data indicated that the motor task was much more difficult for patients than for controls at both difficulty levels of the experiment. In their comment the authors suggest that the patient data of our experiment can be interpreted as showing higher brain activation in premotor and cerebellar regions irrespective of the task difficulty. We disagree with this view. We rather believe that in patients the recruitment of brain areas was already involved close to ceiling during the easy difficulty level of the task. Therefore instead of reducing the difficulty in order to make it easier for the patients we have chosen to perform a second experiment in which controls performed in a modified version of the task, where the difficulty was increased. This involved their motor system in a comparable way to the patients resulting in nearly equal error rates. In this experiment the controls exhibited an activation pattern in which premotor ipsilateral and contralateral areas were recruited just as observed in the patient group in the previous experiment. Based on these findings we have suggested that functional motor compensation in ALS patients relies on existing mechanisms that are also used by controls depending on task difficulty. We agree with Konrad et al. on the importance of controlling variables such as the force of the executed movement and the subjective effort. Nevertheless, these variables can not explain the recruitment of ipsilateral areas as found in our experiments since it has been demonstrated that different levels of force do not change the degree of contralateral vs. ipsilateral sensorimotor cortex activation [1]. Therefore we are confident that the recruitment of ipsilateral premotor areas reflects a difficultydependent compensation mechanism that is not primarily developed following the lesion. At present we are far from understanding the neural correlates underlying reorganization and/or compensation processes during neurodegenerative diseases such as ALS. The rapidly advancing disease in a patient population of mid to elevated age with only very limited treatment options remains a big challenge for research and daily clinical work. It is to hope that LETTER TO THE EDITORS

Selective and interactive neural correlates of visual dimension changes and response changes

In an event-related fMRI study, we investigated the neural correlates of visual dimension and response changes. We used a compound task, which required target selection by a singleton feature, a unique color or motion direction, before the appropriate motor response, which was determined by target orientation, could be selected. Both types of change elicited distinct patterns of activation, with dimension-change-related activation primarily in posterior visual areas and response-related activation primarily in motor-related areas of the parietal and frontal cortices. Response-change-related activation was delayed by about 1 s relative to dimension-change-related activation, suggesting that the latter is elicited by perceptual processes, whereas the former reflects response-related or post-response processes. Although dimension changes and response changes rely on different processes, they are not independent: response facilitation was observed for combined dimension and response repetitions, this facilitation, however, was disrupted by dimension changes.

Shift of activity from attention to motor-related brain areas during visual learning

With practice, we become increasingly efficient at visual object comparisons. This may be due to the formation of a memory template that not only binds individual features together to create an object, but also links the object with an associated response. In a longitudinal fMRI study of object matching, evidence for this link between perception and action was observed as a shift of activation from visual-attentive processing areas along the posterior intraparietal sulcus to hand-sensory and motor-related areas.

Different Neural Correlates of Reward Expectation and Reward Expectation Error in the Putamen and Caudate Nucleus During Stimulus-Action-Reward Association Learning

To select appropriate behaviors leading to rewards, the brain needs to learn associations among sensory stimuli, selected behaviors, and rewards. Recent imaging and neural-recording studies have revealed that the dorsal striatum plays an important role in learning such stimulus-action-reward associations. However, the putamen and caudate nucleus are embedded in distinct cortico-striatal loop circuits, predominantly connected to motor-related cerebral cortical areas and frontal association areas, respectively. This difference in their cortical connections suggests that the putamen and caudate nucleus are engaged in different functional aspects of stimulus-action-reward association learning. To determine whether this is the case, we conducted an event-related and computational model-based functional MRI (fMRI) study with a stochastic decision-making task in which a stimulus-action-reward association must be learned. A simple reinforcement learning model not only reproduced the subject's action selections reasonably well but also allowed us to quantitatively estimate each subject's temporal profiles of stimulus-action-reward association and reward-prediction error during learning trials. These two internal representations were used in the fMRI correlation analysis. The results revealed that neural correlates of the stimulus-action-reward association reside in the putamen, whereas a correlation with reward-prediction error was found largely in the caudate nucleus and ventral striatum. These nonuniform spatiotemporal distributions of neural correlates within the dorsal striatum were maintained consistently at various levels of task difficulty, suggesting a functional difference in the dorsal striatum between the putamen and caudate nucleus during stimulus-action-reward association learning.

Motor-related cortical dynamics to intact movements in tetraplegics as revealed by high-resolution EEG.

We explored the cortical dynamics during movements of an unaffected body part in tetraplegic subjects with chronic spinal cord injury (SCI). The aims were to find out whether the intact movements were associated with a physiological time-varying pattern of activity in the motor-related cortical areas and whether the primary motor area (MI) activation followed a somatotopic distribution. Event-related potentials to self-initiated lip movements were analyzed by means of cortical source imaging of EEG recorded from seven tetraplegic subjects and seven control subjects. Regions of interest (ROIs) were selected on individual MRI and the time-varying electrophysiologic activity (cortical current density, CCD) was estimated on these ROIs and subjected to across-subject analysis. A significant, bilateral movement-related pattern of MI activation was detected during motor task execution in SCI patients as well as in controls. The site of local maxima activation displayed a symmetrical discrete distribution within MI, consistently with a putative somatotopic lip representation, in all the subjects. The supplementary motor area proper (SMAp) was always coactivated with MI and coactivation was characterized by a time course with typical premotion and motion phases over both motor areas. A clear-cut temporal delay between the SMAp and MI activation did not occur either in SCI patients or in controls. These findings obtained with noninvasive neuroelectrical source imaging document that in chronic SCI subjects "executive" motor areas are engaged with a preserved temporal and spatial pattern during preparation and execution of intact movements.

Linear correlation between fractal dimension of EEG signal and handgrip force

Fractal dimension (FD) has been proved useful in quantifying the complexity of dynamical signals in biology and medicine. In this study, we measured FDs of human electroencephalographic (EEG) signals at different levels of handgrip forces. EEG signals were recorded from five major motor-related cortical areas in eight normal healthy subjects. FDs were calculated using three different methods. The three physiological periods of handgrip (command preparation, movement and holding periods) were analyzed and compared. The results showed that FDs of the EEG signals during the movement and holding periods increased linearly with handgrip force, whereas FD during the preparation period had no correlation with force. The results also demonstrated that one method (Katz's) gave greater changes in FD, and thus, had more power in capturing the dynamic changes in the signal. The linear increase of FD, together with results from other EEG and neuroimaging studies, suggest that under normal conditions the brain recruits motor neurons at a linear progress when increasing the force.

Movement Quantity and Frequency Coding in Human Motor Areas

Studies of movement coding have indicated a relationship between functional MRI signals and increasing frequency of movement in primary motor cortex and other motor-related structures. However, prior work has typically used block-designs and fixed-time intervals across the varying movements frequencies that may prevent ready distinction of brain mechanisms related to movement quantity and, especially, movement frequency. Here, we obtained functional MRI signals from humans working in an event-related design to extract independent activation related to movement quantity or movement frequency. Participants tapped once, twice, or thrice at 1, 2, or 3 Hz, and the tapping evoked activation related to movement quantity in the precentral and postcentral gyri, supplementary motor area, cerebellum, putamen, and thalamus. Increasing movement frequency failed to yield activation in these motor-related areas, although linear movement frequency affects occurred in nonmotor regions of cortex and subcortex. Our results do not replicate prior data suggesting movement frequency encoding in motor-related areas; instead we observed movement quantity coding in motor-related brain areas. The discrepancy between prior studies and this study likely relates to methodology concerns. We suggest that the movement quantity relationships in human motor areas and encoding of movement frequency in nonmotor areas may reflect a functional anatomical substrate for mediating distinct movement parameters.

Changes in the centrifugal gating effect on somatosensory evoked potentials depending on the level of contractile force

In this study, we investigated the somatosensory evoked potentials (SEPs) during the preparatory period of self-initiated plantar flexion at different force levels of muscle contraction and elucidated the mechanism behind the centrifugal gating effect on somatosensory information processing. We recorded SEPs following stimulation of the tibial nerve at the popliteal fossa during the preparatory period of a 20% maximal voluntary contraction (MVC) and 50% MVC. The preparatory period was divided into two sub-periods based on the components of movement-related cortical potentials, the negative slope (NS sub-period) and the Bereitschaftspotential (BP sub-period). The subjects were instructed to concentrate on the movement and not to pay attention to the continuous electrical stimulation. Pre-movement SEPs were averaged separately during the two sub-periods under each MVC condition. The mean amplitudes of BP and NS were larger during the 50% MVC than the 20% MVC. As for the components of SEPs, during the NS sub-period the amplitude of P30 under the 50% MVC and N40 under both conditions were significantly smaller than that in the stationary sequence, and N40 amplitude was significantly smaller during the 50% MVC than the 20% MVC. During the BP sub-period, the amplitude of P30 and N40 during the 50% MVC was significantly smaller than during the stationary sequence, while it was not significantly different between the 20% and 50% MVCs. In conclusion, the extent of the centrifugal gating effect on SEPs was dependent on the activities of motor-related areas, which generated the NS and BP.

Neural Systems Underlying Observation of Humanly Impossible Movements: An fMRI Study

Previous studies have indicated that largely overlapping parts of a complex, mainly fronto-parietal, neural network are activated during both observation and execution of an action. If these two processes are inextricably linked, increases of neural activity contingent upon action observation should be found only for movements that can actually be performed. Using functional magnetic resonance imaging, we investigated whether observation of possible and biomechanically impossible movements of fingers activated the same neural systems. Thirteen healthy subjects were scanned during observation of video-clips showing abduction/adduction movements of the right index or the little finger, which were defined as biomechanically possible or impossible according to the range of their angular displacement at the metacarpo-phalangeal joint. The mere observation of possible and impossible hand movements induced a selective activation of left precentral and left inferior frontal regions, thus indicating that motor-related areas map body actions even when they violate the constraints of human anatomy. An increase of the blood oxygen level-dependent signal selectively linked to observation of impossible hand movements was found in sensorimotor parietal regions. Our results suggest that while premotor areas code human actions regardless of whether they are biologically possible or impossible, sensorimotor parietal regions may be important for coding the plausibility of actions.

Gating of SEPs by contraction of the contralateral homologous muscle during the preparatory period of self-initiated plantar flexion

To investigate the centrifugal change in somatosensory information processing caused by contraction of the contralateral homologous muscle, we recorded the somatosensory-evoked potentials (SEPs) during the preparatory period of a self-initiated plantar flexion. The SEPs following stimulation of the right tibial nerve at the popliteal fossa were recorded in nine healthy subjects. Self-initiated plantar flexion of the left ankle was performed once every 5 to 7 s. The electrical stimulation was delivered continuously, and the subjects were instructed to concentrate on the movement and not to pay attention to the electrical stimulation. Based on the components of movement-related cortical potential, Bereitschaftspotential (BP) and Negative slope (NS), the preparatory period was divided into four sub-periods (NS, BP-1, BP-2, and Pre-BP). To obtain pre-movement SEPs, the signals following stimulation in each sub-period were averaged. SEPs were attenuated in the preparatory period, especially in the NS sub-period. The amplitude of N40 component was significantly attenuated compared with that in the stationary state and other sub-periods. The amplitude of P53 and N70 was smaller in the NS sub-period than other pre-movement sub-periods. Since there was no centripetal effect on SEPs in the preparatory period, these findings suggested that the activity of motor-related areas modulated the somatosensory information from the contralateral non-movement limb (centrifugal gating). It was assumed that an inhibition on the somatosensory inputs from contralateral limb was caused by the projection via either the corpus callosum or ipsilateral cortico-cortical projections.