Distinct temporospatial interhemispheric interactions in the human primary and premotor cortex during movement preparation.

The preparation of a voluntary unimanual action requires sequential processing in bihemispheric motor areas. In both animals and humans, activity in the dorsal premotor cortex (PMd) ipsilateral to the moving hand has been demonstrated to precede ipsilateral primary motor cortex (M1) activity. We investigated with double-pulse transcranial magnetic stimulation how right-hemispheric motor areas (rM1, rPMd) modulate left M1 (lM1) during the preparatory period of a finger movement with the dominant right hand. We tested the hypothesis that the influence of higher order motor areas such as rPMd on lM1 (rPMd-lM1) precedes interhemispheric interactions between homologue primary motor areas (rM1-lM1). rPMd-lM1 showed modulation in the early and late phase of movement preparation, whereas the intrinsic state of inhibition between rM1-lM1 was only modulated in the late phase. The present results complement existing hierarchical models of cortical movement control by demonstrating temporospatially distinct involvement of interhemispheric interactions from PMd and M1 during movement preparation.

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title: Intermanual coordination: From behavioural principles to neural-network interactions
abstract: Locomotion in vertebrates and invertebrates has a long history in research as the most prominent example of interlimb coordination. However, the evolution towards upright stance and gait has paved the way for a bewildering variety of functions in which the upper limbs interact with each other in a context-specific manner. The neural basis of these bimanual interactions has been investigated in recent years on different scales, ranging from the single-cell level to the analysis of neuronal assemblies. Although the prevailing viewpoint has been to assign bimanual coordination to a single brain locus, more recent evidence points to a distributed network that governs the processes of neural synchronization and desynchronization that underlie the rich variety of coordinated functions. The distributed nature of this network accounts for disruptions of interlimb coordination across various movement disorders.

title: Functional coupling of human cortical sensorimotor areas during bimanual skill acquisition.
abstract: Bimanual co-ordination of skilled finger movements is a high-level capability of the human motor system and virtually always requires training. Little is known about the physiological processes underlying successful bimanual performance and skill acquisition. In the present study, we used task-related coherence (TRCoh) and task-related power (TRPow) analysis of multichannel surface EEG to investigate the functional coupling and regional activation of human sensorimotor regions during bimanual skill acquisition. We focused on changes in interhemispheric coupling associated with bimanual learning. TRCoh and TRPow were estimated during the fusion of two overlearned unimanual finger-tapping sequences into one novel bimanual sequence, before and after a 30-min training period in 18 normal volunteers. Control experiments included learning and repetition of complex and simple unimanual finger sequences. The main finding was a significant increase in interhemispheric TRCoh selectively in the early learning stage (P < 0.0001). Interhemispheric TRCoh was also present during the unimanual control tasks, but with lower magnitude, even if learning was involved. Training improved bimanual sequence performance (from 58.3+/-24.1 to 83.7+/-15.3% correct sequences). After training, interhemispheric (bimanual) TRCoh decreased again, thereby approaching levels similar to those in the unimanual controls. We propose that the initial increase in TRCoh reflects changes in interhemispheric communication that are specifically related to bimanual learning and may be relayed through the corpus callosum. The present data might also offer a neurophysiological explanation for the clinical observation that patients with lesions of the corpus callosum may show deficits in the acquisition of novel bimanual tasks but not necessarily in the execution of previously learned bimanual activities.

title: Neural interactions between motor cortical hemispheres during bimanual and unimanual arm movements
abstract: Cortico‐cortical connections through the corpus callosum are a major candidate for mediating bimanual coordination. However, aside from the deficits observed after lesioning this connection, little positive evidence indicates its function in bimanual tasks. In order to address this issue, we simultaneously recorded neuronal activity at multiple sites within the arm area of motor cortex in both hemispheres of awake primates performing different bimanual and unimanual movements. By employing an adapted form of the joint peri‐stimulus time histogram technique, we discovered rapid movement‐related correlation changes between the local field potentials (LFPs) of the two hemispheres that escaped detection by time‐averaged cross‐correlation methods. The frequency and amplitude of dynamic modifications in correlations between the hemispheres were similar to those within the same hemisphere. As in previous EEG studies, we found that, on average, correlation decreased during movements. However, a subset of recording site pairs did show transiently increased correlations around movement onset (57% of all pairs and conditions in monkey G, 39% in monkey P). In interhemispheric pairs, these increases were consistently related to the mode of coupling between the two arms. Both the correlations between the movements themselves and the interhemispheric LFP correlation increases were strongest during bimanual symmetric movements, and weaker during bimanual asymmetric and unimanual movements. Increased correlations occurred mainly around movement onset, whilst decreases in correlation dominated during movement execution. The task‐specific way in which interhemispheric correlations are modulated is compatible with the notion that interactions between the hemispheres contribute to behavioural coupling between the arms.

title: Bimanual coordination and interhemispheric interaction.
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title: Transitions between dynamical states of differing stability in the human brain
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title: Dynamics of hemispheric specialization and integration in the context of motor control
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title: Coordination constraints during bimanual versus unimanual performance conditions
abstract: Coordinated behaviour is prominent during daily life activities in various combinations and degrees of complexity. Here the influence of coordination constraints upon motor behaviour is evaluated by contrasting two-finger tapping (in-phase and anti-phase) during bimanual and unimanual conditions. Cortical dynamics was assessed by means of EEG coherence in the beta frequency band (13-30 Hz) and included intrahemispheric, interhemispheric and midline connectivity patterns. Results showed that intrahemispheric connectivity varied strongly in the different coordination tasks, with left hemisphere dominance for bimanual and right hand coordination versus right hemisphere dominance for left hand coordination. Interhemispheric connectivity was fairly similar across coordination tasks, except for the bimanual in-phase configuration that comprised the lowest coherence scores. Midline connectivity was equivalent across coordination tasks, with exception of the bimanual anti-phase assignment that was characterized with increased coherence scores. Across connectivity regions, the lowest coherence scores were obtained for bimanual and right hand coordination performed in the in-phase mode, underlining their basic mode of functioning. Furthermore by evaluating the coordination effort, estimated by the discrepancy between the coordination task and the sum of the individual components, an increased processing for intrahemispheric and midline connections was observed, but not for interhemispheric connections, which supports the general significance of interhemispheric communication for voluntary movement. Overall the current findings indicate a dynamic modulation of functional connectivity patterns according to the coordinative context. It suggests that brain regions within a motor network flexibly couple and decouple to implement the processing requirements associated with coordinated behaviour.

title: The premotor cortex of the monkey
abstract: The relationship of single unit activity to limb movements guided by visuospatial cues supports the view that the premotor cortex is a distinct cortical field within the somatic sensorimotor cortex. The premotor cortex is similar to the precentral motor cortex (MI) in that most of its units are clearly related to voluntary movements but differs from MI by its higher threshold for microstimulation-evoked movements, its cytoarchitecture, and the presence of a larger population of neurons with activity related to the occurrence of visuospatial signals rather than, or in addition to, the movement cued by those signals.

title: Reaching movements with similar hand paths but different arm orientations. II. Activity of individual cells in dorsal premotor cortex and parietal area 5.
abstract: Reaching movements with similar hand paths but different arm orientations. II. Activity of individual cells in dorsal premotor cortex and parietal area 5.  2413-2426, 1997. Neuronal activity in primary motor cortex (MI) is altered when monkeys make reaching movements along similar handpaths at shoulder level with two different arm orientations, either in the natural orientation with the elbow positioned below the level of the shoulder and hand or in an abducted orientation with the elbow abducted nearly to shoulder level. The present study examines to what degree two other cortical areas, the dorsal premotor (PMd) and parietal area 5, also show modulation of cell activity related to arm geometry during reaching. The activity of most (89%) of the 207 cells in PMd recorded while monkeys made reaching movements showed a statistically significant change in activity between orientations [analysis of variation (ANOVA), P < 0.01]. A common effect of arm orientation on cell activity was a change in the overall level of discharge either before, during, and/or after movement (67%, ANOVA, task main effect, P < 0.01). Many cells (76%) showed a statistical change in their response to movement direction (ANOVA, task x direction interaction term, P < 0.01), including changes in dynamic range and changes in the preferred direction of cells that were directionally tuned in both arm orientations. Overall, these effects were similar qualitatively but not as strong quantitatively as those observed in MI. A sample of cells was recorded in area 5 of one monkey. Most (95%) of the 79 area 5 cells showed a change in activity when reaching movements were performed using different arm orientations (ANOVA, P < 0.01). As in PMd and MI, many area 5 cells (56, 71%) showed changes in their tonic discharge before, during, and/or after movement, and 70 cells (89%) showed changes in their response to movement direction (ANOVA, task x direction interaction term, P < 0.01). The observed changes in neuronal activity related to posture and movement in MI, PMd and area 5 demonstrate that single-cell activity in these cortical areas is not simply related to the spatial attributes of hand trajectory but is also strongly influenced by attributes of movement related to arm geometry.

title: Temporary interference in human lateral premotor cortex suggests dominance for the selection of movements. A study using transcranial magnetic stimulation.
abstract: It is known that damage to the left hemisphere can lead to movement deficits, and that patients with apraxia have difficulty in selecting movements. Neurophysiological recording studies and lesion studies have shown that the premotor cortex is important for the selection of movements in monkeys. In this study we used transcranial magnetic stimulation (TMS) to disrupt the processing in human premotor cortex. We applied TMS to normal healthy volunteers over the premotor and primary motor areas while they carried out choice reaction time and simple reaction-time tasks. We measured response times of either hand as subjects were stimulated over the left and right hemisphere separately. We found that we were able to delay responses by stimulating at short cue-stimulus intervals (100-140 ms) over premotor cortex and at longer cue-stimulus intervals (300-340 ms) over primary motor cortex while subjects performed the choice reaction-time task with the contralateral hand. We were also able to delay responses with the ipsilateral hand while stimulating over the left premotor cortex, but not while stimulating over the right premotor cortex or either sensorimotor cortex. Premotor cortex stimulation alone disrupts an early stage of movement selection; motor cortex stimulation disrupts the movements at a later stage of execution. There was no distinguishing short cue-stimulus interval effect when premotor cortex was stimulated in the simple reaction time paradigm, where the movement selection demands of the task are kept to a minimum. We conclude that the premotor cortex is important for selecting movements after a visual cue and that the left hemisphere is dominant for the rapid selection of action.

title: The left parietal and premotor cortices: motor attention and selection
abstract: It is well established that the premotor cortex has a central role in the selection of movements. The role of parts of the parietal cortex in movement control has proved more difficult to describe but appears to be related to the preparation and the redirection of movements and movement intentions. We have referred to some of these processes as motor attention. It has been known since the time of William James that covert motor attention can be directed to an upcoming movement just as visuospatial attention can be directed to a location in space. While some parietal regions, particularly in the right hemisphere, are concerned with covert orienting and the redirecting of covert orienting it may be useful to consider other parietal regions, in the anterior inferior parietal lobule and in the posterior superior parietal lobule, particularly in the left hemisphere, as contributing to motor attention. Such parts of the parietal lobe are activated in neuroimaging experiments when subjects covertly prepare movements or switch intended movements. Lesions or transcranial magnetic stimulation (TMS) affect the redirecting of motor attention. The difficulties apraxic patients experience when sequencing movements may partly be due to an inability to redirect motor attention from one movement to another. The role of the premotor cortex in selecting movements is also lateralized to the left hemisphere. Damage to left hemisphere movement selection mechanisms may also contribute to apraxia. If, however, it remains intact after a stroke then the premotor cortex may contribute to the recovery of arm movements. A group of patients with unilateral left hemisphere lesions and impaired movements in the contralateral right hand was studied. Functional magnetic resonance imaging showed that in some cases the premotor cortex in the intact hemisphere was more active when the stroke-affected hand was used. TMS in the same area in the same patients had the most disruptive effect on movements. In summary, patterns of motor impairment and recovery seen after strokes can partly be explained with reference to the roles of the parietal and premotor cortices in motor attention and selection.

title: Functional specialization in dorsal and ventral premotor areas.
abstract: The premotor cortex (PM) in the bilateral lateral hemisphere of nonhuman primates and the human has been implicated in the sensorial guidance of movements. This is in contrast to more medial motor areas that are involved more in the temporal structuring of movements based on memorized information. The PM is further subdivided into dorsal (PMd) and ventral (PMv) parts. In this chapter, we describe our attempts to find differences in the use of these two areas in a nonhuman primate for programming future motor actions based on visual signals. We show that neurons in the PMv are involved primarily in receiving visuospatial signals and in specifying the spatial location of the target to be reached. In contrast, neurons in the PMd are involved more in integrating information about which arm to use and the target to be reached. Thus, PMd neurons are more implicated than those of the PMv in the preparation for a future motor action.

title: Neural Correlates of Reaching Decisions in Dorsal Premotor Cortex: Specification of Multiple Direction Choices and Final Selection of Action
abstract: We show that while a primate chooses between two reaching actions, its motor system first represents both options and later reflects selection between them. When two potential targets appeared, many (43%) task-related, directionally tuned cells in dorsal premotor cortex (PMd) discharged if one of the targets was near their preferred direction. At the population level, this generated two simultaneous sustained directional signals corresponding to the current reach options. After a subsequent nonspatial cue identified the correct target, the corresponding directional signal increased, and the signal for the rejected target was suppressed. The PMd population reliably predicted the monkey's response choice, including errors. This supports a planning model in which multiple reach options are initially specified and then gradually eliminated in a competition for overt execution, as more information accumulates.

title: The primate premotor cortex: past, present, and preparatory.
abstract: The concept of a separate premotor cortical field involved in the cerebral control of movement went out of favor among neurophysiologists during the quarter century from 1952 to 1977, but recent studies have led to its rehabilitation. The premotor cortex appears to be one of at least three fields within the motor cortex, two others being the primary motor cortex and the supplementary motor cortex. Several proposals have been presented concerning the functional specializations of the premotor cortex. Although no specific hypotheses have very strong support at present, the best evidence favors a role for premotor cortex in the preparation for and the sensory guidance of movement.

title: Premotor and parietal cortex: corticocortical connectivity and combinatorial computations.
abstract: The dorsal premotor cortex is a functionally distinct cortical field or group of fields in the primate frontal cortex. Anatomical studies have confirmed that most parietal input to the dorsal premotor cortex originates from the superior parietal lobule. However, these projections arise not only from the dorsal aspect of area 5, as has long been known, but also from newly defined areas of posterior parietal cortex, which are directly connected with the extrastriate visual cortex. Thus, the dorsal premotor cortex receives much more direct visual input than previously accepted. It appears that this fronto-parietal network functions as a visuomotor controller-one that makes computations based on proprioceptive, visual, gaze, attentional, and other information to produce an output that reflects the selection, preparation, and execution of movements.

title: Distinctions between dorsal and ventral premotor areas: anatomical connectivity and functional properties
abstract: The dorsal and ventral premotor areas, together with the primary motor cortex, are believed to have major roles in preparing and executing limb movements. Recent studies have expanded our knowledge of the dorsal and ventral premotor areas, which occupy the lateral part of area 6 in the frontal cortex. It is becoming clear that these two premotor areas, through involvement in distinct cortical networks, take part in unique aspects of motor planning and decision making. New lines of evidence also implicate the lateral premotor areas in planning motor behavior and selecting actions.

title: Movement-related cortical potentials.
abstract: Movement-related cortical potentials represent averaged electroencephalographic activity before and after a voluntary movement. They begin with a slowly rising negativity, called the Bereitschaftspotential (BP), and progress to a steeper, later negativity starting about 400 msec before the onset of movement, called the negativity slope (NS'). They are followed by the motor potential, which is seen partly before and partly after the movement. The initial slope of motor potential (isMP) occurs just before the onset of electromyographic (EMG) activity, is focal topographically over the primary motor cortex, and probably represents activation of the primary motor cortex. This contralateral focal negativity persists for 30 to 50 msec after the onset of EMG activity, when it then drops off in the central and parietal regions, an event called the parietal peak of motor potential (ppMP). Subsequently, the peak negativity shifts toward the anterior contralateral area, where it reaches the highest negativity of the recording, called the frontal peak of motor potential (fpMP). The fpMP appears to represent feedback from the movement and may originate, in part, from the supplementary motor area. In patients with congenital mirror movements, the isMP occurs bilaterally. In patients with Parkinson's disease and cerebellar disease, the isMP is more diffuse and the fpMP is more posterior than normal. Movement-related cortical potentials are useful research tools, but are not yet appropriate for clinical applications.

title: Interregional long-range and short-range synchrony: a basis for complex sensorimotor processing.
abstract: Communication of distant brain areas provides the basis for integration of complex information in order to adapt to changes in the environment, to process this information, and to generate appropriate behavioral responses necessary for successful behavior in daily life. How is interregional communication realized in the brain? Perceptions and actions are likely to be represented in the brain by large numbers of distributed neurons firing in synchrony. This synchronous activity of distributed neuronal networks can be noninvasively evaluated by multichannel surface electroencephalography (EEG) and the event-related analysis of synchronous EEG signals in the frequency domain. In this chapter we will discuss the role of interregional synchronous activity and its relevance as a mechanism for implementation of successful human complex behavior exemplified within studies of complex finger movements, context-dependent control of complex motor behavior, bimanual motor tasks, visuo-tactile integration, and recovery of motor functions after stroke. These studies provide evidence that synchronous interregional neuronal activity, determined by event-related synchronization (ERS) and desynchronization (ERD), task-related power increases (TRPI) and decreases (TRPD), and event- and task-related coherence (ERCoh, TRCoh) analysis, is one important mechanism for cortical implementation of successful human complex behavior and adaptation to changes in daily life. These results are discussed in the light of recent findings in animal models, substantiating the view of the relevance of interregional synchronous activity for information coding and control of behavior.

title: Bereitschaftspotential and movement‐related potentials: Origin, significance, and application in disorders of human movement
abstract: The existence of a slow negative wave, the Bereitschaftspotential (“BP”), preceding voluntary movement by 1 second or more was first reported more than 40 years ago. There appears to be considerable interindividual differences, but there is general agreement that the initial negativity actually consists of two distinct phases. Uncertainty remains about many other properties and features of the response, including nomenclature, which makes the existing literature difficult to synthesize. The duration of the premovement negativity raises questions about how and when voluntary movement is initiated. Premovement negativities can also be seen before (predictably) externally paced movement, and these have similarities to the BP. Although lateralized generators exist, it is likely that the majority of the early component of the BP (BP1 or early BP), arises from the anterior supplementary motor area (SMA) and more rostral pre‐SMA. The late phase of the BP (BP2 or late BP) is probably generated by activity in both the SMA proper and the contralateral motor cortex. Changes in the BP occur in several movement disorders, notably Parkinson's disease, in which the pattern is consistent with a failure of pre‐SMA activation. The presence (or absence) of a clear preceding negativity can also have diagnostic importance for certain movement disorders.

title: A neurophysiological study of the premotor cortex in the rhesus monkey.
abstract: The frontal agranular cortex consists of at least three major subdivisions: the precentral motor cortex, the supplementary motor cortex, and the premotor cortex. Of these, the premotor cortex is by far the least intensively studied by neurophysiological methods in spite of recent evidence that it is important in higher order aspects of the cerebral control of movement ( Moll and Kuypers , 1977; Roland et al., 1980b ; Halsband and Passingham , 1982). We have accordingly studied neuronal activity in the premotor cortex of Rhesus macaques operantly conditioned to perform a visually guided motor task. We have concluded that many premotor cortex neurons appear to reflect motor set. Further, these and other premotor cortex neurons show activity patterns during and before the execution of an abstractly guided movement that are strikingly similar to what has been observed in association with movements made directly to visuospatial targets. Finally, a functional relationship of some premotor cortex unit activity to the execution of voluntary movement is supported by its close temporal correlation with the onset of movement, a significant correlation with the acceleration of the limb in some cases, and a uniform specificity for movement execution rather than the visuospatial cues that guide the movement.

title: Premotor cortex neurons in macaques: activity before distal and proximal forelimb movements
abstract: Single unit activity was examined in the premotor cortex of three awake, behaving macaque monkeys. Premotor cortex (PM) neurons were found to be active in association with a movement involving specifically the distal forelimb. Other PM neurons were active in relation to more proximal forelimb movements. The spatial distribution of neurons related to distal movements differed from that of neurons related to proximal forelimb movements, the former being focused at a postarcuate region near the genu of the arcuate sulcus and the latter being shifted more posteromedially. The distal movement was triggered by one of the three sensory signals: visual, auditory, and vibrotactile. Of 190 PM neurons related to the distal forelimb movements, 123 (65%) showed similar premovement activity changes irrespective of the modality of the triggering signal. However, a number of neurons (35%) responded preferentially to one or two of the three signals. The modality-specific activity before movements distinguishes PM from the caudally adjacent primary motor cortex.

title: Neuronal activity in cortical motor areas related to ipsilateral, contralateral, and bilateral digit movements of the monkey.
abstract: 1. Single cell activity was studied in the precentral (PCM), premotor (PM), and supplementary (SMA) motor cortex of the monkey to compare magnitudes of activity changes in relation to ipsilateral, contralateral, and bilateral digit movements. 2. Three Japanese monkeys were trained to press a small key with the right or left hand, or with both hands, in accordance with visual instruction signals given 2.6-5.4 s before a visual movement-trigger signal. Great care was taken to train the animal to use only the required part of the limb. As a result of extensive training, electromyographic (EMG) studies revealed that muscle activities before the key press were limited to the digit and hand muscles of the limb instructed to move. No overt increase or decrease in activity was detectable in the proximal limb or body muscles in relation to the key-press movements or instructions. 3. Even though the movement was thus limited to distal forelimb, distinct ipsilateral relationships were observed in 8.2% of the task-related PCM neurons. They changed their activity before ipsilateral and bilateral (but not before contralateral) key press. 4. A majority of the neurons recorded from the digit area of PCM (mostly limited to the anterior bank of the central sulcus) exhibited a contralateral relationship; namely the activity increased or decreased before the onset of the contralateral and bilateral key-press movements. In most of them, the magnitudes of the activity changes before the contralateral and bilateral movements were similar. 5. In proximal limb and trunk areas of PCM and also in the somatosensory cortex, no neurons were found to exhibit distinct relations to any of the key-press movements. 6. In both SMA and PM, a number of neurons exhibited relationships of the type never or only rarely observed in the primary motor cortex. Thirty-seven percent of SMA and 62% of PM neurons exhibited premovement activity changes before all of the key-press movements. The movement-specific type of activity was observed in 28% of SMA and 16% of PM neurons. In these neurons, the activity changes were observed in relation to only one of the right or left key-press movements or exclusively in relation to the bilateral key press. Neuronal activity resembling the majority of the PCM neurons (contralateral type) was observed in 31% of SMA and 13% of PM neurons. 7. Instruction-induced changes in activity were more often found in the secondary than in the primary motor area.(ABSTRACT TRUNCATED AT 400

title: Neuronal activity in the primate supplementary, pre-supplementary and premotor cortex during externally and internally instructed sequential movements
abstract: This study recorded the activity of neurons in the (i) supplementary motor area (SMA), (ii) pre-SMA (the motor area immediately rostral to the SMA), (iii) premotor cortex (PMC) and (iv) primary motor cortex (MI), while the monkey performed a conditional sequential motor task that ensures sequencing of multiple movements to the same manipulandum. This paradigm was chosen in order to prevent the participation of spatial cues in prompting the correct motor sequence. Three different movements (turn-push-pull) were performed under two task conditions: (i) internally determined (I): the monkey had to generate a pre-determined sequence from memory and without visual guidance; (ii) externally triggered (E): the correct sequence of movements was performed by following lights illuminated one after the other. Neuronal activity during the following periods were analyzed: instruction (300 ms following the onset of the auditory instruction signal); delay (interval between the end of the instruction period or the termination of the previous movement and the movement trigger); premovement (interval between the trigger signal and the movement onset); movement (interval between the mechanically-sensed movement onset and the completion of the movement) and reward (500 ms period centered at the time of reward delivery). Pre-SMA neurons were generally more active during the delay and premovement as compared to the movement, instruction and reward periods. Activity in the pre-SMA was more related to E during the pre-movement period, but exhibited a preferential relationship to I in the movement period. SMA neurons were more active when the sequential motor task was internally generated.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Human cortical activity related to unilateral movements. A high resolution EEG study
abstract: IN the present study a modern high resolution electroencephalography (EEG) technique was used to investigate the dynamic functional topography of human cortical activity related to simple unilateral internally triggered finger movements. The sensorimotor area (M1- S1) contralateral to the movement as well as the supplementary motor area (SMA) and to a lesser extent the ipsilateral M1-S1 were active during the preparation and execution of these movements. These findings suggest that both hemispheres may cooperate in both planning and production of simple unilateral volitional acts.

title: Functional coupling and regional activation of human cortical motor areas during simple, internally paced and externally paced finger movements.
abstract: We studied the activation and interaction of cortical motor regions during simple, internally paced and externally paced right-hand finger extensions in healthy volunteers. We recorded EEGs from 28 scalp electrodes and analysed task-related coherence, task-related power and movement-related cortical potentials. Task-related coherence reflects inter-regional functional coupling of oscillatory neuronal activity, task-related power reflects regional oscillatory activity of neuronal assemblies and movement-related cortical potentials reflect summated potentials of apical dendrites of pyramidal cells. A combination of these three analytical techniques allows comprehensive evaluation of different aspects of information processing in neuronal assemblies. For both externally and internally paced finger extensions, movement-related regional activation was predominant over the contralateral premotor and primary sensorimotor cortex, and functional coupling occurred between the primary sensorimotor cortex of both hemispheres and between the primary sensorimotor cortex and the mesial premotor areas, probably including the supplementary motor area. The main difference between the different types of movement pacing was enhanced functional coupling of central motor areas during internally paced finger extensions, particularly inter-hemispherically between the left and right primary sensorimotor cortexes and between the contralateral primary sensorimotor cortex and the mesial premotor areas. Internally paced finger extensions were also associated with additional regional (premovement) activation over the mesial premotor areas. The maximal task-related coherence differences between internally and externally paced finger extensions occurred in the frequency range of 20-22 Hz rather than in the range of maximal task-related power differences (9-11 Hz). This suggests that important aspects of information processing in the human motor system could be based on network-like oscillatory cortical activity and might be modulated on at least two levels, which to some extent can operate independently from each other: (i) regional activation (task-related power) and (ii) inter-regional functional coupling. We propose that internal pacing of movement poses higher demands on the motor system than external pacing, and that the motor system responds not only by increasing regional activation of the mesial premotor system, including the supplementary motor area, but also by enhancing information flow between lateral and mesial premotor and sensorimotor areas of both hemispheres, even if the movements are simple and unimanual.

title: Origin of Human Motor Readiness Field Linked to Left Middle Frontal Gyrus by MEG and PET
abstract: Combined magnetoencephalography and positron emission tomography identified a prior source of activity in the left middle frontal gyrus during uncued movements of the right index finger. Voluntary movements gave rise to a change in the cortical electrical potential known as the Bereitschaftspotential or Readiness Potential, recorded as early as 1500 ms before the onset of movement. The Readiness Field is the magnetic field counterpart to the Bereitschaftspotential. In the present study, magnetoencephalography identified four successively active sources of fluctuation in the Readiness Field in the period from 900 ms before, to 100 ms after, the onset of the movement. The first source to be active was registered between 900 and 200 ms prior to the onset of the movement. This source of initial activity was mapped by positron emission tomography to the middle frontal gyrus, Brodmann area 9. The three sources subsequently to be active were mapped to the supplementary motor area, premotor cortex, and motor cortex (M1), all in the left hemisphere.

title: The Role of Higher-Order Motor Areas in Voluntary Movement as Revealed by High-Resolution EEG and fMRI
abstract: In the human motor cortex structural and functional differences separate motor areas related to motor output from areas essentially involved in higher-order motor control. Little is known about the function of these higher-order motor areas during simple voluntary movement. We examined a simple finger flexion movement in six healthy subjects using a novel brain-imaging approach, integrating high-resolution EEG with the individual structural and functional MRI. Electrical source reconstruction was performed in respect to the individual brain morphology from MRI. Highly converging results from EEG and fMRI were obtained for both executive and higher-order motor areas. All subjects showed activation of the primary motor area (MI) and of the frontal medial wall motor areas. Two different types of medial wall activation were observed with both methods: Four of the subjects showed an anterior type of activation, and two of the subjects a posterior type of activation. In the former, activity started in the anterior cingulate motor area (CMA) and subsequently shifted its focus to the intermediate supplementary motor area (SMA). Approximately 120 ms before the movement started, the intermediate SMA showed a drop of source strength, and simultaneously MI showed an increase of source strength. In the posterior type, activation was restricted to the posterior SMA. Further, three of the subjects investigated showed activation in the inferior parietal lobe (IPL) starting during early movement preparation. In all subjects showing activation of higher-order motor areas (anterior CMA, intermediate SMA, IPL) these areas became active before the executive motor areas (MI and posterior SMA). We suggest that the early activation of the anterior CMA and the IPL may be related to attentional functions of these areas. Further, we argue that the intermediate part of the SMA triggers the actual motor act via the release of inhibition of the primary motor area. Our results demonstrate that a noninvasive, multimodal brain imaging technique can reveal individual cortical brain activity with high temporal and spatial resolution, independent of a priori physiological assumptions.

title: Neuroimage of Voluntary Movement: Topography of the Bereitschaftspotential, a 64-Channel DC Current Source Density Study
abstract: The Bereitschaftspotential (BP) was recorded at 56 scalp positions when 17 healthy subjects performed brisk extensions of the right index finger. Aim of the study was to contribute to our understanding of the physiology underlying the BP and, in particular, to specify the situation at BP onset. For this purpose, the spatial pattern of the BP was analyzed in short time intervals (35 and/or 70 ms) starting 2.51 s before movement onset. For each time segment a spherical model of the BP was calculated by using spline interpolation. Then the spatial distribution of the electric potential at the scalp surface was transformed into a spatial distribution of current source densities (CSD map). Onset times of the BP and onset times of initial CSD-activity ranged between 2.23 and 1.81 s before movement onset. We selected a time window between 1.6 and 1.5 s before movement onset in order to analyze the spatial CSD pattern in each subject. In 10 subjects there was a significant current sink in the scalp area located over medial-wall motor areas (pre-SMA, SMA proper and anterior cingulate cortex: electrode positions C1, C2, FCz, Cz) in the absence of a significant current sink over the primary motor cortex (MI: electrode positions C3, CP3, and CP5). In three subjects significant current sinks were present at both sites and in another three subjects a current sink only over the lateral motor cortex was observed. In one subject no significant current sinks were measured. It is concluded that there is a large group of subjects (13/17) in whom BP at onset is associated with a current sink over medial-wall motor areas. At a later time interval (0.6 to 0.5 s before movement onset), significant current sinks were found in 13 subjects in medial and in 10 subjects in lateral recordings. These data were considered to be consistent with the hypothesis that, at least in a majority of subjects, medial-wall motor areas are activated earlier than lateral motor areas when organizing the initiation of a simple self-paced movement. Surface-recordings of the EEG do not allow further specification of cortical areas, which contribute to the current sinks. But in context with the current literature of the electrophysiology of nonhuman primates and of brain imaging in humans it is suggested that SMA and anterior cingulate cortex contribute to the current sink, the fronto-central midline, and that the primary motor cortex (MI) contributes to the current sink in the scalp area, which is located above MI and closely posterior to it.

title: High resolution DC-EEG mapping of the Bereitschaftspotential preceding simple or complex bimanual sequential finger movement
abstract: The present set of experiments investigated the Bereitschaftspotential (BP) preceding voluntary bimanual sequential simple (task 1) and complex movements (task 2) in supplementary/cingulate and primary motor areas (SCMA, MIs) using 64-channel direct current electroencephalography analysis in 16 right-handed healthy subjects. The results showed that: (1) onset times of BPs preceding the two tasks were significantly earlier at Cz than at C3 and C4, (2) the complex task induced significantly larger amplitudes than the simple task over the SCMA 1.1 s before EMG onset (BP1 period), over the SCMA and both MIs for the BP2 period, extending from the SCMA and MIs to all frontocentral, central, centroparietal, and frontal areas during the motor potential period, (3) task difference prior to 0.96 s mainly appeared in the SCMA rather than in either MI, (4) the BP had a significantly larger amplitude in the SCMA than in the MIs, the differences being asymmetric between the left and the right hemisphere motor areas, and (5) the sinks of BP current source density (CSD) preceding the two tasks were found in the frontocentral midline; and the regions and intensities of CSD maps were larger and stronger in task 2 than they were in task 1 at the same times of the epoch. The results suggested that: (1) the SCMA and MIs participate in bimanual sequential simple or complex movements, (2) the SCMA appears to not only serve as a trigger command for voluntary movement but also seems to design the different motor modes, (3) the amplitude, duration, onset time, CSD region, and intensity of BP all increase with the level of complexity of the movement, (4) the greater the complexity of the action, the earlier the preparation and the larger the extent of activated neuronal populations in the SCMA, (5) activation of the SCMA occurred prior to that of the MI, and (6) the activation suggests an asymmetry between left and right MIs in simultaneous bilateral finger movement, but this asymmetry seems to be less pronounced for complex movements.

title: Temporal dynamics of ipsilateral and contralateral motor activity during voluntary finger movement
abstract: The role of motor activity ipsilateral to movement remains a matter of debate, due in part to discrepancies among studies in the localization of this activity, when observed, and uncertainty about its time course. The present study used magnetoencephalography (MEG) to investigate the spatial localization and temporal dynamics of contralateral and ipsilateral motor activity during the preparation of unilateral finger movements. Eight right‐handed normal subjects carried out self‐paced finger‐lifting movements with either their dominant or nondominant hand during MEG recordings. The Multi‐Start Spatial Temporal multi‐dipole method was used to analyze MEG responses recorded during the movement preparation and early execution stage (−800 msec to +30 msec) of movement. Three sources were localized consistently, including a source in the contralateral primary motor area (M1) and in the supplementary motor area (SMA). A third source ipsilateral to movement was located significantly anterior, inferior, and lateral to M1, in the premotor area (PMA) (Brodmann area [BA] 6). Peak latency of the SMA and the ipsilateral PMA sources significantly preceded the peak latency of the contralateral M1 source by 60 msec and 52 msec, respectively. Peak dipole strengths of both the SMA and ipsilateral PMA sources were significantly weaker than was the contralateral M1 source, but did not differ from each other. Altogether, the results indicated that the ipsilateral motor activity was associated with premotor function, rather than activity in M1. The time courses of activation in SMA and ipsilateral PMA were consistent with their purported roles in planning movements.  Brain Mapp. 23:26–39, 2004.

title: Intracerebral ERD/ERS in voluntary movement and in cognitive visuomotor task.
abstract: In order to study cerebral activity related to preparation and execution of movement, evoked and induced brain electrical activities were compared to each other and to fMRI results in voluntary self-paced movements. Also, the event-related desynchronization and synchronization (ERD/ERS) were studied in complex movements with various degrees of cognitive load. The Bereitschaftspotential (BP) and alpha (8-12 Hz) and beta (16-24 Hz) ERD/ERS rhythms in self-paced simple movements were analyzed in 14 epilepsy surgery candidates. In previous studies, the cortical sources of BP were consistently displayed contralateral to the movement in the primary motor cortex and somatosensory cortex, and bilateral in the supplementary motor area (SMA) and in the cingulate cortex. There were also small and inconstant BP generators in the ipsilateral sensorimotor, premotor, and dorsolateral prefrontal cortex. Alpha and beta ERD/ERS were also observed in these cortical regions. The distribution of contacts showing ERD or ERS was larger than of those showing BP. In contrast to BP, ERD, and ERS frequently occurred in the orbitofrontal, lateral and mesial temporal cortices, and inferior parietal lobule. The spatial location of brain activation for self-paced repetitive movements, i.e., writing simple dots, was studied using event-related functional MRI (fMRI) in 10 healthy right-handed subjects. We observed significant activation in regions known to participate in motor control: contralateral to the movement in the primary sensorimotor and supramarginal cortices, the SMA and the underlying cingulate, and, to a lesser extent, the ipsilateral sensorimotor region. When the fMRI was compared with the map of the brain areas electrically active with self-paced movements (intracerebral recordings; Rektor et al., 1994, 1998, 2001b, c; Rektor, 2003), there was an evident overlap of most results. Nevertheless, the electrophysiological studies were more sensitive in uncovering small active areas, i.e., in the premotor and prefrontal cortices. The BP and the event-related hemodynamic changes were displayed in regions known to participate in motor control. The cortical occurrence of oscillatory activities in the alpha-beta range was clearly more widespread. Four epilepsy surgery candidates with implanted depth brain electrodes performed two visuomotor-cognitive tasks with cued complex movements: a simple task--copying randomly presented letters from the monitor; and a more complex task--writing a letter other than that which appears on the monitor. The second task demanded an increased cognitive load, i.e., of executive functions. Alpha and beta ERD/ERS rhythms were evaluated. Similar results for both tasks were found in the majority of the frontal contacts, i.e., in the SMA, anterior cingulate, premotor, and dorsolateral prefrontal cortices. The most frequent observed activity was ERD in the beta rhythm; alpha ERS and ERD were also present. Significant differences between the two tasks appeared in several frontal areas--in the dorsolateral and ventrolateral prefrontal and orbitofrontal cortices (BA 9, 45, 11), and in the temporal neocortex (BA 21). In several contacts localized in these areas, namely in the lateral temporal cortex, there were significant changes only with the complex task--mostly beta ERD. Although the fMRI results fit well with the map of the evoked activity (BP), several discrepant localizations were displayed when the BP was compared with the distribution of the oscillatory activity (ERD-ERS). The BP and hemodynamic changes are closely related to the motor control areas; ERD/ERS represent the broader physiological aspects of motor execution and control. The BP probably reflects regional activation, while the more widespread ERD/ERS may reflect the spread of task-relevant information across relevant areas. In the writing tasks, the spatial distribution of the alpha-beta ERD/ERS in the frontal and lateral temporal cortices was partially task dependent. The ERD/ERS occurred there predominantly in the more complex of the writing tasks. Some sites were only active in the task with the increased demand on executive functions. In the temporal neocortex only, the oscillatory, but not the evoked, activity was recorded in the self-paced movement. The temporal appearance of changes of oscillatory activities in the self-paced movement task as well as in the cued movement task with an increased load of executive functions raises the interesting question of the role of this region in cognitive-movement information processing.

title: Evidence for a distributed hierarchy of action representation in the brain.
abstract: Complex human behavior is organized around temporally distal outcomes. Behavioral studies based on tasks such as normal prehension, multi-step object use and imitation establish the existence of relative hierarchies of motor control. The retrieval errors in apraxia also support the notion of a hierarchical model for representing action in the brain. In this review, three functional brain imaging studies of action observation using the method of repetition suppression are used to identify a putative neural architecture that supports action understanding at the level of kinematics, object centered goals and ultimately, motor outcomes. These results, based on observation, may match a similar functional-anatomic hierarchy for action planning and execution. If this is true, then the findings support a functional-anatomic model that is distributed across a set of interconnected brain areas that are differentially recruited for different aspects of goal-oriented behavior, rather than a homogeneous mirror neuron system for organizing and understanding all behavior.

title: Behaviour of neurons in monkey peri-arcuate and precentral cortex before and during visually guided arm and hand movements
abstract: SummaryNeuron activity was recorded in monkey cerebral cortex during a visually guided reaching task. Cells located in the banks of the arcuate sulcus at its curvature changed their activity during the period in which the monkey saw a food reward in a certain position, but before it moved to retrieve the reward. A role of these neurons in visual guidance of arm and hand movements is postulated.

title: Transcranial magnetic stimulation and cognitive neuroscience
abstract: Transcranial magnetic stimulation has been used to investigate almost all areas of cognitive neuroscience. This article discusses the most important (and least understood) considerations regarding the use of transcranial magnetic stimulation for cognitive neuroscience and outlines advances in the use of this technique for the replication and extension of findings from neuropsychology. We also take a more speculative look forward to the emerging development of strategies for combining transcranial magnetic stimulation with other brain imaging technologies and methods in the cognitive neurosciences.

title: Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms involved in motor control
abstract: Transcranial magnetic stimulation (TMS) was initially used to evaluate the integrity of the corticospinal tract in humans non‐invasively. Since these early studies, the development of paired‐pulse and repetitive TMS protocols allowed investigators to explore inhibitory and excitatory interactions of various motor and non‐motor cortical regions within and across cerebral hemispheres. These applications have provided insight into the intracortical physiological processes underlying the functional role of different brain regions in various cognitive processes, motor control in health and disease and neuroplastic changes during recovery of function after brain lesions. Used in combination with neuroimaging tools, TMS provides valuable information on functional connectivity between different brain regions, and on the relationship between physiological processes and the anatomical configuration of specific brain areas and connected pathways. More recently, there has been increasing interest in the extent to which these physiological processes are modulated depending on the behavioural setting. The purpose of this paper is (a) to present an up‐to‐date review of the available electrophysiological data and the impact on our understanding of human motor behaviour and (b) to discuss some of the gaps in our present knowledge as well as future directions of research in a format accessible to new students and/or investigators. Finally, areas of uncertainty and limitations in the interpretation of TMS studies are discussed in some detail.

title: Influence of interhemispheric interactions on motor function in chronic stroke
abstract: In patients with chronic stroke, the primary motor cortex of the intact hemisphere (M1intact hemisphere) may influence functional recovery, possibly through transcallosal effects exerted over M1 in the lesioned hemisphere (M1lesioned hemisphere). Here, we studied interhemispheric inhibition (IHI) between M1intact hemisphere and M1lesioned hemisphere in the process of generation of a voluntary movement by the paretic hand in patients with chronic subcortical stroke and in healthy volunteers. IHI was evaluated in both hands preceding the onset of unilateral voluntary index finger movements (paretic hand in patients, right hand in controls) in a simple reaction time paradigm. IHI at rest and shortly after the Go signal were comparable in patients and controls. Closer to movement onset, IHI targeting the moving index finger turned into facilitation in controls but remained deep in patients, a finding that correlated with poor motor performance. These results document an abnormally high interhemispheric inhibitory drive from M1intact hemisphere to M1lesioned hemisphere in the process of generation of a voluntary movement by the paretic hand. It is conceivable that this abnormality could adversely influence motor recovery in some patients with subcortical stroke, an interpretation consistent with models of interhemispheric competition in motor and sensory systems.

title: Interactions between pairs of transcranial magnetic stimuli over the human left dorsal premotor cortex differ from those seen in primary motor cortex
abstract: A single TMS pulse (110% resting motor threshold, RMT) to the left dorsal premotor cortex (PMd) (CS2) suppresses the amplitude of motor evoked potentials (MEPs) from a test pulse (TS) over the right motor cortex (M1), and facilitates MEPs from the left motor cortex. We probed how this interaction was changed by a prior conditioning pulse over PMd (CS1) using a paired pulse TMS design. In the main experiments, the intensity of CS1 was 80% RMT. Basal suppression of right M1 was removed when CS1–CS2 was 1 ms or 5 ms with a similar tendency at 15 ms. Basal facilitation of left M1 was suppressed at CS1–CS2 of 5 ms. A similar time course was seen if CS2 was increased to 100% RMT, but there was no significant effect if CS1 was 70% RMT. Preconditioning PMd with continuous or intermittent theta burst repetitive TMS (cTBS, iTBS) abolished the basal CS2–TS interaction between premotor and motor cortices. Finally, if very short interstimulus intervals between CS1 and CS2 were explored to detect interactions similar to I‐wave facilitation in M1, we found that the basal suppression of right M1 was abolished at CS1–CS2 intervals of 1.8 and 2.8 ms. We suggest that paired pulse TMS may be capable of investigating properties of intrinsic circuits in PMd and that their properties differ from those in the nearby M1. Paired TMS may be a useful method of studying the excitability of intrinsic circuits in non‐primary areas of the motor system.

title: Functional specificity of human premotor–motor cortical interactions during action selection
abstract: Functional connections between dorsal premotor cortex (PMd) and primary motor cortex (M1) have been revealed by paired‐pulse transcranial magnetic stimulation (TMS). We tested if such connections would be modulated during a cognitive process (response selection) known to rely on those circuits. PMd–M1 TMS applied 75 ms after a cue to select a manual response facilitated motor‐evoked potentials (MEPs). MEPs were facilitated at 50 ms in a control task of response execution, suggesting that PMd–M1 interactions at 75 ms are functionally specific to the process of response selection. At 100 ms, PMd–M1 TMS delayed choice reaction time (RT). Importantly, the MEP (at 75 ms) and the RT (at 100 ms) effects were correlated in a way that was hand‐specific. When the response was made with the M1‐contralateral hand, MEPs correlated with slower RTs. When the response was made with the M1‐ipsilateral hand, MEPs correlated with faster RTs. Paired‐pulse TMS confined to M1 did not produce these effects, confirming the causal influence of PMd inputs. This study shows that a response selection signal evolves in PMd early during the reaction period (75–100 ms), impacts on M1 and affects behaviour. Such interactions are temporally, anatomically and functionally specific, and have a causal role in choosing which movement to make.

title: Mechanisms Underlying Functional Changes in the Primary Motor Cortex Ipsilateral to an Active Hand
abstract: Performance of a unimanual hand motor task results in functional changes in both primary motor cortices (M1ipsilateral and M1contralateral). The neuronal mechanisms controlling the corticospinal output originated in M1ipsilateral and the resting hand during a unimanual task remain unclear. Here, we assessed functional changes within M1ipsilateral and in interhemispheric inhibition (IHI) associated with parametric increases in unimanual force. We measured motor-evoked potential (MEP) recruitment curves (RCs) and short-interval intracortical inhibition (SICI) in M1ipsilateral, IHI from M1contralateral to M1ipsilateral, and the influence of IHI over SICI using transcranial magnetic stimulation at rest and during 10, 30, and 70% of maximal right wrist flexion force. EMG from the left resting flexor carpi radialis (FCR) muscle was comparable across conditions. Left FCR MEP RCs increased, and SICI decreased with increasing right wrist force. Activity-dependent (rest and 10, 30, and 70%) left FCR maximal MEP size correlated with absolute changes in SICI. IHI decreased with increasing force at matched conditioned MEP amplitudes. IHI and SICI were inversely correlated at increasing forces. In the presence of IHI, SICI decreased at rest and 70% force. In summary, we found activity-dependent changes in (1) SICI in M1ipsilateral, (2) IHI from M1contralateral to M1ipsilateral, and (3) the influence of IHI over SICI in the left resting hand during force generation by the right hand. Our findings indicate that interactions between GABAergic intracortical circuits mediating SICI and interhemispheric glutamatergic projections between M1s contribute to control activity-dependent changes in corticospinal output to a resting hand during force generation by the opposite hand.

title: Dissociating Arbitrary Stimulus-Response Mapping from Movement Planning during Preparatory Period: Evidence from Event-Related Functional Magnetic Resonance Imaging
abstract: In the present study, we aimed to dissociate the neural correlates of two subprocesses involved in the preparatory period in the context of arbitrary, prelearned stimulus-response (S-R) associations, namely, S-R mapping and movement planning (MP). We teased apart these two subprocesses by comparing three tasks in which the complexity of both S-R mapping and MP were independently manipulated: simple reaction time (SRT) task, go/no-go reaction time (GNGRT) task, and choice reaction time (CRT) task. We found that a more complex S-R mapping, which is the common element differentiating CRT and GNGRT from SRT, was associated with higher brain activation in the left superior parietal lobe (SPL). Conversely, a greater number of planned finger movements, which is the common difference between CRT and both SRT and GNGRT, was associated with higher brain activation in a number of frontal areas, including the left supplementary motor area (SMA), left dorsal premotor cortex (dPM), and left anterior cingulate cortex (ACC). The left-hemisphere dominance for S-R mapping could be related to the fact that arbitrary S-R mapping is often verbally mediated in humans. Overall, these results suggest a clear dissociation in the preparatory-set period between the more abstract role of left SPL in activating the appropriate S-R associations and the more concrete role played by the SMA, dPM, and ACC in preparing the required motor programs.

title: Interhemispheric inhibition in distal and proximal arm representations in the primary motor cortex.
abstract: Interhemispheric inhibitory interactions (IHI) operate between homologous distal hand representations in primary motor cortex (M1). It is not known whether proximal arm representations exhibit comparable effects on their homologous counterparts. We studied IHI in different arm representations, targeting triceps brachii (TB, n = 13), first dorsal interosseous (FDI, n = 13), and biceps brachii (BB, n = 7) muscles in healthy volunteers. Transcranial magnetic stimulation test stimuli (TS) were delivered to M1 contralateral to the target muscle preceded 10 ms by a conditioning stimulus (CS) to the opposite M1 at 110-150% resting motor threshold (RMT). IHI was calculated as the ratio between motor-evoked potential (MEP) amplitudes in conditioned relative to unconditioned trials. Mean RMTs were 38.9, 46.9, and 46.0% of stimulator output in FDI, TB, and BB muscles, respectively. IHI was 0.45 +/- 0.41 (FDI), 0.78 +/- 0.38 (TB), and 0.52 +/- 0.32 (BB, P < 0.01) when test MEP amplitudes were matched and 0.28 +/- 0.17 (FDI) and 0.85 +/- 0.31 (TB, P < 0.05) when TS intensities expressed as percentage RMT were matched. Significant IHI (P < 0.05) was identified with minimal CS intensities (expressed as percentage stimulator output) in the 30 s for FDI, 60 s for TB, and 40 s for BB. Additionally, a CS of roughly 120% RMT suppressed the test MEP but not a test H-reflex in BB, suggesting IHI observed in BB is likely mediated by a supraspinal mechanism. We conclude that IHI differs between different arm muscle representations, comparable between BB and FDI but lesser for TB. This finding suggests the amount of IHI between different arm representations does not strictly follow a proximal-to-distal gradient, but may be related to the role of each muscle in functional movement synergies.

title: Deficient intracortical inhibition (SICI) during movement preparation after chronic stroke
abstract: In healthy subjects, preparation to move is accompanied by motor cortical disinhibition. Poor control of intracortical inhibitory function in the primary motor cortex (M1) might contribute to persistent abnormal motor behavior in the paretic hand after chronic stroke.  Here, we studied GABAergic short intracortical inhibition (SICI) in the ipsilesional M1 in well-recovered chronic stroke patients (n = 14; 63.8 ± 3.0 years) engaged in preparation to move the impaired hand in a reaction time paradigm.  The main finding was an abnormal persistence of SICI in the ipsilesional M1 during movement preparation that was absent in age-matched controls (n = 14). Additionally, resting SICI was reduced in the patient group relative to controls.  Our findings document a deficit of dynamic premovement modulation of intracortical inhibition in the ipsilesional primary motor cortex of patients with chronic stroke. This abnormality might contribute to deficits in motor control of the paretic hand, presenting a possible target for correction in the framework of developing novel therapeutic interventions after chronic stroke.

title: Interhemispheric inhibition of the human motor cortex.
abstract: 1. Using two magnetic stimulators, we investigated the effect of a conditioning magnetic stimulus over the motor cortex of one hemisphere on the size of EMG responses evoked in the first dorsal interosseous (FDI) muscle by a magnetic test stimulus given over the opposite hemisphere. 2. A single conditioning shock to one hemisphere produced inhibition of the test response evoked from the opposite hemisphere when the conditioning‐test interval was 5‐6 ms or longer. We shall refer to this as interhemispheric inhibition. However, the minimum latency of inhibition observed using surface EMG responses may have underestimated the true interhemispheric conduction time. Single motor unit studies suggested values 4‐7 ms longer than the minimum interval observed with surface EMG. 3. Interhemispheric inhibition was seen when the test muscle was active or relaxed. Increasing the intensity of the conditioning stimulus increased the duration of inhibition: increasing the intensity of the test stimulus reduced the depth of inhibition. 4. The conditioning coil had to be placed on the appropriate area of scalp for inhibition to occur. The effect of the conditioning stimulus was maximal when it was applied over the hand area of motor cortex, and decreased when the stimulus was moved medial or lateral to that point. 5. The inhibitory effect on the test stimulus probably occurred at the level of the cerebral cortex. In contrast to the inhibition of test responses evoked by magnetic test stimuli, test responses evoked in active FDI by a small anodal electric shock were not significantly inhibited by a contralateral magnetic conditioning stimulus. Similarly, H reflexes in relaxed forearm flexor muscles were unaffected by conditioning stimuli to the ipsilateral hemisphere. However, inhibition was observed if the experiment was repeated with the muscles active.

title: Inhibitory influence of the ipsilateral motor cortex on responses to stimulation of the human cortex and pyramidal tract
abstract: 1 The ability of the primary motor cortex (M1) to modulate motor responses in ipsilateral hand muscles seems to be important for normal motor control and potentially also for recovery after brain lesions. It is not clear which pathways mediate this ipsilateral modulation. Transcallosal connections have been proposed, but are known to be sparse between cortical hand motor representations in primates. The present study was performed to determine whether descending ipsilateral modulation of motor responses might also be mediated below the cortical level in humans. 2 A paired‐pulse protocol was used, in which motor‐evoked potentials (MEPs) were produced by cortical transcranial magnetic stimulation (cTMS) or by electrical stimulation of the pyramidal tract at the level of the pyramidal decussation (pdTES), in both preactivated and relaxed hand muscles. Paired stimuli were applied at various interstimulus intervals (ISIs) between 2 and 100 ms. The conditioning stimulus (CS) was always magnetic, and delivered to the M1 ipsilateral to the target hand, prior to the test stimulus (TS). The magnetic TS was delivered to the M1 contralateral to the target hand; the electrical TS was applied through electrodes placed over the mastoid process bilaterally. Further experiments included cortical electrical stimulation and H‐reflexes. The MEP amplitudes were averaged separately for each ISI and the control condition (no CS), and expressed as a percentage of the unconditioned response. 3 Conditioning stimulation of the ipsilateral M1 resulted in significant inhibition of magnetically evoked MEPs, and also of MEPs produced by pdTES. Inhibition occurred at ISIs between 6 and 50 ms, and was observed in preactivated and relaxed muscles. Higher CS intensities caused greater inhibition of both cTMS‐ and pdTES‐evoked MEPs. 4 While the conditioning effects on magnetically evoked muscle responses could be explained by a transcallosal mechanism, the effects on pdTES‐evoked MEPs cannot, because they are elicited subcortically and are therefore not susceptible to inhibitory mechanisms transmitted at the cortico‐cortical level. 5 In conclusion, the present results provide novel evidence that the inhibitory influence of the human M1 on ipsilateral hand muscles is to a significant extent mediated below the cortical level, and not only through cortico‐cortical transcallosal connections. They point to a concept of inhibitory interaction between the two primary motor cortices that is relayed at multiple levels along the neuroaxis, thus perhaps providing a structurally redundant system which may become important in case of lesions.

title: Interhemispheric interaction between human dorsal premotor and contralateral primary motor cortex
abstract: We used transcranial magnetic stimulation (TMS) in a paired pulse protocol to investigate interhemispheric interactions between the right dorsal premotor (dPM) and left primary motor cortex (M1) using interstimulus intervals of 4, 6, 8, 10, 12, 16 and 20 ms in ten healthy subjects. A conditioning stimulus over right dPM at an intensity of either 90 or 110% resting motor threshold (RMT) suppressed motor‐evoked potentials (MEPs) evoked in the first dorsal interosseous (FDI) muscle by stimulation of left M1. Maximum effects occurred for interstimulus intervals (ISIs) of 8–10 ms. There was no effect if the conditioning stimulus was applied 2.5 cm lateral, anterior or medial to dPM. The effect differed from previously described M1 interhemispheric inhibition in that the threshold for the latter was greater than 90% RMT, whereas stimulation of the dPM at the same intensity led to significant inhibition. In addition, voluntary contraction of the left FDI (i.e. contralateral to the conditioning TMS) enhanced interhemispheric inhibition from right M1 but had no effect on the inhibition from right dPM. Finally, conditioning to right dPM at 90% RMT reduced short‐interval intracortical inhibition (SICI; at ISI = 2 ms) in left M1 whilst there was no effect if the conditioning stimulus was applied to right M1. We conclude that conditioning TMS over dPM has effects that differ from the previous pattern of interhemispheric inhibition described between bilateral M1s. This may reflect the existence of commissural fibres between dPM and contralateral M1 that may play a role in bimanual coordination.

title: Intermanual Differences in Movement-related Interhemispheric Inhibition
abstract: Interhemispheric inhibition (IHI) between motor cortical areas is thought to play a critical role in motor control and could influence manual dexterity. The purpose of this study was to investigate IHI preceding movements of the dominant and nondominant hands of healthy volunteers. Movement-related IHI was studied by means of a double-pulse transcranial magnetic stimulation protocol in right-handed individuals in a simple reaction time paradigm. IHI targeting the motor cortex contralateral (IHIc) and ipsilateral (IHIi) to each moving finger was determined. IHIc was comparable after the go signal, a long time preceding movement onset, in both hands. Closer to movement onset, IHIc reversed into facilitation for the right dominant hand but remained inhibitory for left nondominant hand movements. IHIi displayed a nearly constant inhibition with a trough early in the premovement period in both hands. In conclusion, our results unveil a more important modulation of interhemispheric interactions during generation of dominant than nondominant hand movements. This modulation essentially consisted of a shift from a balanced IHI at rest to an IHI predominantly directed toward the ipsilateral primary motor cortex at movement onset. Such a mechanism might release muscles from inhibition in the contralateral primary motor cortex while preventing the occurrence of the mirror activity in ipsilateral primary motor cortex and could therefore contribute to intermanual differences in dexterity.

title: Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee.
abstract: P.M. Rossini (Chairman) (Rome, Baly), A.T. Barker (Sheffield, UK), A. Berardelli (Rome, Italy), M.D. Caramia (Rome, Italy), G. Caruso (Naples, Italy), R.Q. Cracco (Brooklyn, NY;, USA), M.R. Dimitrijevid (Houston, TX, USA), M. Hallett ( Bethesda, MD, USA), Y. Katayama (Tokyo, Japan), C.H. Liicking ( Freiburg, Germany), A.L. Maertens de Noordhout (Liege, Belgium), C.D. Marsden (London, UK), N.M.F. Murray (London, UK), J.C. Rothwell (London, UK), M. Swash (London, UK) and C. Tomberg (Brussels, Belgium)

title: The clinical diagnostic utility of transcranial magnetic stimulation: Report of an IFCN committee
abstract: The review focuses on the clinical diagnostic utility of transcranial magnetic stimulation (TMS). The central motor conduction time (CMCT) is a sensitive method to detect myelopathy and abnormalities may be detected in the absence of radiological changes. CMCT may also detect upper motor neuron involvement in amyotrophic lateral sclerosis. The diagnostic sensitivity may be increased by using the triple stimulation technique (TST), by combining several parameters such as CMCT, motor threshold and silent period, or by studying multiple muscles. In peripheral facial nerve palsies, TMS may be used to localize the site of nerve dysfunction and clarify the etiology. TMS measures also have high sensitivity in detecting lesions in multiple sclerosis and abnormalities in CMCT or TST may correlate with motor impairment and disability. Cerebellar stimulation may detect lesions in the cerebellum or the cerebellar output pathway. TMS may detect upper motor neuron involvement in patients with atypical parkinsonism and equivocal signs. The ipsilateral silent period that measures transcallosal inhibition is a potential method to distinguish between different parkinsonian syndromes. Short latency afferent inhibition (SAI), which is related to central cholinergic transmission, is reduced in Alzheimer's disease. Changes in SAI following administration of cholinesterase inhibitor may be related to the long-term efficacy of this treatment. The results of MEP measurement in the first week after stroke correlate with functional outcome. We conclude that TMS measures have demonstrated diagnostic utility in myelopathy, amyotrophic lateral sclerosis and multiple sclerosis. TMS measures have potential clinical utility in cerebellar disease, dementia, facial nerve disorders, movement disorders, stroke, epilepsy, migraine and chronic pain.

title: Multiple nonprimary motor areas in the human cortex.
abstract: We measured the distribution of regional cerebral blood flow with positron emission tomography while three subjects moved their hand, shoulder, or leg. The images were coregistered with each individual's anatomic magnetic resonance scans. The data were analyzed for each individual to avoid intersubject averaging and so to preserve individual gyral anatomy. Instead of inspecting all pixels, we prospectively restricted the data analysis to particular areas of interest. These were defined on basis of the anatomic and physiological literature on nonhuman primates. By examining only a subset of areas, we strengthened the power of the statistical analysis and thereby increased the confidence in reporting single subject data. On the lateral convexity, motor related activity was found for all three subjects in the primary motor cortex, lateral premotor cortex, and an opercular area within the premotor cortex. In addition, there was activation of somatosensory cortex (SI), the supplementary somatosensory area (SII) in the Sylvian fissure, and parietal association areas (Brodmann areas 5 and 40). There was also activation in the insula. We suggest that the activation in the dorsal premotor cortex may correspond with dorsal premotor area (PMd) as described in the macaque brain. We propose three hypotheses as to the probable location of vental premotor area (PMv) in the human brain. On the medial surface, motor-related activity was found for all three subjects in the leg areas of the primary motor cortex and somatosensory cortex and also activity for the hand, shoulder, and leg in the supplementary motor area (SMA) on the dorsal medial convexity and in three areas in the cingulate sulcus. We suggest that the three cingulate areas may correspond with rostral cingulate premotor area, dorsal cingulate motor area (CMAd), and ventral cingulate motor area (CMAv) as identified in the macaque brain. Somatotopic mapping was demonstrated in the primary motor and primary somatosensory cortex. In all three subjects, the arm region lay anterior to the leg region in parietal area 5. Also in all three subjects, the arm region lay anterior to the leg region in the supplementary motor cortex.

title: The mechanisms of interhemispheric inhibition in the human motor cortex
abstract: Transcranial magnetic stimulation can be used to non‐invasively study inhibitory processes in the human motor cortex. Interhemispheric inhibition can be measured by applying a conditioning stimulus to the motor cortex resulting in inhibition of the contralateral motor cortex. Transcranial magnetic stimulation can also be used to demonstrate ipsilateral cortico‐cortical inhibition in the motor cortex. At least two different ipsilateral cortico‐cortical inhibitory processes have been identified: short interval intracortical inhibition and long interval intracortical inhibition. However, the relationship between interhemispheric inhibition and ipsilateral cortico‐cortical inhibition remains unclear. This study examined the relationship between interhemispheric inhibition, short interval intracortical inhibition and long interval intracortical inhibition. First, the effect of test stimulus intensity on each inhibitory process was studied. Second, the effects of interhemispheric inhibition on short interval intracortical inhibition and long interval intracortical inhibition on interhemispheric inhibition were examined. Motor evoked potentials were recorded from the right first dorsal interosseous muscle in 11 right‐handed healthy volunteers. For interhemispheric inhibition, conditioning stimuli were applied to the right motor cortex and test stimuli to the left motor cortex. For short interval intracortical inhibition and long interval intracortical inhibition, both conditioning stimuli and test stimuli were applied to the left motor cortex. With increasing test stimulus intensities, long interval intracortical inhibition and interhemispheric inhibition decreased, while short interval intracortical inhibition increased. Moreover, short interval intracortical inhibition was significantly reduced in the presence of interhemispheric inhibition. Interhemispheric inhibition was significantly reduced in the presence of long interval intracortical inhibition when matched for test motor evoked potential amplitude but the difference was not significant when matched for test pulse intensity. These findings suggest that both interhemispheric inhibition and long interval intracortical inhibition are predominately mediated by low threshold cortical neurons and may share common inhibitory mechanisms. In contrast, the mechanisms mediating short interval intracortical inhibition are probably different from those mediating long interval intracortical inhibition and interhemispheric inhibition although these systems appear to interact.

title: The origin of corticospinal projections from the premotor areas in the frontal lobe
abstract: We determined the origin of corticospinal neurons in the frontal lobe. These neurons were labeled by retrograde transport of tracers after injections into either the dorsolateral funiculus at the second cervical segment or the gray matter of the spinal cord throughout the cervical enlargement. Using retrograde transport of tracer from the arm area of the primary motor cortex, we defined the arm representation in each premotor area in another set of animals. We found that corticospinal projections to cervical segments of the spinal cord originate from the primary motor cortex and from the 6 premotor areas in the frontal lobe. These are the same premotor areas that project directly to the arm area of the primary motor cortex. The premotor areas are located in parts of cytoarchitectonic area 6 on the lateral surface and medial wall of the hemisphere, as well as in subfields of areas 23 and 24 in the cingulate sulcus. The total number of corticospinal neurons in the arm representations of the premotor areas equals or exceeds the total number in the arm representation of the primary motor cortex. The premotor areas collectively comprise more than 60% of the cortical area in the frontal lobe that projects to the spinal cord. Like the primary motor cortex, each of the premotor areas contains local regions that have a high density of corticospinal neurons. These observations indicate that a substantial component of the corticospinal system originates from the premotor areas in the frontal lobe. Each of the premotor areas has direct access to the spinal cord, and as a consequence, each has the potential to influence the generation and control of movement independently of the primary motor cortex. These findings raise serious questions about the utility of viewing the primary motor cortex as the “upper motoneuron” or “final common pathway” for the central control of movement.

title: Complex Movements Evoked by Microstimulation of Precentral Cortex
abstract: Electrical microstimulation was used to study primary motor and premotor cortex in monkeys. Each stimulation train was 500 ms in duration, approximating the time scale of normal reaching and grasping movements and the time scale of the neuronal activity that normally accompanies movement. This stimulation on a behaviorally relevant time scale evoked coordinated, complex postures that involved many joints. For example, stimulation of one site caused the mouth to open and also caused the hand to shape into a grip posture and move to the mouth. Stimulation of this site always drove the joints toward this final posture, regardless of the direction of movement required to reach the posture. Stimulation of other cortical sites evoked different postures. Postures that involved the arm were arranged across cortex to form a map of hand positions around the body. This stimulation-evoked map encompassed both primary motor and the adjacent premotor cortex. We suggest that these regions fit together into a single map of the workspace around the body.

title: Dorsal premotor cortex exerts state-dependent causal influences on activity in contralateral primary motor and dorsal premotor cortex.
abstract: During voluntary action, dorsal premotor cortex (PMd) may exert influences on motor regions in both hemispheres, but such interregional interactions are not well understood. We used transcranial magnetic stimulation (TMS) concurrently with event-related functional magnetic resonance imaging to study such interactions directly. We tested whether causal influences from left PMd upon contralateral (right) motor areas depend on the current state of the motor system, involving regions engaged in a current task. We applied short bursts (360 ms) of high- or low-intensity TMS to left PMd during single isometric left-hand grips or during rest. TMS to left PMd affected activity in contralateral right PMd and primary motor cortex (M1) in a state-dependent manner. During active left-hand grip, high (vs. low)-intensity TMS led to activity increases in contralateral right PMd and M1, whereas activity decreases there due to TMS were observed during no-grip rest. Analyses of condition-dependent functional coupling confirmed topographically specific stronger coupling between left PMd and right PMd (and right M1), when high-intensity TMS was applied to left PMd during left-hand grip. We conclude that left PMd can exert state-dependent interhemispheric influences on contralateral cortical motor areas relevant for a current motor task.

title: The role of ipsilateral premotor cortex in hand movement after stroke
abstract: Movement of an affected hand after stroke is associated with increased activation of ipsilateral motor cortical areas, suggesting that these motor areas in the undamaged hemisphere may adaptively compensate for damaged or disconnected regions. However, this adaptive compensation has not yet been demonstrated directly. Here we used transcranial magnetic stimulation (TMS) to interfere transiently with processing in the ipsilateral primary motor or dorsal premotor cortex (PMd) during finger movements. TMS had a greater effect on patients than controls in a manner that depended on the site, hemisphere, and time of stimulation. In patients with right hemiparesis (but not in healthy controls), TMS applied to PMd early (100 ms) after the cue to move slowed simple reaction-time finger movements by 12% compared with controls. The relative slowing of movements with ipsilateral PMd stimulation in patients correlated with the degree of motor impairment, suggesting that functional recruitment of ipsilateral motor areas was greatest in the more impaired patients. We also used functional magnetic resonance imaging to monitor brain activity in these subjects as they performed the same movements. Slowing of reaction time after premotor cortex TMS in the patients correlated inversely with the relative hemispheric lateralization of functional magnetic resonance imaging activation in PMd. This inverse correlation suggests that the increased activation in ipsilateral cortical motor areas during movements of a paretic hand, shown in this and previous functional imaging studies, represents a functionally relevant, adaptive response to the associated brain injury.

title: Non-invasive brain stimulation: a new strategy to improve neurorehabilitation after stroke?
abstract: Motor impairment resulting from chronic stroke can have extensive physical, psychological, financial, and social implications despite available neurorehabilitative treatments. Recent studies in animals showed that direct epidural stimulation of the primary motor cortex surrounding a small infarct in the lesioned hemisphere (M1(lesioned hemisphere)) elicits improvements in motor function.



In human beings, proof of principle studies from different laboratories showed that non-invasive transcranial magnetic stimulation and direct current stimulation that upregulate excitability within M1(lesioned hemisphere) or downregulate excitability in the intact hemisphere (M1(intact hemisphere)) results in improvement in motor function in patients with stroke. Possible mechanisms mediating these effects can include the correction of abnormally persistent interhemispheric inhibitory drive from M1(intact hemisphere) to M1(lesioned hemisphere) in the process of generation of voluntary movements by the paretic hand, a disorder correlated with the magnitude of impairment. In this paper we review these mechanistically oriented interventional approaches.  These findings suggest that transcranial magnetic stimulation and transcranial direct current stimulation could develop into useful adjuvant strategies in neurorehabilitation but have to be further assessed in multicentre clinical trials.

title: Transcallosal inhibition in cortical and subcortical cerebral vascular lesions
abstract: The excitability of the motor cortex after transcranial magnetic stimulation was investigated in 10 patients with purely subcortical, and in 22 patients with cortical-subcortical cerebrovascular lesions. In the first investigation we applied magnetic double stimuli over both motor cortices with different inter-stimulus intervals. The first (conditioning) stimulus was applied to the affected hemisphere and the second stimulus (test stimulus) to the unaffected side. The responses of the first dorsal interosseal (FDI) muscle, contralateral to the test stimulus, were recorded after applying the test stimulus alone and at inter-stimulus intervals of 5 ms, 7 ms, 15 ms, 30 ms and 60 ms. In a second investigation the patients were asked to activate their non-paretic first dorsal interosseus muscle and the magnetic stimulus was applied over the affected hemisphere. The EMG responses were rectified and averaged. Patients with subcortical cerebral lesions below the centrum semiovale (i.e., having no effect on the transcallosal fibres) displayed a pronounced inhibition of one motor cortex after the stimulation of the contralateral side, comparable with normal subjects. Patients with cortical-subcortical cerebral lesions displayed only partly less inhibition of their motor cortex but the results in this group were not uniform. Since inhibition was preserved in patients with subcortical lesions, which had destroyed the corticospinal tract, we conclude that this inhibition is not mediated through an ipsilateral projection but via a transcallosal route.

title: Interhemispheric inhibition in patients with multiple sclerosis.
abstract: A single focal magnetic stimulus applied to the motor cortex of normal subjects can suppress ongoing voluntary electromyographic activity in ipsilateral small hand muscles. This inhibition is mediated from one motor cortex to the contralateral side via a transcallosal pathway.



We have investigated transcallosal inhibition in 24 patients with definite multiple sclerosis (MS) and in 24 healthy volunteers. A focal magnetic stimulus was applied to the hand area of the motor cortex and the onset latency of the inhibition of the ongoing EMG activity of the ipsilateral first dorsal interosseus muscle was evaluated. Cortico-motor conduction time to the same muscle was revealed, using a magnetic stimulus over the contralateral motor cortex. The difference between these values was calculated as transcallosal conduction time. Cerebral magnetic resonance imaging (MRI) scans including sagittal T2-weighted images were performed in 18 patients.



The depth of inhibition (maximal inhibition as percentage of the baseline EMG) in the MS patients was comparable to normal values, but the transcallosal conduction time was significantly delayed (patients 17.2 +/- 6.4 ms; normal subjects 12.2 +/- 2.6 ms; P < 0.001). The duration of the inhibition was significantly prolonged in MS patients (patients 47.9 +/- 20.9 ms; normal subjects 38.9 +/- 10.1 ms; P = 0.02). Transcallosal conduction time was delayed in 11 (46%) of 24 patients, compared with normal subjects. It exceeded the normal range (mean +/- 2.5 SD) in one normal subject (specificity 96%). No correlation could be found between the size or extent of the lesions obtained from the MRI scan and the onset latency or the depth of the inhibition.



We conclude that conduction over transcallosal connections is significantly slower in patients with MS.

title: Topography of fibers in the human corpus callosum mediating interhemispheric inhibition between the motor cortices
abstract: In 1 split‐brain patient and 13 patients with circumscript surgical lesions within different parts of the corpus callosum (CC), the topography of fibers within the CC mediating an interhemispheric inhibition between the motor cortices was investigated in the phase of a stable disconnection syndrome. The aim of the study was to characterize the system of callosal fibers activated by transcranial magnetic brain stimulation in more detail as a basis for a diagnostic application of this technique. The locations and areas of the lesions were measured on sagittal magnetic resonance (MR) slices and attributed to five segments of the CC, because the borders of the anatomic subdivisions of the CC are not clearly defined. Transcallosal inhibition (TI) of tonic electromyographical hand muscle activity was elicited by focal transcranial magnetic stimulation over the primary motor cortex. In a reference group of normal subjects, TI started after 35.8 ± 3.6 msec had a duration of 24.8 ± 2.7 msec and an estimated transcallosal conduction time of 15.5 ± 3.0 msec (range, 10.2–20.0 msec, n = 24 hands). No significant differences were found for the TI originating from the right and left motor cortices. From the absence and presence of TI in patients with lesions in different parts of the CC it can be concluded that most of the fibers mediating TI pass through the posterior third and anterior fourth segment of the CC, that is, through the posterior half of the trunk of the CC. The clinical findings suggest a role for TI in the performance of fast and complex hand motor tasks.

title: Human Motor Corpus Callosum: Topography, Somatotopy, and Link between Microstructure and Function
abstract: The corpus callosum (CC) is the principal white matter fiber bundle connecting neocortical areas of the two hemispheres. Although an object of extensive research, important details about the anatomical and functional organization of the human CC are still largely unknown. Here we focused on the callosal motor fibers (CMFs) that connect the primary motor cortices (M1) of the two hemispheres. Topography and somatotopy of CMFs were explored by using a combined functional magnetic resonance imaging/diffusion tensor imaging fiber-tracking procedure. CMF microstructure was assessed by fractional anisotropy (FA), and CMF functional connectivity between the hand areas of M1 was measured by interhemispheric inhibition using paired-pulse transcranial magnetic stimulation. CMFs mapped onto the posterior body and isthmus of the CC, with hand CMFs running significantly more anteriorly and ventrally than foot CMFs. FA of the hand CMFs but not FA of the foot CMFs correlated linearly with interhemispheric inhibition between the M1 hand areas. Findings demonstrate that CMFs connecting defined body representations of M1 map onto a circumscribed region in the CC in a somatotopically organized manner. The significant and topographically specific positive correlation between FA and interhemispheric inhibition strongly suggests that microstructure can be directly linked to functional connectivity. This provides a novel way of exploring human brain function that may allow prediction of functional connectivity from variability of microstructure in healthy individuals, and potentially, abnormality of functional connectivity in neurological or psychiatric patients.

title: Uncrossed actions of feline corticospinal tract neurones on lumbar interneurones evoked via ipsilaterally descending pathways
abstract: Effects of stimulation of ipsilateral pyramidal tract (PT) fibres were analysed in interneurones in midlumbar segments of the cat spinal cord in search of interneurones mediating disynaptic actions of uncrossed PT fibres on hindlimb motoneurones. The sample included 44 intermediate zone and ventral horn interneurones, most with monosynaptic input from group I and/or group II muscle afferents and likely to be premotor interneurones. Monosynaptic EPSPs evoked by stimulation of the ipsilateral PT were found in 12 of the 44 (27%) interneurones, while disynaptic or trisynaptic EPSPs were evoked in more than 75%. Both appeared at latencies that were either longer or within the same range as those of disynaptic EPSPs and IPSPs evoked by PT stimuli in motoneurones, making it unlikely that premotor interneurones in pathways from group I and/or II afferents relay the earliest actions of uncrossed PT fibres on motoneurones. These interneurones might nevertheless contribute to PT actions at longer latencies. Uncrossed PT actions on interneurones were to a great extent relayed via reticulospinal neurones with axons in the ipsilateral medial longitudinal fascicle (MLF), as indicated by occlusion and mutual facilitation of actions evoked by PT and MLF stimulation. However, PT actions were also relayed by other supraspinal or spinal neurones, as some remained after MLF lesions. Mutual facilitation and occlusion of actions evoked from the ipsilateral and contralateral PTs lead to the conclusion that the same midlumbar interneurones in pathways from group I or II muscle afferents may relay uncrossed and crossed PT actions.

title: Premotor interneurones contributing to actions of feline pyramidal tract neurones on ipsilateral hindlimb motoneurones
abstract: The aim of the study was to analyse the potential contribution of excitatory and inhibitory premotor interneurones in reflex pathways from muscle afferents to actions of pyramidal tract (PT) neurones on ipsilateral hindlimb motoneurones. Disynaptic EPSPs and IPSPs evoked in motoneurones in deeply anaesthetized cats by group Ia, Ib and II muscle afferents were found to be facilitated by stimulation of the ipsilateral, as well as of contralateral, PT. The ipsilateral actions were evoked by either uncrossed or double‐crossed pathways. The results show that interneurones mediating reflex actions of muscle afferents may be activated strongly enough by PT stimulation to contribute to movements initiated by ipsilateral PT neurones and that PT actions relayed by them might be enhanced by muscle stretches and/or contractions. However, in some motoneurones disynaptic IPSPs and EPSPs evoked from group Ib or II afferents were depressed by PT stimulation. In order to analyse the basis of this depression, the transmitter content in terminals of 11 intracellularly labelled interneurones excited by PT stimulation was defined immunohistochemically and their axonal projections were reconstructed. The interneurones included 9 glycinergic and 2 glutamatergic neurones. All but one of these neurones were mono‐ or disynaptically excited by group I and/or II afferents. Several projected to motor nuclei and formed contacts with motoneurones. However, all had terminal projections to areas outside the motor nuclei. Therefore both inhibitory and excitatory interneurones could modulate responses of other premotor interneurones in parallel with direct actions on motoneurones.

title: Direct demonstration of interhemispheric inhibition of the human motor cortex produced by transcranial magnetic stimulation
abstract: Electromyographic (EMG) responses evoked in hand muscles by a magnetic test stimulus over the motor cortex can be suppressed if a conditioning stimulus is applied to the opposite hemisphere 6–30 ms earlier. In order to define the mechanism and the site of action of this inhibitory phenomenon, we recorded descending volleys produced by the test stimulus through high cervical, epidural electrodes implanted for pain relief in three conscious subjects. These could be compared with simultaneously recorded EMG responses in hand muscles. When the test stimulus was given on its own it evoked three waves of activity (I-waves) in the spinal cord, and a small EMG response in the hand. A prior conditioning stimulus to the other hemisphere suppressed the size of both the descending spinal cord volleys and the EMG responses evoked by the test stimulus when the interstimulus interval was greater than 6 ms. In the spinal recordings, the effect was most marked for the last I-wave (I3), whereas the second I2-wave was only slightly inhibited, and the first I-wave (I1) was not inhibited at all. We conclude that transcranial stimulation over the lateral part of the motor cortex of one hemisphere can suppress the excitability of the contralateral motor cortex.

title: Transcallosal connections of the distal forelimb representations of the primary and supplementary motor cortical areas in macaque monkeys
abstract: The goal of the present neuroanatomical study in macaque monkeys was twofold: (1) to clarify whether the hand representation of the primary motor cortex (M1) has a transcallosal projection to M1 of the opposite hemisphere; (2) to compare the topography and density of transcallosal connections for the hand representations of M1 and the supplementary motor area (SMA). The hand areas of M1 and the SMA were identified by intracortical microstimulation and then injected either with retrograde tracer substances in order to label the neurons of origin in the contralateral motor cortical areas (four monkeys) or, with an anterograde tracer, to establish the regional distribution and density of terminal fields in the opposite motor cortical areas (two monkeys). The main results were: (1) The hand representation of M1 exhibited a modest homotopic callosal projection, as judged by the small number of labeled neurons within the region corresponding to the contralateral injection. A modest heterotopic callosal projection originated from the opposite supplementary, premotor, and cingulate motor areas. (2) In contrast, the SMA hand representation showed a dense callosal projection to the opposite SMA. The SMA was found to receive also dense heterotopic callosal projections from the contralateral rostral and caudal cingulate motor areas, moderate projections from the lateral premotor cortex, and sparse projections from M1. (3) After injection of an anterograde tracer (biotinylated dextran amine) in the hand representation of M1, only a few small patches of axonal label were found in the corresponding region of M1, as well as in the lateral premotor cortex; virtually no label was found in the SMA or in cingulate motor areas. Injections of the same anterograde tracer in the hand representation of the SMA, however, resulted in dense and widely distributed axonal terminal fields in the opposite SMA, premotor cortex, and cingulate motor areas, while labeled terminals were clearly less dense in M1. It is concluded that the hand representations of the SMA and M1 strongly differ with respect to the strength and distribution of callosal connectivity with the former having more powerful and widespread callosal connections with a number of motor fields of the opposite cortex than the latter. These anatomical results support the proposition of the SMA being a bilaterally organized system, possibly contributing to bimanual coordination.

title: Callosal connections of dorso‐lateral premotor cortex
abstract: This study investigated the organization of the callosal connections of the two subdivisions of the monkey dorsal premotor cortex (PMd), dorso‐rostral (F7) and dorso‐caudal (F2). In one animal, Fast blue and Diamidino yellow were injected in F7 and F2, respectively; in a second animal, the pattern of injections was reversed. F7 and F2 receive a major callosal input from their homotopic counterpart. The heterotopic connections of F7 originate mainly from F2, with smaller contingent from pre‐supplementary motor area (pre‐SMA, F6), area 8 (frontal eye fields), and prefrontal cortex (area 46), while those of F2 originate from F7, with smaller contributions from ventral premotor areas (F5, F4), SMA‐proper (F3), and primary motor cortex (M1). Callosal cells projecting homotopically are mostly located in layers II–III, those projecting heterotopically occupy layers II–III and V–VI. A spectral analysis was used to characterize the spatial fluctuations of the distribution of callosal neurons, in both F7 and F2, as well as in adjacent cortical areas. The results revealed two main periodic components. The first, in the domain of the low spatial frequencies, corresponds to periodicities of cell density with peak‐to‐peak distances of approximately 10 mm, and suggests an arrangement of callosal cells in the form of 5‐mm wide bands. The second corresponds to periodicities of approximately 2 mm, and probably reflects a 1‐mm columnar‐like arrangement. Coherency and phase analyses showed that, although similar in their spatial arrangements, callosal cells projecting to dorsal premotor areas are segregated in the tangential cortical domain.

title: Callosal connections of dorsal versus ventral premotor areas in the macaque monkey: a multiple retrograde tracing study
abstract: BackgroundThe lateral premotor cortex plays a crucial role in visually guided limb movements. It is divided into two main regions, the dorsal (PMd) and ventral (PMv) areas, which are in turn subdivided into functionally and anatomically distinct rostral (PMd-r and PMv-r) and caudal (PMd-c and PMv-c) sub-regions. We analyzed the callosal inputs to these premotor subdivisions following 23 injections of retrograde tracers in eight macaque monkeys. In each monkey, 2–4 distinct tracers were injected in different areas allowing direct comparisons of callosal connectivity in the same brain.ResultsBased on large injections covering the entire extent of the corresponding PM area, we found that each area is strongly connected with its counterpart in the opposite hemisphere. Callosal connectivity with the other premotor areas, the primary motor cortex, prefrontal cortex and somatosensory cortex varied from one area to another. The most extensive callosal inputs terminate in PMd-r and PMd-c, with PMd-r strongly connected with prefrontal cortex. Callosal inputs to PMv-c are more extensive than those to PMv-r, whose connections are restricted to its counterpart area. Quantitative analysis of labelled cells confirms these general findings, and allows an assessment of the relative strength of callosal inputs.ConclusionPMd-r and PMv-r receive their strongest callosal inputs from their respective counterpart areas, whereas PMd-c and PMv-c receive strong inputs from heterotopic areas as well (namely from PMd-r and PMv-r, respectively). Finally, PMd-r stands out as the lateral premotor area with the strongest inputs from the prefrontal cortex, and only the PMd-c and PMv-c receive weak callosal inputs from M1.

title: Corpus callosum connections of subdivisions of motor and premotor cortex, and frontal eye field in a prosimian primate, Otolemur garnetti
abstract: The callosal connections of motor and premotor fields in the frontal cortex of galagos were examined by placing multiple tracers into the primary motor area (M1), dorsal premotor area (PMD), ventral premotor area (PMV), supplementary motor area (SMA), and frontal eye field (FEF) following intracortical microstimulation. Retrogradely labeled neurons in the opposite hemisphere were plotted and superimposed onto brain sections stained with myelin and cytochrome oxidase for architectonic analysis. The main callosal connections of M1 and the caudal portion of PMD (PMDc) were with homotopic sites, and the major callosal connections of the rostral portion of PMD (PMDr), SMA, and FEF were with homotopic sites and adjoining cortex in the frontal lobe. In addition, M1 forelimb representation had sparse callosal connections, whereas M1 trunk and face representations, as well as the premotor areas, had dense callosal connections. The sparse interhemispheric connections of the forelimb sector of M1 suggests that the control of each forelimb is largely from the contralateral M1 in galagos, as in other primates.  2008.

title: Frontal Lobe Inputs to the Digit Representations of the Motor Areas on the Lateral Surface of the Hemisphere
abstract: We examined the frontal lobe connections of the digit representations in the primary motor cortex (M1), the dorsal premotor area (PMd), and the ventral premotor area (PMv) of cebus monkeys. All of these digit representations lie on the lateral surface of the hemisphere. We used intracortical stimulation to identify the digit representations physiologically, and then we injected different tracers into two of the three cortical areas. This approach enabled us to compare the inputs to two digit representations in the same animal. We found that the densest inputs from the premotor areas to the digit representation in M1 originate from the PMd and the PMv. Both of these premotor areas contain a distinct digit representation, and the two digit representations are densely interconnected. Surprisingly, the projections from the digit representation in the supplementary motor area (SMA) to the PMd and PMv are stronger than the SMA projections to M1. The projections from other premotor areas to M1, the PMd, and the PMv are more modest. Of the three digit areas on the lateral surface, only the PMv receives dense input from the prefrontal cortex. Based on these results, we believe that M1, the PMd, and the PMv form a densely interconnected network of cortical areas that is concerned with the generation and control of hand movements. Overall, the laminar origins of neurons that interconnect the three cortical areas are typical of “lateral” interactions. Thus, from an anatomical perspective, this cortical network lacks a clear hierarchical organization.

title: Signal-, set-, and movement-related activity in the human premotor cortex
abstract: Single unit recording studies in non-human premotor cortex have revealed neurons with motor-related activity. Other neurons, however, seem to be involved in prior movement selection and preparation processes, and have activity related to visual instruction signals or movement preparation ('set'). We have used single pulse transcranial magnetic stimulation (TMS) to identify similar processes in human subjects. In Experiment 1 subjects performed a cued movement task while being stimulated with TMS over three sites: sensorimotor cortex, posterior premotor cortex and anterior premotor cortex. TMS slowed movements when applied at 140 ms after the visual cue over the anterior premotor site, at 180 ms after the visual cue over the posterior premotor site, and at 220 ms and later after the visual cue over the sensorimotor cortex. The results are consistent with a change from signal to movement-related processing when moving from premotor to motor cortex. In Experiment 2 there was a preparatory set period between the instruction signal that informed subjects which movement to make and the 'go' signal that informed them when to actually make the movement. TMS was applied over the anterior premotor site and the sensorimotor site during the set period. At both sites TMS had similar effects on slowing subsequent movements. The results suggest set activity in both premotor and motor cortices in human subjects.

title: Neural correlates of movement preparation in healthy ageing
abstract: Motor disorders increase dramatically with age; however, little is known about non‐clinical ageing of motor control mechanisms and their respective neural correlates. With the present experiment we aimed to study age effects on advance movement preparation, a key characteristic of motor behaviour that is known to involve premotor and primary motor circuits. The respective brain regions are subject to age‐related brain atrophy of grey and white matter, and we therefore hypothesized that motor preparation mechanisms may be altered in older persons.

title: Motor areas of the medial wall: a review of their location and functional activation.
abstract: Our goal in this review is to provide an anatomical framework for the analysis of the motor functions of the medial wall of the hemisphere in humans and laboratory primates. Converging evidence indicates that this region of the frontal lobe contains multiple areas involved in motor control. In the monkey, the medial wall contains four premotor areas that project directly to both the primary motor cortex and the spinal cord. These are the supplementary motor area (SMA) on the superior frontal gyrus and three motor areas buried within the cingulate sulcus. In addition, there is evidence that a fifth motor field, the pre-SMA, lies rostral to the SMA proper. Recent physiological observations provide evidence for functional differences among these motor fields. In the human, no consensus exists on the number of distinct motor fields on the medial wall. In this review, we summarize the results of positron emission tomography (PET) studies that examined functional activation on the medial wall of humans. Our analysis suggests that it is possible to identify at least four separate cortical areas on the medial wall. Each area appears to be relatively more involved in some aspects of motor behavior than others. These cortical areas in the human appear to be analogous to the pre-SMA, the SMA proper, and two of the cingulate motor areas of the monkey. We believe that these correspondences and the anatomical framework we describe will be important for unraveling the motor functions of the medial wall of the hemisphere.

title: Imaging the premotor areas
abstract: Recent imaging studies of motor function provide new insights into the organization of the premotor areas of the frontal lobe. The pre-supplementary motor area and the rostral portion of the dorsal premotor cortex, the 'pre-PMd', are, in many respects, more like prefrontal areas than motor areas. Recent data also suggest the existence of separate functional divisions in the rostral cingulate zone.

title: Interactions between inhibitory and excitatory circuits in the human motor cortex
abstract: Cortical activity depends on the balance between excitatory and inhibitory influences. Several different excitatory and inhibitory systems in the human motor cortex can be tested by transcranial magnetic stimulation (TMS). While considerable information is known about these different inhibitory and excitatory phenomena individually, how they are related to each other and how they interact is not well understood. Several recent studies have investigated the interactions between some of these circuits by applying them together. It has been found that short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) are mediated by different circuits. LICI appears to inhibit SICI, which may occur through presynaptic GABAB receptors. Interhemispheric inhibition elicited by stimulation of the contralateral motor cortex also inhibits SICI and may share inhibitory mechanisms with LICI. Long-interval afferent inhibition induced by median nerve stimulation inhibits LICI but does not interact with SICI. Based on these results, a model of interactions between different inhibitory systems that can be tested and refined in the future is proposed. Further studies of the interaction between different cortical inhibitory and excitatory circuits should improve our understanding of the functional organization of the motor cortex and allow better interpretation of abnormal findings in disease states. It may also be developed into a new way of studying the pathophysiology of diseases and the effects of intervention.