Timing of bimanual movements in human and non-human primates in relation to neuronal activity in primary motor cortex and supplementary motor area

It has been established that repeated presentation of a transient target motion stimulus such as a constant-velocity ramp leads to the build up of steady state (SS), anticipatory smooth pursuit eye movements after two or three presentations. Each SS response is then composed of the anticipatory component of nonvisual origin, a visual component associated with the stimulus presentation and another nonvisual component that represents the decay of the response after extinction of the stimulus. Here we investigated the interactions that occur when each motion stimulus was itself a sequence containing more than one ramp component. Ramp components had a velocity of 15 degrees /s or 30 degrees /s to left or right and were separated by gaps of 200 ms duration. In an initial experiment, responses to 2-ramp stimuli were examined and compared with responses to the single-ramp stimuli from which they were constituted. We present evidence that the anticipatory, nonvisual components of the double-ramp response result from the linear summation of the nonvisual components of the responses to the constituent single-ramp components. In a 2nd experiment, we examined responses to a wide variety of 4-ramp sequences and again found evidence that, in the SS, the responses were formed from the linear summation of the constituent single-ramp components. Regression analysis performed on the velocity at onset of each ramp component indicated that this nonvisual part of the response was predictive of the upcoming ramp component. To confirm this, unexpected changes were introduced into single ramp components of the 4-ramp sequence after at least five prior presentations of the sequence had allowed a SS response to be established. Subjects continued to initiate a response to the modified component that was appropriate in velocity and direction for the corresponding part of the previous sequence and inappropriate for the newly modified stimulus. This preprogrammed response persisted unmodified for more than 170 ms after onset of the modified ramp component. In contrast, in the second presentation of the new sequence, the anticipatory component of the response was highly correlated with the SS response of the new sequence, but not with that of the prior sequence, showing that the preprogrammed response had been modified very rapidly. Similar behaviour was observed whichever of the 4-ramp components was modified, indicating that the velocity and direction of the anticipatory response to each component had been preprogrammed. The results suggest that velocity information related to at least four elements of a sequence can be temporarily stored and subsequently released with appropriate temporal order to form an anticipatory response throughout the whole sequence.     

Further evidence for excitability changes in human primary motor cortex during ipsilateral voluntary contractions

The present study aimed to further investigate whether the intracortical neural circuits within the primary motor cortex (M1) are modulated during ipsilateral voluntary finger movements. Single- and paired-pulse (interstimulus intervals, ISIs; 3 ms and 12 ms) transcranial magnetic stimulations of the left M1 were applied to elicit motor evoked potential (MEP) in the right first dorsal interosseous (Rt-FDI) muscle during voluntary contractions (10% and 30% maximum voluntary contraction) of the left FDI (Lt-FDI) muscle. F-waves of Rt-FDI muscle were recorded under these left index-finger conditions for ensuring that the excitability changes occur at the supraspinal level. MEPs were also recorded during motor imagery of the left index-finger abduction instead of overt movement. The results showed that, in single-pulse transcranial magnetic stimulation (TMS) paradigm, MEPs in Rt-FDI muscle were markedly enhanced during voluntary contractions of Lt-FDI muscle compared with the complete resting state. In paired-pulse TMS paradigm, the short intracortical inhibition was significantly reduced in proportion to increments of the ipsilateral muscle contraction, whereas the intracortical facilitation had no change. F-wave of Rt-FDI muscle was unchanged under these conditions, while MEP in Rt-FDI muscle was also enhanced during motor imagery of the left index-finger abduction. Based on the present results, it is suggested that the intracortical inhibitory neural circuits may be modulated in the transition from rest to activity of the ipsilateral homonymous muscle. The excitability changes in M1 might be induced by overflows of voluntary drive given to the ipsilateral limb, probably via the transcallosal pathway.     

Single-unit activity related to bimanual arm movements in the primary and supplementary motor cortices

Single units were recorded from the primary motor (MI) and supplementary motor (SMA) areas of Rhesus monkeys performing one-arm (unimanual) and two-arm (bimanual) proximal reaching tasks. During execution of the bimanual movements, the task related activity of about one-half the neurons in each area (MI: 129/232, SMA: 107/206) differed from the activity during similar displacements of one arm while the other was stationary. The bulk of this "bimanual-related" activity could not be explained by any linear combination of activities during unimanual reaching or by differences in kinematics or recorded EMG activity. The bimanual-related activity was relatively insensitive to trial-to-trial variations in muscular activity or arm kinematics. For example, trials where bimanual arm movements differed the most from their unimanual controls did not correspond to the ones where the largest bimanual neural effects were observed. Cortical localization established by using a mixture of surface landmarks, electromyographic recordings, microstimulation, and sensory testing suggests that the recorded neurons were not limited to areas specifically involved with postural muscles. By rejecting this range of alternative explanations, we conclude that neural activity in MI as well as SMA can reflect specialized cortical processing associated with bimanual movements.     

Local field potentials related to bimanual movements in the primary and supplementary motor cortices

We recorded local field potentials (LFP) in primary (MI) and supplementary (SMA) motor areas of rhesus monkey cortex in order to compare movement-evoked potentials (mEP) in bimanual and unimanual movements with single-unit activity recorded concurrently. The mEP was often different during bimanual and unimanual movements (a "bimanual-related" effect), but, unlike the single units, the size of the mEP in both MI and SMA was always greater during bimanual movements than during unimanual movements. This increase primarily reflected an increase in the late positive peak of the mEP, a result that may reflect greater overall cortical activation during bimanual movements. In addition, analysis of the mEP revealed differences between MI and SMA not seen in the single-unit activity. mEP in MI had greater contralateral preference than in SMA. Also, SMA mEP was more correlated to the single-unit activity than in MI. This greater correlation was also more apparent in the late peaks of the mEP than in the early peaks and may reflect a greater influence of recurrent activation in SMA than in MI. Our results further reinforce the idea that unimanual and bimanual movements are represented differently both in MI and in SMA and also show that a complex relationship between spikes of individual neurons and LFP may reflect the different input-output relations of different cortical areas. Electronic Publication     

Evaluation of the effective connectivity of the dominant primary motor cortex during bimanual movement using Granger causality

Granger causality analysis of the whole brain, voxel-by-voxel, was applied to six right-handed subjects performing a classic bimanual movement, to describe the effective connectivity between the activated voxels in the left primary motor cortex (PMC) and other parts of the brain, by choosing the left PMC as a reference region. The results demonstrated that the left and right PMC interact during bimanual movement, and Granger causality mapping implied a possible cause–effect relationship. The supplementary motor area (SMA) and cerebellum were pre-activated during bimanual movement relative to the left PMC, confirming the prior qualitative results concerning the functions of the SMA and cerebellum in hand movements.     

Excitability of the ipsilateral motor cortex during phasic voluntary hand movement

We investigated the influence of self-paced, phasic voluntary hand movement on the excitability of the ipsilateral motor cortex. Single- and paired-pulse transcranial magnetic stimulation (TMS) was applied to the right motor cortex triggered by EMG onset of self-paced movements of individual right hand fingers at intervals ranging from 13 to 2,000 ms. Motor evoked potentials (MEPs) were evaluated in several left arm muscles. Significant suppression of MEP amplitudes was observed when TMS was applied between 35 and 70 ms after EMG onset. This inhibition was diffuse, affecting "adjacent" muscles (those near the homologous muscle in the same extremity) as well as homologous muscles, but more inhibition was observed in adjacent and distal muscles than homologous and proximal muscles. Significant inhibition of ipsilateral motor cortex was produced by index finger movements (both the extensor indicis proprius and the first dorsal interosseus), but not by little finger movement (the abductor digiti minimi). Paired-pulse TMS (at 2- and 10-ms interstimulus intervals) showed a significant increase in intracortical facilitation (ICF) selectively in the homologous muscle when triggered by self-paced movement of the opposite hand, but no change was observed in intracortical inhibition. When stimulation was triggered by self-paced movements, the silent period of the homologous muscle was significantly shortened, but the F-wave and compound muscle action potential were unchanged. Our findings demonstrate that voluntary hand movement exerts an inhibitory influence on a diffuse area of the ipsilateral motor cortex. This inhibitory influence is both time and movement dependent. The inhibitory influence is nonselective, while the facilitatory influence (enhancing ICF) appears to act selectively on the homologous muscles. These effects are most likely mediated by a transcallosal pathway. Electronic Publication     

Selective modulation of interactions between ventral premotor cortex and primary motor cortex during precision grasping in humans

In humans, the rostral part of the ventral premotor cortex (PMv), the homologue of F5 in monkeys, is known to be critically involved in shaping the hand to grasp objects. How does information about hand posture, that is processed in PMv, give rise to appropriate motor commands for transmission to spinal circuits controlling the hand? Whereas PMv is crucial for skilled visuomotor control of the hand, PMv sends relatively few direct corticospinal projections to spinal segments innervating hand muscles and the most likely route for PMv to contribute to the control of hand shape is through cortico-cortical connections with primary motor cortex (M1). If this is the case, we predicted that PMv–M1 interactions should be modulated specifically during precision grasping in humans. To address this issue, we investigated PMv–M1 connections by means of paired-pulse transcranial magnetic stimulation (TMS) and compared whether they were differentially modulated at rest, and during precision versus power grip. To do so, TMS was applied over M1 either in isolation or after a conditioning stimulus delivered, at different delays, over the ipsilateral PMv. For the parameters of TMS tested, we found that, at rest, PMv exerted a net inhibitory influence on M1 whereas, during power grip, this inhibition disappeared and was converted into a net facilitation during precision grip. The finding that, in humans, PMv–M1 interactions are selectively modulated during specific types of grasp provides further evidence that these connections play an important role in control of the hand.     

Reduced muscle selectivity during individuated finger movements in humans after damage to the motor cortex or corticospinal tract

We investigated how damage to the motor cortex or corticospinal tract affects the selective activation of finger muscles in humans. We hypothesized that damage relatively restricted to the motor cortex or corticospinal tract would result in unselective muscle activations during an individuated finger movement task. People with pure motor hemiparesis attributed to ischemic cerebrovascular accident were tested. Pure motor hemiparetic and control subjects were studied making flexion/extension and then abduction/adduction finger movements. During the abduction/adduction movements, we recorded muscle activity from 3 intrinsic finger muscles: the abductor pollicis brevis, the first dorsal interosseus, and the abductor digit quinti. Each of these muscles acts as an agonist for only one of the abduction/adduction movements and might therefore be expected to be active in a highly selective manner. Motor cortex or corticospinal tract damage in people with pure motor hemiparesis reduced the selectivity of finger muscle activation during individuated abduction/adduction finger movements, resulting in reduced independence of these movements. Abduction/adduction movements showed a nonsignificant trend toward being less independent than flexion/extension movements in the affected hands of hemiparetic subjects. These changes in the selectivity of muscle activation and the consequent decrease in individuation of movement were correlated with decreased hand function. Our findings imply that, in humans, spared cerebral motor areas and descending pathways that remain might activate finger muscles, but cannot fully compensate for the highly selective control provided by the primary motor cortex and the crossed corticospinal system.     

Interaction between finger opposition movements and aftereffects of 1Hz-rTMS on ipsilateral motor cortex

One-hertz repetitive transcranial magnetic stimulation (1Hz-rTMS) over ipsilateral motor cortex is able to modify up to 30 min the motor performance of repetitive finger opposition movements paced with a metronome at 2 Hz. We investigated whether the long-lasting rTMS effect on motor behavior can be modulated by subsequent engagement of the contralateral sensorimotor system. Motor task was performed in different experimental conditions: immediately after rTMS, 30 min after rTMS, or when real rTMS was substituted with sham rTMS. Subjects performing the motor task immediately after rTMS showed modifications in motor behavior < or =30 min after rTMS. On the other hand, when real rTMS was substituted with sham stimulation or when subjects performed the motor task 30 min after the rTMS session, the effect was no longer present. These findings suggest that the combination of ipsilateral 1Hz-rTMS and voluntary movement is crucial to endure the effect of rTMS on the movement itself, probably acting on synaptic plasticity-like mechanism. This finding might provide some useful hints for neurorehabilitation protocols.     

Olfactory inputs activate the medial entorhinal cortex via the hippocampus

The lateral and medial regions of the entorhinal cortex differ substantially in terms of connectivity and pattern of activation. With regard to olfactory input, a detailed and extensive physiological map of the olfactory projection to the entorhinal cortex is missing, even if anatomic studies suggest that the olfactory afferents are confined to the lateral and rostral entorhinal region. We studied the contribution of the medial and lateral entorhinal areas to olfactory processing by analyzing the responses induced by lateral olfactory tract stimulation in different entorhinal subfields of the in vitro isolated guinea pig brain. The pattern of synaptic activation of the medial and lateral entorhinal regions was reconstructed either by performing simultaneous multisite recordings or by applying current source density analysis on field potential laminar profiles obtained with 16-channel silicon probes. Current source density analysis demonstrated the existence of a direct monosynaptic olfactory input into the superficial 300 microm of the most rostral part of the lateral entorhinal cortex exclusively, whereas disynaptic sinks mediated by associative fibers arising from the piriform cortex were observed at 100-350 microm depth in the entire lateral aspect of the cortex. No local field responses were recorded in the medial entorhinal region unless a large population spike was generated in the hippocampus (dentate gyrus and CA1 region) by a stimulus 3-5x the intensity necessary to obtain a maximal monosynaptic response in the piriform cortex. In these conditions, a late sink was recorded at a depth of 600-1000 microm in the medial entorhinal area (layers III-V) 10.6 +/- 0.9 (SD) msec after a population spike was simultaneously recorded in CA1. Diffuse activation of the medial entorhinal region was also obtained by repetitive low-intensity stimulation of the lateral olfactory tract at 2-8 Hz. Higher or lower stimulation frequencies did not induce hippocampal-medial entorhinal cortex activation. These results suggest that the medial and the lateral entorhinal regions have substantially different roles in processing olfactory sensory inputs.     

Modulation of short-latency intracortical inhibition in human primary motor cortex during synchronised versus syncopated finger movements

Rhythmic movements are inherently more stable and easier to perform when they are synchronised with a periodic stimulus, as opposed to syncopated between the beats of a pacing stimulus. Although this behavioural phenomenon is well documented, its neurophysiological basis is poorly understood. In a first experiment, we demonstrated that all healthy subjects (N=8) performing index finger abduction in time with an auditory metronome exhibited transitions from syncopation to synchronisation when the metronome tempo was scaled from 0.8 to 2.0 Hz. Subjects' mean transition frequency was 1.7+/-0.2 Hz. In a second experiment, we used paired-pulse transcranial magnetic stimulation to examine short-latency intracortical inhibition (sICI) directed towards the first dorsal interosseous (FDI) muscle in healthy subjects (N=9) who made synchronised and syncopated phasic finger movements in time with metronome pacing of 1.0 Hz. Despite the equivalence between the patterns in terms of task performance and corticospinal excitability of FDI at this movement frequency, there was significantly greater sICI during syncopation than during synchronisation. From this result, we infer that the stability of movement patterns may be contingent upon excitability of inhibitory networks within primary motor cortex.     

Somatotopically arranged inputs from putamen and subthalamic nucleus to primary motor cortex

Employing retrograde transsynaptic transport of rabies virus, we investigated the organization of basal ganglia inputs to hindlimb, proximal and distal forelimb, and orofacial representations of the macaque primary motor cortex (MI). Four days after rabies injections into these MI regions, neuronal labeling occurred in the striatum and the subthalamic nucleus (STN) through the cortico-basal ganglia loop circuits. In the striatum, two distinct sets of the labeling were observed: one in the dorsal putamen, and the other in the ventral striatum (ventromedial putamen and nucleus accumbens). The dorsal striatal labeling was somatotopically arranged and its distribution pattern was in good accordance with that of the corticostriatal inputs, such that the hindlimb, orofacial, or forelimb area was located in the dorsal, ventral, or intermediate zone of the putamen, respectively. The distribution pattern of the ventral striatal labeling was essentially the same in all cases. In the STN, the somatotopic arrangement of labeled neurons was in register with that of corticosubthalamic inputs. The present results suggest that the cortico-basal ganglia motor circuits involving the dorsal putamen and the STN may constitute separate closed loops based on the somatotopy, while the ventral striatum provides common multisynaptic projections to all body-part representations in the MI.     

Influence of the supplementary motor area on primary motor cortex excitability during movements triggered by neutral or emotionally unpleasant visual cues

The stronger anatomo-functional connections of the supplementary motor area (SMA), as compared with premotor area (PM), with regions of the limbic system, suggest that SMA could play a role in the control of movements triggered by visual stimuli with emotional content. We addressed this issue by analysing the modifications of the excitability of the primary motor area (M1) in a group of seven healthy subjects, studied with transcranial magnetic stimulation (TMS), after conditioning TMS of SMA, during emotional and non-emotional visually cued movements. Conditioning TMS of the PM or of contralateral primary motor cortex (cM1) were tested as control conditions. Single-pulse TMS over the left M1 was randomly intermingled with paired TMS, in which a conditioning stimulation of the left SMA, left PM or right M1 preceded test stimulation over the left M1. The subjects carried out movements in response to computerised visual cues (neutral pictures and pictures with negative emotional content). The amplitudes of motor-evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle after paired TMS were measured and compared with those obtained after single-pulse TMS of the left M1 under the various experimental conditions. Conditioning TMS of the SMA in the paired-pulse paradigm selectively enhanced MEP amplitudes in the visual-emotional triggered movement condition, compared with single-pulse TMS of M1 alone or with paired TMS during presentation of neutral visual cues. On the other hand, conditioning TMS of the PM or cM1 did not differentially influence MEP amplitudes under visual-emotional triggered movement conditions. This pattern of effects was related to the intensity of the conditioning TMS over the SMA, being most evident with intensities ranging from 110% to 80% of motor threshold. These results suggest that the SMA in humans could interface the limbic and the motor systems in the transformation of emotional experiences into motor actions. Electronic Publication     

Differential relation of discharge in primary motor cortex and premotor cortex to movements versus actively maintained postures during a reaching task

The activity of cells in primary motor cortex (MI) and dorsal premotor cortex (PMd) were compared during reaching movements in a reaction-time (RT) task, without prior instructions, which required precise control of limb posture before and after movement. MI neurons typically showed strong, directionally tuned activity prior to and during movement as well as large gradations of tonic activity while holding the limb over different targets. The directionality of their movementand posture-related activity was generally similar. Proximal-arm muscles behaved similarly. This is consistent with a role for MI in the moment-to-moment control of motor output, including both movement and actively maintained postures, and suggests a common functional relation for MI cells to both aspects of motor behavior. In contrast, PMd cells were generally more phasic, frequently emitting only strong bursts of activity confined mainly to the behavioral reaction time before movement onset. PMd tonic activity during different postures was generally weaker than in MI, and showed a much more variable relation with their movement-related directional tuning. These results imply that the major contribution of PMd to this RT task occurred prior to the onset of movement itself, consistent with a role for PMd in the selection and planning of visually guided movements. Furthermore, the nature of the relative contribution of PMd to movement versus actively maintained postures appears to be fundamentally different from that in MI. Finally, there was a continuous gradient of changes in responses across the rostrocaudal extent of the precentral gyrus, with no abrupt transition in response properties between PMd and MI.     

Cone inputs in macaque primary visual cortex

To understand the role of primary visual cortex (V1) in color vision, we measured directly the input from the 3 cone types in macaque V1 neurons. Cells were classified as luminance-preferring, color-luminance, or color-preferring from the ratio of the peak amplitudes of spatial frequency responses to red/green equiluminant and to black/white (luminance) grating patterns, respectively. In this study we used L-, M-, and S-cone-isolating gratings to measure spatial frequency response functions for each cone type separately. From peak responses to cone-isolating stimuli we estimated relative cone weights and whether cone inputs were the same or opposite sign. For most V1 cells the relative S-cone weight was <0.1. All color-preferring cells were cone opponent and their L/M cone weight ratio was clustered around a value of -1, which is roughly equal and opposite L and M cone signals. Almost all cells (88%) classified as luminance cells were cone nonopponent, with a broad distribution of cone weights. Most cells (73%) classified as color-luminance cells were cone opponent. This result supports our conclusion that V1 color-luminance cells are double-opponent. Such neurons are more sensitive to color boundaries than to areas of color and thereby could play an important role in color perception. The color-luminance population had a broad distribution of L/M cone weight ratios, implying a broad distribution of preferred colors for the double-opponent cells.     

Mapping of direction and muscle representation in the human primary motor cortex controlling thumb movements

Larger body parts are somatotopically represented in the primary motor cortex (M1), while smaller body parts, such as the fingers, have partially overlapping representations. The principles that govern the overlapping organization of M1 remain unclear. We used transcranial magnetic stimulation (TMS) to examine the cortical encoding of thumb movements in M1 of healthy humans. We performed M1 mapping of the probability of inducing a thumb movement in a particular direction and used low intensity TMS to disturb a voluntary thumb movement in the same direction during a reaction time task. With both techniques we found spatially segregated representations of the direction of TMS-induced thumb movements, thumb flexion and extension being best separated. Furthermore, the cortical regions corresponding to activation of a thumb muscle differ, depending on whether the muscle functions as agonist or as antagonist for flexion or extension. In addition, we found in the reaction time experiment that the direction of a movement is processed in M1 before the muscles participating in it are activated. It thus appears that one of the organizing principles for the human corticospinal motor system is based on a spatially segregated representation of movement directions and that the representation of individual somatic structures, such as the hand muscles, overlap.