New modalities of brain stimulation for stroke rehabilitation.

Stroke is a leading cause of disability, and the number of stroke survivors continues to rise. Traditional neurorehabilitation strategies aimed at restoring function to weakened limbs provide only modest benefit. New brain stimulation techniques designed to augment traditional neurorehabilitation hold promise for reducing the burden of stroke-related disability. Investigators discovered that repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and epidural cortical stimulation (ECS) can enhance neural plasticity in the motor cortex post-stroke. Improved outcomes may be obtained with activity-dependent stimulation, in which brain stimulation is contingent on neural or muscular activity during normal behavior. We review the evidence for improved motor function in stroke patients treated with rTMS, tDCS, and ECS and discuss the mediating physiological mechanisms. We compare these techniques to activity-dependent stimulation, discuss the advantages of this newer strategy for stroke rehabilitation, and suggest future applications for activity-dependent brain stimulation.

Decoupling the cortical power spectrum reveals real-time representation of individual finger movements in humans.

During active movement the electric potentials measured from the surface of the motor cortex exhibit consistent modulation, revealing two distinguishable processes in the power spectrum. At frequencies <40 Hz, narrow-band power decreases occur with movement over widely distributed cortical areas, while at higher frequencies there are spatially more focal power increases. These high-frequency changes have commonly been assumed to reflect synchronous rhythms, analogous to lower-frequency phenomena, but it has recently been proposed that they reflect a broad-band spectral change across the entire spectrum, which could be obscured by synchronous rhythms at low frequencies. In 10 human subjects performing a finger movement task, we demonstrate that a principal component type of decomposition can naively separate low-frequency narrow-band rhythms from an asynchronous, broad-spectral, change at all frequencies between 5 and 200 Hz. This broad-spectral change exhibited spatially discrete representation for individual fingers and reproduced the temporal movement trajectories of different individual fingers.

Operant conditioning of cortical unit activity.

The activity of single neurons in precentral cortex of unanesthetized monkeys (Macaca mulatta) was conditioned by reinforcing high rates of neuronal discharge with delivery of a food pellet. Auditory or visual feedback of unit firing rates was usually provided in addition to food reinforcement. After several training sessions, monkeys could increase the activity of newly isolated cells by 50 to 500 percent above rates before reinforcement.

Language-related potentials specific to human language cortex.

Event-related potentials following silently named object pictures were recorded directly from the exposed left hemisphere of the human cortex at sites whose relation to naming was subsequently established by electrical stimulation mapping. Two simultaneous potential changes are specific to sites where stimulation disrupts naming: slow potentials as premotor sites and focal desynchronization at posterior sites surrounding the Sylvian fissure. These anatomically specific changes are also specific to the task--present with silent naming and absent in a spatial task with the same visual input. Overt speech is also preceded by slow potentials with earliest onset at premotor sites.

Operant conditioning of specific patterns of neural and muscular activity.

In awake monkeys we recorded activity of single "motor" cortex cells, four contralateral arm muscles, and elbow position, while operantly reinforcing several patterns of motor activity. With the monkey's arm held semiprone in a cast hinged at the elbow, we reinforced active elbow movements and tested cell responses to passive elbow movements. With the cast immobilized we reinforced isometric contraction of each of the four muscles in isolation, and bursts of cortical cell activity with and without simultaneous suppression of muscle activity. Correlations between a precentral cell and specific arm muscles consistently appeared under several behavioral conditions, but could be dissociated by reinforcing cell activity and muscle suppression.

Cortical mechanisms controlling limb movement.

Significant advances have been made this past year toward understanding the anatomy and physiology of motor cortical regions. New anatomical tracing techniques have elucidated intrinsic cortical connections as well as inter-areal connectivity. Magnetic stimulation of human cortex has provided new insights about the pathways mediating movements in humans. Neural recording studies in animals have further explored the behavioral variables that may be coded in activity of single units and populations. Recent approaches to neural network modeling offer some hope of synthesizing this wealth of detail into working simulations of networks that mediate motor behavior.

Functions of mammalian spinal interneurons during movement.

The major recent advances in understanding the role of spinal neurons in generating movement include new information about the modulation of classic reflex pathways during fictive locomotion and in response to pharmacological probes. The possibility of understanding movements in terms of spinal representations of a basic set of movement primitives has been extended by the analysis of normal reflexes. Recordings of the activity of cervical interneurons in behaving monkeys has elucidated their contribution to generating voluntary movement and revealed their involvement in movement preparation.

Response properties of spinal interneurons in awake, behaving primates.

This paper reviews studies on spinal interneurons in awake, behaving monkeys inspired by the work of Prof Patrick D. Wall. Early studies documented the sensory responses of spinal interneurons in unanesthetized monkeys to natural cutaneous and proprioceptive stimulation. More recently, cervical interneurons were documented in monkeys performing an active step-tracking task. During alternating wrist movements, most task-related interneurons showed bidirectional activity, firing during both flexion and extension (in surprising contrast to the unidirectional activity of muscles and corticomotoneuronal cells). Premotor interneurons were identified by post-spike effects in spike-triggered averages of forelimb muscle activity. The cells' post-spike effects were generally congruent with their activity in their preferred direction, although many fired during components of movement when their output effects would seem inappropriate. In an instructed delay period task many interneurons showed preparatory delay period activity, much like cortical neurons. Other studies tested the excitability of corticospinal axons to electrical stimulation and demonstrated both post-spike and task-related modulations in excitability. Together, these studies suggest that many behavioral functions of spinal interneurons remain to be revealed by recording their activity in awake, behaving animals.

Distributed processing in the motor system: spinal cord perspective.

Recordings of spinal INs during a flexion/extension wrist task with an instructed delay period have shown directly that many spinal neurons modulate their rate during the preparatory period soon after a visual cue. The onset time and the relation between the delay period activity of spinal INs and the ensuing movement response suggest that this type of activity is not simply related to the forthcoming motor action, but rather reflects a correct match between the visual cue and the motor response. The existence of such activity further supports the notion that the motor system operates in a parallel mode of processing, so that even during early stages of motor processing multiple centers are activated regardless of their anatomical distance from muscles. The firing properties of spinal INs during the performance of the task seem to differ from the comparable properties of motor cortical cells. Spinal INs fire in a highly regular manner--their CV is substantially lower than the observed CV of cortical cells. Also, although neighboring cells tend to have similar response properties, the frequency of significant correlation is lower than for cortical cells and the anatomical extent of the correlation seems to be narrower. The similarity and differences between cortical and spinal cells in terms of response and firing properties suggests that while both type of cells are active in parallel throughout the behavioral phases of the motor task, each may operate in a different mode of information processing.

Control of forelimb muscle activity by populations of corticomotoneuronal and rubromotoneuronal cells.

We review and synthesize evidence on the activity of corticomotoneuronal (CM) and rubromotoneuronal (RM) cells and single motor units in forearm muscles in monkeys performing alternating wrist movements. The CM and RM cells were identified by post-spike facilitation of rectified forelimb EMG activity. RM cells facilitated more muscles per cell (mean: 3.0 of 6 synergist muscles) than CM cells (2.4/6). Both groups had "reciprocal" cells which also suppressed antagonists of their facilitated target muscles. Unlike CM cells, some RM cells cofacilitated flexor and extensor muscles (5.8 or 12 muscles). During performance of a standard ramp-and-hold force tracking task the firing patterns of CM and RM cells, as well as single motor units, fell into distinct response types. Each population had phasic-tonic and tonic cells. Unique to the CM population were cells whose discharge increased during the static hold period; unique to RM cells were bidirectionally responsive and unmodulated neurons. Many motor units showed decrementing discharge. To estimate the ensemble activities of these populations the response histograms of different cells were summed (with force ramps aligned) in proportion to the relative frequency of each cell type. The population response histogram of CM cells was phasic-tonic, consistent with the predominant response type. The population response of RM cells was also phasic-tonic, but showed a shallower phasic modulation relative to discharge that was sustained during both directions of movement. The population histogram of motor units of a muscle was proportional to the average of rectified multiunit EMG, and typically exhibited decrementing activity during the static hold. The effects of excitatory postsynaptic potentials (EPSPs) on firing probability of motoneurons previously documented in intracellular studies are combined with the mean firing rates in the population histograms and the known amplitudes of CM-EPSPs and RM-EPSPs to infer the relative contributions of the supraspinal cells to tonic discharge of active motoneurons. This analysis suggests that for intermediate levels of force, the CM cells would increment motoneuron discharge by about 9 impulses/second (i.p.s.) and RM cells by about 2.4 i.p.s. The analysis also reveals differences in the population activity of CM and RM cells compared to their target motoneurons, which may be due to other input cells and to recruitment properties of motoneurons.

Synaptic interactions mediating synchrony and oscillations in primate sensorimotor cortex.

The appearance of oscillatory modes of 'gamma' activity in many cortical areas of different species has generated interest in understanding their underlying mechanisms and possible functions. This paper reviews evidence from studies on primate motor cortex showing that oscillatory activity entrains many neurons during periods of exploratory manipulative behavior. These oscillatory episodes synchronize widely spread neurons in sensorimotor cortex bilaterally, including descending corticospinal neurons, as evidenced by correlated modulations in EMG activity. The resulting neural synchronization involves task-related and -unrelated neurons similarly, suggesting that it is more likely to play some global role in attention than mediating any obvious interactions involved in coordinating movements. Intracellular recordings have elucidated the strength and types of synaptic interactions between motor cortical neurons that are involved in both normal and oscillatory activity. Spike-triggered averages (STAs) of intracellular membrane potentials have revealed serial connections in the form of unitary excitatory and inhibitory post-synaptic potentials (EPSPs and IPSPs). More commonly, STAs showed large synchronous excitatory or inhibitory potentials (ASEPs and ASIPs) beginning before the trigger spike and composed of multiple unitary events. ASEPs involved synchronous activity in a larger and more widespread group of presynaptic neurons than ASIPs. During oscillatory episodes synchronized excitatory and inhibitory synaptic potentials occurred in varying proportions. EPSPs evoked by stimulating neighboring cortical sites during the depolarizing phase of spontaneous oscillations showed evidence of transient potentiation. These observations are consistent with several functional hypotheses, but fit best with a possible role in attention or arousal.

Encoding of motor parameters by corticomotoneuronal (CM) and rubromotoneuronal (RM) cells producing postspike facilitation of forelimb muscles in the behaving monkey.

This paper compares the properties of corticomotoneuronal (CM) and rubromotoneuronal (RM) cells identified by postspike facilitation (PSF) of rectified EMG activity in the awake monkey. The postspike effects of CM and RM cells in flexors and extensors of the wrist and fingers have been determined, as have the discharge properties of these cells in relation to alternating ramp-and-hold wrist movements. The characteristics of postspike facilitation and postspike suppression (PSS) were similar for RM and CM cells. The magnitude of RM-PSF was weaker than CM-PSF and RM cells showed a stronger preference for facilitation of extensor muscles than CM cells. As with CM cells, the onset of discharge in RM cells preceded the onset of EMG activity in their target muscles. Tonic discharge related to static torque was more prominent in CM cells, whereas phasic discharge was more prominent in RM cells; however, many RM cells showed some tonic activity weakly related to static torque. We conclude that CM and RM cells share many common features; however, RM cells are concerned primarily with the dynamics of muscle contraction.

Responses of primate locus coeruleus and subcoeruleus neurons to stimulation at reinforcing brain sites and to natural reinforcers.

In alert rhesus monkeys the activity of 64-neurons was recorded in the locus coeruleus and subcoeruleus region, collectively referred to as coeruleus (C) neurons. C neurons were identified physiologically by antidromic activation from electrodes in the medial forebrain bundle (MFB) and medial septal nucleus which sustained intracranial self-stimulation (ICSS) behavior, and/or anatomically by their proximity to microlesions at unit recording sites. The following results were obtained: (1) the current intensity that supported the highest rate of MFB and septal ICSS was similar to the current intensity for evoking antidromic responses in C neurons; (2) stimulation in the vicinity of the dopaminergic neurons of nucleus A10 did not activate C neurons; (3) C neurons were antidromically activated by ipsilateral and contralateral MFB shocks; (4) the C axons had slow estimated conduction velocities (1-5 m/sec), and a mean neural refractory period of 0.8 msec; (5) the behaviorally determined refractory period for MFB ICSS was also approximately 0.8 msec; and (6) mean firing rates while the monkey sat quietly were 15 +/- 2 Hz (S.D.) for subcoeruleus cells and 5 +/- 3 Hz for locus coeruleus cells, and activity of most cells changed negligibly during operant responding for apple-sauce reinforcement. These results suggest that the reinforcing effects of ICSS may be mediated by activation of coeruleus cells, but that these cells do not appear to be strongly involved in operant responding for natural reinforcers.

Intracortical connectivity revealed by spike-triggered averaging in slice preparations of cat visual cortex.

Intracortical connectivity was studied in slice preparations of cat's visual cortex by spike-triggered averaging. The experiments documented the unitary postsynaptic potentials underlying the inhibitory and excitatory connections from layer III-IV border cells to supragranular cells, as demonstrated previously by cross-correlation studies. In addition the analysis demonstrated the existence of two excitatory connections, between supragranular and layer V cells, that were not detectable in previous cross-correlation studies.

Increased gamma-range activity in human sensorimotor cortex during performance of visuomotor tasks.

OBJECTIVE: We documented changes in spectral power of human electrocorticograms (ECoG) during performance of sensorimotor tasks. METHODS: In 6 human subjects, ECoGs were recorded simultaneously from 14 subdural cortical sites in forearm sensorimotor cortex. The subjects performed 3 visuomotor tasks: tracking a moving visual target with a joystick-controlled cursor, threading pieces of tubing, and pinching the fingers sequentially against the thumb. Control conditions consisted of passive resting and active extension of the wrist. For each site the spectral power of the ECoG during these behaviors was computed for 5 10 Hz ranges between 10 and 60 Hz. RESULTS: All subjects showed power decreases in the range of 11-20 Hz and power increases in the 31-60 Hz range during performance of the visuomotor tasks, at sites in forearm sensorimotor cortex and adjacent areas. Simple wrist movements often produced little change in power. Three subjects showed episodes of explicit gamma oscillations during the visuomotor tasks. Different sites showed increases in gamma-range power for different tasks, indicating that the spatial distribution of the gamma activity is specific to the tasks. Cross-spectra showed that gamma activity could become synchronized between separate sites during particular tasks. CONCLUSIONS: Synchronized gamma-range activity in human sensorimotor cortex increases with performance of manipulative visuomotor tasks, supporting the hypothesis that coherent gamma oscillations may play a role in sensorimotor integration or attention.

Effects of synchrony between primate corticomotoneuronal cells on post-spike facilitation of muscles and motor units.

Cross-correlating the activity of neighboring motor cortex neurons recorded with independent electrodes in behaving monkeys has revealed synchronization peaks, largely due to common synaptic input. Corticomotoneuronal (CM) cells produced post-spike facilitation (PSF) of rectified forearm electromyograms (EMG); 15 cells synchronized with CM cells showed no PSF. Five pairs of CM cells with overlapping muscle fields exhibited similar synchrony peaks. The contribution of this synchrony to facilitation of common target muscles was assessed by two new methods: selective spike-triggered averaging and convolution. They showed that the PSF is composed predominantly of effects mediated by output of the triggering cell, but may include a broad, shallow component mediated by synchrony with other CM cells.

Oscillatory activity in forelimb muscles of behaving monkeys evoked by microstimulation in the cerebellar nuclei.

Coherent 20-35 Hz (beta) oscillations are a prominent feature of activity in primary motor cortex and muscles of monkeys and humans performing voluntary movements. We found that coherent beta oscillations are also present in the cerebellar nuclei (CN). Two monkeys were operantly conditioned to perform a wrist flexion/extension step-tracking task while we recorded neuronal activity or microstimulated in CN and recorded EMG activity from forelimb muscles. Coherent beta oscillations were found between discharges of some CN neurons and tonically active shoulder, elbow and wrist/finger flexion and extension muscles. Similarly, localized microstimulation pulses in CN evoked transient beta oscillations in widespread forelimb muscles. We conclude that coherent motor system beta oscillations are present in CN and that CN may be an important nodal point for the generation and/or propagation of beta oscillations throughout the motor system.

Changes in power and coherence of brain activity in human sensorimotor cortex during performance of visuomotor tasks.

Electrocorticograms (ECoG) were recorded using subdural grid electrodes in forearm sensorimotor cortex of six human subjects. The subjects performed three visuomotor tasks, tracking a moving visual target with a joystick-controlled cursor; threading pieces of tubing; and pinching the fingers sequentially against the thumb. Control conditions were resting and active wrist extension. ECoGs were recorded at 14 sites in hand- and arm-sensorimotor area, functionally identified with electrical stimulation. For each behavior we computed spectral power of ECoG in each site and coherence in all pair-wise sites. In three out of six subjects, gamma-oscillations were observed when the subjects started the tasks. All subjects showed widespread power decrease in the range of 11-20 Hz and power increase in the 31-60 Hz ranges during performance of the visuomotor tasks. The changes in gamma-range power were more vigorous during the tracking and threading tasks compared with the wrist extension. Coherence analysis also showed similar task-related changes in coherence estimates. In contrast to the power changes, coherence estimates increased not only in gamma-range but also at lower frequencies during the manipulative visuomotor tasks. Paired sites with significant increases in coherence estimates were located within and between sensory and motor areas. These results support the hypothesis that coherent cortical activity may play a role in sensorimotor integration or attention.