Combined endogenous and exogenous disinhibition of intracortical circuits augments plasticity induction in the human motor cortex

BackgroundMotor imagery (MI) engages cortical areas in the human brain similar to motor practice. Corticospinal excitability (CSE) is facilitated during but not after MI practice. We hypothesized that lasting CSE changes could be achieved by associatively pairing this endogenous modulation with exogenous stimulation of the same intracortical circuits.MethodsWe combined MI with a disinhibition protocol (DIS) targeting intracortical circuits by paired-pulse repetitive transcranial magnetic stimulation in one main and three subsequent experiments. The follow-up experiments were applied to increase effects, e.g., by individualizing inter-stimulus intervals, adding neuromuscular stimulation and expanding the intervention period. CSE was captured during (online) and after (offline) the interventions via input-output changes and cortical maps of motor evoked potentials. A total of 35 healthy subjects (mean age 26.1 ± 2.6 years, 20 females) participated in this study.ResultsA short intervention (48 stimuli within ∼90s) increased CSE. This plasticity developed rapidly, was associative (with MI_on, but not MI_off or REST) and persisted beyond the intervention period. Follow-up experiments revealed the relevance of individualizing inter-stimulus intervals and of consistent inter-burst periods for online and offline effects, respectively. Expanding this combined MI/DIS intervention to 480 stimuli amplified the sustainability of CSE changes. When concurrent neuromuscular electrical stimulation was applied, the plasticity induction was cancelled.ConclusionsThis novel associative stimulation protocol augmented plasticity induction in the human motor cortex within a remarkably short period of time and in the absence of active movements. The combination of endogenous and exogenous disinhibition of intracortical circuits may provide a therapeutic backdoor when active movements are no longer possible, e.g., for hand paralysis after stroke.     

Retinotopic mapping of the primary visual cortex - a challenge for MEG imaging of the human cortex

Magnetoencephalography (MEG) can be used to reconstruct neuronal activity with high spatial and temporal resolution. However, this reconstruction problem is ill-posed, and requires the use of prior constraints in order to produce a unique solution. At present there are a multitude of inversion algorithms, each employing different assumptions, but one major problem when comparing the accuracy of these different approaches is that often the true underlying electrical state of the brain is unknown. In this study, we explore one paradigm, retinotopic mapping in the primary visual cortex (V1), for which the ground truth is known to a reasonable degree of accuracy, enabling the comparison of MEG source reconstructions with the true electrical state of the brain. Specifically, we attempted to localize, using a beanforming method, the induced responses in the visual cortex generated by a high contrast, retinotopically varying stimulus. Although well described in primate studies, it has been an open question whether the induced gamma power in humans due to high contrast gratings derives from V1 rather than the prestriate cortex (V2). We show that the beanformer source estimate in the gamma and theta bands does vary in a manner consistent with the known retinotopy of V1. However, these peak locations, although retinotopically organized, did not accurately localize to the cortical surface. We considered possible causes for this discrepancy and suggest that improved MEG/magnetic resonance imaging co-registration and the use of more accurate source models that take into account the spatial extent and shape of the active cortex may, in future, improve the accuracy of the source reconstructions.     

Evaluations of combined premotor and supplementary motor cortex lesions on a visually guided arm movement

The kinematics of a visually guided, multi-joint arm movement were examined before and after combined bilateral premotor and supplementary motor cortex lesions. Two rhesus monkeys were trained to move a manipulandum from a start zone to one of three equally spaced target zones and then return to the initial start zone. Various features of the movement trajectory including space error, time error, peak velocity and turnaround time were quantified and analyzed before and after the premotor and supplementary motor cortex ablations. Statistical analysis showed no major differences in the trajectories toward or away from the target between the pre- and postlesion state. The major difference following the ablation was increase in the time spent in the target zone, reflecting an increase in time spent in redirecting the trajectory. Normalization of the movement duration revealed a slight delay in the initial part of the movement. These results suggest the premotor and supplementary motor cortex are involved in redirecting the trajectory and/or obtaining the target zone during the execution of a complex movement.     

The functional role of the ventral premotor cortex in a visually paced finger tapping task: a TMS study

The accurate control of timed actions is a fundamental aspect of our daily activities. Repetitive movements can be either self-paced or synchronized with an external stimulus. Finger tapping (FT) is a suitable task to study the mechanisms of motor timing in both conditions. The neuronal network supporting motor timing in FT tasks comprises the lateral cerebellum, the lateral and mesial premotor areas as well as parietal sites. It has been suggested that lateral premotor cortices (PMC) are involved in time representation and sensorimotor transformations needed for synchronization. Most studies have focused on the dorsal aspect of PMC (dPMC) whereas the ventral PMC (vPMC) function has been poorly investigated. Here we used an online transcranial magnetic stimulation (TMS) protocol to probe the role of vPMC in an FT task, as compared to a functionally relevant site (dPMC) and an unrelated one. According to the synchronization-continuation paradigm, subjects had to synchronize their tapping to a periodic continuous visual stimulus, and then continue without the external pacer. Two different visual pacers were used: a tapping finger and a hinged tilting bar. We show that TMS reduced the synchronization error when delivered to the vPMC. This effect was larger when the more abstract hinged tilting bar was used as a pacer instead of the finger. No effects were observed in the continuation phase. We hereby offer the first online-TMS evidence of the involvement of vPMC in visually cued FT tasks.     

Action-sound coincidences suppress evoked responses of the human auditory cortex in EEG and MEG

The N1 auditory ERP and its magnetic counterpart (N1[m]) are suppressed when elicited by self-induced sounds. Because the N1(m) is a correlate of auditory event detection, this N1 suppression effect is generally interpreted as a reflection of the workings of an internal forward model: The forward model captures the contingency (causal relationship) between the action and the sound, and this is used to cancel the predictable sensory reafference when the action is initiated. In this study, we demonstrated in three experiments using a novel coincidence paradigm that actual contingency between actions and sounds is not a necessary condition for N1 suppression. Participants performed time interval production tasks: They pressed a key to set the boundaries of time intervals. Concurrently, but independently of keypresses, a sequence of pure tones with random onset-to-onset intervals was presented. Tones coinciding with keypresses elicited suppressed N1(m) and P2(m), suggesting that action-stimulus contiguity (temporal proximity) is sufficient to suppress sensory processing related to the detection of auditory events.     

Functional properties of the primary motor cortex and ventral premotor cortex in the monkey during a visually guided jaw-movement task with a delay period

This study investigated single neuronal activity in the face area of the primary motor cortex (MI) and ventral part of the premotor cortex (PMv) while a monkey performed a visually guided jaw-movement task with a delay period. When the monkey executed the jaw movements, 48 MI and 53 PMv neurons showed statistically significant activities time-locked to jaw movements and were defined as movement-related neurons. The activities of movement-related neurons could be classified into phasic, phasic-tonic and tonic patterns based on the changes in discharge rate. Most of the neurons exhibiting phasic and phasic-tonic activities probably contributed to the initiation of jaw movements, since they exhibited transient responses immediately after the onset of the go-cue indicating the jaw movement. In contrast, the sustained activity of the movement-related neurons exhibiting phasic-tonic and tonic activities may be involved in controlling and/or maintaining jaw position. Sustained activity was also detected during the delay period in 4 MI and 29 PMv neurons and these neurons were defined as set-related neurons. It is thought that these set-related neurons are involved in the preparation for the subsequent jaw movement, since the masticatory muscles showed no significant changes during the delay period. These findings suggest that the MI may be involved predominantly in the initiation and control of jaw movements, and that the PMv may be involved in motor preparation, and may play a role as a higher-order motor area related to the initiation and control of jaw movements.     

Bilateral neuromagnetic activation of human primary sensorimotor cortex in preparation and execution of unilateral voluntary finger movements

Extracranial magnetoencephalographic activity was separately recorded (25 channels) from bilateral primary sensorimotor cortex (M1-S1) of normal right-handers during unilateral finger movements. Standard dipole analysis indicated only a contralateral M1-S1 source for first movement-evoked field (MEF1) peaking at about 115 ms after electromyographic onset. However, the subtraction of the magnetic field generated by this source from the recorded magnetic field disclosed a low-amplitude ipsilateral central-parietal MEF1 that was explained by an ipsilateral M1-S1 source.     

Operant conditioning of single unit activity in parietal cortex

Two rhesus monkeys were trained to control firing patterns of single neurons in parietal cortex (areas 1, 2, 3, 5, 7) using an operant task previously applied to the study of precental units. Twenty-four of 56 (43%) postcentral cells were controlled in contrast to 71 of 136 (52%) precentral units from these and 4 other rhesus monkeys. In addition, monkeys were able to drive precentral units to more sustained tonic firing rates than they could parietal units.An analysis of interspike interval (ISI) distributions showed that, in contrast to precentral units with modal ISIs of 25–50 ms, 50% of parietal units have modal ISIs of 2 ms. Such short ISIs may account for fewer postcentral units reaching control criteria for this particular operant task. Other factors that may contribute to the reduced control of postcentral cells are discussed, particularly the more complex afferent connections to parietal units when compared to precentral pyramidal tract neurons.The data indirectly support conclusions from previous studies that imply that operant control of cortical units is peripherally mediated and does not primarily involve a ‘central’ or ‘open loop’ system.     

Transcranial direct current stimulation of the motor cortex induces distinct changes in thermal and mechanical sensory percepts

Objective

The aim of this single-blinded, complete crossover study was to evaluate the effects of tDCS on thermal and mechanical perception, as assessed by quantitative sensory testing (QST).

Methods

QST was performed upon the radial part of both hands of eight healthy subjects (3 female, 5 male, 25–41 years of age). These subjects were examined before and after cathodal, anodal or sham tDCS, applied in a random order. TDCS was administered for 15 min at a 1 mA current intensity, with the active electrode placed over the left primary motor cortex and the reference electrode above the right orbit.

Results

After cathodal tDCS, cold detection thresholds (CDT), mechanical detection thresholds (MDT), and mechanical pain thresholds (MPT) significantly increased in the contralateral hand, when compared to the baseline condition.

Conclusions

Cathodal tDCS temporarily reduced the sensitivity to A-fiber mediated somatosensory inputs.

Significance

Impairment of these somatosensory percepts suggests a short-term suppression of lemniscal or suprathalamic sensory pathways following motor cortex stimulation by cathodal tDCS.     

Benefit of simultaneous recording of EEG and MEG in dipole localization

PURPOSE: In this study, we tried to show that EEG and magnetoencephalography (MEG) are clinically complementary to each other and that a combination of both technologies is useful for the precise diagnosis of epileptic focus. METHODS: We recorded EEGs and MEGs simultaneously and analyzed dipoles in seven patients with intractable localization-related epilepsy. MEG dipoles were analyzed by using a BTI Magnes 148-channel magnetometer. EEG dipoles were analyzed by using a realistically shaped four-layered head model (scalp-skull-fluid-brain) built from 2.0-mm slice magnetic resonance imaging (MRI) images. RESULTS: (a) In two of seven patients, MEG could not detect any epileptiform discharges, whereas EEG showed clear spikes. However, dipoles estimated from the MEG data corresponding to the early phase of EEG spikes clustered at a location close to that of the EEG-detected dipole. (b) In two of seven patients, EEG showed only intermittent high-voltage slow waves (HVSs) without definite spikes. However, MEG showed clear epileptiform discharges preceding these EEG-detected HVSs. Dipoles estimated for these EEG-detected HVSs were located at a location close to that of the MEG-detected dipoles. (c) Based on the agreement of the results of these two techniques, surgical resection was performed in one patient with good results. CONCLUSIONS: Dipole modeling of epileptiform activity by MEG and EEG sometimes provides information not obtainable with either modality used alone.     

Reward-related activity in the human motor cortex

The human primary motor cortex (M1) participates in motor learning and response selection, functions that rely on feedback on the success of behavior (i.e. reward). To investigate the possibility that behavioral contingencies alter M1 activity in humans, we tested intracortical inhibition with single and paired (subthreshold/suprathreshold) transcranial magnetic stimulation during a slot machine simulation that delivered variable money rewards for three-way matches and required no movement. A two-way match before the third barrel had stopped (increased reward expectation) was associated with more paired-pulse inhibition than no match. Receiving a large reward on the preceding trial augmented this effect. A control task that manipulated attention to the same stimuli produced no changes in excitability. The origin of this reward-related activity is not clear, although dopaminergic ventral tegmental area neurons project to M1, where they are thought to inhibit output neurons and could be the source of the finding. Transcranial magnetic stimulation of M1 may be useful as a quantitative measure of reward-related activity.     

Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex

OBJECTIVE: Repetitive paired-pulse transcranial magnetic stimulation (TMS) at I-wave periodicity has been shown to induce a motor-evoked potential (MEP) facilitation. We hypothesized that a greater enhancement of motor cortical excitability is provoked by increasing the number of pulses per train beyond those by paired-pulse stimulation (PPS). METHODS: We explored motor cortical excitability changes induced by repetitive application of trains of four monophasic magnetic pulses (quadro-pulse stimulation: QPS) at 1.5-ms intervals, repeated every 5s over the motor cortex projecting to the hand muscles. The aftereffects of QPS were evaluated with MEPs to a single-pulse TMS, motor threshold (MT), and responses to brain-stem stimulation. These effects were compared to those after PPS. To evaluate the QPS safety, we also studied the spread of excitation and after discharge using surface electromyograms (EMGs) of hand and arm muscles. RESULTS: Sizes of MEPs from the hand muscle were enhanced for longer than 75min after QPS; they reverted to the baseline at 90min. Responses to brain-stem stimulation from the hand muscle and cortical MEPs from the forearm muscle were unchanged after QPS over the hand motor area. MT was unaffected by QPS. No spreads of excitation were detected after QPS. The appearance rate of after discharges during QPS was not different from that during sham stimulation. CONCLUSIONS: Results show that QPS can safely induce long-lasting, topographically specific enhancement of motor cortical excitability. SIGNIFICANCE: QPS is more effective than PPS for inducing motor cortical plasticity.     

Characterising the central mechanisms of sensory modulation in human swallowing motor cortex.

OBJECTIVE: Pharyngeal stimulation can induce remarkable increases in the excitability of swallowing motor cortex, which is associated with short-term improvements in swallowing behaviour in dysphagic stroke patients. However, the mechanism by which this input induces cortical change remains unclear. Our aims were to explore the stimulus-induced facilitation of the cortico-bulbar projections to swallowing musculature and examine how input from the pharynx interacts with swallowing motor cortex. METHODS: In 8 healthy subjects, a transcranial magnetic stimulation (TMS) paired-pulse investigation was performed comprising a single conditioning electrical pharyngeal stimulus (pulse width 0.2 ms, 240 V) followed by cortical TMS at inter-stimulus intervals (ISI) of 10-100 ms. Pharyngeal sensory evoked potentials (PSEP) were also measured over the vertex. In 6 subjects whole-brain magnetoencephalography (MEG) was further acquired following pharyngeal stimulation. RESULTS: TMS evoked pharyngeal motor evoked potentials were facilitated by the pharyngeal stimulus at ISI between 50 and 80 ms (Delta mean increase: 47+/-6%, P < 0.05). This correlated with the peak latency of the P1 component of the PSEP (mean 79.6+/-8.5 ms). MEG confirmed that the equivalent P1 peak activities were localised to caudolateral sensory and motor cortices (BA 4, 1, 2). CONCLUSIONS: Facilitation of the cortico-bulbar pathway to pharyngeal stimulation relates to coincident afferent input to sensorimotor cortex. SIGNIFICANCE: These findings have mechanistic importance on how pharyngeal stimulation may increase motor excitability and provide guidance on temporal windows for future manipulations of swallowing motor cortex.     

Oscillatory interaction between the hand area of human primary motor cortex and finger muscles during steady-state isometric contraction

Objective

To compare the magnitudes of β-band coherence between the primary motor cortex (M1) and electromyogram (EMG) for finger muscles, and to determine whether M1–EMG coherence is related to the stability of muscle contraction.

Methods

Cortical signals and EMG during steady-state isometric contraction of right thumb muscle (flexor pollicis brevis (FPB)) or right little finger muscle (flexor digiti minimi brevis (FDMB)) were recorded simultaneously with magnetoencephalography system from 13 right-handed healthy subjects.

Results

The magnitudes of β-band M1–EMG coherence and spectral power in the M1 for the FPB muscle were greater than that for the FDMB muscle (P < 0.001 and P < 0.005, respectively). The stability of EMG for the FPB was higher than that for FDMB (P < 0.001). Greater levels of β-band M1–EMG coherence were associated with higher levels of EMG stability (P < 0.05). The mean dipole sources of the FPB muscle were located more laterally, inferiorly and anteriorly than that of FDMB in the M1 hand area (P < 0.005).

Conclusions

The strength of β-band M1–EMG coherence would play an important role in the stability level of finger-muscle contraction.

Significance

The β-band M1–EMG coherence may reflect effective oscillatory interaction between the M1 and finger muscle during steady-state motor output.     

Long-lasting potentiation of synaptic potentials in the motor cortex produced by stimulation of the sensory cortex in the cat: a basis of motor learning

A long-lasting increase in the efficiency of synaptic transmission in the central nervous system has been thought to be one of the bases of learning and memory. To explore the possibility that the motor cortex (area 4γ) itself is involved in motor learning, the existence of long-term potentiation (LTP) was examined by recording excitatory postsynaptic potentials (EPSPs) from motor cortical neurons. Short tetanic intracortical microstimulation (ICMS) of the somatic sensory cortex produced a marked potentiation of the EPSPs in a small group of motor cortical neurons. The results raised the possibility that the input from the sensory cortex participates in motor learning and retention of the learned motor skills.     

Spontaneous locally restricted EEG alpha activity determines cortical excitability in the motor cortex

There is growing interest in the functional meaning of rhythmical brain activity. For oscillatory brain activity around 10 Hz in the human electroencephalogram (EEG) it is discussed whether it is associated with the level of cortical excitation. However, it is not clear whether the relation between 10 Hz EEG oscillatory activity and cortical excitability is a global, locally very unspecific phenomenon or whether focal 10 Hz oscillations in the human brain are a highly specific correlate of the cortical excitation level. To determine this open question, multichannel EEG was combined with transcranial magnetic stimulation (TMS) applied to the primary motor cortex in this study. The present data showed that a motor evoked potential was elicited more easily when alpha power immediately preceding the magnetic pulse was low, and vice versa. Interestingly, this effect was only found for very local EEG alpha activity at sites overlying the cortical motor areas to which the TMS pulses were applied. This was verified using source localization in 3D space. These data provide evidence that the magnitude of motor cortical excitability is determined by the amount of topographically specific alpha oscillations in the sensorimotor cortex.     

Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain

The cytological organization and the timetable of emergence and dissolution of the transient subplate zone subjacent to the developing visual and somatosensory cortex were studied in a series of human and monkey fetal brains. Cerebral walls processed with Nissl, Golgi, electron-microscopic, and histochemical methods show that this zone consists of migratory and postmigratory neurons, growth cones, loosely arranged axons, dendrites, synapses, and glial cells. In both species the subplate zone becomes visible at the beginning of the mid-third of gestation as a cell-poor/fiber-rich layer situated between the intermediate zone and the developing cortical plate. The subplate zone appears earlier in the somatosensory than in the visual area and reaches maximal width at the beginning of the last third of gestation in both regions. At the peak of its size the ratio between the width of the subplate zone and cortical plate in the somatosensory cortex is 2:1 in monkey and 4:1 in man while in the occipital lobe these structures have about equal width in both species. The dissolution of the subplate zone begins during the last third of gestation with degeneration of some subplate neurons and the relocation of fiber terminals into the cortex. The subplate zone disappears faster in the visual than in the somatosensory area. The present results together with our previous findings support the hypothesis that the subplate zone may serve as a "waiting" compartment for transient cellular interactions and a substrate for competition, segregation, and growth of afferents originated sequentially from the brain stem, basal forebrain, thalamus, and from the ipsi- and contralateral cerebral hemisphere. After a variable and partially overlapping time period, these fibers enter the cortical plate while the subplate zone disappears leaving only a vestige of cells scattered throughout the subcortical white matter. A comparison between species indicates that the size and duration of the subplate zone increases during mammalian evolution and culminates in human fetuses concomitantly with an enlargement of cortico-cortical fiber systems. The regional difference in the size, pattern, and resolution of the subplate zone correlates also with the pattern of cerebral convolutions. Our findings indicate that, contrary to prevailing notions, the subplate may not be a vestige of the phylogenetically old network but a transient embryonic structure that expanded during evolution to subserve the increasing number of its connections.     

EEG evidence of stimulus-directed response dynamics in human somatosensory cortex

Dense multichannel recordings of scalp electroencephalogram (EEG) were obtained in the vicinity of primary somatosensory cortex, time-locked to repetitive vibrotactile stimulation of sites on the right index finger of a single human subject. Frequency-domain analysis of cross-trial averages revealed prominent ‘driving' responses in the EEG at the frequency of stimulation, which under specific stimulus conditions displayed pronounced changes in amplitude and topographic organization over brief (4 s) durations of stimulus exposure. The changes were systematic and physiologically coherent, evolving toward driving-response topographies observed in the same subject in conjunction with periodic microstimulation of single mechanoreceptive afferents whose receptive fields occupied corresponding positions on the digit. This dynamic process was orderly and reproducible, and could be controlled by manipulating factors such as the amplitude, frequency, and temporal spacing of the stimuli. The results are tentatively interpreted in light of a previously proposed neurophysiological model of stimulus-driven response plasticity in mammalian somatosensory cortex.     

Reorganization of the projection from the sensory cortex to the motor cortex following elimination of the thalamic projection to the motor cortex in cats; Golgi, electron microscope and degeneration study

Changes of terminal connections of projection fibers from area 2 of the sensory cortex to the motor cortex following chronic lesion in the thalamus were examined using the electron microscope. The lesioned areas included nucleus ventralis anterior, n. ventralis lateralis and rostral part of n. ventralis posterolateralis. The synaptic sites were identified using the Golgi impregnation method to identify postsynaptic neurons in the motor cortex and the axonal degeneration method to identify presynaptic terminals of fibers originating from area 2. The following results were obtained. (1) The number of degenerating terminals per unit area in the motor cortex was increased to nearly twice that in normal animals. (2) The number of degenerating terminals synapsing with stellate cells was not increased but stayed more or less the same as in normal animals. (3) The number of degenerating terminals contacting pyramidal cells increased substantially, to more than twice that in normal animals. (4) These newly formed synapses were found on proximal dendritic shafts of the pyramidal cells in both layers III and V, suggesting that these synapses occupied the spaces where the thalamocortical terminals were located. (5) The functional significance of these newly formed synapses was discussed in relation to the recovery of motor function following thalamic lesion.