Corticomotoneuronal Cells Research Articles

Simultaneous transcranial and transcutaneous spinal direct current stimulation to enhance athletic performance outcome in experienced boxers

Transcranial direct current stimulation (tDCS) is among the rapidly growing experimental approaches to enhance athletic performance. Likewise, novel investigations have recently addressed the effects of transcutaneous spinal Direct Current Stimulation (tsDCS) on motor functions such as reduced reaction time. The impact of tDCS, and tsDCS might be attributed to altered spontaneous neural activity and membrane potentials of cortical and corticomotoneuronal cells, respectively. Given the paucity of empirical research in non-invasive brain stimulation in sports neuroscience, especially in boxing, the present investigation studied the effects of neuromodulation on motor and cognitive functions of professional boxers. The study sample comprised 14 experienced male boxers who received random sequential real or sham direct current stimulation over the primary motor cortex (M1) and paraspinal region (corresponding to the hand area) in two sessions with a 72-h interval. Unlike sham stimulation, real stimulation improved selective attention and reaction time of the experienced boxers [enhanced selective attention (p < 0.0003), diminished right hand (p < 0.0001) and left hand reaction time (p < 0.0006)]. Meanwhile, the intervention left no impact on the participants’ cognitive functions (p > 0.05). We demonstrated that simultaneous stimulation of the spinal cord and M1 can improve the performance of experienced boxers through neuromodulation. The present study design may be extended to examine the role of neurostimulation in other sport fields.

I-waves in motor cortex revisited

I-waves represent high-frequency (~ 600 Hz) repetitive discharge of corticospinal fibers elicited by single-pulse stimulation of motor cortex. First detected and examined in animal preparations, this multiple discharge can also be recorded in humans from the corticospinal tract with epidural spinal electrodes. The exact underpinning neurophysiology of I-waves is still unclear, but there is converging evidence that they originate at the cortical level through synaptic input from specific excitatory interneuronal circuitries onto corticomotoneuronal cells, controlled by GABAAergic interneurons. In contrast, there is at present no supportive evidence for the alternative hypothesis that I-waves are generated by high-frequency oscillations of the membrane potential of corticomotoneuronal cells upon initial strong depolarization. Understanding I-wave physiology is essential for understanding how TMS activates the motor cortex.

Simulation of electromyographic recordings following transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a technique that enables noninvasive manipulation of neural activity and holds promise in both clinical and basic research settings. The effect of TMS on the motor cortex is often measured by electromyography (EMG) recordings from a small hand muscle. However, the details of how TMS generates responses measured with EMG are not completely understood. We aim to develop a biophysically detailed computational model to study the potential mechanisms underlying the generation of EMG signals following TMS. Our model comprises a feed-forward network of cortical layer 2/3 cells, which drive morphologically detailed layer 5 corticomotoneuronal cells, which in turn project to a pool of motoneurons. EMG signals are modeled as the sum of motor unit action potentials. EMG recordings from the first dorsal interosseous muscle were performed in four subjects and compared with simulated EMG signals. Our model successfully reproduces several characteristics of the experimental data. The simulated EMG signals match experimental EMG recordings in shape and size, and change with stimulus intensity and contraction level as in experimental recordings. They exhibit cortical silent periods that are close to the biological values and reveal an interesting dependence on inhibitory synaptic transmission properties. Our model predicts several characteristics of the firing patterns of neurons along the entire pathway from cortical layer 2/3 cells down to spinal motoneurons and should be considered as a viable tool for explaining and analyzing EMG signals following TMS. NEW & NOTEWORTHY A biophysically detailed model of EMG signal generation following transcranial magnetic stimulation (TMS) is proposed. Simulated EMG signals match experimental EMG recordings in shape and amplitude. Motor-evoked potential and cortical silent period properties match experimental data. The model is a viable tool to analyze, explain, and predict EMG signals following TMS.

Transspinal Direct Current Stimulation Produces Persistent Plasticity in Human Motor Pathways

The spinal cord is an integration center for descending, ascending, and segmental neural signals. Noninvasive transspinal stimulation may thus constitute an effective method for concomitant modulation of local and distal neural circuits. In this study, we established changes in cortical excitability and input/output function of corticospinal and spinal neural circuits before, at 0–15 and at 30–45 minutes after cathodal, anodal, and sham transspinal direct current stimulation (tsDCS) to the thoracic region in healthy individuals. We found that intracortical inhibition was different among stimulation polarities, however remained unchanged over time. Intracortical facilitation increased after cathodal and anodal tsDCS delivered with subjects seated, and decreased after cathodal tsDCS delivered with subjects lying supine. Both cathodal and anodal tsDCS increased corticospinal excitability, yet facilitation was larger and persisted for 30 minutes post stimulation only when cathodal tsDCS was delivered with subjects lying supine. Spinal input/output reflex function was decreased by cathodal and not anodal tsDCS. These changes may be attributed to altered spontaneous neural activity and membrane potentials of corticomotoneuronal cells by tsDCS involving similar mechanisms to those mediating motor learning. Our findings indicate that thoracic tsDCS has the ability to concomitantly alter cortical, corticospinal, and spinal motor output in humans.

Corticospinal gating during action preparation and movement in the primate motor cortex.

During everyday actions there is a need to be able to withhold movements until the most appropriate time. This motor inhibition is likely to rely on multiple cortical and subcortical areas, but the primary motor cortex (M1) is a critical component of this process. However, the mechanisms behind this inhibition are unclear, particularly the role of the corticospinal system, which is most often associated with driving muscles and movement. To address this, recordings were made from identified corticospinal (PTN, n = 94) and corticomotoneuronal (CM, n = 16) cells from M1 during an instructed delay reach-to-grasp task. The task involved the animals withholding action for ~2 s until a GO cue, after which they were allowed to reach and perform the task for a food reward. Analysis of the firing of cells in M1 during the delay period revealed that, as a population, non-CM PTNs showed significant suppression in their activity during the cue and instructed delay periods, while CM cells instead showed a facilitation during the preparatory delay. Analysis of cell activity during movement also revealed that a substantial minority of PTNs (27%) showed suppressed activity during movement, a response pattern more suited to cells involved in withholding rather than driving movement. These results demonstrate the potential contributions of the M1 corticospinal system to withholding of actions and highlight that suppression of activity in M1 during movement preparation is not evenly distributed across different neural populations.NEW & NOTEWORTHY Recordings were made from identified corticospinal (PTN) and corticomotoneuronal (CM) cells during an instructed delay task. Activity of PTNs as a population was suppressed during the delay, in contrast to CM cells, which were facilitated. A minority of PTNs showed a rate profile that might be expected from inhibitory cells and could suggest that they play an active role in action suppression, most likely through downstream inhibitory circuits.

Proposed association between the hexanucleotide repeat of C9orf72 and opposability index of the thumb

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by motor neuron and sub-cerebral projection neuron degeneration. We sought to explore the particular susceptibility of humans to neurodegeneration and whether any characteristic human features might predispose to selective vulnerability of the critical motor circuitry in ALS. The pathophysiology of the C9orf72 repeat is not yet understood, despite its role as a common cause of ALS and frontotemporal dementia. Methods: We examined the development of the monosynaptic cortico-motoneuronal system, key to skilled hand movements, measured by the thumb opposability index, and its relationship to the C9orf72 hexanucleotide repeat expansion, a strong predisposing factor for neurodegeneration, using the genomic tool BLAST. Results: We found a statistically significant linear relationship between the C9orf72 hexanucleotide bit score, a measure of genomic conservation of the aligned region across different species, and the thumb opposability index (Pearson’s correlation coefficient of 0.78, p value 0.023). The C9orf72 hexanucleotide repeat was only found in humans, chimpanzees and gorillas, species with higher opposability indices. Conclusions: This may support a role of the hexanucleotide repeat in the same developmental pathways in species with higher prehensility, which may be associated with the selective vulnerability of cortico-motoneuronal cells in humans, manifested most obviously as the ‘split hand’ syndrome in ALS.

Corticomotoneuronal cells are "functionally tuned".

Corticomotoneuronal (CM) cells in the primary motor cortex (M1) have monosynaptic connections with motoneurons. They are one of the few sources of descending commands that directly influence motor output. We examined the contribution of CM cells to the generation of activity in their target muscles. The preferred direction of many CM cells differed from that of their target muscles. Some CM cells were selectively active when a muscle was used as an agonist. Others were selectively active when the same muscle was used as a synergist, fixator, or antagonist. These observations suggest that the different functional uses of a muscle are generated by separate populations of CM cells. We propose that muscle function is one of the dimensions represented in the output of M1.

Timing of Cortico-Muscle Transmission During Active Movement.

Numerous studies have reported large disparities between short cortico-muscle conduction latencies and long recorded delays between cortical firing and evoked muscle activity. Using methods such as spike- and stimulus-triggered averaging of electromyographic (EMG) activity, previous studies have shown that the time delay between corticomotoneuronal (CM) cell firing and onset of facilitation of forelimb muscle activity ranges from 6.7 to 9.8 ms, depending on the muscle group tested. In contrast, numerous studies have reported delays of 60-122 ms between cortical cell firing onset and either EMG or movement onset during motor tasks. To further investigate this disparity, we simulated rapid active movement by applying frequency-modulated stimulus trains to M1 cortical sites in a rhesus macaque performing a movement task. This yielded corresponding EMG modulations, the latency of which could be measured relative to the stimulus modulations. The overall mean delay from stimulus frequency modulation to EMG modulation was 11.5 ± 5.6 ms, matching closely the conduction time through the cortico-muscle pathway (12.6 ± 2.0 ms) derived from poststimulus facilitation peaks computed at the same sites. We conclude that, during active movement, the delay between modulated M1 cortical output and its impact on muscle activity approaches the physical cortico-muscle conduction time.

Strengthening of corticospinal connection through recurrent neural interface

Individuals with neural damage hope to regain their impaired functions. However, therapeutic rehabilitation is lacking. Nishimura et al. (2013) have documented that the strength of neural connections between the motor cortex and the spinal cord can be modified using an autonomous recurrent neural interface that delivers electrical stimuli in the spinal cord and this is triggered by action potentials of corticospinal cells during free behavior. This activity-dependent stimulation modifies the strength of the terminal connections of single corticomotoneuronal cells, which is consistent with the bidirectional spike-timing-dependent plasticity rule previously derived from in vitro experiments. The success of our protocol suggests neurorehabilitative treatments could be possible for patients with damaged pathways.

Spike-timing-dependent plasticity in primate corticospinal connections induced during free behavior.

Motor learning and functional recovery from brain damage involve changes in the strength of synapticconnections between neurons. Relevant invivo evidence on the underlying cellular mechanisms remains limited and indirect. We found that the strength of neural connections between motor cortex and spinal cord in monkeys can be modified with an autonomous recurrent neural interface that delivers electrical stimuli in the spinal cord triggered by action potentials of corticospinal cells during free behavior. The activity-dependent stimulation modified the strength of the terminal connections of single corticomotoneuronal cells, consistent with a bidirectional spike-timing-dependent plasticity rule previously derived from invitro experiments. For some cells, the changes lasted for days after the end of conditioning, but most effects eventually reverted to preconditioning levels. These results provide direct evidence of corticospinal synaptic plasticity invivo at the level of single neurons induced by normal firing patterns during free behavior.

Single-Snippet Analysis for Detection of Postspike Effects

Corticomotoneuronal cells (CMN), located predominantly in the primary motor cortex, project directly to alpha motoneuronal pools in the spinal cord. The effects of CMN spikes on motoneuronal excitability are traditionally characterized by visualizing postspike effects (PSEs) in spike-triggered averages (SpTA; Fetz, Cheney, & German, 1976; Fetz & Cheney, 1980; McKiernan, Marcario, Karrer, & Cheney, 1998) of electromyography (EMG) data. Poliakov and Schieber (1998) suggested a formal test, the multiple-fragment analysis (MFA), to automatically detect PSEs. However, MFA's performance was not statistically validated, and it is unclear under what conditions it is valid. This paper's contributions are a power study that validates the MFA; an alternative test, the single-snippet analysis (SSA), which has the same functionality as MFA but is easier to calculate and has better power in small samples; a simple bootstrap simulation to estimate SpTA baselines with simulation bands that help visualize potential PSEs; and a bootstrap adjustment to the MFA and SSA to correct for nonlinear SpTA baselines.

Asynchronous decoding of finger position and of EMG during precision grip using CM cell activity: Application to robot control

Recent brain-machine interfaces (BMI) have demonstrated the use of intracortical signals for the kinematic control of robotic arms. However, for potential restoration of manual dexterity, two issues remain to be addressed: (1) Can hand and digit movements for dexterous manipulation be controlled in a similar way to arm movements? (2) Can the potentially large signal space for decoding of the many degrees of freedom (dof) of hand and digit movements be minimized? The first question addresses BMI control of dexterous prosthetic devices, while the second addresses the problem of whether few, but identified, neurons might provide adequate decoding. Asynchronous decoding of precision grip finger movement kinematics from identified corticomotoneuronal (CM) cell activity was performed with an artificial neural network (ANN). After training over a given session, the ANNs successfully decoded trial-by-trial movement kinematics. Average accuracy over sessions was in the order of 80% and 50% for data sets of two monkeys respectively. Decoding accuracy increased as a function of (1) number of simultaneously recorded CM cells used for prediction, and (2) size of the sliding input window. Subsequently, a robot digit actuated by pneumatic artificial muscles, fed with the predicted trajectory, mimicked the recorded movement offline. Furthermore, CM cell signals were used for decoding of time-varying hand muscle EMG activity. The performance of EMG prediction tended to increase if CM cells that facilitated this particular muscle (compared to CM cells that facilitated other muscles) were used. These results provide evidence that an anthropomorphic robot finger can be controlled offline by spike trains recorded from identified corticospinal neurons. This represents a step towards neuroprosthetic devices for dexterous hand movements.

Spinal inhibition of descending command to soleus motoneurons is removed prior to dorsiflexion

It has recently been demonstrated that soleus motor-evoked potentials (MEPs) are facilitated prior to the onset of dorsiflexion. The purpose of this study was to examine if this could be explained by removal of spinal inhibition of the descending command to soleus motoneurons. To test this, we investigated how afferent inputs from the tibialis anterior muscle modulate the corticospinal activation of soleus spinal motoneurons at rest, during static contraction and prior to movement. MEPs activated by transcranial magnetic stimulation (TMS) and Hoffmann reflexes (H-reflexes), activated by electrical stimulation of the posterior tibial nerve (PTN), were conditioned by prior stimulation of the common peroneal nerve (CPN) at a variety of conditioning-test (CT) intervals. MEPs in the precontracted soleus muscle were inhibited when the TMS pulse was preceded by CPN stimulation with a CT interval of 35 ms, and they were facilitated for CT intervals of 50-55 ms. A similar inhibition of the soleus H-reflex was not observed. To investigate which descending pathways might be responsible for the afferent-evoked inhibition and facilitation, we examined the effect of CPN stimulation on short-latency facilitation (SLF) and long-latency facilitation (LLF) of the soleus H-reflex induced by a subthreshold TMS pulse at different CT intervals. SLF is known to reflect the excitability of the fastest conducting, corticomotoneuronal cells whereas LLF is believed to be caused by more indirect descending pathways. At CT intervals of 40-45 ms, the LLF was significantly more inhibited compared to the SLF when taking the effect on the H-reflex into account. Finally, we investigated how the CPN-induced inhibition and facilitation of the soleus MEP were modulated prior to dorsiflexion. Whereas the late facilitation (CT interval: 55 ms) was similar prior to dorsiflexion and at rest, no inhibition could be evoked at the earlier latency (CT interval: 35 ms) prior to onset of dorsiflexion. The observation that the CPN-induced inhibition of soleus MEPs disappears prior to onset of dorsiflexion may explain why soleus MEPs are facilitated prior to onset of dorsiflexion contraction. A possible mechanism involves the removal of inhibition of the descending command to the motoneurons at a spinal interneuronal level because the inhibition was seen in LLF and not in SLF, and the MEP inhibition was not observed in the H-reflex. The data illustrate that spinal interneuronal pathways modify descending commands to human spinal motoneurons and influence the size of MEPs elicited by TMS.

Dissociating motor cortex from the motor

During closed-loop control of a brain-computer interface, neurons in the primary motor cortex can be intensely active even though the subject may be making no detectable movement or muscle contraction. How can neural activity in the primary motor cortex become dissociated from the movements and muscles of the native limb that it normally controls? Here we examine circumstances in which motor cortex activity is known to dissociate from movement--including mental imagery, visuo-motor dissociation and instructed delay. Many such motor cortex neurons may be related to muscle activity only indirectly. Furthermore, the integration of thousands of synaptic inputs by individual α-motoneurons means that under certain circumstances even cortico-motoneuronal cells, which make monosynaptic connections to α-motoneurons, can become dissociated from muscle activity. The natural ability of motor cortex neurons under voluntarily control to become dissociated from bodily movement may underlie the utility of this cortical area for controlling brain-computer interfaces.

Feedback Modulation: A Window into Cortical Function

A recent study demonstrates involvement of primary motor cortex in task-dependent modulation of rapid feedback responses; cortical neurons resolve locally ambiguous sensory information, producing sophisticated responses to disturbances.

Synaptic Linkages Between Corticomotoneuronal Cells Affecting Forelimb Muscles in Behaving Primates

To elucidate the cortical circuitry controlling primate forelimb muscles we investigated the synaptic interactions between neighboring motor cortex cells that had postspike output effects in target muscles. In monkeys generating isometric ramp-and-hold wrist torques, pairs of cortical cells were recorded simultaneously with independent electrodes and corticomotoneuronal ("CM") cells were identified by their postspike effects on target forelimb muscles in spike-triggered averages (SpTAs) of electromyographs (EMGs). The response patterns of the cells were determined in response-aligned averages and their synaptic interactions were identified by cross-correlograms of action potentials. The possibility that synchronized firing between cortical cells could mediate spike-correlated effects in the SpTA of EMG was examined in several ways. Sixty-two pairs consisted of one CM cell and a non-CM cell; 15 of these had correlogram peaks of the same magnitude as that of other pairs, but the synchrony peaks did not mediate any postspike effect from the non-CM cell. Twelve pairs of simultaneously recorded CM cells were cross-correlated. Half had features (usually synchrony peaks) in their cross-correlograms and the cells of these pairs also shared some target muscles in common. The other half had flat correlograms and, in most of these pairs, the CM cells affected different muscles. The latter group included pairs of CM cells that facilitated synergistic muscles. These results indicate that common synaptic input specifically affects CM cells that have overlapping muscle fields. Reconstruction of the cortical locations of CM cells affecting 12 different muscles showed a wide and overlapping distribution of cortical colonies of forelimb muscles.

Coherence Between Motor Cortical Activity and Peripheral Discontinuities During Slow Finger Movements

Slow finger movements in man are not smooth, but are characterized by 8- to 12-Hz discontinuities in finger acceleration thought to have a central source. We trained two macaque monkeys to track a moving target by performing index finger flexion/extension movements and recorded local field potentials (LFPs) and spike activity from the primary motor cortex (M1); some cells were identified as pyramidal tract neurons by antidromic activation or as corticomotoneuronal cells by spike-triggered averaging. There was significant coherence between finger acceleration in the approximately 10-Hz range and both LFPs and spikes. LFP-acceleration coherence was similar for flexion and extension movements (0.094 at 9.8 Hz and 0.11 at 6.8 Hz, respectively), but substantially smaller during steady holding (0.0067 at 9.35 Hz). The coherence phase showed a significant linear relationship with frequency over the 6- to 13-Hz range, as expected for a constant conduction delay, but the slope indicated that LFP lagged acceleration by 18 +/- 14 or 36 +/- 8 ms for flexion and extension movements, respectively. Directed coherence analysis supported the conclusion that the dominant interaction was in the acceleration to LFP (i.e., sensory) direction. The phase relationships between finger acceleration and both LFPs and spikes shifted by about pi radians in flexion compared with extension trials. However, for a given trial type the phase relationship with acceleration was similar for cells that increased their firing during flexion or during extension trials. We conclude that movement discontinuities during slow finger movements arise from a reciprocally coupled network, which includes M1 and the periphery.

Subdivisions of primary motor cortex based on cortico-motoneuronal cells.

We used retrograde transneuronal transport of rabies virus from single muscles of rhesus monkeys to identify cortico-motoneuronal (CM) cells in the primary motor cortex (M1) that make monosynaptic connections with motoneurons innervating shoulder, elbow, and finger muscles. We found that M1 has 2 subdivisions. A rostral region lacks CM cells and represents an "old" M1 that is the standard for many mammals. The descending commands mediated by corticospinal efferents from old M1 must use the integrative mechanisms of the spinal cord to generate motoneuron activity and motor output. In contrast, a caudal region of M1 contains shoulder, elbow, and finger CM cells. This region represents a "new" M1 that is present only in some higher primates and humans. The direct access to motoneurons afforded by CM cells enables the newly recognized M1 to bypass spinal cord mechanisms and sculpt novel patterns of motor output that are essential for highly skilled movements.

Do Corticomotoneuronal Cells Predict Target Muscle EMG Activity?

Data from two rhesus macaques were used to investigate the pattern of cortical cell activation during reach-to-grasp movements in relation to the corresponding activation pattern of the cell's facilitated target muscles. The presence of postspike facilitation (PSpF) in spike-triggered averages (SpTAs) of electromyographic (EMG) activity was used to identify cortical neurons with excitatory synaptic linkages with motoneurons. EMG activity from 22 to 24 muscles of the forelimb was recorded together with the activity of M1 cortical neurons. The extent of covariation was characterized by 1) identifying the task segment containing the cell and target muscle activity peaks, 2) quantifying the timing and overlap between corticomotoneuronal (CM) cell and EMG peaks, and 3) applying Pearson correlation analysis to plots of CM cell firing rate versus EMG activity of the cell's facilitated muscles. At least one firing rate peak, for nearly all (95%) CM cells tested, matched a corresponding peak in the EMG activity of the cell's target muscles. Although some individual CM cells had very strong correlations with target muscles, overall, substantial disparities were common. We also investigated correlations for ensembles of CM cells sharing the same target muscle. The ensemble population activity of even a small number of CM cells influencing the same target muscle produced a relatively good match (r >/= 0.8) to target muscle EMG activity. Our results provide evidence in support of the notion that corticomotoneuronal output from primary motor cortex encodes movement in a framework of muscle-based parameters, specifically muscle-activation patterns as reflected in EMG activity.

Functional studies of motor cortex.

Defining functions for neural elements becomes more difficult the more remote they are, in synaptic linkages, from motor neurons. The precentral motor cortex contains a corticomotoneuronal projection system, only one synapse removed from motor neurons. Corticomotoneuronal fibres produce monosynaptic excitation of spinal motor neurons, which is more powerful for those acting distally, innervating extensor muscles of the fingers and intrinsic hand muscles. Latencies and time-course of corticomotoneuronal excitation are defined. Amplitudes of unitary corticomotoneuronal excitatory postsynaptic potentials are very small. Many corticomotoneuronal cells converge on a given motor neuron. Some motor neurons innervating proximally acting muscles appear to receive no corticomotoneuronal excitation. Disynaptic inhibitory actions are produced by corticospinal volleys via the common Ia inhibitory interneuron--possibly reciprocal actions produced over collaterals of corticomotoneuronal fibres. Anatomical divergence of projections of collaterals of an identified corticomotoneuronal fibre is extensive enough to provide both for delivery of synapses to a large number of motor neurons and for the dispersion of specific projections to inhibitory interneurons, to fusimotor neurons and to other interneurons. Functions of corticomotoneuronal elements in motor cortex whose targets have been identified and whose excitatory or inhibitory actions have been specified by cross-correlation have been studied by Fetz & Cheney (J Neurophysiol 1980; 44:751-772).