Classification of Neurons in the Primate Reticular Formation and Changes after Recovery from Pyramidal Tract Lesion.

The reticular formation is important in primate motor control, both in health and during recovery after brain damage. Little is known about the different neurons present in the reticular nuclei. Here we recorded extracellular spikes from the reticular formation in five healthy female awake behaving monkeys (193 cells), and in two female monkeys 1 year after recovery from a unilateral pyramidal tract lesion (125 cells). Analysis of spike shape and four measures derived from the interspike interval distribution identified four clusters of neurons in control animals. Cluster 1 cells had a slow firing rate. Cluster 2 cells had narrow spikes and irregular firing, which often included high-frequency bursts. Cluster 3 cells were highly rhythmic and fast firing. Cluster 4 cells showed negative spikes. A separate population of 42 cells was antidromically identified as reticulospinal neurons in five anesthetized female monkeys. The distribution of spike width in these cells closely overlaid the distribution for cluster 2, leading us tentatively to suggest that cluster 2 included neurons with reticulospinal projections. In animals after corticospinal lesion, cells could be identified in all four clusters. The firing rate of cells in clusters 1 and 2 was increased in lesioned animals relative to control animals (by 52% and 60%, respectively); cells in cluster 2 were also more regular and more bursting in the lesioned animals. We suggest that changes in both membrane properties and local circuits within the reticular formation occur following lesioning, potentially increasing reticulospinal output to help compensate for lost corticospinal descending drive.SIGNIFICANCE STATEMENT This work is the first to subclassify neurons in the reticular formation, providing insights into the local circuitry of this important but little understood structure. The approach developed can be applied to any extracellular recording from this region, allowing future studies to place their data within our current framework of four neural types. Changes in reticular neurons may be important to subserve functional recovery after damage in human patients, such as after stroke or spinal cord injury.

Contributions of descending and ascending pathways to corticomuscular coherence in humans.

Corticomuscular coherence in the beta frequency band (15­30 Hz) has been demonstrated in both humans and monkeys, but its origin and functional role are still unclear. Phase­frequency plots produced by traditional coherence analysis are often complex. Some subjects show a clear linear phase­frequency relationship (indicative of a fixed delay) but give shorter delays than expected; others show a constant phase across frequencies. Recent evidence suggests that oscillations may be travelling around a peripheral sensorimotor loop. We recorded sensorimotor EEGs and EMGs from three intrinsic hand muscles in human subjects performing a precision grip task, and applied directed coherence (Granger causality) analysis to explore this system. Directed coherence was significant in both descending (EEG → EMG) and ascending(EMG → EEG) directions at beta frequencies. Average phase delays of 26.4 ms for the EEG → EMG direction and 29.5 ms for the EMG → EEG direction were closer to the expected conduction times for these pathways than the average delays estimated from coherence phase (7.9 ms). Subjects were sub-divided into different groups, based on the sign of the slope of the linear relation between corticomuscular coherence phase and frequency (positive, negative or zero). Analysis separated by these groups suggested that different relative magnitudes of EEG → EMG and EMG → EEG directed coherence might underlie the observed inter-individual differences in coherence phase.These results confirm the complex nature of corticomuscular coherence with contributions from both descending and ascending pathways.

Convergence of pyramidal and medial brain stem descending pathways onto macaque cervical spinal interneurons.

We investigated the control of spinal interneurons by corticospinal and medial brain stem descending tracts in two macaque monkeys. Stimulating electrodes were implanted in the left pyramidal tract (PT), and the right medial longitudinal fasciculus (MLF), which contains reticulospinal, vestibulospinal, and some tectospinal fibers. Single unit discharge was recorded from 163 interneurons in the intermediate zone of the right spinal cord (segmental levels C(6)-C(8)) in the awake state; inputs from descending pathways were assessed from the responses to stimulation through the PT and MLF electrodes. Convergent input from both pathways was the most common finding (71/163 cells); responses to PT and MLF stimulation were of similar amplitude. Interneuron discharge was also recorded while the animal performed a reach and grasp task with the right hand; the output connections of the recorded cells were determined by delivering intraspinal microstimulation (ISMS) at the recording sites. Convergent input from MLF/PT stimulation was also common when analysis was restricted to cells that increased their rate during grasp (14/23 cells) or to cells recorded at sites where ISMS elicited finger or wrist movements (23/57 cells). We conclude that medial brain stem and corticospinal descending pathways have largely overlapping effects on spinal interneurons, including those involved in the control of the hand. This may imply a more important role for the brain stem in coordinating hand movements in primates than commonly assumed; brain stem pathways could contribute to the restoration of function seen after lesions to the corticospinal tract.

Direct and indirect connections with upper limb motoneurons from the primate reticulospinal tract.

Although the reticulospinal tract is a major descending motor pathway in mammals, its contribution to upper limb control in primates has received relatively little attention. Reticulospinal connections are widely assumed to be responsible for coordinated gross movements primarily of proximal muscles, whereas the corticospinal tract mediates fine movements, particularly of the hand. In this study, we used intracellular recording in anesthetized monkeys to examine the synaptic connections between the reticulospinal tract and antidromically identified cervical ventral horn motoneurons, focusing in particular on motoneurons projecting distally to wrist and digit muscles. We found that motoneurons receive monosynaptic and disynaptic reticulospinal inputs, including monosynaptic excitatory connections to motoneurons that innervate intrinsic hand muscles, a connection not previously known to exist. We show that excitatory reticulomotoneuronal connections are as common and as strong in hand motoneuron groups as in forearm or upper arm motoneurons. These data suggest that the primate reticulospinal system may form a parallel pathway to distal muscles, alongside the corticospinal tract. Reticulospinal neurons are therefore in a position to influence upper limb muscle activity after damage to the corticospinal system as may occur in stroke or spinal cord injury, and may be a target site for therapeutic interventions.

Digit displacement, not object compliance, underlies task dependent modulations in human corticomuscular coherence.

Human sensorimotor EEG shows oscillatory activity at approximately 10 and approximately 20 Hz; the latter frequency is coherent with contralateral EMG. The functional significance of this activity is obscure. A recent study found that corticomuscular coherence varied systematically with increasing lever compliance during a precision grip task. However, since subjects exerted the same force in all conditions, changes in lever compliance also produced changes in how far the digits moved. In this study, we disambiguated whether corticomuscular coherence modulates with object compliance or digit displacement. Subjects performed a precision grip task. Under computer control, the manipulandum could simulate a load of arbitrary compliance (spring constant). Subjects were required to produce a hold-ramp-hold profile of lever displacement, under visual feedback. Subjects first performed tasks with different sized lever movements, against an isotonic load (zero spring constant). Corticomuscular coherence was calculated between left sensorimotor EEG and EMG from five right hand and forearm muscles during the hold phase of the task. Coherence magnitude showed a clear dependence on the extent of digit displacement. In the next task, lever compliance instantaneously changed at the onset of the second hold phase of the task. Corticomuscular coherence modulated not with lever compliance during the analysed hold phase, but with digit displacement during the preceding ramp movement. These data suggest that human corticomuscular coherence is directly related to digit displacement during the preceding movement and not to object compliance. We speculate that corticomuscular coherence may reflect a sensorimotor recalibration, providing updated information about system state following movement.

Manipulation of peripheral neural feedback loops alters human corticomuscular coherence.

Sensorimotor EEG shows approximately 20 Hz coherence with contralateral EMG. This could involve efferent and/or afferent components of the sensorimotor loop. We investigated the pathways responsible for coherence genesis by manipulating nervous conduction delays using cooling. Coherence between left sensorimotor EEG and right EMG from three hand and two forearm muscles was assessed in healthy subjects during the hold phase of a precision grip task. The right arm was then cooled to 10 degrees C for approximately 90 min, increasing peripheral motor conduction time (PMCT) by approximately 35% (assessed by F-wave latency). EEG and EMG recordings were repeated, and coherence recalculated. Control recordings revealed a heterogeneous subject population. In 6/15 subjects (Group A), the corticomuscular coherence phase increased linearly with frequency, as expected if oscillations were propagated along efferent pathways from cortex to muscle. The mean corticomuscular conduction delay for intrinsic hand muscles calculated from the phase-frequency regression slope was 10.4 ms; this is smaller than the delay expected for conduction over fast corticospinal pathways. In 8/15 subjects (Group B), the phase showed no dependence with frequency. One subject showed both Group A and Group B patterns over different frequency ranges. Following cooling, averaged corticomuscular coherence was decreased in Group A subjects, but unchanged for Group B, even though both groups showed comparable slowing of nervous conduction. The delay calculated from the slope of the phase-frequency regression was increased following cooling. However, the size of this increase was around twice the rise in PMCT measured using the F-wave (regression slope 2.33, 95% confidence limits 1.30-3.36). Both afferent and efferent peripheral nerves will be slowed by similar amounts following cooling. The change in delay calculated from the coherence phase therefore better matches the rise in total sensorimotor feedback loop time caused by cooling, rather than just the change in the efferent limb. A model of corticomuscular coherence which assumes that only efferent pathways contribute cannot be reconciled to these results. The data rather suggest that afferent feedback pathways may also play a role in the genesis of corticomuscular coherence.

The effect of carbamazepine on human corticomuscular coherence.

EEG recordings from motor cortex show oscillations at approximately 10 and 20 Hz. The 20-Hz oscillations are coherent with contralateral EMG; in most studies those at 10 Hz are not. However, significant 10-Hz coherence has recently been reported in a group of epileptic patients, all of whom were taking the anticonvulsant drug carbamazepine (CBZ). In a double blind study, we investigated the effects of CBZ on corticomuscular coherence in eight healthy human subjects (all male). Subjects performed a precision grip task against an auxotonic load, whilst left sensorimotor EEG and EMGs from five muscles in the right hand and forearm were recorded. CBZ (100 mg) or a placebo was then given orally, and 6 h later subjects were re-tested. One week separated CBZ and placebo experiments in each subject. Coherence averaged across subjects and muscles during the hold phase of the task was maximal at 21 Hz; it increased significantly (P < 0.05, Z-test) by 89% after CBZ administration. This was significantly greater than a much smaller increase following placebo, which itself may reflect an effect of the time of day when experiments were performed. There was no significant approximately 10-Hz coherence either before or after CBZ administration. CBZ did not significantly alter EEG power at either 10 or 20 Hz. Recently, we showed that diazepam markedly increases the power of approximately 20-Hz motor cortical oscillations with little effect on coherence. We show here that CBZ raises coherence without altering EEG power. This pharmacological dissociation may indicate an important role for corticomuscular coherence in motor control.