The motor cortex uses active suppression to sculpt movement.

Even the simplest movements are generated by a remarkably complex pattern of muscle activity. Fast, accurate movements at a single joint are produced by a stereotyped pattern that includes a decrease in any preexisting activity in antagonist muscles. This premovement suppression is necessary to prevent the antagonist muscle from opposing movement generated by the agonist muscle. Here, we provide evidence that the primary motor cortex (M1) sends a command signal that generates this premovement suppression. Thus, output neurons in M1 sculpt complex spatiotemporal patterns of motor output not only by actively turning on muscles but also by actively turning them off.

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.

Properties of primary motor cortex output to hindlimb muscles in the macaque monkey.

The cortical control of forelimb motor function has been studied extensively, especially in the primate. In contrast, cortical control of the hindlimb has been relatively neglected. This study assessed the output properties of the primary motor cortex (M1) hindlimb representation in terms of the sign, latency, magnitude, and distribution of effects in stimulus-triggered averages (StTAs) of electromyography (EMG) activity recorded from 19 muscles, including hip, knee, ankle, digit, and intrinsic foot muscles, during a push-pull task compared with data reported previously on the forelimb. StTAs (15, 30, and 60 µA at 15 Hz) of EMG activity were computed at 317 putative layer V sites in two rhesus macaques. Poststimulus facilitation (PStF) was distributed equally between distal and proximal muscles, whereas poststimulus suppression (PStS) was more common in distal muscles than proximal muscles (51/49%, respectively, for PStF; 72/28%, respectively, for PStS) at 30 µA. Mean PStF and PStS onset latency generally increased the more distal the joint of a muscle's action. Most significantly, the average magnitude of hindlimb poststimulus effects was considerably weaker than the average magnitude of effects from forelimb M1. In addition, forelimb PStF magnitude increased consistently from proximal to distal joints, whereas hindlimb PStF magnitude was similar at all joints except the intrinsic foot muscles, which had a magnitude of approximately double that of all of the other muscles. The results suggest a greater monosynaptic input to forelimb compared with hindlimb motoneurons, as well as a more direct synaptic linkage for the intrinsic foot muscles compared with the other hindlimb muscles.

EMG activation patterns associated with high frequency, long-duration intracortical microstimulation of primary motor cortex.

The delivery of high-frequency, long-duration intracortical microstimulation (HFLD-ICMS) to primary motor cortex (M1) in primates produces hand movements to a common final end-point regardless of the starting hand position (Graziano et al., 2002). We have confirmed this general conclusion. We further investigated the extent to which the (1) temporal pattern, (2) magnitude, and (3) latency of electromyographic (EMG) activation associated with HFLD-ICMS-evoked movements are dependent on task conditions, including limb posture. HFLD-ICMS was applied to layer V sites in M1 cortex. EMG activation with HFLD-ICMS was evaluated while two male rhesus macaques performed a number of tasks in which the starting position of the hand could be varied throughout the workspace. HFLD-ICMS-evoked EMG activity was largely stable across all parameters tested independent of starting hand position. The most common temporal pattern of HFLD-ICMS-evoked EMG activity (58% of responses) was a sharp rise to a plateau. The plateau level was maintained essentially constant for the entire duration of the stimulus train. The plateau pattern is qualitatively different from the largely bell-shaped patterns typical of EMG activity associated with natural goal directed movements (Brown and Cooke, 1990; Hoffman and Strick, 1999). HFLD-ICMS produces relatively fixed parameters of muscle activation independent of limb position. We conclude that joint movement associated with HFLD-ICMS occurs as a function of the length-tension properties of stimulus-activated muscles until an equilibrium between agonist and antagonist muscle force is achieved.

Cortical output to fast and slow muscles of the ankle in the rhesus macaque.

The cortical control of fast and slow muscles of the ankle has been the subject of numerous reports yielding conflicting results. Although it is generally agreed that cortical stimulation yields short latency facilitation of fast muscles, the effects on the slow muscle, soleus, remain controversial. Some studies have shown predominant facilitation of soleus from the cortex while others have provided evidence of differential control in which soleus is predominantly inhibited from the cortex. The objective of this study was to investigate the cortical control of fast and slow muscles of the ankle using stimulus triggered averaging (StTA) of EMG activity, which is a sensitive method of detecting output effects on muscle activity. This method also has relatively high spatial resolution and can be applied in awake, behaving subjects. Two rhesus macaques were trained to perform a hindlimb push-pull task. Stimulus triggered averages (StTAs) of EMG activity (15, 30, and 60 µA at 15 Hz) were computed for four muscles of the ankle [tibialis anterior (TA), medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus] as the monkeys performed the task. Poststimulus facilitation (PStF) was observed in both the fast muscles (TA, MG, and LG) as well as the slow muscle (soleus) and was as common and as strong in soleus as in the fast muscles. However, while poststimulus suppression (PStS) was observed in all muscles, it was more common in the slow muscle compared to the fast muscles and was as common as facilitation at low stimulus intensities. Overall, our results demonstrate that cortical facilitation of soleus has an organization that is very similar to that of the fast ankle muscles. However, cortical inhibition is organized differently allowing for more prominent suppression of soleus motoneurons.

Hijacking cortical motor output with repetitive microstimulation.

High-frequency repetitive microstimulation has been widely used as a method of investigating the properties of cortical motor output. Despite its widespread use, few studies have investigated how activity evoked by high-frequency stimulation may interact with the existing activity of cortical cells resulting from natural synaptic inputs. A reasonable assumption might be that the stimulus-evoked activity sums with the existing natural activity. However, another possibility is that the stimulus-evoked firing of cortical neurons might block and replace the natural activity. We refer to this latter possibility as "neural hijacking." Evidence from analysis of EMG activity evoked by repetitive microstimulation (200 Hz, 500 ms) of primary motor cortex in two rhesus monkeys during performance of a reach-to-grasp task strongly supports the neural hijacking hypothesis.

Methods for chronic recording of EMG activity from large numbers of hindlimb muscles in awake rhesus macaques.

Studies of the neural control of movement often rely on the ability to record EMG activity during natural behavioral tasks over long periods of time. Increasing the number of recorded muscles and the time over which recordings are made allows more rigorous answers to many questions related to the descending control of motor output. Chronic recording of EMG activity from multiple hindlimb muscles has been reported in the cat but few studies have been done in non-human primates. This paper describes two chronic EMG implant methods that are minimally invasive, relatively non-traumatic and capable of recording from large numbers of hindlimb muscles simultaneously for periods of many months to years.

Stability of output effects from motor cortex to forelimb muscles in primates.

Stimulus-triggered averaging (StTA) of electromyographic (EMG) activity is a form of intracortical microstimulation that enables documentation in awake animals of the sign, magnitude, latency, and distribution of output effects from cortical and brainstem areas to motoneurons of different muscles. In this study, we show that the properties of effects in StTAs are stable and mostly independent of task conditions. StTAs of EMG activity from 24 forelimb muscles were collected from two male rhesus monkeys while they performed three tasks: (1) an isometric step tracking wrist task, (2) an isometric whole-arm push-pull task, and (3) a reach-to-grasp task. Layer V sites in primary motor cortex were identified and microstimuli were applied (15 muA) at a low rate (15 Hz). Our results show that the sign of effects (facilitation or suppression) in StTAs of EMG activity are remarkably stable in the presence of joint angle position changes (96% stable), whole-arm posture changes (97% stable), and across fundamentally different types of tasks such as arm push-pull versus reach-to-grasp (81% stable). Furthermore, comparing effects across different phases of a task also yielded remarkable stability (range, 84-96%). At different shoulder, elbow, and wrist angles, the magnitudes of effects in individual muscles were highly correlated. Our results demonstrate that M1 output effects obtained with StTA of EMG activity are highly stable across widely varying joint angles and motor tasks. This study further validates the use of StTA for mapping and other studies of cortical motor output.

The presence of the casein kinase II phosphorylation sites of Vpu enhances the CD4(+) T cell loss caused by the simian-human immunodeficiency virus SHIV(KU-lbMC33) in pig-tailed macaques.

The simian-human immunodeficiency virus (SHIV)/ macaque model for human immunodeficiency virus type 1 has become a useful tool to assess the role of Vpu in lentivirus pathogenesis. In this report, we have mutated the two phosphorylated serine residues of the HIV-1 Vpu to glycine residues and have reconstructed a SHIV expressing this nonphosphorylated Vpu (SHIV(S52,56G)). Expression studies revealed that this protein was localized to the same intracellular compartment as wild-type Vpu. To determine if this virus was pathogenic, four pig-tailed macaques were inoculated with SHIV(S52,56G) and virus burdens and circulating CD4(+) T cells monitored up to 1 year. Our results indicate that SHIV(S52,56G) caused rapid loss in the circulating CD4(+) T cells within 3 weeks of inoculation in one macaque (CC8X), while the other three macaques developed no or gradual numbers of CD4(+) T cells and a wasting syndrome. Histological examination of tissues revealed that macaque CC8X had lesions in lymphoid tissues (spleen, lymph nodes, and thymus) that were typical for macaques inoculated with pathogenic parental SHIV(KU-1bMC33) and had no lesions within the CNS. To rule out that macaque CC8X had selected for a virus in which there was reversion of the glycine residues at positions 52 and 56 to serine residues and/or compensating mutations occurred in other genes associated with CD4 down-regulation, sequence analysis was performed on amplified vpu sequences isolated from PBMC and from several lymphoid tissues at necropsy. Sequence analysis revealed a reversion of the glycine residues back to serine residues in this macaque. The other macaques maintained low virus burdens, with one macaque (P003) developing a wasting syndrome between months 9 and 11. Histological examination of tissues from this macaque revealed a thymus with severe atrophy that was similar to that of a previously reported macaque inoculated with a SHIV lacking vpu (Virology 293, 2002, 252). Sequence analysis revealed no reversion of the glycine residues in the vpu sequences isolated from this macaque. These results contrast with those from four macaques inoculated with the parental pathogenic SHIV(KU-1bMC33), all of which developed severe CD4(+) T cell loss within 1 month after inoculation. Taken together, these results indicate that casein kinase II phosphorylation sites of Vpu contributes to the pathogenicity of the SHIV(KU-1bMC33) and suggest that the SHIV(KU-1bMC33)/pig-tailed macaque model will be useful in analyzing amino acids/domains of Vpu that contribute to the pathogenesis of HIV-1.