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Transverse sections of the monkey cervical spinal cord from a previous study (Jenny and Inukai, 1983 [1]) were reanalyzed using Neurolucida to create a three-dimensional display of flexor pollicis brevis and abductor pollicis brevis (FAbPBr) motoneurons and dendrites that had been jointly labeled with horse radish peroxidase (HRP). These data were correlated with similar data from a reanalysis of an extensor digitorum communis (EDC) motoneuron pool (Jenny, Cheney, and Jenny, 2018 [2]). The FAbPBr motoneuron columns were located in the C8 (caudal) and T1 segments of the spinal cord and within the most dorsal and medial regions of the motor column pools that innervate hand muscles. Small motoneurons (cell body areas less than 500 µm 2 and presumed to be gamma motoneurons) comprised about four percent of the motoneurons and were located throughout the length of the motoneuron pool. HRP labeled dendrites extended radially (360°) from the motoneuron soma but greater numbers of dendrites were directed either dorsomedial to the base of the dorsal horn or medial to the ventromedial gray matter. The longer HRP labeled dendrites and their branch dendrites usually continued in the same radial direction as when originating from the cell body or proximal dendrite. As such we considered the radial direction of the longer HRP labeled dendrites to be a reasonable estimate of the radial direction of the more distal dendritic trees [2]. Both the EDC and FAbPBr motoneuron groups had a greater number of dendrites oriented in dorsal and medial directions from the motoneuron column. Our data continue to suggest that motoneuron dendritic trees have direction-oriented dendrites that extend toward functional terminal regions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Human Immunodeficiency Virus (HIV) pathogenesis has been closely linked with microbial translocation, which is believed to drive inflammation and HIV replication. Opioid drugs have been shown to worsen this symptom, leading to a faster progression of HIV infection to Acquired Immunodeficiency Syndrome (AIDS). The interaction of HIV and opioid drugs has not been studied at early stages of HIV, particularly in the gut microbiome where changes may precede translocation events. This study modeled early HIV infection by examining Simian Immunodeficiency Virus (SIV)-infected primates at 21 days or less both independently and in the context of opioid use. Fecal samples were analyzed both for 16S analysis of microbial populations as well as metabolite profiles via mass spectrometry. Our results indicate that changes are minor in SIV treated animals in the time points examined, however animals treated with morphine and SIV had significant changes in their microbial communities and metabolic profiles. This occurred in a time-independent fashion with morphine regardless of how long the animal had morphine in its system. Globally, the observed changes support that microbial dysbiosis is occurring in these animals at an early time, which likely contributes to the translocation events observed later in SIV/HIV pathogenesis. Additionally, metabolic changes were predictive of specific treatment groups, which could be further developed as a diagnostic tool or future intervention target to overcome and slow the progression of HIV infection to AIDS.

Neuromuscular control of voluntary movement may be simplified using muscle synergies similar to those found using non-negative matrix factorization. We recently identified synergies in electromyography (EMG) recordings associated with both voluntary movement and movement evoked by high-frequency long-duration intracortical microstimulation applied to the forelimb representation of the primary motor cortex (M1). The goal of this study was to use stimulus-triggered averaging (StTA) of EMG activity to investigate the synergy profiles and weighting coefficients associated with poststimulus facilitation, as synergies may be hard-wired into elemental cortical output modules and revealed by StTA. We applied StTA at low (LOW, ∼15 μA) and high intensities (HIGH, ∼110 μA) to 247 cortical locations of the M1 forelimb region in two male rhesus macaques while recording the EMG of 24 forelimb muscles. Our results show that 10-11 synergies accounted for 90% of the variation in poststimulus EMG facilitation peaks from the LOW-intensity StTA dataset while only 4-5 synergies were needed for the HIGH-intensity dataset. Synergies were similar across monkeys and current intensities. Most synergy profiles strongly activated only one or two muscles; all joints were represented and most, but not all, joint directions of motion were represented. Cortical maps of the synergy weighting coefficients suggest only a weak organization. StTA of M1 resulted in highly diverse muscle activations, suggestive of the limiting condition of requiring a synergy for each muscle to account for the patterns observed. SIGNIFICANCE STATEMENT Coordination of muscle activity and the neural origin of potential muscle synergies remains a fundamental question of neuroscience. We previously demonstrated that high-frequency long-duration intracortical microstimulation-evoked synergies were unrelated to voluntary movement synergies and were not clearly organized in the cortex. Here we present stimulus-triggered averaging facilitation-related muscle synergies, suggesting that when fundamental cortical output modules are activated, synergies approach the limit of single-muscle control. Thus, we conclude that if the CNS controls movement via linear synergies, those synergies are unlikely to be called from M1. This information is critical for understanding neural control of movement and the development of brain-machine interfaces., (Copyright © 2018 the authors 0270-6474/18/388759-13$15.00/0.)

Transverse sections of the monkey cervical spinal cord from a previous study (Jenny and Inukai, 1983) were reanalyzed using Neurolucida to create a three-dimensional display of extensor digitorum communis (EDC) motoneurons and proximal dendrites that had been labeled with horse radish peroxidase (HRP). The EDC motoneuron pool was located primarily in the C8 and T1 segments of the spinal cord. Small motoneurons (cell body areas less than 500 μm 2 and presumed to be gamma motoneurons) comprised about ten percent of the motoneurons and were located throughout the length of the motoneuron pool. Most small motoneurons were oblong in shape and had one or two major dendrites originating from the cell body in the transverse plane of section. The majority of the HRP labeled dendritic trees were directed either superiorly, dorsal-medially to the mid zone area between the base of the dorsal horn and the upper portion of the ventral horn, or medially to the ventromedial gray matter. The longer HRP labeled dendrites usually continued in the same radial direction as when originating from the cell body. As such we considered the radial direction of the longer proximal HRP labeled dendrites to be a reasonable estimate of the radial direction of the more distal dendritic tree. Our data suggest that the motoneuron dendritic tree as seen in transverse section has direction-oriented dendrites that extend toward functional terminal regions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Primary motor cortex has been studied for more than a century, yet a consensus on its functional contribution to movement control is still out of reach. In particular, there remains controversy as to the level of control produced by motor cortex ("low-level" movement dynamics vs. "high-level" movement kinematics) and the role of sensory feedback. In this review, we present different perspectives on the two following questions: What does activity in motor cortex reflect? and How do planned motor commands interact with incoming sensory feedback during movement? The four authors each present their independent views on how they think the primary motor cortex (M1) controls movement. At the end, we present a dialogue in which the authors synthesize their views and suggest possibilities for moving the field forward. While there is not yet a consensus on the role of M1 or sensory feedback in the control of upper limb movements, such dialogues are essential to take us closer to one., (Copyright © 2017 the American Physiological Society.)

Simplifying neuromuscular control for movement has previously been explored by extracting muscle synergies from voluntary movement electromyography (EMG) patterns. The purpose of this study was to investigate muscle synergies represented in EMG recordings associated with direct electrical stimulation of single sites in primary motor cortex (M1). We applied single-electrode high-frequency, long-duration intracortical microstimulation (HFLD-ICMS) to the forelimb region of M1 in two rhesus macaques using parameters previously found to produce forelimb movements to stable spatial end points (90-150 Hz, 90-150 μA, 1,000-ms stimulus train lengths). To develop a comprehensive representation of cortical output, stimulation was applied systematically across the full extent of M1. We recorded EMG activity from 24 forelimb muscles together with movement kinematics. Nonnegative matrix factorization (NMF) was applied to the mean stimulus-evoked EMG, and the weighting coefficients associated with each synergy were mapped to the cortical location of the stimulating electrode. Synergies were found for three data sets including 1 ) all stimulated sites in the cortex, 2 ) a subset of sites that produced stable movement end points, and 3 ) EMG activity associated with voluntary reaching. Two or three synergies accounted for 90% of the overall variation in voluntary movement EMG whereas four or five synergies were needed for HFLD-ICMS-evoked EMG data sets. Maps of the weighting coefficients from the full HFLD-ICMS data set show limited regional areas of higher activation for particular synergies. Our results demonstrate fundamental NMF-based muscle synergies in the collective M1 output, but whether and how the central nervous system might coordinate movements using these synergies remains unclear. NEW & NOTEWORTHY While muscle synergies have been investigated in various muscle activity sets, it is unclear whether and how synergies may be organized in the cortex. We have investigated muscle synergies resulting from high-frequency, long-duration intracortical microstimulation (HFLD-ICMS) applied throughout M1. We compared HFLD-ICMS synergies to synergies from voluntary movement. While synergies can be identified from M1 stimulation, they are not clearly related to voluntary movement synergies and do not show an orderly topographic organization across M1., (Copyright © 2017 the American Physiological Society.)

Stimulus-triggered averaging (StTA) of forelimb muscle electromyographic (EMG) activity was used to investigate individual forelimb muscle representation within the primary motor cortex (M1) of rhesus macaques with the objective of determining the extent of intra-areal somatotopic organization. Two monkeys were trained to perform a reach-to-grasp task requiring multijoint coordination of the forelimb. EMG activity was simultaneously recorded from 24 forelimb muscles including 5 shoulder, 7 elbow, 5 wrist, 5 digit, and 2 intrinsic hand muscles. Microstimulation (15 µA at 15 Hz) was delivered throughout the movement task and individual stimuli were used as triggers for generating StTAs of EMG activity. StTAs were used to map the cortical representations of individual forelimb muscles. As reported previously (Park et al. 2001), cortical maps revealed a central core of distal muscle (wrist, digit, and intrinsic hand) representation surrounded by a horseshoe-shaped proximal (shoulder and elbow) muscle representation. In the present study, we found that shoulder and elbow flexor muscles were predominantly represented in the lateral branch of the horseshoe whereas extensors were predominantly represented in the medial branch. Distal muscles were represented within the core distal forelimb representation and showed extensive overlap. For the first time, we also show maps of inhibitory output from motor cortex, which follow many of the same organizational features as the maps of excitatory output. NEW & NOTEWORTHY While the orderly representation of major body parts along the precentral gyrus has been known for decades, questions have been raised about the possible existence of additional more detailed aspects of somatotopy. In this study, we have investigated this question with respect to muscles of the arm and show consistent features of within-arm (intra-areal) somatotopic organization. For the first time we also show maps of how inhibitory output from motor cortex is organized., (Copyright © 2017 the American Physiological Society.)

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., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

While a large body of evidence supports the view that ipsilateral motor cortex may make an important contribution to normal movements and to recovery of function following cortical injury (Chollet et al. 1991; Fisher 1992; Caramia et al. 2000; Feydy et al. 2002), relatively little is known about the properties of output from motor cortex to ipsilateral muscles. Our aim in this study was to characterize the organization of output effects on hindlimb muscles from ipsilateral motor cortex using stimulus-triggered averaging of EMG activity. Stimulus-triggered averages of EMG activity were computed from microstimuli applied at 60-120 μA to sites in both contralateral and ipsilateral M1 of macaque monkeys during the performance of a hindlimb push-pull task. Although the poststimulus effects (PStEs) from ipsilateral M1 were fewer in number and substantially weaker, clear and consistent effects were obtained at an intensity of 120 μA. The mean onset latency of ipsilateral poststimulus facilitation was longer than contralateral effects by an average of 0.7 ms. However, the shortest latency effects in ipsilateral muscles were as short as the shortest latency effects in the corresponding contralateral muscles suggesting a minimal synaptic linkage that is equally direct in both cases., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The abuse of opiates such as morphine in synergy with HIV infection not only exacerbates neuropathogenesis but significantly impacts behavioral attributes in HIV infected subjects. Thus, the goal of the current study was to characterize behavioral perturbations in rhesus macaques subjected to chronic morphine and SIV infection. Specifically, we assessed three behavioral tasks: motor skill (MS), forelimb force (FFT) and progressive ratio (PR) tasks. After collecting baseline control data (44 weeks) and data during the morphine-only dependency period (26 weeks), a subset of animals were productively infected with neurovirulent strains of SIVmac (R71/E17) for an additional 33 weeks. A general pattern in the results is that behavioral decline occurred with high CSF viral loads but not necessarily with high plasma viral loads. Compared to saline controls, all treated animals showed significant decreases in performance on all three behavioral tasks during the morphine-only dependency period. During the post infection period, only the morphine plus SIV group showed a significant further decline and this only occurred for the MS task. Taken together, these data demonstrate a clear effect of morphine to produce behavioral deficits and also suggest that morphine can act synergistically with SIV/HIV to exacerbate behavioral deficits.

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., (Copyright © 2015 the American Physiological Society.)

High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) is increasingly being used to deduce how the brain encodes coordinated muscle activity and movement. However, the full movement repertoire that can be elicited from the forelimb representation of primary motor cortex (M1) using this method has not been systematically determined. Our goal was to acquire a comprehensive M1 forelimb representational map of movement endpoints elicited with HFLD-ICMS, using stimulus parameters optimal for evoking stable forelimb spatial endpoints. The data reveal a 3D forelimb movement endpoint workspace that is represented in a patchwork fashion on the 2D M1 cortical surface. Although cortical maps of movement endpoints appear quite disorderly with respect to movement space, we show that the endpoint locations in the workspace evoked with HFLD-ICMS of two adjacent cortical points are closer together than would be expected if the organization were random. Although there were few obvious consistencies in the endpoint maps across the two monkeys tested, one notable exception was endpoints bringing the hand to the mouth, which was located at the boundary between the hand and face representation. Endpoints at the extremes of the monkey's workspace and locations above the head were largely absent. Our movement endpoints are best explained as resulting from coactivation of agonist and antagonist muscles driving the joints toward equilibrium positions determined by the length-tension relationships of the muscles., (Copyright © 2014 the authors 0270-6474/14/3415722-13$15.00/0.)

Background: Magnetic resonance imaging (MRI) after deep brain stimulation (DBS) carries the risk of heating at the lead-contacts within the brain., Objective/hypothesis: To compare the effect of single- and dual-channel DBS implantable pulse generator (IPG) configurations on brain lead-contact heating during 3T MRI., Methods: A phantom with bilateral brain leads and extensions connected to two single-channel IPGs or a dual-channel right or left IPG was utilized. Using a transmit/receive head coil, seven scan sequences were conducted yielding a range of head-specific absorption rates (SAR-H). Temperature changes (ΔT) at the bilateral 0 and 3 lead-contacts were recorded, and normalized temperatures (ΔT/SAR-H) and slopes defining the ΔT/SAR-H over the SAR-H range were compared., Results: Greater heating was strongly correlated with higher SAR-H in all configurations. For each scan sequence, the ΔT/SAR-H of single-channel left lead-contacts was significantly greater than the ΔT/SAR-H of either dual-channel configuration. The slope defining the relationship between ΔT and SAR-H for the single-channel left lead (1.68°C/SAR-H) was significantly greater (p < 0.0001) than the ΔT/SAR-H slope for the single-channel right lead (0.97°C/SAR-H), both of which were significantly greater (p < 0.0001) than the ΔT/SAR-H slopes of left or right leads (range 0.68 to 0.70°C/SAR-H) in the dual-channel configurations. There were no significant differences in ΔT/SAR-H slope values between the dual-channel configurations., Conclusion: DBS hardware configuration using bilateral single-channel versus unilateral dual-channel IPGs significantly affects DBS lead-contact heating during 3T MRI brain scanning.

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.

Electrical stimulation of the brain was one of the first experimental methods applied to understanding brain organization and function and it continues as a highly useful method both in research and clinical applications. Intracortical microstimulation (ICMS) involves applying electrical stimuli through a microelectrode suitable for recording the action potentials of single neurons. ICMS can be categorized into single-pulse stimulation; high-frequency, short-duration stimulation; and high-frequency, long-duration stimulation. For clinical and experimental reasons, considerable interest focuses on the mechanism of neural activation by electrical stimuli. In this article, we discuss recent results suggesting that action potentials evoked in cortical neurons by high-frequency electrical stimulation do not sum with the natural, behaviorally related background activity; rather, high-frequency stimulation eliminates and replaces natural activity. We refer to this as neural hijacking. We propose that a major component of the mechanism underlying neural hijacking is excitation of axons by ICMS and elimination of natural spikes by antidromic collision with stimulus-driven spikes evoked at high frequency. Evidence also supports neural hijacking as an important mechanism underlying the action of deep brain stimulation in the subthalamic nucleus and its therapeutic effect in treating Parkinson's disease.

High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) applied to motor cortex is recognized as a useful and informative method for corticomotor mapping by evoking natural-appearing movements of the limb to consistent stable end-point positions. An important feature of these movements is that stimulation of a specific site in motor cortex evokes movement to the same spatial end point regardless of the starting position of the limb. The goal of this study was to delineate effective stimulus parameters for evoking forelimb movements to stable spatial end points from HFLD-ICMS applied to primary motor cortex (M1) in awake monkeys. We investigated stimulation of M1 as combinations of frequency (30-400 Hz), amplitude (30-200 μA), and duration (0.5-2 s) while concurrently recording electromyographic (EMG) activity from 24 forelimb muscles and movement kinematics with a motion capture system. Our results suggest a range of parameters (80-140 Hz, 80-140 μA, and 1,000-ms train duration) that are effective and safe for evoking forelimb translocation with subsequent stabilization at a spatial end point. The mean time for stimulation to elicit successful movement of the forelimb to a stable spatial end point was 475.8 ± 170.9 ms. Median successful frequency and amplitude were 110 Hz and 110 μA, respectively. Attenuated parameters resulted in inconsistent, truncated, or undetectable movements, while intensified parameters yielded no change to movement end points and increased potential for large-scale physiological spread and adverse focal motor effects. Establishing cortical stimulation parameters yielding consistent forelimb movements to stable spatial end points forms the basis for a systematic and comprehensive mapping of M1 in terms of evoked movements and associated muscle synergies. Additionally, the results increase our understanding of how the central nervous system may encode movement.

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.

Neuronal damage is a hallmark feature of HIV-associated neurological disorders (HANDs). Opiate drug abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Opiates such as morphine have been shown to enhance HIV transactivation protein Tat-mediated toxicity in both human neurons and neuroblastoma cells. In the present study, we demonstrate reduced expression of the tropic factor platelet-derived growth factor (PDGF)-B with a concomitant increase in miR-29b in the basal ganglia region of the brains of morphine-dependent simian immunodeficiency virus (SIV)-infected macaques compared with the SIV-infected controls. In vitro relevance of these findings was corroborated in cultures of astrocytes exposed to morphine and HIV Tat that led to increased release of miR-29b in exosomes. Subsequent treatment of neuronal SH-SY5Y cell line with exosomes from treated astrocytes resulted in decreased expression of PDGF-B, with a concomitant decrease in viability of neurons. Furthermore, it was shown that PDGF-B was a target for miR-29b as evidenced by the fact that binding of miR-29 to the 3'-untranslated region of PDGF-B mRNA resulted in its translational repression in SH-SY5Y cells. Understanding the regulation of PDGF-B expression may provide insights into the development of potential therapeutic targets for neuronal loss in HIV-1-infected opiate abusers.

Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Opiates are well known to modulate immune responses by preventing the development of cell-mediated immune responses. Their effect on the pathogenesis of HIV-1 infection however remains controversial. Using the simian immunodeficiency virus/macaque model of HIV pathogenesis, we sought to explore the impact of morphine on disease progression and pathogenesis. Sixteen rhesus macaques were divided into two groups; four were administered saline and 12 others morphine routinely. Both groups of animals were then inoculated with SIVmacR71/17E and followed longitudinally for disease pathogenesis. The morphine group (M+V) exhibited a trend towards higher mortality rates and retardation in weight gain compared to the virus-alone group. Interestingly, a subset of M+V animals succumbed to disease within weeks post-infection. These rapid progressors also exhibited a higher incidence of other end-organ pathologies. Despite the higher numbers of circulating CD4+ and CD8+ T cells in the M+V group, CD4/CD8 ratios between the groups remained unchanged. Plasma and CSF viral load in the M+V group was at least a log higher than the control group. Similarly, there was a trend toward increased virus build-up in the brains of M+V animals compared with controls. A novel finding of this study was the increased influx of infected monocyte/macrophages in the brains of M+V animals.

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.

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., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

In this study, forelimb organizations and output properties of the supplementary motor area (SMA) and the dorsal cingulate motor area (CMAd) were assessed and compared with primary motor cortex (M1). Stimulus-triggered averages of electromyographic activity from 24 muscles of the forelimb were computed from layer V sites of 2 rhesus monkeys performing a reach-to-grasp task. No clear segregation of the forelimb representation of proximal and distal muscles was found in SMA. In CMAd, sites producing poststimulus effects in proximal muscles tended to be located caudal to distal muscle sites, although the number of effects was limited. For both SMA and CMAd, facilitation effects were more prevalent in distal than in proximal muscles. At an intensity of 60 microA, the mean latencies of M1 facilitation effects were 8 and 12.1 ms shorter and the magnitudes approximately 10 times greater than those from SMA and CMAd. Our results show that corticospinal neurons in SMA and CMAd provide relatively weak input to spinal motoneurons compared with the robust effects from M1. However, a small number of facilitation effects from SMA and CMAd had latencies as short as the shortest ones from M1 suggesting a minimum linkage to motoneurons as direct as that from M1.

Motor output capabilities of the forelimb representation of dorsal motor area (PMd) and ventral motor area (PMv) were compared with primary motor cortex (M1) in terms of latency, strength, sign, and distribution of effects. Stimulus-triggered averages (60 microA) of electromyographic activity collected from 24 forelimb muscles were computed at 314 tracks in 2 monkeys trained to perform a reach-to-grasp task. The onset latency and magnitude of facilitation effects from PMd and PMv were significantly longer and 7- to 9-fold weaker than those from M1. Proximal muscles were predominantly represented in PMd and PMv. A joint-dependent flexor or extensor preference was also present. Distal and proximal muscle representations were intermingled in PMd and PMv. A gradual increase in latency and decrease in magnitude of effects were observed in moving from M1 surface sites toward more anterior sites in PMd. For many muscles, segregated areas producing suppression effects were found along the medial portion of PMd and adjacent M1. Although some facilitation effects from PMd and PMv had onset latencies as short as those from M1 in the same muscle, suggesting equal direct linkage, the vast majority had properties consistent with a more indirect linkage to motoneurons either through corticocortical connections with M1 and/or interneuronal linkages in the spinal cord.

Our work characterizes the effects of opiate (morphine) dependence on auditory brainstem and visual evoked responses in a rhesus macaque model of neuro-AIDS utilizing a chronic continuous drug delivery paradigm. The goal of this study was to clarify whether morphine is protective, or if it exacerbates simian immunodeficiency virus (SIV)-related systemic and neurological disease. Our model employs a macrophage tropic CD4/CCR5 coreceptor virus, SIV(mac)239 (R71/E17), which crosses the blood-brain barrier shortly after inoculation and closely mimics the natural disease course of human immunodeficiency virus infection. The cohort was divided into three groups: morphine only, SIV only, and SIV + morphine. Evoked potential (EP) abnormalities in subclinically infected macaques were evident as early as 8 weeks postinoculation. Prolongations in EP latencies were observed in SIV-infected macaques across all modalities. Animals with the highest cerebrospinal fluid viral loads and clinical disease showed more abnormalities than those with subclinical disease, confirming our previous work (Raymond et al., J Neurovirol 4:512-520, 1998; J Neurovirol 5:217-231, 1999; AIDS Res Hum Retroviruses 16:1163-1173, 2000). Although some differences were observed in auditory and visual evoked potentials in morphine-treated compared to morphine-untreated SIV-infected animals, the effects were relatively small and not consistent across evoked potential type. However, morphine-treated animals with subclinical disease had a clear tendency toward higher virus loads in peripheral and central nervous system tissues (Marcario et al., J Neuroimmune Pharmacol 3:12-25, 2008) suggesting that if had been possible to follow all animals to end-stage disease, a clearer pattern of evoked potential abnormality might have emerged.

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.

Macaque monkeys infected with various neurovirulent forms of simian immunodeficiency virus (SIV) represent highly effective models, not only of systemic acquired immunodeficiency virus (AIDS), but also neuroAIDS. Behavioral studies with this model have clearly established that SIV-infected monkeys show both cognitive and motor impairments resembling those that have been reported in human immunodeficiency virus (HIV)-infected humans. This paper combines data from a number of behavioral studies in SIV-infected macaque monkeys to obtain an overall estimate of the frequency of impairments in various motor and cognitive domains. The results were then compared to similar data from studies of HIV-infected humans. Whereas cognitive functions are most commonly impaired in HIV-infected humans, motor function is the domain most commonly impaired in SIV-infected monkeys. Electrophysiological studies in SIV-infected macaques have revealed deficits in motor-, somatosensory-, visual-, and auditory-evoked potentials that also resemble abnormalities in human HIV infection. Abnormalities in motor-evoked potentials were among the most common evoked potential deficits observed. Although differences in behavioral profiles of human HIV disease and SIV disease in monkeys exist, the results, nevertheless, provide strong validation for the use of macaque models for translational studies of the virology, immunology, pathophysiology, and treatment of neuroAIDS.

Morphine is known to prevent the development of cell-mediated immune (CMI) responses and enhance expression of the CCR5 receptor in monocyte macrophages. We undertook a study to determine the effect of morphine on the neuropathogenesis and immunopathogenesis of simian immunodeficiency virus (SIV) infection in Indian Rhesus Macaques. Hypothetically, the effect of morphine would be to prevent the development of CMI responses to SIV and to enhance the infection in macrophages. Sixteen Rhesus Macaques were divided into three experimental groups: M (morphine only, n = 5), VM (morphine + SIV, n = 6), and V (SIV only, n = 5). Animals in groups M and VM were given 2.5 mg/kg of morphine sulfate, four times daily, for up to 59 weeks. Groups VM and V were inoculated with SIVmacR71/17E 26 weeks after the beginning of morphine administration. Morphine prevented the development of enzyme-linked immunosorbent spot-forming cell CMI responses in contrast to virus control animals, all of which developed CMI. Whereas morphine treatment had no effect on viremia, cerebrospinal fluid viral titers or survival over the time course of the study, the drug was associated with a tendency for greater build-up of virus in the brains of infected animals. Histopathological changes in the brains of animals that developed disease were of a demyelinating type in the VM animals compared to an encephalitic type in the V animals. This difference may have been associated with the immunosuppressive effect of the drug in inhibiting CMI responses.

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.

Following bilateral injection of manganese (Mn) into the rat's motor cortex, electrical stimulation of the cortex is shown to increase the transport, uptake and accumulation of Mn in the corticospinal tract (CST), as assessed by manganese-enhanced magnetic resonance imaging (MEI). T(1)-weighted gradient echo images were acquired in 3-D and displayed in different orientations to anatomically delineate the CST pathway from cortex to spinal cord (SC) at the thoracic level. T(1)-maps of the SC were produced from spin-echo based image data to demonstrate the distribution of the T(1) properties of the SC tissue and to quantitatively assess the T(1)-change occurring in the CST due to the presence of Mn therein. Implications for improving the tract tracing ability with the proposed in vivo approach and its application to spinal cord injury (SCI) research are discussed in terms of aiding future experimental investigations of neuroplasticity following an injury.

The goal of this study was to assess the motor output capabilities of the forelimb representation of the supplementary motor area (SMA) in terms of the sign, latency and strength of effects on electromyographic (EMG) activity. Stimulus triggered averages of EMG activity from 24 muscles of the forelimb were computed in SMA during a reach-to-grasp task. Poststimulus facilitation (PStF) from SMA had two distinct peaks (15.2 and 55.2 ms) and one poststimulus suppression (PStS) peak (32.4 ms). The short onset latency PStF and PStS of SMA were 5.5 and 16.8 ms longer than those of the primary motor cortex (M1). The average magnitudes (peak increase or decrease above baseline) of the short and long latency PStF and PStS from SMA at 60 microA were 13.8, 11.3 and -11.9% respectively. In comparison, M1 PStF and PStS magnitudes at 15 microA were 50.2 and -23.8%. Extrapolating M1 PStF magnitude to 60 microA yields a mean effect that is nearly 15 times greater than the mean PStF from SMA. Moreover, unlike M1, the facilitation of distal muscles from SMA was not significantly greater than the facilitation of proximal muscles. We conclude that the output from SMA to motoneurons is markedly weaker compared with M1 raising doubts about the role of SMA corticospinal neurons in the direct control of muscle activity.

Stimulus-triggered averaging (StTA) of electromyographic (EMG) activity from 24 simultaneously recorded forelimb muscles was used to investigate properties of primary motor cortex (M1) output in the macaque monkey. Two monkeys were trained to perform a reach-to-grasp task requiring multijoint coordination of the forelimb. EMG activity was recorded from 24 forelimb muscles including 5 shoulder, 7 elbow, 5 wrist, 5 digit, and 2 intrinsic hand muscles. Microstimulation (15 microA at 15 Hz) was delivered throughout the movement task. From 297 stimulation sites in M1, a total of 2,079 poststimulus effects (PStE) were obtained including 1,398 poststimulus facilitation (PStF) effects and 681 poststimulus suppression (PStS) effects. Of the PStF effects, 60% were in distal and 40% in proximal muscles; 43% were of extensors and 47% flexors. For PStS, the corresponding numbers were 55 and 45% and 36 and 55%, respectively. M1 output effects showed extensive cofacilitation of proximal and distal muscles (96 sites, 42%) including 47 sites that facilitated at least one shoulder, elbow, and distal muscle, 45 sites that facilitated an elbow muscle and a distal muscle, and 22 sites that facilitated at least one muscle at all joints. The muscle synergies represented by outputs from these sites may serve an important role in the production of coordinated, multijoint movements. M1 output effects showed many similarities with red nucleus output although red nucleus effects were generally weaker and showed a strong bias toward facilitation of extensor muscles and a greater tendency to facilitate synergies involving muscles at noncontiguous joints.

Simian immunodeficiency virus has been shown to cause acquired immunodeficiency syndrome in macaque monkeys. Data gathered from clinical examination and fundus photography have shown that the lentivirus is capable of the induction of choroidal lesions and retinal hemorrhages in the macaque. These findings demonstrate the potential value of the macaque monkey eye as a model of the retinal pathology routinely seen in human AIDS patients.

The purpose of this study was to systematically map the forelimb area of primary motor cortex (M1) in rhesus macaques in an effort to investigate further the organization of motor output to distal and proximal muscles. We used stimulus-triggered averaging (StTAing) of electromyographic activity to map the cortical representation of 24 simultaneously recorded forelimb muscles. StTAs were obtained by applying 15 microA stimuli to M1 sites while the monkey performed a reach and prehension task. Motor output to body regions other than the forelimb (e.g., face, trunk, and hindlimb) was identified using repetitive intracortical microstimulation to evoke movements. Detailed, muscle-based maps of M1 revealed a central core of distal (wrist, digit, and intrinsic hand) muscle representation surrounded by a "horseshoe"-shaped zone of proximal (shoulder and elbow) muscle representation. The core distal and proximal zones were separated by a relatively large region representing combinations of both distal and proximal muscles. On the basis of its size and characteristics, we argue that this zone is not simply the result of stimulus-current spread, but rather a distinct zone within the forelimb representation containing cells that specify functional synergies of distal and proximal muscles. Electrode tracks extending medially from the medial arm of the proximal muscle representation evoked trunk and hindlimb responses. No distal or proximal muscle poststimulus effects were found in this region. These results argue against the existence of a second, major noncontiguous distal or proximal forelimb representation located medially within the macaque M1 representation.

Human immunodeficiency virus (HIV-1) infects the central nervous system (CNS) early in the course of disease progression and leads to some form of neurological disease in 40-60% of cases. Both symptomatic and asymptomatic HIV-infected subjects also show abnormalities in evoked potentials. As part of an effort to further validate an animal model of the neurological disease associated with lentiviral infection, we recorded multimodal sensory evoked potentials (EPs) from nine rhesus macaques infected with passaged strains of SIVmac (R71/E17), prior to and at 1 month intervals following inoculation. The latencies of forelimb and hindlimb somatosensory evoked potentials (SEP) and flash visual evoked potentials (VEP) were measured. Within 14 weeks of inoculation, all but two animals had progressed to end-stage disease (rapid progressors). The two animals with slowly progressing disease (AQ15 and AQ94) had postinoculation life spans of 109 and 87 weeks, respectively. No significant changes were observed in evoked potentials recorded during the control period or at any time in the animals with slowly progressing disease. However, all of the monkeys with rapidly progressing disease exhibited increases in latency for at least one evoked potential type. The overall mean increases in somatosensory and visual evoked potential peak latencies for the rapid progressors were 22.4 and 25.3%, respectively. For comparison, the changes in slow progressors were not significant (1.8 and -1.9%, respectively). These results, coupled with our previous finding of slowed motor evoked potentials in the same cohort of macaques (Raymond et al.: J Neurovirol 1999;5:217-231), demonstrate a broad and somewhat variable pattern of viral injury to both sensory and motor system structures, resembling the findings in HIV-infected humans. These results coupled with our earlier work demonstrating cognitive and motor behavioral impairments in the same monkeys support the use of the SIVmac-infected rhesus macaque as a model of AIDS-related neurological disease.

It has been hypothesized that the magnocellular red nucleus (RNm) contributes to compensation for motor impairments associated with lesions of the pyramidal tract. To test this hypothesis, we used stimulus triggered averaging (StTA) of electromyographic (EMG) activity to characterize changes in motor output from the red nucleus after lesions of the pyramidal tract. Three monkeys were trained to perform a reach and prehension task. EMG activity was recorded from 11 forearm muscles including one elbow, five wrist, and five digit muscles. Microstimulation (20 microA at 20 Hz) was delivered throughout the movement task to compute StTAs. Two monkeys served as controls. In a third monkey, 65% of the left pyramidal tract had been destroyed by an electrolytic lesion method five years before recording. The results demonstrate a clear pattern of postlesion reorganization in red nucleus-mediated output effects on forearm muscles. The normally prominent extensor preference in excitatory output from the RNm (92% in extensors) was greatly diminished in the lesioned monkey (59%). Similarly, suppression effects, which are normally much more prominent in flexor than in extensor muscles (90% in flexors), were also more evenly distributed after recovery from pyramidal tract lesions. Because of the limited excitatory output from the RNm to flexor muscles that normally exists, loss of corticospinal output would leave control of flexors particularly weak. The changes in RNm organization reported in this study would help restore function to flexor muscles. These results support the hypothesis that the RNm is capable of reorganization that contributes to the recovery of forelimb motor function after pyramidal tract lesions.

Studies of the neural control of movement often require or benefit from long-term recording of EMG activity from large numbers of muscles involved in a particular motor task. While chronic recording of EMG activity has been described in a number of previous monkey studies, the number of muscles recorded has been somewhat limited and the implantation approach has been highly invasive procedures. This paper presents two EMG implant fabrication and surgical implantation methods that are suitable for use in monkeys, relatively non-traumatic and capable of simultaneous recording from 24 or more muscles.

The presence of postspike facilitation (PSpF) in spike-triggered averages of electromyographic (EMG) activity provides a useful means of identifying cortical neurons with excitatory synaptic linkages to motoneurons. Similarly the presence of postspike suppression (PSpS) suggests the presence of underlying inhibitory synaptic linkages. The question we have addressed in this study concerns the extent to which the presence and strength of PSpF and PSpS from corticomotoneuronal (CM) cells correlates with the magnitude of covariation in activity of the CM cell and its target muscles. For this purpose, we have isolated cells during a reach and prehension task during which the activity of 24 individual proximal and distal forelimb muscles was recorded. These muscles show broad coactivation but with a highly fractionated and muscle specific fine structure of peaks and valleys. Covariation was assessed by computing long-term (2 s) cross-correlations between CM cells and forelimb muscles. The magnitude of cross-correlations was greater for muscles with facilitation effects than muscles lacking effects in spike-triggered averages. The results also demonstrate a significant relationship between the sign of the postspike effect (facilitation or suppression) and the presence of a peak or trough in the cross-correlation. Of all the target muscles with facilitation effects in spike-triggered averages (PSpF, PSpF with synchrony, or synchrony facilitation alone), 89.5% were associated with significant cross-correlation peaks, indicating positively covarying muscle and CM cell activity. Seven percent of facilitation effects were not associated with a significant effect in the cross-correlation, whereas only 3.4% of effects were associated with correlation troughs. In contrast, of all the muscles with suppression effects in spike-triggered averages, 38.9% were associated with significant troughs in the cross-correlation, indicating an inverse relation between CM cell and muscle activity consistent with the presence of suppression. Fifty-five percent of suppression effects was associated with correlation peaks, whereas 5.6% was not associated with a significant effect in the cross-correlation. Limiting the analysis to moderate and strong facilitation effects, the magnitude of PSpF was correlated weakly with the magnitude of the cell-muscle cross-correlation peak. Nevertheless, the results show that although many CM cell-target muscle pairs covary during the reach and prehension task in a way consistent with the sign and strength of the CM cell's synaptic effects on target motoneurons, many exceptions exist. The results are compatible with a model in which control of particular motoneuron pools reflects not only the summation of signals from many CM cells but also signals from additional descending, sensory afferent, and intrinsic spinal cord neurons. Any one neuron will make only a small contribution to the overall activity of the motoneuron pool. In view of this, it is not surprising that relationships between postspike effects and CM cell-target muscle covariation are relatively weak with many apparent incongruities.

HIV-1 causes cognitive and motor deficits and HIV encephalitis (HIVE) in a significant proportion of AIDS patients. Neurological impairment and HIVE are thought to result from release of cytokines and other harmful substances from infected, activated microglia. In this study, the quantitative relationship between microglial activation and neurological impairment was examined in the simian immunodeficiency model of HIVE. Macaque monkeys were infected with a passaged, neurovirulent strain of simian immunodeficiency virus, SIV(mac)239(R71/17E). In concurrent studies, functional impairment was assessed by motor and auditory brainstem evoked potentials and by measurements of cognitive and motor behavioral deficits. Brain tissue was examined by immunohistochemistry using two markers of microglia activation, MHC-II and matrix metalloproteinase-9 (MMP-9). The inoculated animals formed two groups: rapid progressors, which survived 6-14 weeks postinoculation, and slow progressors, which survived 87-109 weeks. In the rapid progressors, two patterns of MHC-II expression were present: (1) a widely disseminated pattern of MHC-II expressing microglia and microglial nodules in cortical gray matter and subcortical white matter, and (2) a more focal pattern in which MHC-II expressing microglia were concentrated into white matter. Animals exhibiting both patterns of microglial activation showed mild to severe changes in cognitive and motor behavior and evoked potentials. All rapid progressors showed expression of MMP-9 in microglia located in subcortical white matter. In the slow progressors MHC-II and MMP-9 staining was similar to uninoculated control macaques, and there was little or no evidence of HIVE. These animals showed behavioral deficits at the end of the disease course, but little changes in evoked potentials. Thus, increases in MHC-II and MMP-9 expression are associated with development of cognitive and motor deficits, alterations in evoked potentials, and rapid disease progression., (Copyright 1999 Academic Press.)

The pattern of neurological disease caused by human immunodeficiency virus (HIV) infection of the central nervous system (CNS) was investigated using a macaque model of acquired immune defiency syndrome (AIDS). Seven of nine macaques inoculated with neurovirulent simian imunodeficiency virus (SIVmac ) developed AIDS within 3 months. Four of these had clinically obvious neurological disease and extensive conduction defects in the form of latency increases in evoked potential (EP) responses. Neuropathologically, all four animals had disseminated white matter disease in the form of multifocal, perivascular and nodular parenchymal mononuclear cell infiltrates, along with extensive involvement of the cortical grey matter, leptomeninges and intracranial portions of cranial nerves. A brisk multinucleated giant cell (MGC) response was a frequent accompaniment in the affected areas. Three of the animals in this group also showed spongiform vacuolation in the occipital grey matter, a lesion described only rarely in HIV encephalitis. In the remaining three animals, there was only minimal evidence of overt neurological impairment or conduction defects. These animals had only mild to moderate neuropathological changes and lesions were virtually confined to the white matter regions of the brain. MGC responses were rare or absent in the CNS of these animals. Neuropathological findings in this SIVmac model have therefore shown good correlation with the severity of clinical and neurophysiological changes, and are reminiscent of HIV-1 encephalitis. More importantly, white matter involvement was a consistent finding in the affected macaques, regardless of the duration and severity of disease, or type of virus inoculated, suggesting an unusual susceptibility for lentiviral infection in these regions of the macaque CNS.

A number of studies have shown that simian immunodeficiency virus (SIV) infection in rhesus macaques parallels many aspects of HIV disease in humans. The purpose of this study was to further characterize the rhesus macaque infected with neurovirulent SIV as a model of neuroAIDS. Using a motor skill task, our objective was to detect SIV-related movement impairments in behaviorally trained macaques. The motor skill task required retrieval of a food pellet from a cup in a rotating turntable across a range of speeds. Nine monkeys were infected with neurovirulent strains of SIVmac (R71/17E): four monkeys served initially as controls pre-inoculation. Seven monkeys developed simian AIDS within 4 months of inoculation (rapid progressors), and two survived more than 18 months post-inoculation (slow progressors). Of the rapid progressors, five exhibited significant deficits in this task, most showing a gradual decline in performance terminating in a sharp drop to severely impaired levels of performance. One slow progressor (AQ15) showed no performance declines. The other slow progressor (AQ94) showed a significant decrease in maximum speed that was concurrent with the onset of clinical signs. For AQ94, the role of sickness behavior related to late stage simian AIDS could not be ruled out. These results demonstrate that motor system impairment can be detected early in the course of SIV infection in rhesus macaques, further establishing the SIVmac-infected macaque monkey as a viable model of neuroAIDS.

Previous work using bone marrow passaged SIVmac239 (simian immunodeficiency virus) has shown that macrophage tropic strains of this virus enter the rhesus macaque brain early following inoculation (Sharma et al, 1992; Desrosiers et al, 1991; Zhu et al, 1995; and Narayan et al, 1997). As part of an effort to more fully characterize the extent of neurologic impairment associated with SIV infection of the brain, we used transcranial electrical stimulation of motor cortex and the spinal cord to evoke EMG potentials in two forelimb (EDC and APB) and two hindlimb (LG and AH) muscles. The latencies, magnitudes and thresholds of motor evoked potentials (MEPs) recorded from nine monkeys infected with neurovirulent SIVmac R71/17E were compared to pre-inoculation records from the same monkeys. Seven of nine monkeys developed simian AIDS within 4 months of inoculation and were euthanized. Two monkeys remained free of AIDS-related clinical illness for over 18 months following inoculation. Six of the seven monkeys with rapidly progressing disease showed post-inoculation latency increases ( > or = 2 s.d. of control) in at least one cortical MEP. Increases in cortical MEP latency ranged from 21-97% in different monkeys. All seven rapidly progressing animals showed post-inoculation increases in at least one spinal cord MEP latency. Maximum spinal cord MEP latency increases ranged from 22-147%. Increases in central conduction time (CCT) ranged up to 204% and exceeded two standard deviations of control in four monkeys. Neither of the two monkeys with slowly progressing disease showed significant increases in either cortical or spinal cord MEP latency or CCT. Only the monkeys with rapidly progressing disease exhibited classic AIDS-related neuropathology, although there was no consistent relationship between the severity of neuropathology and the extent of MEP abnormalities. In conclusion, our results demonstrate clear deficits in the functional integrity of both central and peripheral motor system structures associated with SIV infection and further support the use of SIV-infected rhesus macaques as a model of neuro-AIDS.

It is well established that HIV infection can lead to motor/cognitive disorders in humans. A number of studies have shown that simian immunodeficiency virus (SIV) infection in rhesus macaques parallels many aspects of HIV disease in humans. The purpose of this study was to define further the SIV-infected rhesus macaque as a model of neuro-AIDS. Our objective was to detect movement-related impairments in behaviorally trained, SIV-infected macaques using both simple and choice reaction time tasks. Reaction times (RTs), movement times (MTs), and error types were examined. Nine monkeys were infected with neurovirulent strains of SIVmac, four of which served initially as controls before their inoculation. Seven of the nine monkeys developed simian AIDS within 4 months of inoculation (rapid progressors), while two monkeys survived for more than 1 year postinoculation (slow progressors). Of the rapid progressors, four exhibited slowed reaction times and six showed movement time slowing. One rapid progressor showed evidence of a strategy shift to overcome impaired motor abilities. Monkeys with rapidly progressing SIV-related disease consistently show behavioral abnormalities reflecting underlying neuronal injury. Although the slow progressors also showed RT and/or MT slowing, a role for nonspecific factors related to late-stage simian AIDS could not be ruled out in these cases. The results demonstrate that motor impairments associated with SIV infection in rhesus macaques can be detected using RT and MT measures, further establishing the SIVmac-infected macaque monkey as a viable model of neuro-AIDS.

We used spike-triggered averaging of rectified electromyographic activity to determine whether corticomotoneuronal (CM) cells produce postspike effects in muscles of both proximal and distal forelimb joints in monkeys performing a reach and prehension task. Two monkeys were trained to perform a self-paced task in which they reached forward from a starting position to retrieve a food reward from a small cylindrical well. We compiled spike-triggered averages from 22 to 24 separate forelimb muscles at both proximal (shoulder, elbow) and distal (wrist, digits, intrinsic hand) joints. Of 174 cells examined, 112 produced postspike effects in at least one of the target muscles. Of those cells, 45.5% produced postspike effects in both proximal and distal forelimb muscles. A nearly equal number (44.7%) produced postspike effects in distal muscles only, whereas a clear minority (9.8%) produced postspike effects in only proximal muscles. The majority of CM cells (71.4%) produced effects in two or more muscles, with an average muscle field of 3.1 +/- 2.1 (mean +/- SD) for facilitation plus suppression. Of 345 postspike effects identified, 70.7% were facilitation effects and 29.3% were suppression effects. The large majority of effects (72.2%) were in distal muscles. When averaged by joint, the latency and peak magnitude of postspike facilitation showed a stepwise increase from proximal to distal joints. The results of this study show that the majority of CM cells engaged in coordinated forelimb reaching movements facilitate and/or suppress muscles at multiple joints, including muscles at both proximal and distal joints. The results also show that CM cells make more frequent and more potent terminations in motoneuron pools of distal compared with proximal muscles.

Nine rhesus macaques (Macaca mulatta) were inoculated with a combination of two passaged strains of SIVmac (R71 and 17E), both of which are known to be neurovirulent. Auditory brainstem responses (ABRs) were recorded at regular intervals from these animals both before and after inoculation. Increases in ABR peak and interpeak latency were observed corresponding to progression of SIV disease. Post-inoculation increases in latency were observed for all five peaks of the ABR and for interpeak intervals I-V and III-V. The largest increases in latency were associated with end-stage disease. Within 14 weeks of inoculation, all but two animals developed end-stage simian AIDS and were euthanized. Histopathological examination revealed multifocal lesions in the cerebral gray and white matter as well as in the auditory structures of the brainstem. In most animals, ABR changes were accompanied by evidence of underlying neuropathology. However, cases of severe neuropathology with no ABR abnormalities and vice versa were also noted. Though in a much shorter time frame, SIVmac R71/17E produced both physiological and histopathological abnormalities similar to those associated with HIV disease in humans. These results further support the SIVmac R71/17E infected rhesus macaque as an animal model of HIV related neurological disease in humans.

Astrocyte activation has been postulated to be a major contributor to functional changes in the brain of AIDS patients. We assessed astrocyte activation in the simian immunodeficiency virus (SIV) model. Four groups of macaque brains were examined: uninoculated controls, animals inoculated with virus that did not cause disease, animals inoculated with virus that caused AIDS but did not cause encephalitis, and animals with SIV encephalitis. We examined expression of calbindin-D-28K, a calcium binding protein that is upregulated in astrocytes during excitotoxic events, as well as glial fibrillary acidic protein (GFAP). The presence of calbindin in astrocytes was confirmed by double-labeling using confocal microscopy. Increases in calbindin staining were most apparent in the white matter, but increases in GFAP staining were most apparent in middle layers of the cerebral cortex. Six of the seven animals with SIV encephalitis had calbindin immunoreactive astrocytes in the subcortical white matter, corpus callosum, internal capsule, cerebral peduncle, pontine white matter, and cerebellar white matter. Very rarely, a few, very lightly calbindin-immunoreactive astrocytes were present in the uninoculated control brains. The increase in calbindin expression by astrocytes in SIV encephalitis suggests that these cells are subject to calcium toxicity. In uninoculated control macaques, and in macaques inoculated with virus that did not cause disease, GFAP-immunoreactive astrocytes were present throughout the subcortical white matter and in layer I, but very few were found in layers III-V of the cerebral cortex. Two animals that died of AIDS without encephalitis had somewhat higher numbers of GFAP immunoreactive astrocytes in middle cortical layers. In seven animals that received passaged neurovirulent virus and developed both AIDS and encephalitis, the number of GFAP-immunoreactive astrocytes in middle cortical layers was high, indicating widespread astrocyte activation.

We used stimulus-triggered averaging (StTA) of electromyographic (EMG) activity to investigate two major questions concerning the functional organization of the magnocellular red nucleus (RNm) for reaching movements in the macaque monkey. The first is whether the clear preference toward facilitation of extensor muscles we have reported in previous studies for distal (wrist and digit) forelimb muscles also exists for proximal muscles (shoulder and elbow). The second question is whether distal and proximal muscles may be cofacilitated from RNm suggesting the representation of functional muscle synergies for coordinated reaching movements. Two monkeys were trained to perform a prehension task requiring multijoint coordination of the forelimb. EMG activity was recorded from 24 forelimb muscles including 5 shoulder, 7 elbow, 5 wrist, 5 digit, and 2 intrinsic hand muscles. Microstimulation (20 microA at 20 Hz) was delivered throughout the movement task. From 137 microstimulation sites in the RNm, a total of 977 poststimulus effects was obtained including 733 poststimulus facilitation effects (PStF) and 244 poststimulus suppression effects (PStS). Of the PStF effects, 58% were obtained from distal muscles; 42% from proximal muscles. Digit muscles were more frequently facilitated (35%) than the wrist, elbow, or shoulder muscles (20, 24, and 18%, respectively). The intrinsic hand muscles were infrequently facilitated (3%). At all joints tested, PStF was more common in extensor muscles than flexor muscles. This extensor preference was very strong for shoulder (85%), wrist (85%), and digit muscles (94%) and weaker for elbow muscles (60%). Of the PStS effects, 65% were in distal muscles and 35% in proximal muscles. Interestingly, the flexor muscles were more frequently inhibited from RNm than extensor muscles. At 72% of stimulation sites, at least two muscles were facilitated. The majority of these sites (61%) cofacilitated both proximal and distal muscles. At the remaining sites (39%), PStF was observed in either the proximal (17%) or distal muscles (22%). Facilitation most often involved combinations of shoulder, elbow, and distal muscles (30%) or shoulder and distal muscles (26%). Only rarely were intrinsic hand muscles part of the total muscle synergy. Our results show that the RNm 1) controls both proximal and distal muscles but the strength of influence is biased toward distal muscles, 2) preferentially controls extensor muscles not only at distal forelimb joints but also at proximal joints, and 3) output zones cofacilitate synergies of proximal and distal muscles involved in the control of forelimb reaching movements.