Structural plasticity of motor cortices assessed by voxel-based morphometry and immunohistochemical analysis following internal capsular infarcts in macaque monkeys.

Compensatory plastic changes in the remaining intact brain regions are supposedly involved in functional recovery following stroke. Previously, a compensatory increase in cortical activation occurred in the ventral premotor cortex (PMv), which contributed to the recovery of dexterous hand movement in a macaque model of unilateral internal capsular infarcts. Herein, we investigated the structural plastic changes underlying functional changes together with voxel-based morphometry (VBM) analysis of magnetic resonance imaging data and immunohistochemical analysis using SMI-32 antibody in a macaque model. Unilateral internal capsular infarcts were pharmacologically induced in 5 macaques, and another 5 macaques were used as intact controls for immunohistochemical analysis. Three months post infarcts, we observed significant increases in the gray matter volume (GMV) and the dendritic arborization of layer V pyramidal neurons in the contralesional rostral PMv (F5) as well as the primary motor cortex (M1). The histological analysis revealed shrinkage of neuronal soma and dendrites in the ipsilesional M1 and several premotor cortices, despite not always detecting GMV reduction by VBM analysis. In conclusion, compensatory structural changes occur in the contralesional F5 and M1 during motor recovery following internal capsular infarcts, and the dendritic growth of pyramidal neurons is partially correlated with GMV increase.

Pharmacological inactivation of the primate posterior insular/secondary somatosensory cortices attenuates thermal hyperalgesia.

BACKGROUND: We previously established a macaque model of central post-stroke pain (CPSP) and confirmed the involvement of increased activity of the posterior insular cortex (PIC) and secondary somatosensory cortex (SII) to somatosensory stimuli in mechanical allodynia by a combination of imaging techniques with local pharmacological inactivation. However, it is unclear whether the same intervention would be effective for thermal hyperalgesia. Therefore, using the macaque model, we examined behavioural responses to thermal stimuli following pharmacological inactivation of the PIC/SII. METHODS: Two CPSP model macaques were established based on collagenase-induced unilateral hemorrhagic lesions in the ventral posterolateral nucleus of the thalamus. To evaluate pain perception, withdrawal latencies to thermal stimuli of 37, 45, 50, 52, and 55 °C to hands were measured. Several weeks after the lesion induction, pharmacological inactivation of the PIC/SII by microinjection of muscimol was performed. The effect of inactivation on withdrawal latency was assessed by comparison with withdrawal latency after vehicle injection. RESULTS: Several weeks after induction of the thalamic lesions, both macaques demonstrated a reduction in withdrawal latencies to thermal stimulation (<50 °C) on the contralesional hand, indicating the occurrence of thermal hyperalgesia. When the PIC/SII were inactivated by muscimol, the withdrawal latencies to thermal stimuli of 50 and 52 °C were significantly increased compared to those after vehicle injection. CONCLUSIONS: Our data emphasize that increased activity in the PIC/SII after appearance of thalamic lesions can contribute to abnormal pain of multiple modalities, and the modulation of PIC/SII activity may be a therapeutic approach for thermal hyperalgesia. SIGNIFICANCE: CPSP is caused by stroke lesions in the sensory system and characterized by mechanical allodynia or thermal hyperalgesia. Inactivation of the PIC/SII has an analgesic effect on mechanical allodynia; however, it is not clear whether the same intervention could reduce thermal hyperalgesia. Here, using the macaque model, we demonstrated that inactivation of these cortices reduces hypersensitivity to thermal stimuli. This result emphasizes that increased PIC/SII activity can contribute to abnormal pain of multiple modalities.

Diffuse Optical Tomography Using fNIRS Signals Measured from the Skull Surface of the Macaque Monkey.

Diffuse optical tomography (DOT), as a functional near-infrared spectroscopy (fNIRS) technique, can estimate three-dimensional (3D) images of the functional hemodynamic response in brain volume from measured optical signals. In this study, we applied DOT algorithms to the fNIRS data recorded from the surface of macaque monkeys' skulls when the animals performed food retrieval tasks using either the left- or right-hand under head-free conditions. The hemodynamic response images, reconstructed by DOT with a high sampling rate and fine voxel size, demonstrated significant activations at the upper limb regions of the primary motor area in the central sulcus and premotor, and parietal areas contralateral to the hands used in the tasks. The results were also reliable in terms of consistency across different recording dates. Time-series analyses of each brain area revealed preceding activity of premotor area to primary motor area consistent with previous physiological studies. Therefore, the fNIRS-DOT protocol demonstrated in this study provides reliable 3D functional brain images over a period of days under head-free conditions for region-of-interest-based time-series analysis.

Accounting for the valley of recovery during post-stroke rehabilitation training via a model-based analysis of macaque manual dexterity.

Background: True recovery, in which a stroke patient regains the same precise motor skills observed in prestroke conditions, is the fundamental goal of rehabilitation training. However, a transient drop in task performance during rehabilitation training after stroke, observed in human clinical outcome as well as in both macaque and squirrel monkey retrieval data, might prevent smooth transitions during recovery. This drop, i.e., recovery valley, often occurs during the transition from compensatory skill to precision skill. Here, we sought computational mechanisms behind such transitions and recovery. Analogous to motor skill learning, we considered that the motor recovery process is composed of spontaneous recovery and training-induced recovery. Specifically, we hypothesized that the interaction of these multiple skill update processes might determine profiles of the recovery valley. Methods: A computational model of motor recovery was developed based on a state-space model of motor learning that incorporates a retention factor and interaction terms for training-induced recovery and spontaneous recovery. The model was fit to previously reported macaque motor recovery data where the monkey practiced precision grip skills after a lesion in the sensorimotor area in the cortex. Multiple computational models and the effects of each parameter were examined by model comparisons based on information criteria and sensitivity analyses of each parameter. Result: Both training-induced and spontaneous recoveries were necessary to explain the behavioral data. Since these two factors contributed following logarithmic function, the training-induced recovery were effective only after spontaneous biological recovery had developed. In the training-induced recovery component, the practice of the compensation also contributed to recovery of the precision grip skill as if there is a significant generalization effect of learning between these two skills. In addition, a retention factor was critical to explain the recovery profiles. Conclusions: We found that spontaneous recovery, training-induced recovery, retention factors, and interaction terms are crucial to explain recovery and recovery valley profiles. This simulation-based examination of the model parameters provides suggestions for effective rehabilitation methods to prevent the recovery valley, such as plasticity-promoting medications, brain stimulation, and robotic rehabilitation technologies.

Non-human Primate Models to Explore the Adaptive Mechanisms After Stroke.

The brain has the ability to reconstruct neural structures and functions to compensate for the brain lesions caused by stroke, although it is highly limited in primates including humans. Animal studies in which experimental lesions were induced in the brain have contributed to the current understanding of the neural mechanisms underlying functional recovery. Here, I have highlighted recent advances in non-human primate models using primate species such as macaques and marmosets, most of which have been developed to study the mechanisms underlying the recovery of motor functions after stroke. Cortical lesion models have been used to investigate motor recovery after lesions to the cortical areas involved in movements of specific body parts. Models of a focal stroke at the posterior internal capsule have also been developed to bridge the gap between the knowledge obtained by cortical lesion models and the development of intervention strategies because the severity and outcome of motor deficits depend on the degree of lesions to the region. This review will also introduce other stroke models designed to study the plastic changes associated with development and recovery from cognitive and sensory impairments. Although further validation and careful interpretation are required, considering the differences between non-human primate brains and human brains, studies using brain-lesioned non-human primates offer promise for improving translational outcomes.

Structural Plastic Changes of Cortical Gray Matter Revealed by Voxel-Based Morphometry and Histological Analyses in a Monkey Model of Central Post-Stroke Pain.

Central post-stroke pain (CPSP) is a chronic pain caused by stroke lesions of somatosensory pathways. Several brain imaging studies among patients with CPSP demonstrate that the pathophysiological mechanism underlying this condition is the maladaptive plasticity of pain-related brain regions. However, the temporal profile of the regional plastic changes, as suggested by brain imaging of CPSP patients, as well as their cellular basis, is unknown. To investigate these issues, we performed voxel-based morphometry (VBM) using T1-weighted magnetic resonance imaging and immunohistochemical analysis with our established CPSP monkey model. From 8 weeks after a hemorrhagic lesion to the unilateral ventral posterolateral nucleus of the thalamus, the monkeys exhibited significant behavioral changes that were interpreted as reflecting allodynia. The present VBM results revealed a decrease in gray matter volume in the pain-related areas after several weeks following the lesion. Furthermore, immunohistochemical staining in the ipsilesional posterior insular cortex (ipsi-PIC) and secondary somatosensory cortex (ipsi-SII), where the significant reduction in gray matter volume was observed in the VBM result, displayed a significant reduction in both excitatory and inhibitory synaptic terminals compared to intact monkeys. Our results suggest that progressive changes in neuronal morphology, including synaptic loss in the ipsi-PIC/SII, are involved in theCPSP.

Time- and area-dependent macrophage/microglial responses after focal infarction of the macaque internal capsule.

We quantitatively investigated temporal changes of macrophages and microglia (MΦ/MG) after focal infarction of the internal capsule using a macaque model we recently established. Immunoreactivity for Iba1, a general marker for MΦ/MG, in the periinfarct core gradually increased from 0 days to 2-3 weeks after infarction, and the increased immunoreactivity continued at least until 6 months; no study in rodents has reported increased Iba1-immunoreactive cells for so long. Retrograde atrophy or degeneration of neurons in layer V of the primary motor cortex, where the descending motor tract originates, was seen as secondary damage. Here we found that Iba1-positive MΦ/MG transiently increased in layer V during several weeks after the infarction. Therefore, the time course of MΦ/MG activation differs between the perilesional area and the remote brain area where secondary damage occurs to tissue initially preserved after the infarct. Detailed analyses using the functional phenotype markers CD68, CD86, and CD206, as well as cytokines released by cells with each phenotype, suggest an anti-inflammatory role for activated MΦ/MG both in the periinfarct core during the chronic phase and in the primary motor cortex.

Functional near-infrared-spectroscopy-based measurement of changes in cortical activity in macaques during post-infarct recovery of manual dexterity.

Because compensatory changes in brain activity underlie functional recovery after brain damage, monitoring of these changes will help to improve rehabilitation effectiveness. Functional near-infrared spectroscopy (fNIRS) has the potential to measure brain activity in freely moving subjects. We recently established a macaque model of internal capsule infarcts and an fNIRS system for use in the monkey brain. Here, we used these systems to study motor recovery in two macaques, for which focal infarcts of different sizes were induced in the posterior limb of the internal capsule. Immediately after the injection, flaccid paralysis was observed in the hand contralateral to the injected hemisphere. Thereafter, dexterous hand movements gradually recovered over months. After movement recovery, task-evoked hemodynamic responses increased in the ventral premotor cortex (PMv). The response in the PMv of the infarcted (i.e., ipsilesional) hemisphere increased in the monkey that had received less damage. In contrast, the PMv of the non-infarcted (contralesional) hemisphere was recruited in the monkey with more damage. A pharmacological inactivation experiment with muscimol suggested the involvement of these areas in dexterous hand movements during recovery. These results indicate that fNIRS can be used to evaluate brain activity changes crucial for functional recovery after brain damage.

The Ventral Striatum is a Key Node for Functional Recovery of Finger Dexterity After Spinal Cord Injury in Monkeys.

In a recent study, we demonstrated that the ventral striatum (VSt) controls finger movements directly during the early recovery stage after spinal cord injury (SCI), implying that the VSt may be a part of neural substrates responsible for the recovery of dexterous finger movements. The VSt is accepted widely as a key node for motivation, but is not thought to be involved in the direct control of limb movements. Therefore, whether a causal relationship exists between the VSt and motor recovery after SCI is unknown, and the role of the VSt in the recovery of dexterous finger movements orfinger movements in general after SCI remains unclear. In the present study, functional brain imaging in a macaque model of SCI revealed a strengthened functional connectivity between motor-related areas and the VSt during the recovery process for precision grip, but not whole finger grip after SCI. Furthermore, permanent lesion of the VSt impeded the recoveryof precision grip, but not coarse grip. Thus, the VSt was needed specifically for functional recovery of dexterous finger movements. These results suggest that the VSt is the key node of the cortical reorganization required for functional recovery of finger dexterity.

Brain activity changes in a monkey model of central post-stroke pain.

Central post-stroke pain (CPSP) can occur after stroke in the somatosensory pathway that includes the posterolateral region of the thalamus. Tactile allodynia, in which innocuous tactile stimuli are perceived as painful, is common in patients with CPSP. Previous brain imaging studies have reported plastic changes in brain activity in patients with tactile allodynia after stroke, but a causal relationship between such changes and the symptoms has not been established. We recently developed a non-human primate (macaque) model of CPSP based on thalamic lesions, in which the animals show behavioral changes consistent with the occurrence of tactile allodynia. Here we performed functional magnetic resonance imaging under propofol anesthesia to investigate the changes in brain activation associated with the allodynia in this CPSP model. Before the lesion, innocuous tactile stimuli significantly activated the contralateral sensorimotor cortex. When behavioral changes were observed after the thalamic lesion, equivalent stimuli significantly activated pain-related brain areas, including the posterior insular cortex (PIC), secondary somatosensory cortex (SII), anterior cingulate cortex (ACC), and amygdala. Moreover, when either PIC/SII or ACC was pharmacologically inactivated, the signs of tactile allodynia were dampened. Our results show that increased cortical activity plays a role in CPSP-induced allodynia.

Premotor Cortical-Cerebellar Reorganization in a Macaque Model of Primary Motor Cortical Lesion and Recovery.

Neuromotor systems have the capacity for functional recovery following local damage. The literature suggests a possible role for the premotor cortex and cerebellum in motor recovery. However, the specific changes to interactions between these areas following damage remain unclear. Here, we demonstrate potential rewiring of connections from the ipsilesional ventral premotor cortex (ip-PMv) to cerebellar structures in a nonhuman primate model of primary motor cortex (M1) lesion and motor recovery. Cerebellar connections arising from the ip-PMv were investigated by comparing biotinylated dextran amine (BDA) between two groups of male Macaca mulatta: M1-lesion/motor recovery group and intact group. There were more BDA-labeled boutons and axons in all ipsilesional deep cerebellar nuclei (fastigial, interposed, and dentate) in the M1-lesion/recovery group than in the intact group. The difference was evident in the ipsilesional fastigial nucleus (ip-FN), and particularly observed in its middle, a putative somatosensory region of the ip-FN, which was characterized by absent or little expression of aldolase C. Some of the altered projections from the ip-PMv to ip-FN neurons were confirmed as functional because the synaptic markers, synaptophysin and vesicular glutamate transporter 1, were colocalized with BDA-labeled boutons. These results suggest that the adult primate brain after motor lesions can reorganize large-scale networks to enable motor recovery by enhancing sensorimotor coupling and motor commands via rewired fronto-cerebellar connections.SIGNIFICANCE STATEMENT Damaging the motor cortex causes motor deficits, which can be recovered over time. Such motor recovery may result from functional compensation in remaining neuromotor areas, including the ventral premotor cortex. We investigated compensatory changes in neural axonal outputs from ventral premotor to deep cerebellar nuclei in a monkey model of primary motor cortical lesion and motor recovery. The results showed an increase in premotor projections and synaptic formations in deep cerebellar nuclei, especially the sensorimotor region of the fastigial nucleus. Our results provide the first evidence that large-scale reorganization of fronto-cerebellar circuits may underlie functional recovery after motor cortical lesions.

Neuronal and microglial localization of secreted phosphoprotein 1 (osteopontin) in intact and damaged motor cortex of macaques.

We previously reported that mRNA encoding secreted phosphoprotein 1 (SPP1), also known as osteopontin, is preferentially expressed in large neurons in layer V of the macaque motor cortex, most of which are presumed to be corticospinal tract neurons. As a first step to elucidating the cellular function of SPP1 in macaque neurons, we examined the localization of SPP1 in the primary motor cortex (M1) of the macaque by using immunohistochemistry. SPP1 immunoreactivity was found to be localized in the cell bodies of neurons, but not outside the cells, indicating that SPP1 was not secreted from these neurons. The results of electron microscope analysis and double-labeling analysis with marker proteins suggested that SPP1 was localized in the mitochondria of neurons. The distributions of SPP1 in the neurons corresponded to those of integrin αV, a putative receptor for SPP1. The distribution of SPP1 was also investigated in macaques whose M1 had been lesioned. We found that SPP1 was secreted by proliferated microglia in the lesioned area. Double-labeling analysis indicated that SPP1 immunoreactivity in the microglia was colocalized with CD44, another putative receptor for SPP1. Success rates in the small-object-retrieval task were positively correlated with SPP1 immunoreactivity in the neurons in the perilesional area. SPP1 has multiple roles in the macaque motor cortex, and it may be a key protein during recovery of hand movement after brain damage.

Functional near-infrared spectroscopy for monitoring macaque cerebral motor activity during voluntary movements without head fixation.

We developed an fNIRS system for monitoring macaque cerebral motor activity during voluntary movements without head fixation. fNIRS data at 27 channels in 7.5 mm spatial interval were calibrated by simulating light propagation through the macaque cranial tissues. The subject was instructed to repeatedly (75 times) retrieve a food pellet with alternating left or right hands from a food well for each session. We detected significant increases in oxygenated hemoglobin (Hb) and decrease in deoxygenated Hb in the primary motor area (M1) contralateral to the hand used. In more rostral and ventral regions in both hemispheres, the hemodynamic similarly changed regardless of used hand. Direct feeding to the mouth eliminated activity in the hand M1 whereas that at bilateral ventral regions (mouth M1 area) remained. Statistical analyses for the hemodynamics between left/right-hand use revealed the location of each hand M1 in either hemisphere. In these regions, the maximum amplitude and time of the maximum amplitude in the hemodynamic response evoked by food retrieval were highly correlated with the time associated with food retrieval. We could assign each channel to an appropriate functional motor area, providing proof of principle for future studies involving brain damage models in freely moving macaque monkeys.

Gaps in Understanding Mechanism and Lack of Treatments: Potential Use of a Nonhuman Primate Model of Oxaliplatin-Induced Neuropathic Pain.

The antineoplastic agent oxaliplatin induces an acute hypersensitivity evoked by cold that has been suggested to be due to sensitized central and peripheral neurons. Rodent-based preclinical studies have suggested numerous treatments for the alleviation of oxaliplatin-induced neuropathic pain, but few have demonstrated robust clinical efficacy. One issue is that current understanding of the pathophysiology of oxaliplatin-induced neuropathic pain is primarily based on rodent models, which might not entirely recapitulate the clinical pathophysiology. In addition, there is currently no objective physiological marker for pain that could be utilized to objectively indicate treatment efficacy. Nonhuman primates are phylogenetically and neuroanatomically similar to humans; thus, disease mechanism in nonhuman primates could reflect that of clinical oxaliplatin-induced neuropathy. Cold-activated pain-related brain areas in oxaliplatin-treated macaques were attenuated with duloxetine, the only drug that has demonstrated clinical efficacy for chemotherapy-induced neuropathic pain. By contrast, drugs that have not demonstrated clinical efficacy in oxaliplatin-induced neuropathic pain did not reduce brain activation. Thus, a nonhuman primate model could greatly enhance understanding of clinical pathophysiology beyond what has been obtained with rodent models and, furthermore, brain activation could serve as an objective marker of pain and therapeutic efficacy.

CRMP2-binding compound, edonerpic maleate, accelerates motor function recovery from brain damage.

Brain damage such as stroke is a devastating neurological condition that may severely compromise patient quality of life. No effective medication-mediated intervention to accelerate rehabilitation has been established. We found that a small compound, edonerpic maleate, facilitated experience-driven synaptic glutamate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic-acid) receptor delivery and resulted in the acceleration of motor function recovery after motor cortex cryoinjury in mice in a training-dependent manner through cortical reorganization. Edonerpic bound to collapsin-response-mediator-protein 2 (CRMP2) and failed to augment recovery in CRMP2-deficient mice. Edonerpic maleate enhanced motor function recovery from internal capsule hemorrhage in nonhuman primates. Thus, edonerpic maleate, a neural plasticity enhancer, could be a clinically potent small compound with which to accelerate rehabilitation after brain damage.

Comprehensive analysis of area-specific and time-dependent changes in gene expression in the motor cortex of macaque monkeys during recovery from spinal cord injury.

The present study aimed to assess the molecular bases of cortical compensatory mechanisms following spinal cord injury in primates. To accomplish this, comprehensive changes in gene expression were investigated in the bilateral primary motor cortex (M1), dorsal premotor cortex (PMd), and ventral premotor cortex (PMv) after a unilateral lesion of the lateral corticospinal tract (l-CST). At 2 weeks after the lesion, a large number of genes exhibited altered expression levels in the contralesional M1, which is directly linked to the lesioned l-CST. Gene ontology and network analyses indicated that these changes in gene expression are involved in the atrophy and plasticity changes observed in neurons. Orchestrated gene expression changes were present when behavioral recovery was attained 3 months after the lesion, particularly among the bilateral premotor areas, and a large number of these genes are involved in plasticity. Moreover, several genes abundantly expressed in M1 of intact monkeys were upregulated in both the PMd and PMv after the l-CST lesion. These area-specific and time-dependent changes in gene expression may underlie the molecular mechanisms of functional recovery following a lesion of the l-CST.

Late-onset hypersensitivity after a lesion in the ventral posterolateral nucleus of the thalamus: A macaque model of central post-stroke pain.

Central post-stroke pain (CPSP) can occur as a result of a cerebrovascular accident in the ventral posterolateral nucleus (VPL) of the thalamus. Developing therapeutic interventions for CPSP is difficult because its pathophysiology is unclear. Here we developed and characterized a macaque model of CPSP. The location of the VPL was determined by magnetic resonance imaging (MRI) and extracellular recording of neuronal activity during tactile stimulation, after which a hemorrhagic lesion was induced by injecting collagenase type IV. Histological analysis revealed that most of the lesion was localized within the VPL. Several weeks after the injection, the macaques displayed behavioral changes that were interpreted as reflecting the development of both mechanical allodynia and thermal hyperalgesia. Immunohistochemistry revealed that microglial and astrocytic activation in the perilesional areas lasted at least 3 months after injection. The present model reproduced the symptoms of patients suffering from CPSP, in which both mechanical allodynia and thermal hyperalgesia often develop several weeks after cerebrovascular accident. Further, the long-lasting glial activation revealed here may be characteristic of primate brains following injury. The present model will be useful not only for examining the neurological changes underlying CPSP, but also for testing therapeutic interventions for CPSP.

Brain activity changes in a macaque model of oxaliplatin-induced neuropathic cold hypersensitivity.

The antineoplastic agent oxaliplatin induces a painful peripheral neuropathy characterized by an acute cold hypersensitivity. There is a lack of effective treatments to manage oxaliplatin-induced cold hypersensitivity which is due, in part, to a lack of understanding of the pathophysiology of oxaliplatin-induced cold hypersensitivity. Thus, brain activity in oxaliplatin-treated macaques was examined using functional magnetic resonance imaging (fMRI). Oxaliplatin treatment reduced tail withdrawal latency to a cold (10 °C) stimulus, indicating cold hypersensitivity and increased activation in the secondary somatosensory cortex (SII) and the anterior insular cortex (Ins) was observed. By contrast, no activation was observed in these areas following cold stimulation in untreated macaques. Systemic treatment with an antinociceptive dose of the serotonergic-noradrenergic reuptake inhibitor duloxetine decreased SII and Ins activity. Pharmacological inactivation of SII and Ins activity by microinjection of the GABAA receptor agonist muscimol increased tail withdrawal latency. The current findings indicate that SII/Ins activity is a potential mediator of oxaliplatin-induced cold hypersensitivity.

Expression of secreted phosphoprotein 1 (osteopontin) in human sensorimotor cortex and spinal cord: Changes in patients with amyotrophic lateral sclerosis.

Secreted phosphoprotein 1 (SPP1, also known as osteopontin) is expressed in large pyramidal neurons in the primary motor cortex (M1) of certain primate species, including macaque monkeys, but not of rodents. Based on this, we suggested that SPP1 expression may reflect the functional or structural specialization of highly developed corticospinal systems. In the present study, we further characterized SPP1 in the human central nervous system by investigating its expression in the primary somatosensory cortex (S1) and spinal cord, in addition to M1. Although a small number of SPP1-positive pyramidal neurons were observed in S1, the number was smaller than that in M1. In the cervical segment of the spinal cord, SPP1 was principally expressed in choline acetyltransferase-positive motor neurons in lamina IX. We also examined SPP1 expression in patients with amyotrophic lateral sclerosis (ALS), a disease characterized by the degeneration of motor neurons. When SPP1 expression was compared in neurons of the same size range, expression in both M1 and the spinal cord of ALS patients was lower than that of subjects without ALS. SPP1 expression was especially reduced in surviving large neurons in both M1 and the spinal cord of ALS patients. The results further support the concept that SPP1 has a role in the specialization of motor projection neurons and suggest that its reduced expression may be implicated in the neurodegeneration seen in ALS.

Neural Activity during Voluntary Movements in Each Body Representation of the Intracortical Microstimulation-Derived Map in the Macaque Motor Cortex.

In order to accurately interpret experimental data using the topographic body map identified by conventional intracortical microstimulation (ICMS), it is important to know how neurons in each division of the map respond during voluntary movements. Here we systematically investigated neuronal responses in each body representation of the ICMS map during a reach-grasp-retrieval task that involves the movements of multiple body parts. The topographic body map in the primary motor cortex (M1) generally corresponds to functional divisions of voluntary movements; neurons at the recording sites in each body representation with movement thresholds of 10 µA or less were differentially activated during the task, and the timing of responses was consistent with the movements of the body part represented. Moreover, neurons in the digit representation responded differently for the different types of grasping. In addition, the present study showed that neural activity depends on the ICMS current threshold required to elicit body movements and the location of the recording on the cortical surface. In the ventral premotor cortex (PMv), no correlation was found between the response properties of neurons and the body representation in the ICMS map. Neural responses specific to forelimb movements were often observed in the rostral part of PMv, including the lateral bank of the lower arcuate limb, in which ICMS up to 100 µA evoked no detectable movement. These results indicate that the physiological significance of the ICMS-derived maps is different between, and even within, areas M1 and PMv.