Behavioral Assessment of Manual Dexterity in Non-Human Primates

The corticospinal (CS) tract is the anatomical support of the exquisite motor ability to skillfully manipulate small objects, a prerogative mainly of primates1. In case of lesion affecting the CS projection system at its origin (lesion of motor cortical areas) or along its trajectory (cervical cord lesion), there is a dramatic loss of manual dexterity (hand paralysis), as seen in some tetraplegic or hemiplegic patients. Although there is some spontaneous functional recovery after such lesion, it remains very limited in the adult. Various therapeutic strategies are presently proposed (e.g. cell therapy, neutralization of inhibitory axonal growth molecules, application of growth factors, etc), which are mostly developed in rodents. However, before clinical application, it is often recommended to test the feasibility, efficacy, and security of the treatment in non-human primates. This is especially true when the goal is to restore manual dexterity after a lesion of the central nervous system, as the organization of the motor system of rodents is different from that of primates1,2. Macaque monkeys are illustrated here as a suitable behavioral model to quantify manual dexterity in primates, to reflect the deficits resulting from lesion of the motor cortex or cervical cord for instance, measure the extent of spontaneous functional recovery and, when a treatment is applied, evaluate how much it can enhance the functional recovery

Asymmetric and distant effects of a unilateral lesion of the primary motor cortex on the bilateral supplementary motor areas in adult macaque monkeys

A restricted lesion of the hand area in the primary motor cortex (M1) leads to a deficit of contralesional manual dexterity, followed by an incomplete functional recovery, accompanied by plastic changes in M1 itself and in other cortical areas on both hemispheres. Using the marker SMI-32 specific to pyramidal neurons in cortical layers III and V, we investigated the impact of a focal unilateral M1 lesion (hand representation) on the rostral part (F6) and caudal part (F3) of the supplementary motor area (SMA) in both hemispheres in nine adult macaque monkeys compared with four intact control monkeys. The M1 lesion induced a consistent interhemispheric asymmetry in density of SMI-32-positive neurons in F3 layer V (statistically significant in 8 of 9 lesioned monkeys), highly correlated with the lesion volume and with the duration of functional recovery, but not with the extent of functional recovery itself. Such interhemispheric asymmetry was neither present in the intact monkeys, as expected, nor in F6 in all monkeys. In addition, the M1 lesion also impacted on the basal dendritic arborization of F3 layer V neurons. Neuronal density was clearly less affected by the M1 lesion in F3 layer III compared with layer V. We interpret the remote effect of M1 lesion onto the density of SMI-32-positive neurons and dendritic arborization in the SMAs bilaterally as the consequence of multiple factors, such as changes of connectivity, diaschisis and various mechanisms involved in cortical plasticity underlying the functional recovery from the M1 lesion. SIGNIFICANCE STATEMENT The motor system of macaque monkeys, in addition to be similarly organized as in humans, is a good candidate to study the impact of a focal lesion of the main contributor to voluntary movements, the primary motor cortex (M1), on non-primary motor cortical areas also involved in manual dexterity, both at behavioral and structural levels. Our results show that a unilateral permanent lesion of M1 hand area in nine monkeys affects the interhemispheric balance of the number of SMI-32-positive pyramidal neurons in the cortical layer V of the supplementary motor area, in a way strongly correlated to the lesion volume and duration of the incomplete functional recovery

Whole-scalp EEG mapping of somatosensory evoked potentials in macaque monkeys

High-density scalp EEG recordings are widely used to study whole-brain neuronal networks in humans non-invasively. Here, we validate EEG mapping of somatosensory evoked potentials (SSEPs) in macaque monkeys (Macaca fascicularis) for the long-term investigation of large-scale neuronal networks and their reorganisation after lesions requiring a craniotomy. SSEPs were acquired from 33 scalp electrodes in five adult anaesthetized animals after electrical median or tibial nerve stimulation. SSEP scalp potential maps were identified by cluster analysis and identified in individual recordings. A distributed, linear inverse solution was used to estimate the intracortical sources of the scalp potentials. SSEPs were characterised by a sequence of components with unique scalp topographies. Source analysis confirmed that median nerve SSEP component maps were in accordance with the somatotopic organisation of the sensorimotor cortex. Most importantly, SSEP recordings were stable both intra- and interindividually. We aim to apply this method to the study of recovery and reorganisation of large-scale neuronal networks following a focal cortical lesion requiring a craniotomy. As a prerequisite, the present study demonstrated that a 300-mm2 unilateral craniotomy over the sensorimotor cortex necessary to induce a cortical lesion, followed by bone flap repositioning, suture and gap plugging with calcium phosphate cement, did not induce major distortions of the SSEPs. In conclusion, SSEPs can be successfully and reproducibly recorded from high-density EEG caps in macaque monkeys before and after a craniotomy, opening new possibilities for the long-term follow-up of the cortical reorganisation of large-scale networks in macaque monkeys after a cortical lesion

Use-dependent cortical processing from fingertips in touchscreen phone users

Cortical activity allotted to the tactile receptors on fingertips conforms to skilful use of the hand [1-3]. For instance, in string instrument players, the somatosensory cortical activity in response to touch on the little fingertip is larger than that in control subjects [1]. Such plasticity of the fingertip sensory representation is not limited to extraordinary skills and occurs in monkeys trained to repetitively grasp and release a handle as well [4]. Touchscreen phones also require repetitive finger movements, but whether and how the cortex conforms to this is unknown. By using electroencephalography (EEG), we measured the cortical potentials in response to mechanical touch on the thumb, index, and middle fingertips of touchscreen phone users and nonusers (owning only old-technology mobile phones). Although the thumb interacted predominantly with the screen, the potentials associated with the three fingertips were enhanced in touchscreen users compared to nonusers. Within the touchscreen users, the cortical potentials from the thumb and index fingertips were directly proportional to the intensity of use quantified with built-in battery logs. Remarkably, the thumb tip was sensitive to the day-to-day fluctuations in phone use: the shorter the time elapsed from an episode of intense phone use, the larger the cortical potential associated with it. Our results suggest that repetitive movements on the smooth touchscreen reshaped sensory processing from the hand and that the thumb representation was updated daily depending on its use. We propose that cortical sensory processing in the contemporary brain is continuously shaped by the use of personal digital technology

Whole-scalp EEG mapping of somatosensory evoked potentials in macaque monkeys

High-density scalp EEG recordings are widely used to study whole-brain neuronal networks in humans non-invasively. Here, we validate EEG mapping of somatosensory evoked potentials (SSEPs) in macaque monkeys (Macaca fascicularis) for the long-term investigation of large-scale neuronal networks and their reorganisation after lesions requiring a craniotomy. SSEPs were acquired from 33 scalp electrodes in five adult anaesthetized animals after electrical median or tibial nerve stimulation. SSEP scalp potential maps were identified by cluster analysis and identified in individual recordings. A distributed, linear inverse solution was used to estimate the intracortical sources of the scalp potentials. SSEPs were characterised by a sequence of components with unique scalp topographies. Source analysis confirmed that median nerve SSEP component maps were in accordance with the somatotopic organisation of the sensorimotor cortex. Most importantly, SSEP recordings were stable both intra- and interindividually. We aim to apply this method to the study of recovery and reorganisation of large-scale neuronal networks following a focal cortical lesion requiring a craniotomy. As a prerequisite, the present study demonstrated that a 300-mm2 unilateral craniotomy over the sensorimotor cortex necessary to induce a cortical lesion, followed by bone flap repositioning, suture and gap plugging with calcium phosphate cement, did not induce major distortions of the SSEPs. In conclusion, SSEPs can be successfully and reproducibly recorded from high-density EEG caps in macaque monkeys before and after a craniotomy, opening new possibilities for the long-term follow-up of the cortical reorganisation of large-scale networks in macaque monkeys after a cortical lesion

Follow-up of cortical activity and structure after lesion with laser speckle imaging and magnetic resonance imaging in nonhuman primates

The nonhuman primate model is suitable to study mechanisms of functional recovery following lesion of the cerebral cortex (motor cortex), on which therapeutic strategies can be tested. To interpret behavioral data (time course and extent of functional recovery), it is crucial to monitor the properties of the experimental cortical lesion, induced by infusion of the excitotoxin ibotenic acid. In two adult macaque monkeys, ibotenic acid infusions produced a restricted, permanent lesion of the motor cortex. In one monkey, the lesion was monitored over 3.5 weeks, combining laser speckle imaging (LSI) as metabolic readout (cerebral blood flow) and anatomical assessment with magnetic resonance imaging (T2-weighted MRI). The cerebral blood flow, measured online during subsequent injections of the ibotenic acid in the motor cortex, exhibited a dramatic increase, still present after one week, in parallel to a MRI hypersignal. After 3.5 weeks, the cerebral blood flow was strongly reduced (below reference level) and the hypersignal disappeared from the MRI scan, although the lesion was permanent as histologically assessed post-mortem. The MRI data were similar in the second monkey. Our experiments suggest that LSI and MRI, although they reflect different features, vary in parallel during a few weeks following an excitotoxic cortical lesion

Whole-scalp EEG mapping of somatosensory evoked potentials in macaque monkeys

High-density scalp EEG recordings are widely used to study whole-brain neuronal networks in humans non-invasively. Here, we validate EEG mapping of somatosensory evoked potentials (SSEPs) in macaque monkeys (Macaca fascicularis) for the long-term investigation of large-scale neuronal networks and their reorganisation after lesions requiring a craniotomy. SSEPs were acquired from 33 scalp electrodes in five adult anaesthetized animals after electrical median or tibial nerve stimulation. SSEP scalp potential maps were identified by cluster analysis and identified in individual recordings. A distributed, linear inverse solution was used to estimate the intracortical sources of the scalp potentials. SSEPs were characterised by a sequence of components with unique scalp topographies. Source analysis confirmed that median nerve SSEP component maps were in accordance with the somatotopic organisation of the sensorimotor cortex. Most importantly, SSEP recordings were stable both intra- and interindividually. We aim to apply this method to the study of recovery and reorganisation of large-scale neuronal networks following a focal cortical lesion requiring a craniotomy. As a prerequisite, the present study demonstrated that a 300-mm(2) unilateral craniotomy over the sensorimotor cortex necessary to induce a cortical lesion, followed by bone flap repositioning, suture and gap plugging with calcium phosphate cement, did not induce major distortions of the SSEPs. In conclusion, SSEPs can be successfully and reproducibly recorded from high-density EEG caps in macaque monkeys before and after a craniotomy, opening new possibilities for the long-term follow-up of the cortical reorganisation of large-scale networks in macaque monkeys after a cortical lesion

Variability of manual dexterity performance in non-human primates (Macaca fascicularis)

The goal of this study was to quantify the inter-individual and intra-individual variability of manual (digits) skill in adult macaque monkeys, over a motor learning phase and, lateron, when motor skills were consolidated. The hypothesis is that several attributes of the stable manual dexterity performance can be predicted from learning characteristics. The behavioral data were collected from 20 adult Macaca fascicularis, derived from their dominant hand, defined as the hand exhibiting a better performance than theother. Two manual dexterity tasks were tested: (i) the modified Brinkman board task, consisting in the retrieval of food pellets placed in 50 slots ina board, using the precision grip (opposition of the thumb and index finger);(ii) the reach and grasp drawer task, in which the grip force and the load force were continuously monitored while the monkey opened a drawer against a resistance, before grasping a pellet inside the drawer. The hypothesis was verified for the performance of manual dexterity after consolidation, correlated with the initial score before learning. Motor habit, reflected by the temporal order of sequential movements executed in the modified Brinkman board task, was established very early during the learning phase. As mostly expected, motor  learning led to an optimization of manual dexterity parameters, such as score, contact time, as well as a decrease in intra-individual variability. Overall,the data demonstrate the substantial inter-individual variability of manual dexterity in non-human primates, to be considered for further pre-clinical applications based on this animal model

Variability of manual dexterity performance in non-human primates ( Macaca fascicularis )

The goal of this study was to quantify the inter-individual and intra-individual variability of manual (digits) skill in adult macaque monkeys, over a motor learning phase and, lateron, when motor skills were consolidated. The hypothesis is that several attributes of the stable manual dexterity performance can be predicted from learning characteristics. The behavioral data were collected from 20 adult Macaca fascicularis, derived from their dominant hand, defined as the hand exhibiting a better performance than theother. Two manual dexterity tasks were tested: (i) the modified Brinkman board task, consisting in the retrieval of food pellets placed in 50 slots ina board, using the precision grip (opposition of the thumb and index finger);(ii) the reach and grasp drawer task, in which the grip force and the load force were continuously monitored while the monkey opened a drawer against a resistance, before grasping a pellet inside the drawer. The hypothesis was verified for the performance of manual dexterity after consolidation, correlated with the initial score before learning. Motor habit, reflected by the temporal order of sequential movements executed in the modified Brinkman board task, was established very early during the learning phase. As mostly expected, motor  learning led to an optimization of manual dexterity parameters, such as score, contact time, as well as a decrease in intra-individual variability. Overall,the data demonstrate the substantial inter-individual variability of manual dexterity in non-human primates, to be considered for further pre-clinical applications based on this animal model