REVIEW

Training-induced Recovery of Manual Dexterity after a Lesionin the Motor Cortex
Noriyuki Higo

Neuroscience Research Institute, National Institute of Advanced Industrial Scienceand Technology (AIST), Ibaraki, Japan(Received for publication on August 13, 2009)(Revised for publication on August 24, 2009)(Accepted for publication on September 17, 2009)

Cerebral injury, such as stroke, cause functional deficits; however some functions can recoverwith postlesion rehabilitative training. Several recent studies using rodents and monkeys havereported the effects of postlesion training on functional recovery after brain injury. We present
herein an overview of recent animal experimental studies on the effects of postlesion motor
training on brain plasticity and motor recovery. Our study in the macaque monkey reported
the effects of hand motor training on motor recovery after lesioning of the primary motor cortex (M1). In monkeys that had undergone intensive daily training after the lesion, manual dexterity recovered to previous levels. Relatively independent digit movements, including those of
precision grip, were restored in the trained monkeys. While hand movements recovered tosome extent in the monkeys without postlesion training, these monkeys frequently used alternative grips to grasp a small object instead of the precision grip. These findings suggest thatrecovery after M1 lesions includes both training-dependent and training-independent processes, and that recovery of precision grip requires intensive postlesion training. Recent results ofboth brain imaging and gene expression analyses suggest that functional and structural changes may occur in uninjured motor areas during recovery of hand function after M1 lesions. In
particular, our preliminary results suggest that structural changes in ventral premotor cortex
neurons may participate in functional compensation of precision grip. (Keio J Med 59 (1) : 4－9,
March 2010)

Keywords: hand, neuronal plasticity, primates, recovery of function, rehabilitation

Introduction

ined under specific postlesion conditions. The extent of
postlesion training-induced functional recovery can thus
be determined. In addition, the underlying mechanisms
can be investigated. Recently, brain imaging techniquessuch as functional magnetic resonance imaging (fMRI)
have been applied to human stroke patients to investigatechanges in brain activity during functional recovery.4-9
However, using animal models of brain injury, it is possible to investigate both the molecular and anatomicalbasis of functional recovery in addition to changes inbrain activity. Herein, we provide an overview of recent
studies in which experimental animals were used to investigate the effects of postlesion rehabilitative training

Some brain functions can recover following cerebral
injury such as stroke, and appropriate rehabilitative training is thought to facilitate the process of recovery. However, it remains largely unclear how rehabilitative training promotes functional recovery. Several recent studies
have reported the effects of postlesion training and large
contributions have been made not only by clinical research using human patients1-3 but also by basic researchon rodents and monkeys. In this basic research, brain injury is artificially induced in a specific region of the animal brain, and recovery of function can then be exam-

Presented at the 1630th Meeting of The Keio Medical Society in Tokyo, July 2, 2009.
Reprint requests to: Dr. Noriyuki Higo, Systems Neuroscience Group, Neuroscience Research Institute, National Institute of Advanced Industrial Science andTechnology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Japan, Tel: +81-29-861-5848, Fax: +81-29-861-5849, E-mail: n.higo@aist.go.jp
4Keio J Med 2010; 59 (1): 4－9

5

Fig. 1 (A) Lesioned areas superimposed on intracortical microstimulation (ICMS) maps of M1. Movements elicited at threshold andsensory responses to light tactile stimuli are indicated by symbols. Some electrode penetration sites yielded no responses to ICMS atcurrent strengths up to 50 μA or to sensory stimulation. Hatching indicates areas of histologically confirmed lesions. Oblique lines
within the hatching indicate that the lesion included layer 5, where efferent projections to the spinal cord originate. 42 Dotted lines
indicate the presumed border between M1 and the premotor cortex, which were determined by movement thresholds, sulcal landmarks,
and cytoarchitecture as visualized by Nissl staining.4 3-4 5 CS: central sulcus. (B) Normal and ibotenic acid-lesioned areas of M1.
Ibotenic acid injection resulted in loss of neurons and gliosis. (C) Schematic figure showing the relationship between change in rate ofsuccess and change in grip form in trained monkeys. While the monkeys could not retrieve the food pellets at all immediately after M1
lesions, their motor performance improved progressively during the post-lesion training period. In the middle of the recovery process,they frequently employed alternative grips, holding the food pellet between the tip of the index finger and around the proximal jointof the thumb. Thereafter, the precision grip was again employed. At the point when grip strategy changed, the monkeys frequently
failed to retrieve the pellets because of inadequate coordination between digits. (D) In the untrained monkeys, many alternative grips,
involving holding of the food pellet between the tip of the index finger and around the proximal joint of the thumb, were observed
during the recovery period. In contrast to the trained monkeys, these alternative grips were not replaced by the precision grip. This
figure is modified from our previous report (Murata Y, et al.: J Neurophysiol 2008; 99: 773-786).17

6Higo N: Training-induced Recovery after Brain Injury

on brain plasticity and motor recovery.
Effects of Postlesion Training on Motor Recovery
Experimental studies using mice and rats have the advantage of availability of large numbers of subjects, thus
many experiments have been conducted in such rodent
models to elucidate the most effective training methods
for functional recovery. For example, recovery of forelimb motor function was observed in brain-lesioned ratsthat had undergone motor training in object retrieval using the affected forelimb.1 0 In contrast, similar recovery
was not observed with full-body motion training using arunning wheel. 1 0 Moreover, functional recovery was
found to be promoted by a combination of rehabilitative
motor training and electrical stimulation around the injured region of the brain.11 Biernaskie, et al. conducted
an experiment in rats to determine how efficacy of rehabilitation differs depending on when motor training commences. In this experiment, recovery of forelimb movements was compared among groups that began motor
training 5, 14, or 30 days after lesioning of motor cortex.
Level of recovery was highest in the group that had begun motor training 5 days after lesioning, the earliest
commencement of the three groups.1 2 In contrast, another study reported that movement immediately after brain
injury increases the initial injury.1 3 Excessive glutamate
concentration has been implicated in this use-dependent
increase in brain injury.1 4-1 6 The findings of Biernaskie,
et al. indicate that motor training immediately after injury has larger effects on functional recovery, probably because the increase in brain plasticity during this period
induces functional reorganization of uninjured brain regions, despite increasing the initial injury.
We examined the process of functional recovery after
brain injury in the macaque monkey, as it has cerebral
and musculoskeletal structures similar to those of humans. We induced a lesion in the primary motor area(M1) of the cerebral cortex, from which a large portionof the motor output projections to the spinal cord originate, and examined the recovery of motor function. 1 7
Among motor functions, the recovery of dexterous handfunction, a characteristic of some primate species such as
humans, apes, and macaque monkeys, has been investigated in detail1 8, 1 9 because of its importance for humanquality of life.
Initially, we examined the hand movements of themonkeys prior to lesion induction when retrieving small
food pellets. Before lesioning, all monkeys retrieved thefood pellet using a precision grip, with the index fingertip and thumb tip in finger-to-thumb opposition. We thenmapped the motor representation in M1 using intracortical microstimulation techniques (Fig. 1A), in which atungsten microelectrode was advanced into the motor
cortex perpendicular to the cortical surface to a depth of
5 to 15 mm under ketamine anesthesia. Electrode pene-

trations were spaced at 2 mm intervals, and electricalmicrostimulation up to 50 μA was applied to evoke
movement at each electrode penetration site. Ibotenic
acid, a neurotoxic drug, was then injected intracorticallyto destroy the hand area of M1. In the ibotenic acid-injected region, irreversible loss of cortical neurons andproliferation of glial cells occurred (Fig. 1B). Immediately after lesion induction, paralysis, including complete
loss of digit movements, was observed in the hand contralateral to the lesioned motor cortex. After the lesion,
we divided the monkeys into two groups: those given intensive post-lesion motor training and those without any
post-lesion training, and compared motor recovery in thetwo groups.
Over the first several weeks after lesioning, index finger movement followed by thumb movement were observed in both postlesion-trained and untrained monkeys.
Postlesion training comprised intensive daily training (1hour per day, 5 days per week) using a task involving retrieval of small food pellets from cylindrical wells. In
postlesion trained monkeys, behavioral indices used toevaluate manual dexterity recovered to the same level asin the prelesion period after 1 or 2 months of training.
Many alternative grip strategies, such as holding thefood pellet between the tip of the index finger andaround the proximal joint of the thumb, were observed
during the middle stage of recovery (Fig. 1C). Overtime, the location of the food pellet on the thumbchanged from proximal (around the metacarpophalangeal
joint) to distal (around the interphalangeal joint). During
the subsequent period, which featured a transient decrease
and then another increase in rate of success, use of the
precision grip gradually increased (Fig. 1C). At 1 to 2
months after lesioning, precision grip was used as often
as prior to lesioning. Thus, transfer from alternative grips
to the precision grip occurred despite the transient decrease in rate of success in postlesion-trained monkeys.
Even in the postlesion-untrained monkeys, both success rate and hand movements recovered to some extent(Fig. 1D). Similar to the trained monkeys, the untrainedmonkeys used alternative grips for several weeks after
lesioning; however, in contrast, alternative grips were
not replaced by precision grip (Fig. 1D). These findings
indicate that recovery includes both training-dependentand training-independent processes. In particular, the recovery of precision grip may be promoted by intensive
postlesion motor training.
Mechanisms of Compensation Involved
in Functional Recovery
Neuronal cells that have been lost do not regenerate
when a mature brain is injured. It is therefore thoughtthat some functional compensation occurs in uninjured
cerebral regions as a basis for training-induced functional recovery. Several previous studies using rats andKeio J Med 2010; 59 (1): 4－9

7

Fig. 2 (A) The five motor-related areas in cerebral cortex of the macaque monkey. The primate motor cortex is organized into distinct
areas based on structural and functional criteria, which are hierarchically arranged to coordinate fine movements of the digits andlimbs.2 9-3 1 Among the motor areas, the primary motor area (M1) has the largest number of corticospinal connections, the motor output
projections to the spinal cord. When M1 is injured, other motor areas are thought to compensate for the function of the injured area.
Our preliminary results in a brain imaging study suggest that the ventral premotor area plays a role in compensation for dexterous
hand movements (dotted line). (B) Example of mRNA expression of Growth-associated protein-43 (GAP-43). GAP-43 is one of themolecules whose expression has been found to be related to axonal sprouting and structural alteration of synapses.3 2-3 4 Our recent
findings indicate that mRNA expression of GAP-43 increased in the ventral premotor area during the recovery of hand function afterM1 lesions.

squirrel monkeys reported that the functional motor representation map around the region of injury in the motor
cortex changes with rehabilitative motor training. 2 0, 2 1
These studies involved induced injury of the brain in theforelimb movement area of motor cortex, and showedthat the forelimb area reappeared in the region surrounding the lesion during training-induced functional recovery. Another study also reported that the functional motor
representation map in regions of cortex remote from injury changes during functional recovery if the region ofbrain injury is large.2 2 It is thought that these changes in
the motor representation map are involved in functional
compensation after brain lesions. In addition, structuralchanges of neuronal cells have also been reported as thebasis of functional compensation.2 0, 2 3-2 6 One study reported that rats with enriched rehabilitative training of
the affected forelimb exhibited enhanced dendritic com-

plexity and length of layer 5 pyramidal cells in motor
cortex compared with those without postlesion training. 2 7 This is a remarkable example of the effects of
postlesion motor training on the structure of neuronalcells.
As indicated above, our study showed that recovery of
precision grip was observed in the macaque monkey
with postlesion training even after most of the hand areain M1 had been lesioned. It is thought that M1 is required for precision grip,2 8 and we confirmed that neurons in the ibotenic acid-injected region did not regenerate. Uninjured brain regions may thus have compensatedfor the function of the lesioned area in M1. In primate
cerebral cortex, several motor-related cortical areas exist
in addition to M1 (Fig. 2A),2 9-3 1 and are candidate areas
for functional compensation after M1 lesions. Changes
in brain activity may be involved in this functional com-

8

Higo N: Training-induced Recovery after Brain Injury

pensation. To detect changes in brain activity, we performed a brain imaging study using positron emission
tomography (PET) scanning with oxygen-15 labeled water, and measured regional blood flow in the brain, whichis expected to increase with increased brain activity. We
examined brain activity while monkeys performed a task
involving precision grip in retrieving a small object froma slit. Preliminary results indicated that activity of theventral premotor area increased during functional recovery after lesioning of M1.
We also examined reorganization of neural circuits,
which may have occurred as the basis for the observedchanges in brain activity. To investigate whether reorganization of neural circuits occurs during functional recovery, we focused on gene expression of plasticity-related molecules. Growth-associated protein-43 (GAP-43)
is one of the molecules whose expression have beenshown to be related to axonal sprouting and structural alteration of synapses.3 2-3 4 Our previous studies indicatedthat this molecule plays important roles in memory function in the primate brain 3 5- 4 0 and the development ofsensory4 1 and motor projections3 8 (Fig. 2B). Our preliminary gene expression analysis suggests that GAP-43mediated remodeling of axon terminals occurred during
recovery, especially in the excitatory neurons of the ventral premotor area (Fig. 2B). The results of both brain
imaging and gene expression analyses suggest that structural changes may occur in the ventral premotor cortex
neurons after M1 lesions, and that premotor cortex neurons may participate in functional compensation for precision grip.
Future Perspectives
There have been only a small number of studies of theeffects of postlesion rehabilitative training on functional
recovery after brain injury, and further research is needed
to clarify these effects. Because the central nervous system and musculoskeletal structures of rodents are quite
different from those of primates, the importance of research using monkeys will increase in applying researchfindings to the clinical treatment of human patients. For
example, as described above, an experiment was conducted to compare the efficacies of rehabilitative motor
training initiated at different time points after injury of
the brain in the rat.1 2 It is important that similar experiments be conducted in monkey models of brain injury to
determine the effects of early rehabilitation in primates.
Moreover, only fragmentary knowledge exists concerning the basis of training-induced functional recovery
after brain injury, such as changes in the functional motor representation map of motor cortex and dendritic
structures of neurons. Future studies at the level of neural circuits will be important in fully determining themechanisms of functional recovery following brain injury. In particular, it will be important to understand how

postlesion rehabilitative training induces the anatomicalchanges in the central nervous system that result in functional recovery. It will also be important to examinefunctional recovery at the molecular level, such as exploration of gene expression profiles by DNA microarray
analysis. Although it is challenging to determine thechanges that occur in the brain during functional recovery from the molecular to the behavioral level, this will
no doubt yield findings of great clinical value.
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