REVIEW
Brain plasticity in health and disease
Barbro B Johansson
Division for Experimental Brain Research, Department of Clinical Neuroscience, Lund University,
Wallenberg Neuroscience Center, Lund, Sweden(Received for publication on August 2, 2004)

Abstract. Research during the last decades has greatly increased our understanding of brain plasticity, i.e. how neuronal circuits can be modiﬁed by experience, learning and in response to brain lesions.
Currently available neuroimaging techniques that make it possible to study the function of the humanbrain in vivo have had an important impact. Cross-modal plasticity during development is demonstrated by cortical reorganization in blind or deaf children. Early musical training has lasting effects
in shaping the brain. Albeit the plasticity is largest during childhood, the adult brain retains a capacity
for functional and structural reorganization that earlier has been underestimated. Resent research on
Huntington’s disease has revealed the possibility of environmental interaction even with dominant
genes. Scientiﬁcally based training methods are now being applied in rehabilitation of patients after
stroke and trauma, and in the sensory retraining techniques currently applied in the treatment of focal
hand dystonia as well as in sensory re-education after nerve repair in hand surgery. There is evidence
that frequent participation in challenging and stimulating activities is associated with reduced cognitive
decline during aging. The current concept of brain plasticity has wide implication for areas outside
neuroscience and for all human life. (Keio J Med 53 (4): 231–246, December 2004)
Key words: neuronal plasticity, development, dystonia, stroke, aging

Introduction
The unique evolution of the human brain is the basis
for the development of human culture, science andtechnology. Our neurons are tuned in close interaction
with our environment, our own activities and thoughts.
Interaction between genes and environment is evident
from the global variations in customs, languages, andculture. Ernesto Lugano, an Italian psychiatrist may
have introduced the term plasticity in neurosciences as
early as 1906.1 However, the important studies in thisﬁeld were initiated by Donald Hebb, who more thanhalf a century ago postulated that neuronal corticalconnections are strengthened and remodeled by ourexperience.2 He showed that rats that were allowed torun around freely in his house were better learners andhad better memory capacity than rats housed in thelaboratory.3 Many studies have shown that an activitystimulating environment has multiple effects on thebrain including increasing the number of neuronalconnections.4–9

Dendritic spines, i.e. tiny protrusions on the dendrites (Fig. 1)10 are the primary postsynaptic targets of
excitatory glutaminergic synapses in the mature brain,
and they have been proposed as primary sites of synaptic plasticity.11,12 The dendritic tree is covered with avariety of excitable synaptic channels operating on different time scales and with activity-dependent sensitivity enabling a sophisticated neuronal plasticity.13 The
spine cytoskeleton consists of actin ﬁlaments, and video
recordings from hippocampal neurons expressing actin
tagged with ﬂuorescent protein have shown that theshape of spines can change rapidly,14 events that areaccompanied by changes in calcium inﬂux and decay.15,16 With a technique enabling in vivo images ofneurons expressing green ﬂuorescent protein, the lifetime of superﬁcial pyramidal spines in the mouse barrel
cortex has been observed to vary greatly.17 About 20%of spines disappeared from one day to the next, a loss
that was balanced by formation of new spines. About
60% of dendritic spines persisted for at least 8 days, andof those 17% had disappeared one months after the

Presented at the 1345th Meeting of the Keio Medical Society in Tokyo, February 10, 2004.
Reprint requests to: Dr. Barbro B Johansson, Wallenberg Neuroscience Center, BMC A13, SE- 221 84 Lund, Sweden, telephone: þ46-46-222
0621, facsimile: þ46-46-222 0626, e-mail: Barbro.Johansson@neurol.lu.se
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Fig. 1 Pyramidal neurons in cortical layer III in male 4 months’ old spontaneously hypertensive rats housed in standard environment (S), or
housed in an enriched environment (E). Standard housing ¼ 3 rats in each cage; enriched housing ¼ 8 rats in larger cages with opportunities forvarious activities. The environmental enrichment signiﬁcantly increases dendritic branching and number of dendritic spines (insertions). (Reproduce from, Johansson BB, et al: In: Bazan NG, et al eds, Maturation Phenomenon in Cerebral Ischemia IV, Berlin Heidelberg, Springer
Verlag, 2001; 77-23, Copyright 8 (2001), with permission from Springer Verlag). Scale bar ¼ 25 mm; in the insertions scale bar ¼ 5 mm.

imaging began. Serial-section electron microscopy ofimaged dendritic segments revealed retrospectively thatspine sprouting and retraction are associated with synapse formation and elimination. Trimming every otherwhisker, which induced a rapid and robust remodelingof whisker representation, increased the pool of transient spines present for only a day or less in the corticalrepresentation areas of the trimmed whiskers.17 Thus,
experience-depending plasticity of cortical receptiveﬁelds was accompanied by increased synapse turnover.
There may, however, be regional differences in theplasticity of dendritic spines. Using a similar in vivotechnique in the visual cortex the majority of spines inlayer V pyramidal neurons were more stable.18 Axonsand dendrites need guidance for proper orientation, anda number of guidance molecules or surface receptors
have been identiﬁed. An expression of a common
attractant in the neuropil, and activation of its corresponding receptors in axons of one neuron and dendrites of another, might be essential for neuronal network formation during development and plasticity.19
As will be exempliﬁed in the following sections,in addition to strengthening contacts between individual neurons, cortical representation areas, ‘‘corticalmaps’’ can be modiﬁed by sensory input, experience,
training (Fig. 2)20 and in response to brain lesions.
Synaptic plasticity and number and turnover of dendritic spines in cortical horizontal connections arelikely to underlie cortical map reorganization.21,22
Activity-depending modiﬁcation of synaptic connection
and reorganization of adult cortical areas are thought toinvolve long-term potentiation (LTP) and long-term
depression (LDT), mechanisms by which information isstored in the mammalian central nervous system.23,24
Despite 30 years research the detailed mechanisms
remain unclear.25 LTP is accompanied by an enhanced
local excitability of pyramidal neuron dendrites.26 In a
recent study LTP, induced by intracellular electricalmicro stimulation, expanded movement representation and induced dendritic hypertrophy in rat sensorimotor cortex.27 Glutamate, the main excitatoryneurotransmitter plays a crucial role, and cortical
map reorganization in the primary somatosensory
cortex can be prevented by blockade of N-methyl-d-Keio J Med 2004; 53 (4): 231–246

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Fig. 2 The somatosensory cortex of the hand in a monkey before (A) and after (B) repetitive speciﬁc tactile stimulation of the tip of the second ﬁnger (black areas). (Reproduce from, Jenkins WM, et al: J Neurophysiol 1990; 63: 82–104, Copyright 8 (1990), with permission from The
American Physiological Society).

aspartate (NMDA)-receptors. Gamma-aminobutyricacid (GABA)-A receptor antagonists facilitate LTP induction, and the induction can be blocked by GABA-A
receptor agonists.28,29 Also AMPA receptors play animportant role.30 Transmitters released by diffuse
neuromodulatory systems that originates in subcorticalregions and send long projection axons to the cortex,
i.e. noradrenalin (locus coeruleus), acetylcholine (nucleus basalis), dopamine (lateral tegmentum), andserotonin (raphe nuclei), can modify the threshold for
activity-dependent synaptic plasticity, maybe through afacilitation of NMDA receptor-gated process.31–34 Another modulator of cerebral cortex synaptic function isnitric oxide35 that has been shown to interact withdopamine and acetylcholine to induced corticostriatal
synaptic plasticity.36 The molecular mechanisms behind
activity-dependent modiﬁcation of synaptic connections
and reorganization of cortex in the adult brain arecomplex and still not fully understood, and they arelikely to differ with the regions studied.22,37
Skill learning but not strength training induces cortical reorganization.38,39 Exercise induces angiogenesis
but does not alter movement representations in thecortex.40 It has recently been reported that corticalsynaptogenesis and motor map reorganization occur
during late but not early phase of motor skill learning,
and that synaptogenesis precedes map reorganization.

It was proposed that motor map reorganization andsynapse formation do not contribute to the initial acquisition of motor skills but represent the consolidationof motor skill that occurs during late stages of training.41 There is increasing evidence that non-neuronalcells, in particular astrocytes, have essential roles inplasticity. Astrocytes are responsible for regulating thesynaptic environment and for maintaining appropriate
levels of neurotransmitters and neurotrophins, and theyinﬂuence neuronal signaling, number of synapses andplay a role in non-synaptic transmission.42–46
Neural stem cells, deﬁned by their ability to bothself-renew and to differentiate to produce matureprogeny cells and neurons, are present in the subventricular zone and in the hippocampus in the adulthuman brain.47,48 Animal studies have shown thatneurogenesis can be stimulated by many factors including trophic factors, hormones, drugs, environmentand brain lesions. Environmental enrichment enhances
the survival of newly formed neurons in the hippocampus of intact rats and mice and enhances spatial
memory.49–51
One important factor restricting brain plasticity
after brain lesions is that myelin in the central nervous system contains proteins that inhibit axonal outgrowth.52,53 The myelin inhibitors share a common
receptor and blockage of the receptor promotes CNS

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repair and functional recovery.54 Some promising
results with antibodies against this receptor have beenreported after spinal and focal brain lesions in animalstudies.55–57
Interestingly, inosine, a naturally occurring metabolite, has likewise been reported to stimulate axonal
growth in the rat corticospinal tract,58 and to induce
axonal rewiring and promote behavioral outcome after
focal brain ischemia.59 It is an important area of research still at the experimental level.
Neuroimaging Methods Used in the Study ofBrain Plasticity
Brain plasticity in the human brain can be studied
with several neuroimaging techniques with different
temporal and spatial resolution. Thus the temporal
resolution varies from minutes in positron emission
tomography (PET), seconds in functional magnetic
resonance (fMRI) and milliseconds in magnetoencephalography (MEG), which makes MEG best
suited for studying temporal spatial patterns of brain
activity, that is, where and when the activation starts,
and its temporal spread to other regions.60 Because of
the better spatial resolution in fMRI, the wider availability of the technique and the possibility to combinewith other MRI techniques, fMRI has been widely usedin studies on brain plasticity.61–63
Transcranial magnetic stimulation, TMS, is anotherneurophysiological technique allowing studies of brain
functions with a millisecond resolution, which hasdeveloped into a popular non-invasive tool for studying
the human brain.64–66 A pulsed magnetic ﬁeld createscurrent ﬂow in the brain and can temporarily excite or
inhibit synaptic efﬁciency in speciﬁc areas and alter
brain function.64–66 Multiple overlapping motor representations are functionally connected through an extensive horizontal network. By changing the strength ofhorizontal connections between motor neurons, functionally different neuronal assemblies can form. Delivery of multiple single pulses of TMS does not leave
any lasting effect, but repetitive TMS can produce effectthat last for some time after the stimulation period.
The cortical motor and sensory representations of eachhand exert inhibitory inﬂuences on the homonymous
representation in the opposite hemisphere.67 Cutaneous anesthesia of the right hand enhances spatial acuity
and cortical processing in the left hand,68 and tourniquet-induced anesthesia of the right hand improves
tactile discrimination and grip strength, lasting at least
15 minutes after anesthesia and associated withincreased fMRI activation in the right primary motor
cortex.69 Furthermore, repetitive TMS over the left
frontal cortex can enhance analogical reasoning,70 andthe encoding of a motor memory in the primary motor

cortex can be enhanced by TMS stimulation in healthy
volunteers.71
Brain Plasticity in the Development and in the
Adult Human Brain
During the early childhood there is a considerable
capacity for cross-modal plasticity72 with redundantconnections between auditory and visual areas that
gradually decrease between 6 and 36 months of age.73
Speech processing and auditory localization activate thevisual cortex in congenitally blind humans,74,75 andblind humans localize sound sources better than sighted
subjects.76 Cerebral organization for language functions differs in deaf and hearing subjects, and sign language activates different regions in hearing and deaf
signers.77 The sensorimotor cortical representation of
the reading ﬁnger is expanded in blind Braille readers78
and ﬂuctuates with the daily reading activity.79 Furthermore, tactile acuity is signiﬁcantly superior in blind
subjects, independently of the degree of childhood vision, light perception level, or Braille reading.80 Linguistic differences have been demonstrated in corticalorganization for language in adult individuals with lesshemispheric asymmetry in Chinese than in English andSpanish language.81
Exposure to musical training in early life shapes thebrain, and the brains of musicians have been extensively studied as models of neuroplasticity.82–84 Pianists
have to memorize long and complex bimanual ﬁnger
sequences, and to translate musical symbols into motor
sequences during sight-reading. Long-term motor
training and continued practice of complicated bimanual motor activity lead to changes in the brain structure and representation of the brain cortical motor
maps. The anterior part of the corpus callosum, consisting of nerve ﬁbers connecting frontal motor-related
regions and prefrontal regions crucial for the coordination of bimanual motor activity, is larger in musiciansthat started musical training before the age of 7 than inmusicians without an early start, or in a control population.85 With diffusion tensor imaging, a techniquethat allows evaluation of the architecture of the brain
white matter, adult subjects with musical training since
early childhood differ signiﬁcantly from control subjects
in areas suggesting both cognitive and motor effectsof early musical training.86 Another example is theincreased cortical representation of the ﬁngers of theleft hand in string players that correlates with the age at
which the person had begun to play.87,88
Auditory experiences during early postnatal development are important in shaping the functional development of auditory cortical representation, and musicians have increased areas in the auditory cortex for
functions important for music such as timbre.89,90 The

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functional anatomy of musical perception, i.e. brain
activation during a passive music listening task, differs
signiﬁcantly between musicians and non-musicians.91
Although the developing brain is clearly more plastic
than the adult brain, neuronal connections are continuously remodeled by experience and by performanceof speciﬁc and complex movements during motor andcognitive learning, and memory processes involve brain
plasticity. Rapid and transient alteration of corticalrepresentation areas are seen during learning tasks,
most likely related to unmasking of previously existing
connections, perhaps as a result of decreased inhibition
and increased synaptic efﬁcacy in existing neuronal circuits.92 Flexible short-term modulations are importantin the acquisition of new skills, and can lead to structural changes in the intracortical and subcortical networks as the skill becomes more established and automatic.93 Even mental practice on a piano keyboard canchange the cortical representation of ﬁnger ﬂexors andextensor muscles in adult subjects.94
Another example of structural plasticity in the adulthuman brain comes from a study on London taxi drivers, who have a 2-year-long training period in special
localization before qualifying as drivers. The volume ofgray matter in the right posterior hippocampus, which
stores a spatial representation of the environment, isgreater than in controls, and the volume increase correlates signiﬁcantly with the amount of time spentlearning to be and practicing as a licensed taxi driver.95
The failure to ﬁnd an association between hippocampal
volume and navigation expertise in other subjects supports the conclusion that the difference in volume is not
an innate genetic difference, but reﬂect the detail and/or duration of training and use of the spatial representation necessary in the daily work of the drivers.96
Examples of the interaction between a dominantgene and environment have been demonstrated in
Huntington’s disease, a late onset progressive genetic
disorder characterized by motor dysfunction, personality and cognitive disturbances leading to dementia andpremature death. In a transgenic mice model of
Huntington’s disease, environmental stimulation signiﬁcantly delayed the onset of the disease andimproved life expectancy.97–99 In human patients with
Huntington’s disease the cannabinoid CB1 receptors
are lost from the basal ganglia output nuclei prior to
the development of other neuropathology,100 and theimprovement during environmental enrichment in an
animal model correlated with delayed loss of cannabinoid CB1 receptors.101 Furthermore, differential clinical and motor control function and different age onset
have been reported in pairs of monozygotic twins with
Huntington’s disease, demonstrating that environmental factors can interact even with dominant genes inhumans.102,103

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Maladaptive Brain Plasticity
Focal hand dystonia, often called writer’s cramp ormusician’s cramp, is a disabling condition that so far has
been very difﬁcult to treat with physiotherapy or othermethods. Thus, a recent long-tem outcome study on 21
violin and viola players with focal dystonia an average
13.8 years after onset of symptoms showed that only
38% had been able to maintain their professional
careers.104 Focal hand dystonia is now considered to
be a disorder of maladaptive plasticity. In adult monkeys it has been shown that frequent very rapid timesynchronous movements during vigorous practicing cancause a degradation of the sensory feedback controllingﬁne motor movements, resulting in fusion of the distinct
cortical representation of the individual ﬁngers.105 The
abnormal sensory representation interferes with motor
control, and abnormal motor control strengthens thesensory abnormality, and the positive feedback loop
reinforces the dystonic condition. The sensory representation abnormalities parallel focal hand dystonia in
the primate model.106 Patients with focal hand dystonia
have impaired intracortical inhibition and abnormal
cortical activations during movements with affectedmuscles,107–109 and the regional cerebral blood ﬂow
correlates with the severity of symptoms.110 Compared
to control individuals, patients with dystonia havesigniﬁcantly reduced levels of the inhibitory neurotransmitter GABA in the sensorimotor cortex andlentiform nuclei contralateral to the affected hand as
demonstrated with in vivo magnetic resonance spectroscopy.111 Based on the hypothesis that successfultreatment should be aimed at restoring the normal
representation areas of sensory feedback from thehand, methods based on relearning principles havebeen developed, and substantial improvement has beenreported from three centers including a one year follow
up study.112–115 The clinical improvement is associatedwith altered somatosensory cortical organization.115 A
recent voxel-based morphometry study has demonstrated increase in the gray matter in the hand representation area of primary somatosensory cortex,
and to a lesser extent in primary motor cortex inpatients compared to controls, suggesting that there
might be a hereditary component predisposing for the
syndrome.116
Embouchure dystonia is a focal task-speciﬁc disorderin professional brass and woodwind players involving
abnormal non-coordinated movements and involuntarymuscle contraction of lip, jaw, and tongue muscles used
to control the ﬂow of air into a mouthpiece while playing.117 It is often so disabling that the musicians have tolimit or give up their occupation. There is evidence that
abnormal somatosensory reorganization contributes tothe disorder.118 Thus, in a study comparing 8 patients

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and 8 control subjects, the patient’s digit and thumbrepresentations were shifted in a lateral direction towards the lip representational zone. Furthermore, thepatient’s upper lip showed decreased sensitivity compared to their lower lips, an asymmetry that was absent
in controls.
A strong correlation between the subjective strengthof tinnitus and reorganization of the auditory cortex inindividuals with hearing loss and tinnitus has led to the
proposal that this is another examples of maladaptive
plasticity.119
Brain Plasticity due to Lack of Sensory Input toan Intact Brain
Lack of sensory input due to amputation, peripheral nerve lesions or local anesthesia, leads to rapid
cortical remodeling with a distorted cortical representation and enlarged and overlapping cortical receptive ﬁelds.120–123 By simultaneous recording ofextracellular activity from somatosensory cortex, thethalamus, and trigeminal brainstem area in adult rats,
an immediate and simultaneous transient reorganization was produced by subcutaneous lidocain injection,
demonstrating that peripheral sensory deafferentation
triggers a system-wide reorganization, and that spatiotemporal cortical plasticity is paralleled by subcorticalreorganization.124 Studies on monkeys several years
after an amputation have indicated that much of thelarge-scale cortical reorganization that occurs after amajor loss of peripheral inputs reﬂects the sprouting or
expansion of afferents from the remaining forelimbstump into deprived territories of the spinal cord andbrain stem. Since the topographic representation of
the body is greatly magniﬁed in the cortex, the subcortical changes can result in dramatic cortical mapchanges.125,126 Reorganization of the motor efferents
to muscles has been demonstrated by a combinationof intracortical microstimulation of primary motor
cortex and in vivo labeling of corticospinal neurons.127
Stimulation in the deefferented forelimb cortex evokedshoulder stump, trunk and orofacial movements,
whereas stimulation in the deefferented hindlimb cortex
evoked hip stump, trunk and tail movements. No unresponsive zones were found in the deprived cortex. The
reorganization in sensory afferents along with reorganization of the motor efferents to muscles may provide
a basis for phantom sensations of movements in the
missing forelimb.126 A recent fMRI study from humanamputees indicates that, in addition to primary sensory
cortex, somatosensory cortex, thalamus, posterior parietal cortex, and prefrontal cortex may be involved in
the phantom sensation.128 Central maladaptive plasticity has also been proposed to contribute to phantom
pain.129,130 Repetitive transcranial magnetic stimula-tion of the contralateral parietal cortex can transiently
but not lastingly ameliorate phantom limb pain, supporting the hypothesis that phantom pain at least inpart is due to a dysfunctional activity in the parietal
cortex.131
Reconstruction of injured peripheral nerves is achallenging surgical problem. There is no microsurgical
technique that makes it possible to reinstate the prelesion axonal connections, and the cortical representation of the reinnervation of the hand will be
defragmentated.132 The axonal growth is slow, and thereinnervation of a hand therefore takes time. Sensory
hand training has usually not started until the timereinnervation is taken place. However, because functional reorganization of the cortex occurs rapidly after
changes in peripheral input, timing of the onset of
sensory-relearning may be critical.133 A new concept isthat sensory relearning programs, aimed at reﬁnementof the distorted receptor ﬁelds, should start early to try
to normalize the hand map and improve processing at ahigh-order cortical level. This can be done by taking
advantage of the fact that sensory deprivation in one
sensory system can have effect of the function of theothers due to a continued functional interplay between
the different association areas in the adult brain.72 The
hearing sense has a high capacity to discriminate
between complex patterns of frequencies, and whentouched, individual textures are associated with speciﬁc
friction sounds. The hypothesis that hearing would be
able to take over functions normally devoted to touch
after lesions to the hand has led to the development ofa Sensor Glove system, which stereophonically transposes the friction sound elicited by active touch. Thus
the individual can listen to what the hand is touching
and the training can be initiated before the reinnervation of the hand takes place. Preliminary results from aprospective clinical randomized study indicate that useof this re-learning system improves recovery of tactile
discrimination in the nerve-injured hand (132).
Lesion-induced and Training Induced Brain Plasticity
Despite permanent tissue loss most surviving stroke
patients regain some function with time. In 1973 a neuroanatomist wrote in a paper based on his own experience after a stroke ‘‘since regeneration of transectioned
central axons has never been convincingly demonstrated in higher mammals, it seems that one must resort to the assumption that intact ﬁbers take over fromthe damaged ones’’.134 That is indeed the case andmany molecular and neurophysiological mechanisms
have been proposed to take part in lesion-induced brain
plasticity.66,135–142
That reorganization of cortical representation after
brain injury could be the neurophysiological model ofKeio J Med 2004; 53 (4): 231–246

the bases of recovery from cortical lesions was ﬁrst
suggested by Jenkins and Merzernich,143 a hypothesisthat has been supported by many later studies. A lesion
to a small portion of the cortical motor hand representation in monkeys results in a further loss of hand territory in the adjacent undamaged cortex. Retraining ofskilled hand use improves behavioral recovery andprevents tissue loss, and the hand representation may
expand into regions formerly occupied by representationsof the elbow and shoulder.144 Similarly, corticalreorganization of primary somatosensory cortex isassociated with sensorimotor skill recovery after cortical lesions in adult monkeys,145 and cortical reorganization induced by motor learning is associated withsynaptogenesis.146
The spontaneous postischemic functional improvement after an ischemic infarct in the hand representation area of primary motor cortex has been studied inmonkeys.147 An initial post infarct motor impairmentof the contralateral hand was followed by a gradualimprovement over three months. Intracortical microstimulation mapping at 12 weeks revealed substantial
enlargement of the hand representation in the ventral
premotor cortex remote from the lesion. The enlargement was proportional to the amount of hand representation destroyed, that is the greater the damage tointracortical pathways, the greater the plasticity in intact areas.147
In addition to training-induced alteration in corticalmaps, there is evidence that the post-ischemic environment can inﬂuence functional outcome after
brain lesions.148–151 Thus, environmental enrichment
improves functional outcome after experimental brain
infarcts,152,153 increases the number of dendritic
spines,9 alters gene expression pattern,154,155 inﬂuences the lesion-induced progenitor cell differentiation156
augments the effect of training,157 and interacts withdrug treatment.158 Furthermore, it enhances the efﬁcacy of neocortical transplantation.159,160 Similar
results have been obtained after striatal transplantationin animal models of Parkinson’s disease.161
The mechanisms that mediate functional recovery
after stroke may differ depending on time after the
stroke, lesion site and degree of recovery.137,139,140,162
A controversial question has been to what extent
changes in the intact hemisphere are responsible forgood outcome in human stroke patients. Early PET
studies on blood ﬂow distribution during ﬁnger movements in a previously paretic hand demonstrated complex patterns of activation with multiple areas of increased activation on both sides, and with large
individual variations.163,164 Later studies with fMRI
suggest that the activation in intact regions in thelesioned hemisphere is most closely related to good recovery in human patients.165–168 Thus, Carey et al.,165237

who studied the effect of training several years after
stroke onset, demonstrated a shift of activation fromthe intact to the lesion side in connection with improved
function. A comparison between patients with poor andgood recovery indicated that patients with poor recovery
were more likely to recruit a number of motor-related
brain regions during a motor task, whereas patients withmore complete recovery were likely to have a taskrelated brain activation that were more similar to control subjects with no stroke.166 Likewise, results fromstudies evaluating the effect of transcranial magnetic
stimulation on motor performance of the paretic handof chronic stroke patients indicated that recovered function in a paretic hand of chronic stroke patients relies
predominantly on reorganized activity within sensorimotor regions in the affected hemisphere.169–171 However, it has been proposed that in some patients with subcortical lesions and severe damage to the corticospinal
tract, a slow recovery might be obtained by the utilization of the intact contralateral sensorimotor cortices.172
Thus most data today indicate that the substrate for
improved functional recovery is mainly in regions ipsilateral to the lesion, and that high activity in the intact
hemisphere is connected with less good recovery. In
agreement with the concept of inter-hemispheric inhibition described earlier,67–69 the primary motor cortexof the intact hemisphere could inﬂuence functional recovery through trans-callosal connections. Interestingly,
a very recent study indicated an abnormally high interhemispheric inhibitory drive from the intact to the affected hemisphere during voluntary movement by theparetic hand.173 The authors commented that it is conceivable that this abnormality could adversely inﬂuencemotor recovery in some patients with subcorticalstroke, clearly an issue for future investigations. If so, itwould be expected that transient deafferentation of theintact side67–69 would improve the motor function on
the weak side.
Basic research on brain plasticity has lead to introduction of new techniques in neurorehabilitation. One
such method, based on extensive studies in monkeys by
Taub and coworkers, is constraint-induced training.174–175 Already in 1940 it was observed that monkeys with lesions to one pyramidal tracts failed to use
the affected limb, and that the use of the weak limb
could be improved if the unaffected limb was restrained.176 By preventing the patients from using
the healthy arm and hand and thus intensify the training, together with what the authors call shaping that
includes making a task successively more difﬁcult, thecortical representation maps can change together withimproved performance.177–178 The major part of theeffect is probably caused by the intense training and therelative importance of preventing movement in the intact hand is unclear.179 A multisite randomized trial to238evaluate the therapeutic success, the inﬂuence of poststroke time before starting the training, and the persistence of any effect over 2 years, is ongoing in theUSA.180 Good effects have been obtained also withtechniques such as training with robots that do not
require any immobilization of the intact side.181–185
The intensity of the training seems to be a crucial factor
in the studies reported beneﬁcial effects of speciﬁctraining.
Training with a mirror is another interesting
approach. Arm amputees can experience the perception of movement of a phantom limb while looking at a
mirror reﬂection of the moving, intact arm superimposed on the perceived phantom. To provide illusory visual feedback of movement such use of amirror has been tried in rehabilitation of hemiparetic
patients.186–187 Theoretically this method is interestingin light of current knowledge of the so-called mirror
neuron system. Seeing a purposeful action activates
neurons in the prefrontal regions that are activatedboth by performing and observation of purposefulactions,188–190 neurons that have connections withmany regions of the brain and are thought to be essential for the human capacity to imitate and understandother persons intention. Virtual reality is another technique that is under evaluation.191 Mental training
activates most of the same circuitry in the brain asreal action does,94,192 and mental practice is anothermethod preliminary reported to be of value.193
Cognitive deﬁciencies are common among stroke
patients and memory problems, attention and ability toconcentrate are likely to inﬂuence all training. Thus, theeffect of mental practice after stroke is related to theworking memory capacity of the patients.194 Most
stoke patients have better function in the shoulder andupper arm than in the hand. Since there is competition
among body parts for territory in the sensorimotor cortex (Fig. 2), reducing the sensory input from surrounding areas by transient deafferentation of the upper arm
during hand motor practice dramatically improved
hand motor function, including some activities of dailyliving.195
It should be stressed that few of these new techniques have been properly evaluated in larger clinicalstudies yet. However, the promising neurobiologicalresearch is changing the attitude to neurorehabilitation.
Collaboration between basic and applied science willcontinue to be important for further progress. Most of
the spontaneous functional sensorimotor improvement
occurs within the ﬁrst 3–6 months after a stroke, andthat is the optimal time for rehabilitation. However,speciﬁc training can alter cortical representation areas
even years after stroke.165 An important aspect is thattraining has to be continued to keep up functional
gains. Clinical studies indicate that the patient’s atti-

Johansson BB: Brain plasticity in health and diseasetude, activities and social interaction inﬂuence functional outcome and quality of life after brain lesions.
Rehabilitation strategies that are meaningful for theindividual patient are likely to be the most effective.150
Additional ways of enhancing brain plasticity is being tested in animals, including the trials to ﬁnd ways toenhance axonal outgrowth mentioned in the introduction.52–59 Another area of great interest is whether
lesion-induced stem cell proliferation can have beneﬁcial effects after brain lesions. As demonstrated by several recent reviews,196–199 many studies have shown amarked increase in stem cell/progenitor cell proliferation in hippocampus and the subventricular zone after
global and focal brain ischemia. That endogenous
neural precursors can be induced to differentiate into
mature neurons in adult mammalian neocortex andform long-distance cortico-thalamic and cortico-corticoconnections has been shown in a model of apoptotic
selective death of cortical pyramidal neurons.200,201 In
another model of selective neuronal death, global
ischemia, intraventricular infusion of FGF-2 and epidermal growth factor (EGF) during 4 days markedly
increased regeneration of hippocampal pyramidal neurons with electrophysiological evidence that the neurons were integrated into the existing brain circuitry,
and it was proposed that the new cells contributed tothe amelioration of neurological deﬁcits observed in thetreated rats.202 After focal brain ischemia, proliferating
cells from the subventricular zone migrate to the striatum after large striato-cortical lesions induced by atransient MCA occlusion, a small part of which may
develop into medium sized striatal neurons.203,204
However, no study has so far demonstrated integration
into neuronal circuits or functional effects of neurogenesis after focal brain ischemia. It is possible that cellor tissue transplantation may be more successful, an issue with many aspects that will not be dealt with here.
Aging and Brain Plasticity
To what extent environmental factors can inﬂuence
the aging processes is controversial. In experimental
animals, environmental and social interactions can partially offset age-related decrease and fragmentation of
the somatosensory cortical maps.205 14 days of exposure to an enriched environment in 28-month-old micesigniﬁcantly enhanced spatial memory and synaptophysin levels in hippocampus and frontoparietal cortex.206
Mice living in an enriched environment from the age of
10 to 20 months had a ﬁvefold higher hippocampal
neurogenesis together with signiﬁcantly better learning
ability and exploratory behavior than control rats ina standard environment.207 Twin studies have shownthat brain volume, the size of corpus callosum andthe size of the ventricles are highly genetically deter-

Keio J Med 2004; 53 (4): 231–246

mined whereas more variability has been found in
the gyral and sulcal patterns.208–210 In a large twin
study about 60% of the variance of the temporal
horns and 80% of the variance of corpus callosum
were considered to be attributable to genetic components compared to 40% of the variance of hippocampal volume, suggesting that the environment or
gene-environmental interactions have greater control
in modifying hippcampal size,211 a conclusion that is
consistent with results from an MRI study of hippocampus in monozygotic twins with discordant cognitive
abilities.212
Studies with PET and fMRI indicate that elderly
people activate more regions than younger even forsimple motor task, with no difference in accuracy but
increase in reaction time and greater activation in thesame areas as activated in the young, and with recruitment of additional cortical and subcortical areas.213–215
It has been interpreted to support the notion that an
adaptable and plastic motor network is able to respondto age related structural and neurochemical changes inorder to maintain performance levels.214,215 In an episodic memory-encoding task older adults engaged muchof the same neural circuitry as younger subjects. In addition, age-related differences in prefrontal and temporal activity were observed during successful episodic
encoding. One difference was a bilateral activity inprefrontal regions in the older subjects compared to aleft activation in young.216 More bilateral patterns ofprefrontal activity in older adults than in younger adults
have also been shown during working memory and visual attention tasks, suggesting that older adults may
use selective compensatory mechanisms in processing
information.217
The effect of practice and of cognitive ageing has
been studied in a large longitudinal study of elderly
community residents in the UK.218 Age-relatedchanges were relatively slight between 49 and 70 years
and much more marked between 70 and 80 years.
However, the population average effect of practice waslarge relative to the age-related change, and the variation between individuals increased with age. This study
provided signiﬁcant empirical evidence that individuals
age at markedly different rates. A large populationbased studies of older persons in the USA in a modelthat controlled for baseline level of cognition, age, sex,
race and education, demonstrated that frequent participation in cognitively stimulating activities was associated with signiﬁcantly reduced cognitive decline inolder persons, an effect that remained when the investigators controlled for depressive symptoms and chronic
medical conditions.219 Furthermore, frequent participation of cognitive stimulating activities appeared
to be associated with reduced risk for Alzheimer’s
disease.220,221

239

Aging is accompanied by a decline in muscle
strength and ability to maintain submaximal force.
However, skilled ﬁnger movement training improves
the ability to control submaximal pinch force, handsteadiness and manual speed also in elderly individuals.222 An investigation with magnetic resonance spectroscopy in different brain regions before and after 5
weeks of memory training in healthy elderly showedthat memory improvement was accompanied by elevation of creatine and choline signals in the hippocampus.
Interestingly, those considered to be at risk for neuronal dysfunction because of low neurometabolites atbaseline demonstrated the largest increases after training.223
A Finnish study in which the participants weregrouped according to their own identiﬁcation with age
suggested an association between perceptions of personal aging and physical and psychological well being.224 Another study on Swedish and Canadian samples of older adults suggested that subjective healthshould be added to the growing number of individualdifferent variable that are predictive of episodic memory change in very old age.225 Together with the recent
demonstrations on neurobiological effects of expectation, including activation of endorphin pathways inindividuals with pain226 metabolic activation pattern indepression227 and dopamine release in Parkinson’s disease,228 the data suggest that individual variations in
self-conﬁdence, expectation and attitude towards life
events, in addition to genetic factors, may help in
explaining the larger inter-individual variations in cognitive performance with increasing age.218 Remarkableachievements in the graphic arts, architecture and music
have often been accomplished in later life,229,230 and as
mentioned above, the cognitive variance between individuals at high age is large. Creativity may vary with thespeciﬁc ﬁeld evaluated231 or change rather than declinewith age.232 In an extensive sample of more than 1,900
works by 172 classical composers, Simonton compared
their last works, ‘‘swan songs’’, with their earlier work
as to melodic originality, melodic variation, repertoire
popularity, aesthetic signiﬁcance, listener accessibility,
performance duration, and thematic size. The composers’ swan songs tended to score lower in melodic originality and performance but higher in repertoire popularity and aesthetic signiﬁcance.233
There are many anecdotal reports that performing
musicians and conductors live long and active lives.
Legendary conductors like Arturo Toscanini, Leopold
Stokowski and Arthur Fiedler have had long and productive careers that has led to the proposal that symphony conductors are a remarkably long-lived group. In
a 20-year follow study of 437 active and former conductors of major regional and community symphonyand opera orchestras in the United States, published in240

Johansson BB: Brain plasticity in health and disease

the Statistical Bulletin in the US234 the over all mortality was 38% lower than in the general population
with the largest difference (56%) in the 50–59 age
range and a 34% reduction in the ages 80 and over.
However, it was pointed out that the results on conductors parallel the results of a study demonstratingthat the mortality among top corporative executives
was much more favorable than the mortality among
business executive at all levels of accomplishment in theUSA. The conclusion was that the data support thetheory that work fulﬁllment and worldwide recognitionof professional accomplishments are important determinants of health and longevity. One personal experience from Japan is that I was present when Asahina
Takashi, then 91, conducted the Japan New Philharmonic orchestra in the Sumida Triphony Hall in Tokyoin 1999, an excellent performance that got very longand enthusiastic ovations.
Like conductors, many legendary pianists have
performed high up in the ages. The degree of skill
maintenance for older expert pianists is predicted by
the amount of practice.235 In a study comparing older
expert and amateur pianists both groups showed thenormal pattern of age-related reductions in standard
measures for general processing speed. Whereas performance on music-related tasks showed similar agegraded decline for amateur pianists, the average performance level for the expert pianists was only slightly
below that of young expert pianists.235 When pianistsof a wide experience and age range were tested on
measures of musical memory and musical perceptual
speed, the results indicated that high levels of experience in the older participants partially attenuated thenegative effects of age on the memory and speed
tasks.236
Studies on longevity in the population in Okinawa
are in agreement with the concept that genetic factors
interact with life style, self-conﬁdence and social networks, as well as with diet.237,238 The Japanese twins,
Kin san and Gin san, who if I am correctly informed
became famous after singing in the Japanese TV at theage of 100, were seen in international newspapers at theage of 107 when Gin-san, apparently the most active ofthe two that lived a little longer, was planting a tree
while the sister was looking on sitting in a wheelchair.
That is to me an excellent example that old individuals
can still enjoy life and that in spite of the same genes
there might be some differences that can be inﬂuenced
by attitude and activities.
Concluding Remarks
Our brain is continuously changing and it is important what we do and what we think. A healthy brain canform new dendrites, spines and synapses throughout

our lifetime even if we need to activate more neuralcircuits for speciﬁc tasks than when we were young.
Brain damage is still and will remain a serious problem.
However, current basic and clinical data indicate thatthe possibilities to stimulate brain plasticity after a lesion are larger than earlier believed, and the progress
made in neurorehabilitation is promising. The concept
on brain plasticity has wide implication also for areas
outside neuroscience such as hand surgery.132,133 For
the ﬁrst time is seems that we have ways to successfully
treat focal hand dystonia.112–115 We cannot prevent
aging but the way we live out lives may inﬂuence theaging process. That the environment and our activities
inﬂuence our lives is basic human knowledge; what is
new is that we are starting to understand a little of how
it happens.
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