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Kleim JA, Jones TAPrinciples of experience-dependent neural plasticity: implications for rehabilitation after brain damage. J Speech Lang Hear Res 51:S225-S239



This paper reviews 10 principles of experience-dependent neural plasticity and considerations in applying them to the damaged brain. Neuroscience research using a variety of models of learning, neurological disease, and trauma are reviewed from the perspective of basic neuroscientists but in a manner intended to be useful for the development of more effective clinical rehabilitation interventions. Neural plasticity is believed to be the basis for both learning in the intact brain and relearning in the damaged brain that occurs through physical rehabilitation. Neuroscience research has made significant advances in understanding experience-dependent neural plasticity, and these findings are beginning to be integrated with research on the degenerative and regenerative effects of brain damage. The qualities and constraints of experience-dependent neural plasticity are likely to be of major relevance to rehabilitation efforts in humans with brain damage. However, some research topics need much more attention in order to enhance the translation of this area of neuroscience to clinical research and practice. The growing understanding of the nature of brain plasticity raises optimism that this knowledge can be capitalized upon to improve rehabilitation efforts and to optimize functional outcome.
Principles of Experience-Dependent
Neural Plasticity: Implications for
Rehabilitation After Brain Damage
Purpose: This paper reviews 10 principles of experience-dependent neural plasticity
and considerations in applying them to the damaged brain.
Method: Neuroscience research using a variety of models of learning, neurological
disease, and trauma are reviewed from the perspective of basic neuroscientists but
in a manner intended to be useful for the development of more effective clinical
rehabilitation interventions.
Results: Neural plasticity is believed to be the basis for both learning in the intact brain
and relearning in the damaged brain that occurs through physical rehabilitation.
Neuroscience research has made significant advances in understanding experience-
dependent neural plasticity, and these findings are beginning to be integrated with
research on the degenerative and regenerative effects of brain damage. The qualities
and constraints of experience-dependent neural plasticity are likely to be of major
relevance to rehabilitation efforts in humans with brain damage. However, some
research topics need much more attention in order to enhance the translation of
this area of neuroscience to clinical research and practice.
Conclusion: The growing understanding of the nature of brain plasticity raises
optimism that this knowledge can be capitalized upon to improve rehabilitation efforts
and to optimize functional outcome.
KEY WORDS: rehabilitation, recovery, plasticity
euroscientists studying rehabilitation are often asked questions
about the specific therapies that should be included in clinical
treatment programs. Unfortunately, findings from animal models
of neurological disorders do not automatically translate to specific
recommendations for the clinic. Rather, our role is to study neurobiological
phenomenon related to functional recovery and to identify fundamental
principles that may help to guide the optimization of rehabilitation. Over
the last several decades, neuroscience research has begun to characterize
the adaptive capacity of the central nervous system (plasticity). The exist-
ing data strongly suggest that neurons, among other brain cells, possess
the remarkable ability to alter their structure and function in response to
a variety of internal and external pressures, including behavioral training.
We will go so far as to say that neural plasticity is the mechanism by which
the brain encodes experience and learns new behaviors. It is also the mech-
anism by which the damaged brain relearns lost behavior in response to
rehabilitation. By understanding the basic principles of neural plasticity
that govern learning in both the intact and damaged brain, identification of
the critical behavioral and neurobiological signals that drive recovery can
Jeffrey A. Kleim
McKnight Brain Institute, University of Florida,
Gainesville, and Brain Rehabilitation
Research Center, Malcom Randall
VA Hospital, Gainesville
Theresa A. Jones
University of Texas at Austin
Journal of Speech, Language, and Hearing Research Vol. 51 S225S239 February 2008 D American Speech-Language-Hearing Association
begin. The goal of the present article is to provide a re-
view of some principles of neural plasticity that we hope
will be useful for clinical research and, ultimately, treat-
ment. Companion articles in this issue discuss the trans-
lation of these principles to the treatment of aphasia
(Raymer et al., 2007) and impairments in motor speech
(Ludlow et al., 2007) and swallowing (Robbins et al., 2007).
Part 1: Relearning After Brain
Damage Why Learning Matters
Currently, Learning Is Our Best Hope
for Remodeling the Damaged Brain
In neuroscience research, the approaches to improv-
ing function after brain damage fall into two major
categories: (a) efforts to limit the severity of the initial in-
jury to minimize loss of function and (b) efforts to reor-
ganize the brain to restore and compensate for function
that has already been compromised or lost. The first
approach is obviously important; however, even in those
benefiting from early treatment, many will go on to have
severe long-term disabilities. Thus, there is a critical
need to understand how brain structure and function
can be driven to remodel in the days, months, and years
after brain damage. Neuroscience research has made
major advances in understanding the brain, but we
are far from understanding brain circuitry at the level
needed to place new neurons and neural connections in
just the right places to restore a lost function. Fortu-
nately, there is another way to create functionally ap-
propriate neural connections. We can capitalize upon the
way the brain normally does this that is, via learning.
There is overwhelming evidence to indicate that the
brain continuously remodels its neural circuitry in order
to encode new experiences and enable behavioral change
(Black, Jones, Nelson, & Greenough, 1997; Grossman,
Churchill, Bates, Kleim, & Greenough, 2002). Research
on the neurobiology of learning and memory suggests
that, for each new learning event, there is some nec-
essary and sufficient change in the nervous system that
supports the learning (Coop er, 2005; Donegan &
Thompson, 1991; Hebb, 1949; Kandel, 2001; Rose, 1991).
This neuroplasticity is, itself, driven by changes in
behavioral, sensory, and cognitive experiences. In our
view, this endogenous process of functionally appropri-
ate reorganization in healthy brains is also the key to
promoting reorganization of remaining tissue in the
damaged brain. This approach of using the process of
learning, alone and in combination with other therapies,
to promote adaptive neural plasticity is a growing focus
of research in animal models of brain damage (Johansson,
2000, 2003; Jones et al., 2003; Jones, Hawrylak, Klintsova,
& Greenough, 1998; Monfils, Plaut z, & Kleim, 2005).
Trans lation of this research to humans is likely to be
enhanced by consideration of principles of experience-
dependent neural pl asticity, as overviewed in Part 2 of
this article.
Learning Reorganizes the Damaged Brain
Even in the Absence of Rehabilitation
Learning is an essential component of brain adap-
tation to brain damage even when there are no overt
rehabilitation efforts. One of the most reliable behavioral
consequences of brain damage is that individuals de-
velop compensatory behavioral strategies to perform daily
activities in the presence of lost function (Gazzaniga,
1966; Gentile, Green, Nieburgs, Schmelzer, & Stein,
1978; Kwakkel, Kollen, & Lindeman, 2004). These self-
taught behaviors are potentially among the most sig-
nificant behavioral changes of an individuals adult life.
Animal research has indicated that these compensatory
behaviors can be key drivers of what is often thought of
as the normal response to brain damage (Jones et al.,
1998; Morgan, Huston, & Pritzel, 1983). For example,
reliance on the less-affected limb after unilateral ce-
rebral damage is associated with major restructuring
and neuronal growth in the contra-to-lesion hemisphere
(Adkins, Voorhies, & Jones, 2004; Jones & Schallert,
1994; Jones, Kleim, & Greenough, 1996). Thus, a brain
that one may attempt to reorganize with rehabilitative
training is one that is being, and likely already has been,
driven to reorganize by compensatory behavioral changes.
Such self-taught behavioral changes can be adaptive
and major contributors to functional outcome (e.g.,
Whishaw, 2000). However, they can also be maladaptive
and interfering with improvements in function that
could be obtained using rehabilitative training. For ex-
ample, after unilateral brain damage, although reliance
on the less-affected body side is associated with major
neuroplastic changes in the unaffected hemisphere, this
reliance may also limit the propensity of individuals to
engage in behaviors that improve function of the
impaired body side (Allred, Maldonado, Hsu, & Jones,
2005; Mark & Taub, 2004).
Brain Damage Changes the Way
the Brain Responds to Learning
Learning involves changes in genes, synapses, neu-
rons, and neuronal networks within specific brain re-
gions. Brain damage results in many changes in neurons
and non-neuronal brain cells that can alter these learn-
ing processes. In add iti on to the loss of tissue at the
site of the primary injury, brain damage causes major
neurodegenerative and neuroplastic changes in con-
nected regions. When a brain region loses some of its
connections, it undergoes a cascade of changes related to
the clearance of degenerating debris, the remodeling of
S226 Journal of Speech, Language, and Hearing Research Vol. 51 S225S239 February 2008
neuronal processes, and the production of new neural
connections (synapses) by remaining inputs, a process
termed reactive synaptogenesis (Kelley & Steward,
1997). Brain damage can also result in both a time-
dependent disruption of function (diaschisis) and long-
lasting functional changes, such as the altered cortical
excitability reported after cerebral stroke ( Bütefisch,
Netz, Wes sling, Seitz, & Homberg, 2003; Murase,
Duque, Mazzocchio, & Cohen, 2004; Witte, Bidmon,
Schiene, Redecker, & Hagemann, 2000). It is not sur-
prising that learning would be dramatically altered
when it involves the very neurons and neural connec-
tions that are undergoing regenerative and degenera-
tive responses to the injury or that have been chronically
altered in excitability. These effects of brain damage
may be related to both deficiencies and enhancements in
learning that need to be considered when translating
rules of learning to individuals with brain damage.
Part 2: Principles of Experience-
Dependent Neural Plasticity
and Their Translation to
the Damaged Brain
Table 1 lists principles of experience-dependent plas-
ticity derived from decades of basic neuroscience research
that are likely to be especially relevant to rehabilitation
after brain damage. This is hardly a comprehensive list,
but it is one that highlights some factors that researchers
have found relevant to rehabilitation outcome and to
experience-dependent plasticity in models of learning
and brain damage recovery. These principles are dis-
cussed in the context of their influence on brain plasticity
in the intact and damaged brain.
Principle 1: Use It or Lose It
Neural circuits not actively engaged in task perfor-
mance for an extended period of time begin to degrade.
This was first systematically demonstrated by Hubel
and Wiesel in the 1960s in their visual deprivation ex-
periments. They found that depriving a kittens eye of
light reduced the number of neurons in the visual cortex
that responded to light (Hubel & Wiesel, 1965). Further
work extended the finding to adult cortex and also
showed that the reduction in neuronal responses to light
was accompan ied by a decrease in synap se number
(Fifkova, 1969). Similar results were reported in owl
monkey somatosensory cortex, where neurons respon-
sive to tactile stimulation of the hand are found. I n
29 months after rem oval of a single digit, neurons
throughout its entire cortical representation region were
now responsive to the adjacent digits and skin surfaces
of the palm (Merzenich et al., 1984). Auditory depriva-
tion also causes a loss of sound representation (Reale,
Brugge, & Chan, 1987) and a decrease in synapse num-
ber (Perier, Buyse, Lechat, & Stenuit, 1986) in the cor-
tex. In developing rats, restriction of movement results
in poorly developed Purkinje neurons in the cerebullum
(Pascual, Hervias, Toha, Valero, & Figueroa, 1998). It is
important to point out that, in many cases, sensory
deprivation results not in a total loss of cortical function
but rather an apparent reallocation of cortical territory.
Deprivation of one sensory modality may cause its
corresponding cortical area to be at least partially taken
over by another modality. For example, functional mag-
netic resonance imaging (fMRI) in blind subjects shows
activation of visual cortical areas during tactile tasks
such as Braille reading (Sadato et al., 1996), whereas deaf
subjects show auditory cortical activ ation to visual
stimuli (Finney, Fine, & Dobkins, 2001). This is an im-
portant concept for rehabili tation research for two
reasons. The first reason is that failing to engage a brain
system due to lack of use may lead to further degrada-
tion of function. Thus, for example, as prop ose d by
Robbins et al. (2007), tube feeding may permit the disuse
of the neural circuitry involved in swallowing, which in
turn may lead to a further loss of swallowing function.
The second reason is that functional recovery may be
Table 1. Principles of experience-dependent plasticity.
Principle Description
1. Use It or Lose It Failure to drive specific brain functions can lead to functional degradation.
2. Use It and Improve It Training that drives a specific brain function can lead to an enhancement of that function.
3. Specificity The nature of the training experience dictates the nature of the plasticity.
4. Repetition Matters Induction of plasticity requires sufficient repetition.
5. Intensity Matters Induction of plasticity requires sufficient training intensity.
6. Time Matters Different forms of plasticity occur at different times during training.
7. Salience Matters The training experience must be sufficiently salient to induce plasticity.
8. Age Matters Training-induced plasticity occurs more readily in younger brains.
9. Transference Plasticity in response to one training experience can enhance the acquisition of similar behaviors.
10. Interference Plasticity in response to one experience can interfere with the acquisition of other behaviors.
Kleim & Jones: Principles of Plasticity S227
supported, at least in part, by shifting novel function to
residual brain areas.
Behavioral experiences after brain damage can also
protect neurons and networks that would otherwise be
lost after the injury. In both rats and monkeys, focal
ischemic lesions to the motor cortex result in a loss of
the ability to elicit movements in adjacent regions of
the cortex (Barbay et al., 2005; Nudo & Milliken, 1996).
However, this loss is prevented and functional reorga-
nization is promoted as a result of rehabilitative train-
ing in a skilled reaching task (Kleim, Bruneau, et al.,
2003; Nudo, Wise, et al., 1996). Combining rehabilita-
tive training with constraint of the ipsilesional arm in
humans with unilateral strokes improves the function
of the impaired limb and promotes greater movement-
associated activation in the remaining cortex of the
injured hemisphere (e.g., Liepert et al., 2000; Sterr et al.,
2002; Taub, 2000; Taub, Uswatte, & Morris, 2003; Wolf
et al., 1989). Mimicking this therapeutic approach in
rats (using limb-restricting vests combined with train-
ing) beginning 7 days after striatal hemorrhagic injury
results in markedly improved function on measures of
skilled reaching and posturalmotor asymmetries in
comparison to either rehabilitative training alone or con-
straint of one limb alone (DeBow, Davies, Clarke, &
Colbourne, 2003; Maclellan, Grams, Adams, & Colbourne,
2005). Constraint plus training was also associated with a
reduction in tissue loss in the damaged striatum (DeBow
et al., 2003). As discussed in Raymer et al. (2007), several
studies support the importance of language use for
maintenance and improvements in language abilities. It
is also possible to overuse impaired functions, an issue
of relevance to timing and intensity of interventions
after some types of brain damage, as discussed in the
Principle 5 section.
Principle 2: Use It and Improve It
In contrast to the experiments showing how a lack of
use can degrade brain function, several studies in intact
animals have shown how plasticity can be induced within
specific brain regions throu gh extended training.
Monkeys trained to perf orm fine dig it movements by
retrieving small food pellet s out of a well had an in-
crease in digit representation areas within primary
motor cortex (Nudo, Mill iken, et al., 1996). Similarly,
rats trained to rea ch outside of their cage to retrieve
food rewards had an increa se in distal forepaw rep-
resentations within motor cortex (Kleim, Barba y, &
Nudo, 1998). Synaptogenesis (Kleim, Barbay, et al.,
2002, 2004) and increased synaptic responses (Monfils
& Teskey, 2004) were found within these same cortical
areas. Reorganization of representations within audi-
tory (Weinberger & Bakin, 1998) and somatosensory
(Recanzone, Merzenich, & Schreiner, 1992) cortex has
also been demonstrated following sensory discrimination
training. Thus, the improvements in sensory and motor
performance brought about by skill training are accom-
panied by profound plasticity with in the cerebral cor-
tex. It is hypothesized that similar neural changes occur
in response to rehabilitation and mediate functional
A great deal of research indicates that behavioral
experience can enhance behavioral performance and
optimize restorative brain plasticity after brain damage.
It has l ong been known that housing animals in com-
plex environments pre- and/or postinjury can enhance
functional recovery (e.g., Kolb & Gibb, 1991; Xerri &
Zennou-Azogui, 20 03; reviewed in Will, Galani, Kelche,
& Rosenzweig, 2004). In recent years, investigat ors
have focused on the effects of more directe d training
experience. Motor skill training after unilateral cortical
damage has been found to both improve motor function
and to drive restorative neural plasticity in remaining
cortical regions (Castro-Alamancos & Borrel, 1995; Nudo,
Milliken, et al., 1996; Jones, Chu, Grande, & Gregory, 1999;
Biernaskie & Corbett, 2001). For example, after unilat-
eral sensorimotor cortex lesions, a several-week period of
acrobatic training (training rats to traverse an obstacle
course) was found to improve behavioral function and
increase reactive synaptic plasticity in the contralateral
cortex compared with controls receiving simple exercise
(Jones, Chu, Grande, & Gregory, 1999; see also Biernaskie
& Corbett, 2001). Dendritic growth and synaptogenesis in
the cortex contralateral to unilateral cortical damage in
rats has been found to be dependent upon postinjury
behavioral experiences with the less-affected body side
(Jones et al., 1998). Rehabilitative training has also be-
come increasingly viewed as a means of enhancing the
potency of other therapeutic approach es, such as grafts
of fetal tissue, provision of neuronal precursors, and
other treatments intended to promote restorative plas-
ticity (reviewed in Johansson, 2000). Unilateral reach
training with the impaired limb, for example, was found
to markedly enhance the survival of fetal tissue grafts
placed into the site of frontal cortical aspiration lesions
in rats (Riolobos et al., 2001). The combination of the
training and grafts produced improvements in reaching
ability that were not found as a result of either inde-
pendent manipulation.
Principle 3: Specificity
In research on the neurobiology of learning and
memory, a basic distinction is made between the engram
itself (the brain changes that are the memory) versus
the changes that modulate the strength of the engram
(Cahill & McGaugh, 1996). In many studies, learning or
skill acquisition, rather than mere use, seem to be re-
quired to produce significant changes in patterns of
S228 Journal of Speech, Language, and Hearing Research Vol. 51 S225S239 February 2008
neural connectivity. For example, motor skill acquisi-
tion is associated with the changes in gene expression,
dendritic growth, synapse addition,and neuronal activ-
ity in the motor cortex and cerebellum (Black, Isaacs,
Anderson, Alcantara, & Greenough, 1990; Kleim, Lussnig,
Schwarz, Comery, & Greenough, 1996; Monfils et al., 2005;
Nudo, 2003). In humans, skill acquisition is associated
with changes in activation patterns in the motor cortex
as revealed by fMRI (e.g., Karni et al., 1998; Ungerleider,
Doyon, & Karni, 2002) and in movement representations
as revealed using transcranial magnetic stimulation
(TMS; e.g., Muellbacher, Ziemann, Boroojerdi, Cohen,
& Hallett, 2001; Pascual-Leone et al., 1995; Perez,
Lungholt, Nyborg, & Nielsen, 2004). Repetition of pre-
viously acquired motor movements, however, has not
been found to result in significant synapse addition or
map expansion in motor cortex in animal models (Plautz
et al., 2000; Kleim, Cooper, & VandenBerg, 2002). Sim-
ilarly, human participants who were trained to make
skilled ankle movements exhibited enhanced corti-
cospinal excitability, whereas participants who were
trained to repeat unskilled movements did not (Perez
et al., 2004). In rats with unilateral motor cortical in-
farcts, several weeks of motor rehabilitation in skilled
reaching with the impaired forelimb improved function
and resulted in a major increase in the cortical territory
in which forelimb movements could be evoked in com-
parison with controls. However, performance of unskilled
movements was not sufficient to reproduce the effects of
skilled reach training on motor maps, consistent with find-
ings in intact animals (Kleim, Cooper, & VandenBerg, 2002;
Remple, Bruneau, VandenBerg, Goertzen, & Kleim, 2001).
Learning-induced brain changes also show regional
specificity. For example, unilateral training in reach-and-
grasp tasks in rats causes dendritic growth in the motor
cortex contralateral to the trained limb but has only sub-
tle effects on the ipsilateral motor cortex (Greenough,
Larson, & Withers, 1985; Withers & Greenough, 1989).
The synaptic and motor map changes occurring with
training and sensory manipulations are also localized to
specific cortical subregions. For example, Kleim et al.
(1998) found training-induced changes in motor map
topography and synapse number within caudal but not
rostral areas of the forelimb motor cortex in rats.
Learning to be afraid of a simple auditory stimulus is
believed to critically involve synaptic plasticity in the
amygdala, but learning to distinguish between closely
related auditory stimuli also involves auditory cortex
(LeDoux, 2000).
Thus, specific forms of neural plasticity and con-
comitant behavioral changes are dependent upon specific
kinds of experience. The implication for rehabilitation is
that training in a specific modality may change a limited
subset of the neural circuitry involved in the more general
function and, therefore, influence the capacity to acquire
behaviors in nontrained modalities (see Principle 9:
Transference and Principle 10: Interference sections). For
example, as suggested in the companion article (Ludlow
et al., 2007), training in swallowing after stroke may
not automatically generalize to training in voice produc-
tion (Huang, Carr, & Cao, 2002). In aphasia research,
several findings support limits in the generalization of
trained language abilities (reviewed in Raymer et al.,
2007). As previously mentioned, when learning involves
a brain region that is undergoing damage-induced re-
modeling of neuronal circuitry, there are also likely to
be major differences in learning effects compared with
intact brains. This might provide a special opportunity
to guide the restructuring of this brain region with ap-
propriate behaviors, as suggested both in the cortical
tissue bordering a lesion (Nudo, Milliken, et al., 1996)
and in regions remote from, but connected to, the site
of primary injury (Adkins, Bury, & Jones, 2002; Jones
et al., 1998).
Principle 4: Repetition Matters
Simply engaging a neural circuit in task per for-
mance is not sufficient to drive plasticity (see Principle
3: Specificity section). Re petition of a newly learn ed (or
relearned) behavior may be required to induce lasting
neural changes. For ex ample, rats traine d on a skilled
reaching task do not show increases in synaptic strength
(Monfils & Teskey, 2004), increases in synapse number,
or map reorganization (Kleim et al., 2004) until after sev-
eral days of training, despite making significant behav-
ioral gains. Thus, some forms of plasticity require not only
the acquisition of a skill but also the continued perfor-
mance of that skill over time. It is hypothesized that
the plasticity brought about through repetition repre-
sents the instantiation of skill within neural circuitry,
making the acquired behavior resistant to decay in
the absence of training (Monfils et al., 2005). The same
phenomenon has been observed in studies of electrical
stimulationinduced increases in synaptic strength
within cortex. Racine, Chapman, Trepel, Teskey, &
Milgram (1995) examined the effects of daily stimula-
tion on cortical field potentials in rats with chronically
implanted electrodes. Enduring long-term potentiation
(LTP) of synaptic responses within sensorimotor cortex
required 5 days of stimulation and did not reach asymptote
until Day 15.
The role of repetition in driving plasticity and con-
comitant learning may be critical for rehabilitation.
Plasticity may represent a surrogate marker of func-
tional recovery indicative of behavioral change that is
resistant to decay. We suggest that a sufficient level of
rehabilitation is likely to be required in order to get the
subject over the hump”—that is, repetition may be
needed to obtain a level of improvement and brain
Kleim & Jones: Principles of Plasticity S229
reorganization sufficient for the patient to continue to
use the affected function outside of therapy and to main-
tain and make further functional gains.
Principle 5: Intensity Matters
In addition to the repetition, the intensity of stim-
ulation or training can also affect the induction of neural
plasticity. Animals trained on a skilled reaching task to
perform 400 reaches per day had increases in synapse
number within motor cortex (Kleim, Barbay, et al., 2001),
whereas animals trained to reach 60 times per day did not
have such increases (Luke, Allred, & Jones, 2004). Sim-
ilar effects have been found in stimulation experiments.
Low-intensity stimulation can induce a weakening of
synaptic responses (long-term depression), whereas higher
intensity stimulation will induce long-term potentiation
(Lisman & Spruston, 2005). Transcranial magnetic stim-
ulation experiments within human motor cortex have
shown that stimulation trains consisting of 1,800 pulses,
but not 150 pulses, were sufficient to induce lasting in-
creases in motor-evoked potential amplitudes (Peinemann
et al., 2004). Intensity is clearly an important factor in
aphasia rehabilitation, as reviewed in Raymer et al. (2007).
One potential negative side effect of training in-
tensity after brain damage is that it is possible to over-
use impaired extremities in a manner that worsens
function. This seems to require both an extreme amount
of use and that the overuse occur during an early vul-
nerable period. Schallert and others have found that
forcing rats to rely on the impaired forelimb ( by placing
them in limb-restricting vests for 24 hr/day) for the first
7 days after unilateral sensorimotor cortex lesions ex-
aggerated tissue loss and worsened functional outcome
compared with rats permitted to use both forelimbs
(Humm, Kozlowski, James, Gotts, & Schallert, 1998;
Kozlowski, James, & Schallert, 1996; see also DeBow et al.,
2004). This effect appears to be due to an exaggeration
of excitotoxicity in vulnerable tissue surrounding the
primary injury (Humm, Kozlowski, Bland, James, &
Schallert, 1999). Griesbach and colleagues (Griesbach,
Gomez -Pinilla, & Hovda, 2004; Griesbach, Hovda,
Molteni, Wu, & Gomez-Pinilla, 2004) have also found
that a voluntary exercise regime (wheel running) pro-
vided in the first 6 days after traumatic brain injury
reduced the expression of plasticity-related molecules
in the hippocampus. In contrast, exercise that was de-
layed until 2 weeks postlesion enhanced expression o f
s ome of the same molecules and improved functional
outcome in spatial memory tests. The sensitivity to
overuse e ffects also de pends upon th e na ture of the
injury (Woodlee & Schallert, 2006). In unilateral
models of Parkinsons disease in rats, the neurotoxin
6-hydroxydopamine is used to produce damage to do-
pamine producing neurons in one hemisphere. Forced
use of the forelimb before or shortly after the neu-
rotoxin infusion has been found to reduce lo ss of
dopamine-producing cells in the substantia nigra and
to enhance behavioral function. However, the benefit of
forced forelimb use is lost if the manipulation is delayed
until a week after the neurotoxin exposure (Cohen,
Tillerson, Smith, Schallert, & Zigmond, 2003; Tillerson
et al., 2001).
Principle 6: Time Matters
The neural plasticity underlying learning can be
best thought of as a process rather than as a single mea-
surable event. Indeed, it is a complex cascade of mo-
lecular, cellular, structural, and physiological events (e.g.,
Kandel, 2001; Rose, 1991). Certain forms of plasticity
appear to precede and even depend upon others. Thus,
the nature of the plasticity observed and its behavioral
relevance may depend on when one looks at the brain.
For example, during motor skill training, gene expres-
sion precedes synapse formation (Kleim et al., 1996),
which in turn precedes motor map reorganization (Kleim
et al., 2004). In addition, the stability of the plastic change
may also depend upon the time after training. Stimula-
tion experiments have shown that enhanced synaptic re-
sponses are more susceptible to degradation during early
phases of stimulation than later (Trepel & Racine, 1998).
It has long been known that the stable consolidation of
memories requires time (Dudai, 2004; Wiltgen, Brown,
Talton, & Silva, 2004).
The time factor may be even more critical after
brain damage given the dynamic changes in the neural
environment that are occurring independent of any
rehabilitation. As previously mentioned, there are ma-
jor cascades of neuronal reactions to brain damage
that occur over periods of months or longer (Badan, Platt,
et al., 2003; Kelley & Steward, 1997). A consideration
in the timing of behavioral treatments may be whether
treatment is primarily neuroprotective in nature that
is, sparing of neuron death and loss of neural connec-
tions or whether the treatment works primarily by
driving reorganization of remaining connections, as typ-
ically proposed for rehabilitative training. These are
not indepen dent p rocesses becaus e neurons that are
driven to form new synaptic connections are likely to
receive more signals promoting of survival (e.g., Purves,
Snider, & Voyvodic, 1988), but they are likely to vary,
temporally, in their sensitivity to behavioral experience
If therapy promotes neural restructuring, then it
should work anytime, but there may be time windows in
which it is particularly effective in directing the lesion-
induced reactive plasticity. Biernaskie, Chernenko, &
Corbett (2004) found that a 5-week period of rehabilita-
tion initiated 30 days after cerebral infarcts was far less
S230 Journal of Speech, Language, and Hearing Research Vol. 51 S225S239 February 2008
effective in improving functional outcome and in pro-
moting growth of cortical dendrites than the same regimen
initiated 5 days postinfarct. Norrie, Nevett-Duchcherer,
& Gorassini (2005) found that a 3-week period of motor
rehabilitative training improved stepping function in
rats even when it was delayed until 3 months after a
spinal cord injury. Nevertheless, the training was consid-
erably more effective when administered shortly after the
injury. Nudo and colleagues previously found that early
training in skilled reaching after focal motor cortical in-
farcts in squirrel monkeys prevents a loss of movement
representations in peri-lesion cortex (Nudo, Wise, et al.,
1996). Barbay et al. (2005) recently found that training
delayed until 1 month after the injury was effective in pro-
ducing other changes in movement represent ations
and in improving function, but it failed to prevent the
loss of movement representations in peri-infarct cortex
that was found in monkeys receiving earlier training.
As discussed in Raymer et al. (2007), aphasia treatment
initiated in the chronic phase can result in major functional
improvements, but meta-analysis indicates that the effect
sizes are greatest when initiated during the acute post-
injury period (Robey, 1998). A better understanding of
the neural processes responsible for this time-dependent
sensitivity may lead to ways of reinstigating this sen-
sitivity at later time periods.
Time delays may also allow for the greater estab-
lishment of self-taught compensatory behaviors, some of
which may interfere with rehabilitative training efforts.
As mentioned in the previous section, there are also
time-dependent vulnerabilities in use-dependent exag-
geration of excitotoxicity. Obstacles in translating these
rat research results to humans include the need for
much more basic information on time-dependent inter-
actions between learning and brain adaptation to brain
damage and the need to better understand how time
windows in short-lived rodents (rats only live È23 years)
may translate to those found in humans recovering from
brain damage.
Principle 7: Salience Matters
In order for an organism to effectively function, there
must be a system in place to weigh the importance of any
given experience such that it can be encoded. Research
using auditory tones as classical conditioning stimuli has
provided evidence for such a system and demonstrated
that plasticity within the auditory cortex is dependent
upon the salience of the experience. In this paradigm,
animals are trained to recognize a tone of a specific fre-
quency in order to receive a reward. Thus, one tone be-
comes more salient than the others. Animals trained in
such a manner show an increase in the representation of
the salient tone within the auditory cortex (Weinberger,
2004). Simply playing the tone without the reward does
not alter the topography of the auditory maps. However, if
the tone is paired with stimulation of the basal forebrain
cholinergic system, thought to mediate attention, a similar
reorganization is observed (Dimyan & Weinberger, 1999;
Kilgard & Merzenich, 1998). Furthermore, selective lesions
of the cholinergic neurons within the basal forebrain pre-
vents learning and auditory cortex reorganization (Kudoh,
Seki, & Shibuki, 2004). Similarly, human subjects trained
on a tone discrimination task had reduced activity within
auditory cortex in response to the trained tone when given
an acet ylcholine ant agonist ( T hiel, B entley, & Dolan,
2002). Although this pheno menon is more difficult to
demonstrate within motor systems, some indirect evi-
dence is available. Stefan, Wycislo, & Classen (2004),
using a paired associative stimula tion (PAS) consisting
of repetitive application of single electric stimulus, de-
livered to the right median nerve, paired with single-pulse
TMS of the right abductor pollicis brevis muscle repre-
sentation in motor cortex. This protocol leads to an en-
hancement of motor-evoked potential (MEP) amplitude in
the muscle to future stimulation of the cortex. However,
PAS failed to induce plasticity when the subjects atten-
tion was directed away from the target hand during stim-
ulation. Furthermore, training-dependent cortical plasticity
was enhanced when subjects were administered an acetyl-
choline agonist (Meintzschel & Ziemann, 2006). In rat
motor cortex, disruption of the cholinergic system pre-
vented motor map reorganization and impaired skill
learning (Conner, Chiba, & Tuszynski, 2005). These ex-
periments demonstrate that there is a neural system
that mediates saliency and that engaging this system is
critical for driving experience-dependent plasticity.
Saliency is already an important consideration in
the treatment of many neurological disorders, including
aphasia and motor speech disorders. However, a better
understanding of the neural processes underlying the
modulation of recovery processes by saliency may be use-
ful for optimizing treatment. Very few studies have di-
rectly examined the effects of saliency on recovery of
function and associated plasticity, but there is a wealth
of evidence showing that acetylcholine is involved, and
this may be due, in part, to its contribution to saliency of
experiences. Conner et al. (2005) demonstrated that le-
sions of the basal forebrain cholinergic system prevented
reorganization of movement representation within motor
cortex after cortical damage and impaired motor recov-
ery. Administration of acetylcholine agonists can also
enhance recovery after brain damage (Brown, Gonzalez,
& Kolb, 2000). It has long been known that emotions
modulate the strength of mem ory consolidation (re-
viewed in McGaugh, 2004). Sufficient motivation and
attention are also, of course, essential to promoting en-
gagement in the task. For example, rats will voraciously
engage in rehabilitative reaching if it earns them pal-
atable food treats. Providing stimulation of a rewarding
Kleim & Jones: Principles of Plasticity S231
circuit in the brain (the ventral tegmental area) has also
been f ound to be extremely effective in promoting per-
formance of rehabilitative reaching tasks in rats (Castro-
Alamancos & Borrel, 1995).
Principle 8: Age Matters
It is clear that neuroplastic responses are altered in
the aged brain (Nieto-Sampedro & Nieto-Diaz, 2005).
Experience-dependent synaptic potentiation (Rosenzweig
& Barnes, 2003), synaptogenesis (Greenough, McDonald,
Parnisari, & Camel, 1986) and cortical map reorganization
(Coq & Xerri, 2001) are all reduced with aging. Normal
aging is associated with widespread neuronal and syn-
aptic atrophy (Salat et al., 2004) and physiological de-
gradation (Pitcher, Ogston, & Miles, 2003). Indeed, aging
may be analogous to an insidious brain insult, and some
have argued that plasticity is the mechanism by which
the brain compensates for aging. Cognitive decline may
reflect the progressive failure of plasticity processes in
compensating for age-related impairments. Nevertheless,
the aging brain is also clearly responsive to experience,
even though the brain changes may be less profound
and/or slower to occur than those observed in younger
brains (e.g., Green, Greenough, & Schlumpf, 1983; van
Praag, Shubert, Zhao, & Gage, 2005). Furthermore, there
is evidence in both humans and animal models that the
effects of aging vary with lifespan experiences and are
generally better in individuals with greater physical and
mental activity (reviewed in Churchill et al., 2002).
The effects of brain damage vary with developmen-
tal age in young animals (reviewed in Kolb et al., 2000).
The neuroplastic responses to brain damage are also
altered in aging animals. In adult rats, lesions that
cause loss of connections to subregions of the hippocam-
pus trigger the sprouting of new connections, which takes
about 2 months to complete. The onset of sprouting is
within 24 days after the lesion in young adult rats, but
in aged animals, it is initiated in about 20 days (Hoff,
Scheff, Benardo, & Cotman, 1982; McWilliams & Lynch,
1979). Reduced expression of plasticity-related mole-
cules, increased accumulation of neurotoxic factors, and
altered temporal profiles of these changes have also been
found after stroke-like injuries in rats (Badan et al.,
2003; Sato et al., 2001). Ischemic injury in young adult
rats triggers increases in the production of new neurons
(neurogenesis). This ne uro gen ic respon se is greatly
reduced in aged rats compared with y oung adults (Jin
et al., 2004). Several studies have also found that the
infarct sizes produced by experimental ischemia are
much greater in older animals than in young animals
(Davis et al., 1997; Kharlamov, Kharlamov, & Armstrong,
2000; Rosen, Dinapoli, Nagamine, & Crocco, 2005), per-
haps because of a reduced capacity of old neurons to deal
with the metabolic challenge of ischemic insult (e.g.,
Hoyer & Krier, 1986; Davis et al., 1997; Siqueira, Cimarosti,
Fochesatto, Salbego, & Netto, 2004). It is not surprising
that larger infarcts can lead to greater disability. How-
ever, not all studies using animal models have found
significant differences in the behavioral and brain effects
of damage produced in young adult versus aged animals.
Zhao, Puurunen, Schallert, Sivenius, & Jolkkonen (2005),
for example, found that recovery of sensorimotor deficits
after unilateral cortical infarcts was similar in aged
animals and young animals when these groups were
compared with age-matched intact control animals (see
also Shapira, Sapir, Wengier, Grauer, & Kadar, 2002).
Although there has been little research on the effects of
rehabilitative training after brain damage in aged an-
imals, healthy old animals clearly benefit from complex
motor skills training (Churchill, Stanis, Press, Kushelev, &
Greenough, 2003), exercise (Adlard, Perreau, & Cotman,
2005; Fordyce, Starnes, & Farrar, 1991), and exposure to
complex and social environments (Green et al., 1983;
Greenough et al., 1986).
Principle 9: Transference
Transference refers to the ability of plasticity within
one set of neural circuits to promote concurrent or sub-
sequent plasticity. This phenomenon has been recently
demonstrated in human motor cortex with skill learning
and TMS. Training on a fine digit movement task in-
duces an increase in corticospinal excitability and an
expansion of hand muscle representation in primary
motor cortex (Pascual-Leone et al., 1995). A similar in-
crease in excitability can be induced through application
of repetitive transcranial magnetic stimulation (rTMS)
to motor cortex (Peinemann et al., 2004). When TMS was
applied to mo tor cortex synchronously during skill
training, it enhanced skill acquisition (Bütefisch, Khurana,
Kopylev, & Cohen, 2004). Similar findings have been
reported in association with recovery after stroke (Hummel
& Cohen, 2006). Anodal transcranial direct current stim-
ulation of the affected hemisphere in humans with uni-
lateral stroke has been found to result in transient
improvements in motor function (Hummel et al., 2005).
Peripheral stimulation of the pharynx has been found to
enlarge its cortical represent ation and to improve
swallowing function in stroke survivors (Fraser et al.,
2002; Hamdy, Rothwell, Aziz, Singh, & Thompson, 1998).
As noted in the companion article by Robbins et al. (2007),
coupling training with peripheral or central stimulation
may be necessary to drive the tranference effects into a
functionally beneficial direction. Direct electrical stimu-
lation of the motor cortex after ischemic insult enhanced
motor recovery (Adkins-Muir & Jones, 2003), enhanced
synaptic responses (Teskey, Flynn, Goertzen, Monfils, &
Young, 2003), and mot or map reorganization ( Kleim,
Bruneau, et al., 2003; Plautz et al., 2003) when coupled
with rehabilitative training. Combining rehabilitative
S232 Journal of Speech, Language, and Hearing Research Vol. 51 S225S239 February 2008
training with rTMS of the affected hemisphere early af-
ter stroke was found to improve motor function (Khedr,
Ahmed, Fathy, & Rothwell, 2005). In addition to elec-
trical stimulation, previous behavioral experience can also
promote subsequent plasticity. For example, it has long
been known that rats housed in complex environments
have better functional outcomes after various types of
brain damage compared with rats housed in standard
laboratory environments (reviewed in Will et al., 2004).
Although learning may be needed to promote the
formation of functionally appropriate synaptic connec-
tions after brain damage, exercise may be more appro-
priate for promoting a fertile environment to support
these changes. Exercise results in angiogenesis in the
motor cortex (Kleim, Cooper, & VandenBerg, 2002; Swain
et al., 2003) and cerebellum (Black et al., 1990) and in ex-
pression of factors (neurotrophins) that promote neuronal
growth and survival of vulnerable neurons in the spinal
cord, hippocampus, and other brain regions (reviewed in
Cotman & Berchtold, 2002; Kleim et al., 2003; Vaynman
& Gomez-Pinilla, 2005). After traumatic brain injury or
spinal cord injury in animal models, appropriately timed
exercise has been found to robustly elevate neurotrophic
factors and other plasticity-related molecules and to im-
prove functional outcome (e.g., Griesbach, Gomez-Pinella,
et al., 2004; Molteni, Zheng, Ying, Gomez-Pinilla, & Twiss,
2004; Ying, Roy, Edgerton, & Gomez-Pinilla, 2005).
Principle 10: Interference
Neural plasticity often has a favorable connotation
when described in the context of recovery of function.
However, plasticity can also serve to impede behavioral
change. Interference refers to the ability of plasticity within
a given neural circuitry to impede the induction of new, or
expression of existing, plast icity within that same
circuitry. This, in turn, can impair learning. Although
some types of noninvasive cortical stimulation applied
during or shortly before skill training may enhance
motor learning (Bütefisch et al., 2004; Floel & Cohen,
2006), other forms can be disruptive of learning. For
example, transcranial direct current stimulation given
after training reduced the training-dependent increases
in cortical excitability (Rosenkranz, Nitsche, Tergau, &
Paulus, 2000). Similarly, swallowing function can be
both enhanced (Fraser et al., 2002) and impaired (Power
et al., 2004) by peripheral stimulation, as discussed in
Robbins et al. (2007). Rodent experiments of spatial learn-
ing have shown that saturation of synaptic potentiation
within the hippocampus, a brain structure critical for
spatial learning, impairs subsequent learning (Moser,
Krobert, Moser, & Morris, 1998). Presumably, synchro-
nizing training with stimulation improves performance
because the behavioral signals driving plasticity during
training are augmented by the presence of the extra
stimulation. When stimulation is applied outside of the
training experience, in addition to potentially disrupting
the memory consolidation process, it may induce plas-
ticity that is not shaped by behavioral signals and is,
therefore, detrimental to performance. This has specific
implications for how adjuvant stimulation might be ap-
plied to enhance recovery after brain damage.
It is also possible for behavioral experience to drive
plasticity within residual brain areas in a direction that
will impede optimal behavioral recovery. Brain damage
survivors may develop compensatory strategies that are
easier to perform (bad habits) than more difficult but
ultimately more effective strategies acquired through
rehabilitation. These strategies might be adopted earlier
and used with much greater frequency than those guided
in therapy. The ease of learning certain compensatory
behaviors may also be facilitated after brain damage.
After small unilateral sensorimotor cortex lesions, rats
have a reduction in apparent aiming errors when learn-
ing a new skilled reaching task with the less-affected
forelimb compared with intact rats, and this is related to
enhanced neuroplastic changes in the contralesional
motor cortex (Allred & Jones, 2004; Bury & Jones, 2002,
2004; Hsu & Jones, 2005). In humans, transient virtual
lesions of the motor cortex also enhance some function in
the ipsilesional hand (Kobayashi, Hutchinson, Theoret,
Schlaug, & Pascual-Leone, 2004; see also Takeuchi, Chuma,
Matsuo, Watanabe, & Ikoma, 2005). However, over-reliance
on less-affected modalities m ay also exaggerate impair-
ments. Early sk ill training that was focused on the
ipsilesional limb of rats with unilateral infarct s was
found to greatly worsen subsequent per formance and
decreased use of the impaired forelimb (Allred et al., 2005),
suggesting that it contributed to learned nonuse (Mark &
Taub, 2004; Taub, 2000). When maladaptive, these self-
taught compensatory strategies may induce plasticity that
will have to be overcome with subsequent rehabilitation
and other treatment approaches (see e.g., Celnik & Cohen,
2004; Fregni & Pascual-Leone, 2006; Taub et al., 2003).
Another reason to consider interference effects is
that a therapy that benefits one skill may interfere with
performance of another. Furthermore, as brain injury
may change the neural response during learning, it may
also change sensitivities to interference effects. For ex-
ample, providing explicit instruction on how to perform a
motor sequence task was found to improve implicit
motor learning in healthy controls, whereas the same
instructions interfered with learning in subjects with
strokes (Boyd & Winstein, 2006).
Neuroscience research has yielded a great deal of
information on the nature of experience-dependent brain
Kleim & Jones: Principles of Plasticity S233
plasticity, and there is reason for optimism that our un-
derstanding of this can be capitalized upon to improve
functional outcome after brain damage. This work
strongly supports the use of rehabilitative training as a
tool to improve brain reorganization and functional out-
come. However, many issues that are likely to be critical
for optimizing rehabilitation remain poorly understood
and require greater attention by neuroscientists. A better
understanding is needed of how training experiences
interact with neural reactions to the brain damage, with
self-taught compensatory behavioral changes, and with
age, as well as how to combine rehabilitative training
with other treatment approaches. Of particular impor-
tance is the need to understand time windows in which
training can be optimally and safely applied. Transla-
tion of these findings to rehabilitative treatment will
also normally require intermediate steps, including ex-
perimental research using human subjects and compu-
tational models. This may be especially true for disorders
that are challenging to model in detail in animals, such as
some cognitive and motor disorders of speech and lan-
guage (see Ludlow et al., 2007; Raymer et al., 2007). Con-
tinued momentum in human experimental neuroscience
research shows promise for improving the bridge be-
tween animal research findings and clinical application
(reviewed in Floel & Cohen, 2006). Hopefully, the trans-
lational relevance of future research will be improved by
greater interaction between basic and clinical research-
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Received February 27, 2006
Accepted February 7, 2007
DOI: 10.1044/1092-4388(2008/018)
Contact author: Jeffrey A. Kleim, Brain Rehabilitation
Research Center (151A), Malcom Randall VA Hospital,
1610 SW Archer Road, Gainesville, FL 32610.
Kleim & Jones: Principles of Plasticity S239
... Neurorestorative interventions, such as physical and occupational therapy, attempt to harness principles of experience dependent plasticity to restore, recruit, and retrain circuitry in the injured brain [9], thereby improving function and lessening disability. Several motor rehabilitation interventions have been used in preclinical settings to gain insight into functional and neurological recovery after ICH. ...
Full-text available
Few certainties exist regarding the optimal type, timing, or dosage of rehabilitation after stroke. Despite differing injury mechanisms and recovery patterns following ischemic and hemorrhagic stroke, most translational stroke research is conducted after ischemia. As we enter the era of personalized medicine, exploring subtype-specific treatment efficacy is essential to optimizing recovery. Our objective was to characterize common rehabilitation interventions used after in vivo preclinical intracerebral hemorrhage (ICH) and assess the impact of post-ICH rehabilitation (vs. no-rehabilitation) on recovery of motor function. Following PRISMA guidelines, a systematic review (Academic Search Complete, CINAHL, EMBASE, Medline, PubMed Central) identified eligible articles published up to December 2022. Risk of bias (SYRCLE) and study quality (CAMARADES) were evaluated, and random-effects meta-analysis was used to assess treatment efficacy in recovery of forelimb and locomotor functions. Thirty articles met inclusion criteria, and 48 rehabilitation intervention groups were identified. Most used collagenase to model striatal ICH in young, male rodents. Aerobic exercise, enriched rehabilitation, and constraint-induced movement therapy represented ~ 70% of interventions. Study quality was low (median 4/10, range 2–8), and risk of bias was unclear. Rehabilitation provided modest benefits in skilled reaching, spontaneous impaired forelimb use, and locomotor function; however, effects varied substantially by endpoint, treatment type, and study quality. Rehabilitation statistically improves motor function after preclinical ICH, but whether these effects are functionally meaningful is unclear. Incomplete reporting and variable research quality hinder our capacity to analyze and interpret how treatment factors influence rehabilitation efficacy and recovery after ICH.
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Interventions to preserve functional independence in older adults are critically needed to optimize ‘successful aging’ among the large and increasing population of older adults in the United States. For most aging adults, the management of chronic diseases is the most common and impactful risk factor for loss of functional independence. Chronic disease management inherently involves the learning and adaptation of new behaviors, such as adopting or modifying physical activity habits and managing weight. Despite the importance of chronic disease management in older adults, vanishingly few individuals optimally manage their health behavior in the service of chronic disease stabilization to preserve functional independence. Contemporary conceptual models of chronic disease management and health habit theory suggest that this lack of optimal management may result from an underappreciated distinction within the health behavior literature: the behavioral domains critical for initiation of new behaviors (Initiation Phase) are largely distinct from those that facilitate their maintenance (Maintenance Phase). Psychological factors, particularly experiential acceptance and trait levels of openness are critical to engagement with new health behaviors, willingness to make difficult lifestyle changes, and the ability to tolerate aversive affective responses in the process. Cognitive factors, particularly executive function, are critical to learning new skills, using them effectively across different areas of life and contextual demands, and updating of skills to facilitate behavioral maintenance. Emerging data therefore suggests that individuals with greater executive function are better able to sustain behavior changes, which in turn protects against cognitive decline. In addition, social and structural supports of behavior change serve a critical buffering role across phases of behavior change. The present review attempts to address these gaps by proposing a novel biobehavioral intervention framework that incorporates both individual-level and social support system-level variables for the purpose of treatment tailoring. Our intervention framework triangulates on the central importance of self-regulatory functioning, proposing that both cognitive and psychological mechanisms ultimately influence an individuals’ ability to engage in different aspects of self-management (individual level) in the service of maintaining independence. Importantly, the proposed linkages of cognitive and affective functioning align with emerging individual difference frameworks, suggesting that lower levels of cognitive and/or psychological flexibility represent an intermediate phenotype of risk. Individuals exhibiting self-regulatory lapses either due to the inability to regulate their emotional responses or due to the presence of executive functioning impairments are therefore the most likely to require assistance to preserve functional independence. In addition, these vulnerabilities will be more easily observable for individuals requiring greater complexity of self-management behavioral demands (e.g. complexity of medication regimen) and/or with lesser social support. Our proposed framework also intuits several distinct intervention pathways based on the profile of self-regulatory behaviors: we propose that individuals with intact affect regulation and impaired executive function will preferentially respond to ‘top-down’ training approaches (e.g., strategy and process work). Individuals with intact executive function and impaired affect regulation will respond to ‘bottom-up’ approaches (e.g., graded exposure). And individuals with impairments in both may require treatments targeting caregiving or structural supports, particularly in the context of elevated behavioral demands.
Purpose: To estimate the effect of integrating custom-designed hand therapy video games (HTVG) with contralaterally controlled functional electrical stimulation (CCFES) therapy. Methods: Fifty-two stroke survivors with chronic (>6 months) upper limb hemiplegia were randomized to 12 weeks of CCFES or CCFES + HTVG. Treatment involved self-administration of technology-mediated therapy at home plus therapist-administered CCFES-assisted task practice in the lab. Pre- and post-treatment assessments were made of hand dexterity, upper limb impairment and activity limitation, and cognitive function. Results: No significant between-group differences were found on any outcome measure, and the average magnitudes of improvement within both groups were small. The incidence of technical problems with study devices at home was greater for the CCFES + HTVG group. This negatively affected adherence and may partially explain the absence of effect of HTVG. At end-of-treatment, large majorities of both treatment groups had positive perceptions of treatment efficacy and expressed enthusiasm for the treatments. Conclusion: This study makes an important contribution to the research literature on the importance of environmental factors, concomitant impairments, and technology simplification when designing technology-based therapies intended to be self-administered at home. This study failed to show any added benefit of HTVG to CCFES (NCT03058796).
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Common EOM paresis includes the abducens, trochlear and oculomotor neurons. This article reviews the pathways as well as recommendations for treatment.
Introduction The physical activity level in patients hospitalised for rehabilitation across multiple diagnoses is low. Moderate to severe acquired brain injury further reduces activity levels as impaired physical and cognitive functioning affect mobility independence. Therefore, supervised out-of-bed mobilisation and physical activity training are essential rehabilitation strategies. Few studies have measured the physical activity patterns in the early phases of rehabilitation after moderate to severe brain injury. Objectives To map and quantify physical activity patterns in patients admitted to brain injury rehabilitation. Further, to investigate which factors are associated with activity and if the early physical activity level is associated with functional outcome at discharge. Methods This observational study includes patients admitted to rehabilitation after moderate to severe acquired brain injury. Mobility and physical activity patterns are measured continuously during rehabilitation at two separate seven-day periods using a wearable activity tracker. Activity will be categorised into four levels and presented descriptively. Linear and logistic regression models will analyse associations between descriptive variables and activity levels. Discussion This protocol describes an observational study investigating patients' mobility and physical activity patterns with moderate to severe acquired brain injury during in-hospital rehabilitation. The ability to increase the amount of mobilisation and physical activity in subgroups may have profound consequences on the rehabilitation outcome. Furthermore, data from this study may be used to inform a large variety of trials investigating physical rehabilitation interventions. (NCT05571462).
Purpose This study reports pilot data for a novel intervention, ECoLoGiC-Tx, delivered to four people with moderate to severe aphasia. ECoLoGiC-Tx addresses language and communication in unstructured, participant-led conversation. The speech-language pathologist (SLP) uses a framework to choose turns that facilitate a social interaction. When communication breakdown occurs, the SLP implements a least-to-most hierarchy to maximize the people with aphasia's (PWA's) independence in self-repair. ECoLoGiC-Tx draws its theoretical underpinnings from conversation analysis and theories of rehabilitation, including principles of complexity, neuroplasticity, and learning. Method Four PWA attended 60-min sessions twice weekly for 10 weeks. Assessment occurred at pretreatment, posttreatment, and 6-week maintenance. Outcomes included established discourse measures for conversation and monologue, tests of language and functional communication, and patient-/family-reported outcome measures (P/FROMs). Discourse samples were collected three times per assessment. Interrater reliability and fidelity for assessment and treatment procedures are reported. Results Participants presented with Broca's aphasia (one moderate, one severe) or conduction aphasia (one moderate, one severe). Each demonstrated improvements in discourse, test batteries, and P/FROMs. They all demonstrated reduced aphasia severity measured by the Western Aphasia Battery–Revised at posttreatment or maintenance. Change in conversation and monologue was robust for three participants, but was mixed for one person (P1: moderate Broca's aphasia). P/FROMs indicated improvement at posttreatment and maintenance for all participants. Most treatment gains were maintained at 6-week follow-up. Conclusions This study provides promising results for ECoLoGiC-Tx to improve language function of people with chronic moderate to severe aphasia. Generalization occurred to tests, functional communication, spontaneous conversation, and structured monologue tasks.
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Unilateral damage to the forelimb representation area of the sensorimotor cortex in adult rats increases dendritic arborization of layer V pyramidal neurons of the contralateral homotopic cortex. Arbor size was maximum at approximately 18 d postlesion, following which there was a partial elimination, or pruning, of dendritic processes. These neural changes were closely associated with behavioral events. The overgrowth of dendrites was related in time to disuse of the contralateral (to the lesion) forelimb and over-reliance on the ipsilateral forelimb for postural and exploratory movements. The pruning of dendrites was related to a return to more symmetrical use of the forelimbs. To investigate the possibility that lesion-induced asymmetries in motor behavior contributed to dendritic arborization changes, movements of the forelimb ipsilateral to the lesion were restricted during the period of dendritic overgrowth through the use of one-holed vests. This interfered with the increase in dendritic arborization. In contrast, animals that were allowed to use both forelimbs, or only the forelimb ipsilateral to the lesion, showed the expected increases. When sham-operated rats were forced to use only one forelimb, no significant increases in arborization were found. Therefore, neither a lesion nor asymmetrical limb use alone could account for the dendritic overgrowth--it depended on a lesion-behavior interaction. Furthermore, greater sensorimotor impairments were found when the dendritic growth was blocked, suggesting that the neural growth and/or associated limb-use behavior were related to functional recovery from the cortical damage. Finally, in a second experiment, immobilization of the impaired limb during the pruning period did not prevent the elimination of processes. Thus, the pruning of neural processes was not related simply to the recovery of more symmetrical forelimb use. There may be a period early after brain damage during which marked neural structural changes can occur in the presence of adequate behavioral demand.
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Long-term potentiation and long-term depression require postsynaptic depolarization, which many current models attribute to backpropagating action potentials. New experimental work suggests, however, that other mechanisms can lead to dendritic depolarization, and that backpropagating action potentials may be neither necessary nor sufficient for synaptic plasticity in vivo
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Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.
This chapter focuses on learning and memory and its neural bases. Learning and memory is a major topic in the field of psychology. Here also, both descriptive mechanical models and formal mathematical models have been developed. In the past, psychologists studying learning have generated a rich data base from behavioral experimentation. For example, much of the research in the Pavlovian conditioning has been designed to determine the ways in which temporal, logical, and qualitative relationships between stimuli (CS and US) influence learning. From this body of empirical knowledge, they have developed very successful models, in the form of sets of abstract learning rules that are able to account for many of the experimental findings. The strength of this approach has been that the theoretical models are able to integrate and deduce a wide range of learning phenomena and make predictions that lead to new experiments. A weakness of this approach, from the perspective of a neurobiologist, is that these psychological models do not make contact with the biological systems that underlie the behavioral phenomena.
Changes in the cerebral metabolism and the excitability of brain areas remote from an ischaemic brain lesion have been reported in animals and humans and implicated as a mechanism relevant to functional recovery. The aim of the present study was to determine whether changes in the inhibitory and excitatory activity in motor cortex of the non‐affected hemisphere are present in stroke patients, and whether these changes are related to the extent of the patients’ recovery of function. Transcranial magnetic stimulation (TMS) was used to study the first dorsal interosseus muscle (FDI) of the non‐affected hand in 13 patients with good recovery of hand function after stroke, and was compared with left hemispheric stimulation in 13 healthy age‐matched volunteers. In the first experiment, paired‐pulse TMS with the conditioning stimulus (CS) set at 80% of the subject’s motor threshold (MT) and interstimulus intervals (ISIs) of 2, 3, 10 and 15 ms was used. In the second experiment, different intensities of CS were used to study its inhibitory effect on a succeeding suprathreshold test stimulus at an ISI that was kept constant at 2 ms. In a third experiment, the rise in motor evoked potential (MEP) amplitudes with increasing stimulus intensities was measured. In two additional control experiments, the effect of left versus right hemispheric stimulation in normal volunteers and good versus poor recovery of hand function in patients after stroke on the excitability of inhibitory and excitatory activity was studied. MT, mean test MEP and recruitment curves were similar in patients and healthy volunteers. In those patients with good recovery, paired‐pulse excitability was increased at ISIs of 2 and 3 ms, similar to healthy volunteers at ISIs of 10 and 15 ms. When tested with different CS intensities at an ISI of 2 ms, inhibitory activity was similar in patients and healthy subjects at small CS intensities, but faded rapidly at higher CS intensities in patients. In contrast, in patients with poor recovery, this increase in cortical excitability at higher CS intensities was not seen. The similarity of MT, mean test MEP and recruitment curves in patients and healthy volunteers indicates that the overall corticomotoneuronal excitability has not changed in patients. The similarity of the inhibitory effect at low CS intensities in the patients with good recovery and healthy subjects, and the steeper increase of conditioned MEP amplitude at higher CS intensities in the recovering patients suggest that in the patients’ contralesional motor cortex the balance of excitatory and inhibitory activity was shifted towards an increase of excitatory activity in the neuronal circuits tested at ISIs of 2 and 3 ms. This shares similarities to mechanisms implicated as relevant for reorganizational processes after experimental brain injury and may be relevant for functional recovery after stroke. The absence of changes in cortical excitability in patients with poor recovery supports the relevance of our findings for recovery.
The purpose of this study was to examine if a delay in rehabilitative motor training after spinal cord injury affects functional motor recovery. We studied a skilled motor task in which rats traversed a raised horizontal ladder and we quantified errors in accurate stepping, i.e., foot slips between rungs. After lesions to the dorsal quadrant of the thoracic (T 8 ) spinal cord that aimed to unilaterally sever the corticospinal and rubrospinal tracts, rats were re-trained to walk across the ladder, either immediately after injury or after a 3-mo delay. Before training, the error rate in accurate stepping of the affected hindlimb was similar in the immediately (69.4 ± 5.3%) and delay (62.7 ± 4.1%; means ± SE)-trained animals (not significantly different), suggesting that accurate stepping did not improve spontaneously if rats were not exposed to the ladder. After a 3-wk course of training (30 runs across the ladder per day, 5 day/wk), improvements in accurate stepping performance were greater if training was implemented immediately after injury. On average, immediately trained animals improved stepping performance by 61.5 ± 28.2%, whereas the delay trained group improved by only 34.9 ± 28.8% (significantly different). The degree of damage to the corticospinal and rubrospinal tracts was very similar in the two groups of animals, indicating that differences in lesion size did not contribute to the differences in performance improvement. Animals with large lesions to the corticospinal and rubrospinal tracts (>70%) displayed poor recovery from training (especially for delay-trained animals), suggesting that these two pathways were important in mediating improvements in accurate stepping. In addition, recovery of stepping-like reflexes appeared not to contribute to the recovery of accurate stepping given that the time course of reflex recovery was not related to the time course of recovery of accurate stepping. We conclude that training of a skilled motor task that relies on descending control is more beneficial when initiated immediately after a partial spinal cord injury.