Neuroscientific Principles Underlying Reorganization After Brain Injury
Submitted by: Cherie R. Percaccio*
Michael P. Kilgard**
From: *Post-doctoral Fellow
Psychology Department, College of Liberal Arts
Institute for Neuroscience Research
The University of Texas
Austin, Texas 78712
**Associate Professor
Neuroscience Program
School of Behavioral and Brain Sciences, GR 41
University of Texas at Dallas
Richardson, Texas 75083-0688
Send reviews, proofs to: Michael P. Kilgard
Neuroscience Program
School of Behavioral and Brain Sciences, GR 41
University of Texas at Dallas
Richardson, Texas 75083-0688
kilgard@utdallas.edu
(972) 883-2339
(972) 883-2491 FAX
Biographies:
Cherie Percaccio is a post-doctoral fellow in Theresa Jones’ lab at The University of
Texas in Austin. She completed her bachelor’s degree in psychology from Texas A&M in 1999,
a master’s degree in human development and early childhood disorders in 2001, and a master’s
in cognition and neuroscience in 2002, both from UTD. In 2006, she earned her Ph.D. in
cognition and neuroscience at UTD in Dr. Kilgard’s lab. Mike Kilgard is an Associate Professor
in the Cognition and Neuroscience Program at The University of Texas at Dallas. In 1993, he
completed his bachelor’s degree in molecular and cell biology from The University of California,
Berkeley, and in 1998, earned his Ph.D. in Neuroscience from The University of California, San
Francisco. Collectively, their research interests relate to the general principles that underlie the
remarkable self-organizing capacity of the cerebral cortex, including the continual reorganization
to optimize function in particular environments and more dramatic forms of reorganization that
occur in response to injury. Dr. Percaccio’s research focuses on cholinergic modulation of
plasticity in motor cortex and its application to stroke rehabilitation. The Kilgard lab uses
targeted behavioral manipulations and stimulation of the cholinergic system to direct auditory
cortex physiology. Regardless of which circumstance stimulates plasticity, understanding how
brain networks can be driven to reorganize is critical for the development of rehabilitative
therapies.
Research Summary
Animal models of plasticity permit a detailed level of analysis of the neurochemical,
structural, and physiological factors of brain reorganization that are not possible in humans.
Since abnormal responses to sensory stimuli interfere with the brain’s ability to develop and
learn properly, our research focuses on understanding how the brain adapts to the changing needs
of the environment. We have documented the consequences of housing in enriched
environments (inclusive of social, physical, and sensory stimulation) on auditory evoked
potentials compared to those of rats housed in an isolated, boring environment (Engineer et al.,
2004; Percaccio et al., 2005). We learned several things about how experience contributes to
brain development, including that enrichment rapidly (within 2 weeks) and robustly (3-fold)
increases the brain’s response to sensory stimuli in both young and adult rats (Figure 1).
Young enriched rats, standard housed as adults
Standard housed young rats, enriched as adults
A. B. C.
Figure 1. A) After 1 week of differential
D. housing, the grand mean average auditory evoked
potentials of enriched and standard-housed rats
were indistinguishable. B) After 2 weeks of
differential housing, responses of young rats in
the enriched environment were larger than
responses from rats in the standard environment.
C) By 5 weeks of differential housing, responses
of young enriched rats were three times the
amplitude of standard-housed rats. D) After
moving to the enriched environment, the
responses of adult rats were larger than responses
from rats in the standard environment. The gray
shaded regions represent the standard error of the
mean for each group.
However, the brain responds just as rapidly to the negative effects that result from a lack of
stimulation. The ultimate goal of our research is to learn how to direct the brain’s innate ability
to remodel sensory networks to help individuals recover lost skills and develop new ones.
Introduction
Since the brain is composed of 100 billion cells with more than a hundred trillion
connections, the consequences of damage are likely to be widespread and unique. Given that
there may be more than 1 million pediatric head injuries this year and tens of thousands of
children with life-long disabilities as a result (Brain Injury Resource Foundation, 2006),
understanding how to manipulate neuronal repair and regeneration is critical to tailor therapies
appropriate to each individual. The location and timing of an injury determine the degree to
which cognitive, language, social, sensory, and motor skills are affected. Conventional forms of
therapy, including speech, occupational and physical therapy, may be effective because they
enhance the amount and type of experience with the affected modality. Although experience
changes brain organization throughout the life span, a permissive environment, including injury-
induced neurogenesis (Ramaswamy et al., 2005; Itoh et al., 2005), may exist for up to several
months after injury during which these types of experiences can enhance cortical reorganization
(Dash et al., 2001; Kernie et al., 2001).
Stages of Injury
Best practice in the treatment of brain injury seems to be to enhance neuroprotection in
the acute phase of injury and plasticity during the chronic phase of injury (reviewed in Stein and
Hoffman, 2003). Inhibitory pharmacological agents administered during the early post-injury
period lessen the impact of the trauma on adjacent tissue (reviewed in Marklund et al., 2006), so
it will be available for reorganization (Carmichael and Chesselet, 2002). Excitation at this time
will cause excessive neurotransmitter release that is toxic to neurons (Humm et al., 1999). For
example, forced use of the impaired limb early after a motor cortex lesion increases the size of
the lesion and impairs functional recovery (Humm et al., 1998), whereas at later periods,
constraint-induced movement therapy increases the area of cortex responsive to stimulation of
the impaired limb (Friel et al., 2000). These results indicate that excitation is better suited for the
chronic stages of recovery. Behavioral therapies are the best choice with which to enhance
neurogenesis and stimulate reorganization. Pharmacological agents may also have a place in the
chronic stage of recovery (Goldstein, 2003), but should be used with caution in pediatric
populations. They can have uncertain effects on the developing nervous system, and may not be
effective unless coupled with behavioral experience, anyway. For example, rats with motor
cortex lesions whose movements are restricted during drug administration do not recover
(Feeney et al., 1982). Moreover, in the absence of postinjury behavioral rehabilitation, the tissue
surrounding the lesion continues to undergo degenerative changes (Nudo et al., 1996), related to
the “use it or lose it” phenomenon. Collectively, these results indicate that it is the right types of
behavioral experiences that enhance sprouting and regeneration of damaged pathways.
Cortical Plasticity
Sensory networks in the brains of animals and humans are continually remodeled to
optimize goal-oriented behaviors based on environmental circumstances. Although occasionally,
the cognitive, sensory, or motor impairments resulting from a brain injury gradually diminish,
most often the individual develops compensatory behaviors to adapt to the deficit and
accomplish the goal. For example, over 2 weeks, rats learn to use subtle compensatory strategies
to successfully reach for food (Whishaw, 2000). After injury, behavioral compensation is
possible because adjacent healthy tissue takes over the neurochemical and physiologic functions
of the damaged tissue. Reorganization can be as extreme as the injury-induced takeover of
visual cortex by auditory projections (Sur et al., 1988), but also includes more subtle forms, such
as behavioral improvements resulting from meaningful practice (Jenkins et al., 1990; Recanzone
et al. 1992a). Collectively, these results indicate that this innate ability to reorganize can be
driven by experience. However, any beneficial form of reorganization requires appropriate
experiences at the appropriate time to drive the growth of new synaptic connections that replace
those lost after brain injury.
There may be dramatic individual differences in the “appropriateness” of experiences
depending on the location and size of the lesion relative to pre-existing cortical receptive fields.
The location and size of pre-existing receptive fields depends on an individual’s history of
experiences, and can be enhanced or degraded depending on environmental exposure or skill
acquisition (Xerri et al., 1998; Engineer et al., 2004). Hence, conventional forms of therapy may
benefit one individual and either cause no change or be damaging to another (i.e., result in loss of
cortical area and the formation of undesirable connections). Although, enriched environments
and activities are beneficial for brain development at all ages (Engineer et al., 2004; Percaccio et
al., 2005), and specifically, may aid in recovery after traumatic brain injury (Hamm et al., 1996),
it may be more helpful to focus meaningful therapy on the specific modality affected by the
injury (Biernaskie and Corbett, 2001). The basic principles of neuroscience research can help us
determine, and understand why, certain forms of therapy are more appropriate than others for a
unique individual with a unique brain injury.
Rehabilitation
Since cortical reorganization determines recovery of function after a brain injury,
rehabilitative therapy can be used to guide plasticity (reviewed in Nudo, 2003). Whereas these
results suggest that practice with the affected modality expands the region of the cortex
responsive to stimulation, meaningless repetition of drills, at best, does not encourage the desired
regions of the cortex to expand. Rats that repeatedly ran on an exercise wheel did not have new
connections in the brain (Kleim et al., 2002). Only rats that learn new skills have new
connections in motor cortex (Kleim et al., 1998; Plautz et al., 2000). At worst, repetition
strengthens maladaptive cortical networks, resulting in undesirable behavioral sequel (i.e., Zandt
et al., 2006) . Repeated sensory stimulation only alters cortical response properties when stimuli
are used to make behavioral judgments (Recanzone et al., 1992b; Recanzone et al., 1993).
Several neuromodulators, including dopamine, norepinephrine, and acetylcholine, regulate
cortical plasticity and learning, and are increased during motivated and attentive states (Gu,
2002). High levels of attention increase the firing rates and response synchronization of cortical
neurons (i.e., neurons that fire together, wire together) (Steinmetz et al., 2000; Recanzone and
Wurtz, 2000; Treue and Maunsell, 1999). Taken together, these results indicate that while
manipulating sensory experiences to focus on the affected modality, clinicians can make therapy
activities fun to increase motivation and manageably difficult to increase attention.
Cholinergic Activity
Nucleus basalis in the forebrain releases acetylcholine and is active anytime anything
behaviorally relevant occurs in the environment (Richardson and Delong, 1991). Depleting
cholinergic activity with antagonists prevents experience-dependent and injury-induced
plasticity, while enhancing cholinergic activity with agonists facilitates cortical plasticity and
learning (reviewed in Rasmusson, 2000). Traumatic brain injuries depress cholinergic activity
(DeAngelis et al., 1994; Schmidt and Grady, 1995; Dixon et al., 1996, 1997a), perhaps limiting
the effectiveness of traditional forms of therapy. Even though behavior may appear to have
recovered (i.e., development of effective compensatory behaviors mediated by other
neurotransmitters, adjacent tissue, etc.), the brain is extrasensitive to subsequent insults on the
cholinergic system (Dixon et al. 1994). Specifically, cholinergic activity is essential for cortical
plasticity and experience-dependent recovery from brain damage (Conner et al., 2005).
However, pairing electrical activation of nucleus basalis with sensory stimuli (i.e., making
irrelevant stimuli seem really important) expands the corresponding area of the cortex in rats
(Kilgard & Merzenich, 1998), and has the potential to facilitate recovery.
Accentuating Rehabilitation
From a clinical standpoint, the effectiveness of therapy can be substantially increased
with very specific activities that encourage reorganization of the affected neural pathways. For a
comprehensive list of the clinical symptoms of auditory, visual, and vestibular processing
disorders that may result from a traumatic brain injury, and some practical activities with which
to effectively stimulate recovery, refer to the book Sensory Processing Disorders by Dr. Michelle
MacAlpine (2006). The activities are fun for children and it is easy to increase task difficulty to
capitalize on acetylcholine release and maximize the potential for beneficial plasticity.
Although behavioral activity alone can improve recovery of function, recovery may be
accelerated if paired with manipulation of major excitatory neurotransmitter systems to create a
permissive neural environment. Amphetamines, for example, increase several diffuse
neuromodulators including noradrenaline, dopamine, serotonin, and acetylcholine, and have a
positive influence even when administered only as a single dose at the beginning of therapy
(Feeney et al., 1982). Activating the cholinergic system with agonists after traumatic brain
injury improves cognitive and motor performance and biochemical markers of brain activity
(Dixon et al., 1997b; Verbois et al., 2003). However, targeted manipulation of the cholinergic
system, and specifically of cholinergic neurons in nucleus basalis that project to the cortex, is
likely to have a greater effect on plasticity (i.e., faster and more specific) than drugs. Research is
currently underway to identify and develop cutting-edge treatments that aid recovery of function
after central nervous system damage, including cell transplantation to enhance growth factor
production and promote neuro- and synapto- genesis (Mahmood et al., 2005) and stimulation
implants. Thalamic deep-brain stimulation decreases the severity of hand tremors in individuals
with Parkinson’s disease (Pahwa et al., 2006), suggesting that stimulation may also be a safe and
effective long-term treatment for other disorders of brain function. Combined with behavioral
rehabilitation, nucleus basalis stimulation may be able to increase physiological plasticity and
behavioral function in individuals with brain injuries.
Conclusions
While the complex neurochemistry of learning remains poorly understood, the literature
suggests that the act of learning, or rather relearning after brain injury, depends on the ability to
attach meaning and significance to sensory experiences. Collectively, these results indicate that
rehabilitative activities for people with brain injury should include meaningful sensory activities
to stimulate the reorganization of the affected sensory or motor systems gradually over time.
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