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					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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