Introduction: The Researcher's Life 1


Chapter 4 The Next Frontier in Neuroscience? Believe It or Not, It's Physiological Psychology



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Chapter 4
The Next Frontier in Neuroscience?
Believe It or Not, It's Physiological Psychology


Timothy M. Barth
Texas Christian University

Congress declared the 1990s as the "Decade of the Brain". The idea, I think, was to devote the nineties to the study of neurological and neuropsychological disorders in the hopes of finding treatments or cures for diseases, such as Parkinson's, Huntington's, Alzheimer's, Attention Deficit Disorder, stroke, head trauma, and many others. Like so many past ventures, neuroscientists and clinicians approached this challenge by blending basic and applied science in an attempt to gain a better understanding of disease and discover new treatments. Progress was made. However, we find ourselves in a familiar situation: the ultimate goal has not yet been achieved. We will likely move into the next century with the feeling that we have been very productive, but that somehow we still have fallen short of the mark. We can easily justify this state of affairs by reasoning that these are complex problems that need more time for study and experimentation. Although I believe this to be an accurate assessment, I would take this a step further by stating that research in the 21st Century will likely bring with it a noticeable change in emphasis. I believe behavioral studies of brain function and dysfunction will once again come to the forefront of neuroscience and that this will likely bring us closer to attaining our stated goals.

Before I address the issue of why I think the discipline of physiological psychology will come to the forefront of neuroscience, we must first consider the multidisciplinary nature of neuroscience research. In order to do this, an idea from one of my former mentors, Dr. Steve Wise, comes to mind. Wise likened the field of neuroscience to a chair, with each leg representing a necessary foundational field of inquiry. For example, one leg represents neuroanatomical research (morphological study of the brain), another, neurophysiological research (the study of the electrical properties of the brain), a third, neuropharmacological research (the study of brain chemistry), and the fourth leg, neurobehavioral research (the study of brain-behavior relationships). He reasoned that if any of these legs were removed, then the chair would fall and research would fail or stagnate.

The fourth leg of the neuroscience chair consists of two disciplines: physiological psychology and neuropsychology. Experimentation within the field of physiological psychology may be viewed as }basic research." Results from these studies provide foundational knowledge regarding brain-behavior relationships, such as what areas of the brain are involved in learning and memory. Often there is an obvious application to clinical or applied issues, but the intent of the research is to reveal basic mechanisms. These studies usually require invasive techniques that manipulate the nervous system. Experimentally destroying or electrically stimulating the brain, the administration of drugs directly into the nervous system, or measuring neurochemical levels from a brain area are examples of invasive techniques. These procedures necessarily use animals as subjects because it is considered unethical and risky to invade the human nervous system for experimental reasons.

Research in neuropsychology mostly focuses on applied questions, specifically those aimed directly at understanding neurodegenerative disorders (i.e., Parkinsons disease) and nervous system trauma (i.e., brain or spinal cord injury resulting from a car accident or stroke). Neuropsychological research uses brain-imaging technology in conjunction with behavioral assessment. An exciting brain-imaging technique currently used is functional magnetic resonance imaging (fMRI). This technique represents a non-invasive method of visualizing the metabolic activity of brain areas while the person is engaged in some cognitive or sensorimotor task. Ideally, the results from both physiological psychology and neuropsychology laboratories would be integrated to help us understand the behavioral side of neuroscience.

It is clear that in recent history, behavioral studies of the brain and physiological psychology have taken a back seat to the other three disciplines. Currently, there are only a few basic science journals devoted to behavioral studies of brain function compared to the total number of journals devoted solely to neuroscience. There are roughly 50 or 60 neuroscience journals, of which perhaps less than 10 publish predominately behavioral studies. Even the word "psychology" seems to have disappeared from the titles of these journals. For example, the APA journal once named The Journal of Physiological and Comparative Psychology is now two journals, The Journal of Comparative Psychology and Behavioral Neuroscience. The Psychonomic Society journal Physiological Psychology is now Psychobiology. You may begin to wonder if the field of psychology has become the crazy aunt kept hidden in the attic. Although I think that idea might be a little extreme, I do think that experimental psychology has been speaking with a softer voice in recent times.

Another recent trend is that many academic departments of psychology are hiring neuroanatomists, neurophysiologists, or neuropharmacologists, rather than someone trained in the basic principles of psychology. I believe this trend can be attributed to the development of neuroscience as a major field of study at the undergraduate level, and the desire to integrate behavioral science with the other natural sciences. Faculty in the departments of biology, chemistry, pharmacology, mathematics, physics, and psychology typically maintain neuroscience programs, so it might make sense that there would be crossover hiring. If there is reason for concern, it is in the desire for the continuance of neuroscience research that integrates the basic principles and approach of experimental psychology with other sciences. In other words, neuroscientists must continue to engage in those very long and tedious behavioral experiments that require numerous control groups and take months of data collection that are so typical of experimental psychology. It does not matter if this type of research is done in psychology, pharmacology, biology, or chemistry departments. It is the emphasis on behavioral analysis, experimental design, and statistics (i.e. the training of experimental psychologists) that is important. This approach is crucial, because without it the field of neuroscience will advance very slowly.

At the 1997 Society for Neuroscience meeting (New Orleans), there were 951 sessions, each of which typically had 10-20 presentations. This data mean that there were close to 15,000 presentations at our annual meeting! Perhaps it will put things into perspective if I point out there were only 179 sessions under the theme Neural Basis of Behavior, or roughly 2500 presentations. You can interpret these data in a couple of different ways. On one hand, you could say that only 17% of the research in the field focuses on brain /behavior relationships. On the other, you might conclude that 2500 presentations at a single meeting certainly does not suggest a dying field. Both interpretations are probably accurate (There were only about 13,000 presentations at the 1998 meeting in Los Angeles, with 14 % being in the Neural Basis of Behavior sessions). However, I predict that research focusing on neurobehavioral questions will increase dramatically over the next 15 years. I say this because in 1997 and 1998 a large part of the remaining presentations at the annual neuroscience meeting (i.e., those that did not include behavioral analysis) suggested that the brain, and indeed the neuron, are dynamic. That is, the nervous system has the potential for change in structure, relative neurochemistry, and electrical reactiveness. These dynamic events have brought to the forefront of neuroscience the idea of "neural plasticity." What could these dynamic events be related to? The obvious answer is that neural plasticity is related to behavioral plasticity. In other words, dynamic changes in the brain most likely reflect a concomitant change in behavior, cognition, or emotion. For example, neural plasticity is viewed as the mechanism of learning and the basis for recovery of function after brain damage. Ultimately, neuroscientists must be able to construct experiments that allow for correlations between neural and behavioral plasticity. One very important place they will find the tools to attain this goal is in the discipline of experimental psychology.

Ultimately the trends in neuroscience research must lean towards behavioral or psychological studies, why has there been a relative paucity of study in the area upto this point? I think part of the answer has to do with our fascination for the most current technology. For example, the recent history of neuroscience has featured the development of high resolution brain imaging, simultaneous recording of single-neurons in various parts of the nervous system, transplantation of fetal neurons into the brains of adult organisms, the measurement of neurotransmitter levels in the brains of animals while they perform simple behaviors, more accurate techniques for counting neurons and glia in the brain, methods for patch-clamping dendrites, techniques that allow for the visualization of dying neurons, more accurate methods for measuring cerebral blood flow, and the list goes on and on. Technology allows us to do things that we never thought were possible. The development of new technology is exciting: it is what we call "cutting edge" science. However, cutting edge science does not stop here, because the impact of technological development is gauged by the how it is applied to important questions. I think the current and intense interest in neural plasticity suggests that it is time for this new technology to be applied to questions about behavioral plasticity.

Although the development of new technology will put you on the cutting edge, its application to the study of behavior brings with it still new and significant challenges. In his book, Brain Plasticity and Behavior, Bryan Kolb (1995) writes, "Behavior is not sexy, but it is as difficult to study as molecules" (p 10). Kolb believes that most people think understanding behavior is a simple task. After all, most of us observe the behavior of others everyday. However, to study the complexities of behavior, scientists commit themselves to a tedious and time-consuming journey.



Setting the Stage for the 21st Century

One example of what I consider to be sophisticated behavioral analysis may be found in the area of sensorimotor behavior. Whishaw and colleagues have provided a detailed analysis of forelimb and paw use in a variety of rodents (Whishaw, Sarna, & Pellis, 1998) and linked these behaviors to the corticospinal pathway (i.e., a neural pathway that originates in the motor cortex and terminates in the spinal cord). Whishaw has used the Eshkol-Wachman Movement Notation (EWMN) in order to identify the specific sequences of movement used in }handling" different foods during eating. The EWMN allows for behavior to be described in terms of changes in limb segments (i.e., part of the limb that lies between two joints, or a joint and the extremity) in relation to the body, the environment, or the next limb segment. This type of analysis led Whishaw and colleagues to gain a better understanding of the normal movement sequences used in eating and how they are changed after damage to the corticospinal pathway (Whishaw & Coles, 1996; Whishaw, Dringenburg, & Pellis, 1992; Whishaw & Gorny, 1994; Whishaw & Pellis, 1990; Whishaw, Pellis, Gorny, & Pellis, 1991). You could imagine using this behavioral analysis to study the motor dysfunction of patients with movement disorders (i.e., Parkinsons disease, Huntingtons disease, head trauma) and the effects of various treatments (i.e., drug or physical rehabilitation).

In the area of cognitive behavior, much of the recent work with rodents has focused on establishing behavioral dissociations among brain areas involved in memory. These studies typically attempt to link different aspects of cognition (i.e., spatial memory, temporal memory, or attention) with specific neural substrates (i.e., hippocampus, prefrontal cortex, parietal cortex). To attain this goal, variations of standard tests of memory (i.e., radial arm maze, Morris Water Maze, delayed nonmatching to sample, conditioned discriminations) have been used in very creative ways (Jackson, Kesner, & Amann, 1998; Ragozzino & Kesner, 1999). It may take weeks or months to train animals on these tasks, create a brain lesion, and then test for any amnesic effects.

A question regarding the incorporation of these techniques into a research program is }Are they worth the effort?" Recent history suggests that the majority of neuroscientists have not taken on this burden. However, this situation will change as curiosity regarding the dynamic brain increases. Could the crazy aunt in the attic become the wise sage of the 21st century? At the very least I am confident that with the beginning of the new century there will be a new emphasis on sophisticated behavioral analyses that will ultimately help elucidate the nature of the dynamic changes taking place in the brain. In other words, it is time for the fourth leg of the neuroscience chair to take center stage.

Sophisticated behavioral analyses will be critical if we are to accomplish the goals set by Congress with the Decade of the Brain. Although understanding the neuropathology and etiology of neurological disorders is essential, in the end the neuropsychologists will evaluate the effectiveness of proposed treatments on behavioral grounds. Does the treatment lead to a higher quality of life for those individuals affected by the disease? This question can only be answered through the study and measurement of behavior, and not with experiments that limit their scope to neuron morphology, physiology and chemistry. Ideally, the 21st century will bring a true and equal marriage between neuroscience and behavioral science. In the case of neurological disorders, the development of new and effective treatments will include a more complete understanding of the behavioral syndrome and an application of the current models of neural plasticity. I believe that this approach will allow us to evaluate the effectiveness of proposed treatments better and to understand why these treatments have (or do not have) beneficial effects.

For example, the number of accepted treatments for Parkinsons disease has expanded considerably in the past five years. The need for new treatments is based on the problem that long-term drug therapy with levodopa (i.e., the most widely used drug treatment) leads to a return of the Parkinsonian symptoms and additional behavioral dysfunction in most cases. Two examples of new treatments are the surgical procedure known as }pallidotomy" (i.e., carefully destroying the ventral pallidum, a brain area found towards the bottom of the forebrain), and a new drug called }ropinirole." To assess the effectiveness of these treatments accurately, we must have a clear understanding of the behavioral syndrome associated with Parkinsons disease. This understanding will allow us to determine the extent to which the new treatments alleviate Parkinsonian symptoms, as well as if the treatments generate new and unwanted behaviors or additional behavioral dysfunction. Although some researchers have taken this approach and produced some positive results (Masterman, et al., 1998; Sethi, et al., 1998), the future will likely bring with it a more extensive analysis of the behavioral effects of these treatments.

At the neural level, it is possible that plasticity has been diminished in Parkinsons patients. For example, some animal studies have suggested that one area of the brain affected in Parkinsons disease, the neostriatum, is a region that controls the acquisition and generation of motor sequences (Aldridge & Berridge, 1998; Graybiel, 1998). Is it possible that one symptom of Parkinsons disease may be characterized as an impairment in motor learning? If so, the brain of the person with Parkinsons disease may be deficient in forms of neural plasticity. This finding would be important because models of neural plasticity have been associated with particular chemical and electrical events that can be manipulated through the administration of drugs very different from those currently used to treat Parkinsons disease. Thus, a more complete knowledge of the behavioral syndrome associated with Parkinsons disease (i.e., through neuropsychological testing), combined with basic research findings regarding neural and behavioral plasticity done with animals, could yield the most effective treatment strategies. Although research in this area would require knowledge of the present neural models of plasticity and pharmacologic manipulations, the fruits of the approach would ultimately require behavioral assessment of treatment effectiveness.

The following is a review of some of the current models of neural plasticity and how they may relate to the mission set forth in the Decade of the Brain. These models emphasize dynamic changes in neuron morphology and synaptic activity. The first section, }Does the Brain Control Behavior or Does Behavior Control the Brain?," discusses the influence of the environment on brain morphology and function. For example, what are the effects of an enriched environment on brain anatomy and behavior? Does an enriched environment increase neural and behavioral plasticity? I also introduce the idea that our behavior has significant impact on brain anatomy. In the next section, the neocortex takes center stage as the best example of a dynamic brain. In this section, }My, What a Dynamic Cortex You Have!," I discuss changes in the physiology of the cortex following sensory and motor experience. In the final model, I outline how behavioral experience may affect the communication between neurons. }The Synapse is a Two-Way Street", outlines new developments in neuronal communication and how they might reveal the neural mechanism of learning. After discussing these models of neural plasticity, I will focus on the study of recovery of function following brain damage, the possibility that magnesium supplements could prove to be beneficial, and demonstrate how some of these principles can be applied to a detailed behavioral analysis. I will conclude with some thoughts on future directions that combine physiological psychology, neuroscience, and neuropsychology.



Some Recent Advances in Neural Plasticity

Does the Brain Control Behavior or Does Behavior Control the Brain?

Consider the following scenario. Al and Pete die at about the same age and leave their brains to science. They were roughly of the same height and weight. When the two brains are compared, it is discovered that Al has a heavier brain with a thicker neocortex. What is a possible reason for this difference? You may be surprised to find out that the differences in brain weight and cortical thickness are probably due to the growth of dendrites and increased number of glia in Al's brain. It is almost certainly not due to a larger number of neurons. Moreover, the differences in brain size are likely due to individual differences in their environment. That the morphology of neurons and number of glia have the potential for change is not a new concept. In fact, experiments done in the 1960s and 70s by Rosenzweig and colleagues suggested that being reared in an enriched environment can lead to differences like those described in the scenario with Al and Pete (Bennett, Diamond, Kretch, & Rosenzweig, 1964; Diamond et al., 1966; Diamond, Lindner, & Raymond, 1967; Globus, Rosenzweig, Bennett, & Diamond, 1973; Rosenzweig, Bennett, & Diamond, 1972a; 1972b; Rosenzweig, Kretch, Bennett, & Zolman, 1962). More recent studies indicate that a relatively short period of exposure (i.e., 4 days) to the enriched environment may be sufficient to produce some of these morphological changes (Wallace, Killman, Withers, & Greenough, 1992).

In the studies by Rosenzweig and others, researchers put infant rats into "enriched environments" where they had opportunities to interact with other rats, toys, bridges, and ladders. These environments promoted social interaction, exploratory behavior, and the development of motor skills; they also produced anatomical changes in several brain areas---the most dramatic appeared to be in the neocortex. Gross physical changes in the neocortex included increased length, thickness, area, and weight. Given these changes it is somewhat surprising that relative neuronal density was actually decreased when compared to control rats. In contrast, the density of glial cells was actually increased along with the diameter of capillaries (Diamond, Kretch, & Rosenzweig, 1964; Sirevaag & Greenough, 1987; Szeligo & Leblond, 1977). Moreover, increases in the extent of dendritic branching (Greenough, Volkmar, & Juraska, 1973; Holloway, 1966; Volkmar & Greenough, 1972) and the number of dendritic spines (Globus et al, 1973) were found in rats reared in the complex environment. This latter finding suggests that there might also be an increase in the number of synapses, a result verified in later studies (Bhide & Bedi, 1984; Turner & Greenough, 1983). However, more recent data suggest that although the number of dendritic spines is increased, the spine density actually decreases (Kolb, 1995). Thus, although the number of synapses per neuron may actually increase, these synapses are farther apart.

The animal research data suggest the brain reacts to the environment in ways that indicate an increase in neural plasticity. The next question is whether there are any data that suggest this increase in neural plasticity translates into a correlated change in behavioral plasticity. In other words, does being reared in an enriched environment translate into a behavioral advantage? The answer to this question may be found in a convent in Mankato, Minnesota. The now famous Sisters of Mankato constitute a remarkable field study with far-reaching implications. Some of the nuns living in the convent have chosen to challenge their minds even as they grow old. These nuns earn college degrees, teach, hold current-events seminars, play Jeopardy, and work brainteasers. What is startling is that the nuns who have chosen this lifestyle are living longer and do not appear to be as susceptible to neurodegenerative diseases, such as Alzheimer's disease, when compared to the general population. An exciting aspect of this field study is that the nuns of Mankato have donated their brains to neuroscience. David Snowden of the Sanders-Brown Center on Aging at the University of Kentucky will be examining their brains in ways very similar to those methods used in the enriched environment studies with rats. He expects to show that these nuns have significantly more cortex, dendritic branching, and synapses than their counterparts who have not engaged in the brain exercises. Moreover, he expects to show the "active" nuns recover better from strokes or other types of brain trauma. This result would be similar to the findings that "enriched" rats with cortical lesions show an acceleration of recovery from either cognitive or sensorimotor deficits when compared to their counterparts who lived in more standard housing conditions (Dalyrymple-Alford & Kelche, 1987; Einon, Morgan, & Will, 1980; Gentile, Behshti, & Held, 1987; Held, Gordon, & Gentile, 1985; Hughes, 1965;).

An enriched environment provides numerous novel stimuli for examination and a potential for the development of new motor skills. Thus, the corresponding changes in the neocortex may be due to the environment as a whole rather than any specific experience. If progress is to be made in linking the neuroanatomical changes to behavior, studies that focus on a specific behavioral experience are necessary. Greenough and his colleagues (Greenough, Larson, & Withers, 1985) found that rats trained to reach for food placed in a tube showed an increase in the number of dendritic branches in the forelimb motor cortex contralateral to the used limb. Moreover, if both forelimbs were used in a bimanual task, branches in the motor cortex of both hemispheres increased (Kolb, 1995). Similar changes found in the occipital cortex were found in rats trained on a complex maze (Chang & Greenough, 1982: Greenough, Juraska, & Volkmar, 1979). Likewise, motor skill learning (i.e. rats trained on an obstacle course) caused an increase in the number of synapses in the cerebellum (Kleim et al.,1998). These studies suggest that specific experiences may enhance neuroanatomical plasticity. Interestingly enough, the dendritic changes correlated with task-specific practice are qualitatively different from those associated with enriched environments. Exposure to the enriched environment reportedly causes dendritic changes in the basilar dendrites (i.e., dendrites at the base of the cell body) whereas task specific changes are related to growth of apical dendrites (i.e., dendrites at the top of the cell body). The significance of this difference in apical vs. basilar dendritic growth is largely undetermined.

The results from the enriched environment studies, the effects of task-specific practice, as well as the potential data collected from the Sisters of Mankato raise an interesting and important question about the brain and behavior. To what extent does behavior affect the structure, physiology, and chemistry of the brain? We tend to think of the brain as a master control system, determining our actions, sensations, motivations, and thoughts. However, is it more accurate to suggest there is a closed loop between the brain and behavior where the brain generates behavior which in turn may cause a change in the brain? Kolb (1995) addresses this possibility: " The idea that activity might change the heart or muscles is seldom questioned. The possibility that behavior could change the structure and function of the brain is seldom considered" (p 5). The next frontier in neuroscience will no doubt include an intense examination of this issue. This idea is elaborated in the next section.

"My What a Dynamic Cortex You Have!"

Experience not only affects the morphology of neurons, but it can also affect their physiology. Perhaps one of the most important discoveries in the past 30 years of neuroscience research was that the somatosensory and motor homunculi in the neocortex can be modified. Researchers construct the somatosensory and motor representations of the body on the basis of receptive-field mapping (primary somatosensory cortex) and microstimulation (primary motor cortex) studies. For example, researchers determine somatosensory receptive fields by lowering a small insulated platinum wire into the postcentral gyrus of an anesthetized cat, monkey, or rat and recording the electrical activity of single neurons while tactile stimulation is applied to different parts of the body. If the tactile stimulation causes a change in the electrical activity, then the part of the body being stimulated is considered part of the receptive field of the neuron. They repeat this procedure throughout the primary somatosensory cortex until the entire body is "mapped." The primary motor cortex is mapped by sending a small amount of electrical current through an electrode and into the precentral gyrus in an attempt to elicit movement of some part of the body. The procedure is repeated until the entire body is mapped. Once we thought these somatosensory and motor maps of the body were unmodifiable or hard-wired; however, now we know they are dynamic. That is, the order of the somatotopic and motor maps can be changed, a phenomenon called cortical reorganization.

The malleability of the sensory map in the primary somatosensory cortex has been shown using several different manipulations. Perhaps the first demonstration of cortical reorganization was in response to deafferentation. For example, we know there is a part of the primary somatosensory cortex that corresponds to the ring finger. What happens to the cortical map if the ring finger is amputated? Because there is no longer a finger present to send sensory information into the nervous system and eventually the cortex, does the "ring finger area" simply go silent or does it somehow change? Merzenich and colleagues showed that if peripheral sensory nerves are damaged or if a digit was amputated, there was a change in the organization of the somatosensory cortex (Merzenich & Kaas, 1982; Merzenich et al., 1983a,b, 1984). Specifically, the once ring finger area of the somatosensory cortex may respond to tactile stimulation of another finger. In other words, the receptive fields of neurons in the somatosensory cortex have changed in response to the alteration of sensory information. Chen, Corwell, Yaseen, Hallet, & Cohen (1998) reported similar results have recently been reported in human. amputees. In another example, Jenkins, Merzenich, Ochs, Allard, & Guic-Robles (1990) trained owl monkeys on a task that produced repeated tactile stimulation of the fingers Subsequent mapping of the hand representation in the primary somatosensory cortex revealed an expansion of the finger areas stimulated in the task.

A similar result can be found in the primary motor cortex. For example, when Sanes, Suner, & Donoghue (1990) damaged the motor neurons that control whisker movement in rats, microstimulation of the whisker motor cortex area elicited movements of other muscles in the face indicating reorganization. In another experiment, Nudo, Jenkins, and Merzenich (1990) repeatedly stimulated the forelimb representation in the motor cortex of adult rats. The microstimulation elicited movement of the forelimb and eventually expanded the cortical representation.

The potential for reorganization in the neocortex of laboratory animals appears to be relevant for understanding brain-behavior relationships in humans. For example, Pascual-Leone and colleagues (1993) demonstrated that blind participants, who were well-trained in Braille, had an expanded finger representation in the hemisphere opposite to the "reading" hand (1993). In contrast, blind participants who did not use Braille often, showed no expansion. Researchers measured the size of the representation by using focal transcranial magnetic stimulation. In a second study using the same technique, Cohen et al. (1997) showed that people who were blind from birth demonstrated a somatosensory representation of the hand in the visual cortex! Thus, it is becoming clear that behavioral experience can have a strong influence on the morphology and physiology of the neocortex.



The Synapse is a Two-way Street

In the late 1940s D.O. Hebb argued that the neural basis of learning and memory would include the facilitation of synaptic activity. Hebb talked about "strengthening" synaptic activity through "reverberating" neural circuits triggered by a repeated experience. In the 1970s, the phenomenon of long-term potentiation (LTP) was discovered (Bliss & Gardner-Medwin, 1973; Bliss & Lomo, 1973). Researchers demonstrated that synaptic transmission is facilitated when it is preceded by intense high-frequency stimulation of the presynaptic neuron. For example, let us say you record the electrical resting membrane potential of the postsynaptic neuron and it is -70 mV. A low-level electrical stimulation of the presynaptic neuron causes a change in the postsynaptic membrane of about 5 mV. We know that this change in the postsynaptic membrane potential is due to the interaction between neurotransmitter being released by the presynaptic neuron and the postsynaptic receptors. LTP occurs if the presynaptic membrane is given an intense tetanic stimulation, and is manifested by a greater change in the postsynaptic membrane potential when the low-level stimulation is once again given. Following tetanic stimulation, the low-level electrical stimulation now causes a change in the postsynaptic membrane of about 8 mV. This "potentiated response" may last for hours, days, or weeks (Racine, Milgram, & Hafner, 1983). It is important to realize that in order for LTP to occur there must be the co-occurrence of electrical activity in the pre- and postsynaptic neurons. That is, there must be an action potential in the pre-synaptic neuron that leads to a change in the electrical membrane potential of the post-synaptic neuron. LTP appears to be similar to the "strengthening" of synapses first discussed by Hebb almost 30 years prior to its discovery. Moreover, LTP is currently believed to be a synaptic basis for learning and memory. You can imagine that an experience or behavior that is repeated over and over, may lead to the same potentiation of synaptic activity observed after tetanic electrical stimulation. Thus, the facilitated synaptic response may be the basis for a change in behavior (i.e., a learned response) or recollection of some event (memory).

How the potentiated response comes about in LTP? According to Hebb, strengthening a synapse requires a reverberating neural circuit. This view may imply that signals are sent in both directions across the synapse. The traditional model of communication between neurons is that an action potential is triggered at the axon hillock and is transported down the axon to the axon terminal without diminishing in strength. After the action potential arrives at the terminal, calcium enters and neurotransmitter is released into the synapse. The neurotransmitter moves across the synapse until it interacts with postsynaptic receptors. The interaction between neurotransmitter and receptor causes a local change in the electrical potential of the postsynaptic neuron. This local change is "graded" because it diminishes in strength as it moves toward the cell body and hillock. Local changes at different receptor sites are summated together in the cell body, and if there is enough of a change in the electrical membrane potential, then an action potential is fired and the process starts all over again. An important part of the traditional model is that information moves away from the "sending" or presynaptic neuron and towards the axon hillock of the "receiving" or postsynaptic neuron. Recent evidence suggests that this scenario, although logical and relatively easy to understand, greatly oversimplifies what is occurring at the level of the synapse. Moreover, the recent evidence may help us to understand how LTP comes about.

There is recent evidence that nitric oxide (a soluble gas) might serve as a retrograde messenger across the synapse allowing for the reverberating activity theorized by Hebb. Some of the neurons that contain receptors for the neurotransmitter glutamate allow for the entry of calcium into a cell when activated (e.g., the glutamate receptor called NMDA [N-methyl-D-aspartate]). It appears that the influx of calcium causes the release of nitric oxide from the postsynaptic membrane back into the synapse and onto the presynaptic axon terminal. Because nitric oxide readily diffuses through a cell membrane, it is possible that the retrograde message leads to a "strengthening" of synaptic activity. Indeed, if nitric oxide is prevented from leaving the postsynaptic membrane, then LTP cannot be maintained for more than 1 hour (Haley, Wilcox, & Chapman, 1992).

The evidence for nitric oxide as a retrograde messenger is surprising. However, what is even more eye-opening is the possibility that action potentials may work backwards from the cell body to the dendrites. Using a patch-clamping method on dendrites, Stuart and Sakmann (1994) showed that once an action potential is triggered in the traditional way, there is a back-propagation of the signal to the dendrites in some neurons. Patch-clamping uses smooth edged, tiny electrodes that press up against the cell membrane and allow for the recording of electrical activity at various locations along the neuron without damaging it. This event may trigger the release of a retrograde messenger such as nitric oxide. If this is the case, then the postsynaptic neuron is essentially "telling" the sending neuron that indeed it has just fired a neural impulse. Indeed, the reverberating circuit once proposed by Hebb now has a mechanism by which neuronal communication can go in both directions and cause a "strengthening" or facilitation of the synaptic activity.

Although the demonstration of LTP and the possibility that nitric oxide works as a retrograde messenger are thought to be major discoveries that validate the ideas of Hebb, the behavioral significance of these events remains largely undetermined. Attempts at studying the relationship between LTP and behavior have mostly relied on correlational studies. For example, Morris, Halliwell, & Bowery (1989) have suggested that LTP is the basis for spatial memory because drugs that block the action of glutamate at NMDA receptors block both the induction of LTP and the acquisition of a spatial memory task. Other examples include the facilitation of LTP via neural pathways that do not utilize the NMDA receptor (Buonomano & Merzenich, 1998; Racine & Trepel, 1997; Williams & Johnston, 1998). This finding may be important because it suggests there may be multiple memory systems, each having a different neural basis (Baudry, 1998).

An important test of the relationship between LTP and behavioral learning would be to show that during the acquisition of the learned response there is a facilitation of synaptic activity. For example, a relationship between LTP and spatial memory has been proposed because there appears to be a common neurochemical and neuroanatomical basis. Aspiring researchers could conduct he following studies to link this physiological and behavioral process more causally. Consider the hypothesis that the hippocampus is an important area for both LTP and spatial memory. We know that LTP can be induced at synapses within this neural structure specifically at the junction between the entorhinal cortex and the dentate gyrus of the hippocampus, the dentate gyrus and cells of the CA3 subfield, and the CA3 and CA1 subfield. A researcher could permanently implant microelectrodes into the hippocampus at one (or more) of these locations in rats, and then each animal could be trained on a spatial memory task. The microelectrodes would record the electrical activity of neurons in the hippocampus while the animal is learning the task. If potentiated synaptic activity is the basis for spatial memory, then as the rat learns the task there should be a voltage increase in the electrical potentials within the hippocampus that endures for days or weeks. Moreover, both the acquisition of the spatial memory task and the increase in electrical activity should be blocked by the administration of glutamate blocking agents. Although parallel neurophysiologic, pharmacologic, and behavioral studies have suggested these predicted results (Brown, Chapman, Kairiss, & Keenan, 1988; Castro, Silbert, McNaughton, & Barnes, 1989; Skelton, Scarth, Wilkie, Miller, & Phillips, 1987) to my knowledge there has been only one well-controlled experiment establishing a causal link (Izquierdo, 1995).

Our discussion of neural plasticity suggests the brain has the capacity for dynamic changes in cell morphology, synaptic activity, and receptive-field physiology. This potential for change within the nervous system is truly fascinating and it opens the door for considerable research in the next century. The nature of the research is what will be important. The emphasis could be on discovering the cellular and neurochemical basis that allows for these neural plastic changes to take place. On the other hand, the future could bring to the forefront of the field the need to understand the behavioral conditions that drive these changes. Are these models of neural plasticity the keys to understanding ways to enhance learning or recovery of behavioral function after brain trauma or stroke? Do they provide a window that allows us to see what must be done in order to provide a better quality of life for the Alzheimer's or Parkinson's patient? These latter questions can only be answered by bringing together the current technology with sophisticated behavioral analyses. To answer these questions it will be extremely important to challenge the correlations between neural and behavioral change. There is little doubt about there being sufficient motivation to continue the development of technology that will allow us to demonstrate new ways the nervous system can change. However, there must also be motivation to measure the sometimes subtle changes in behavior that are the driving force behind these neural events (Fox, Warrington, Seiffer, Agnew, & Rossor, 1998; Gelb, Oliver, & Gilman, 1998). Now more than ever we should engage in the tedious and time-consuming work of behavioral studies of brain function if we are to understand the significance of LTP, dendritic growth, and cortical reorganization.

To demonstrate this approach more clearly, I will now turn to a specific question that has been the focus of research in my laboratory: recovery of functions after brain injury. Researchers have made considerable progress in the last 20 years. The vast majority of progress has been in the understanding of what happens to the brain when there is a stroke or head-injury. We now know there is a cascade of neurochemical, cellular, and physiological events that are triggered by damage to the brain. These events lead to brain damage that is secondary to the initial trauma and may continue for minutes, hours, days, or weeks. It is generally believed that we must develop pharmacological treatments that will prevent or limit the occurrence of these events. However, does reducing the severity of these secondary events lead to a restoration of function? If so, does the drug provide a long-term solution? Do the treatments have beneficial effects on all behavioral aspects of the syndrome? Can pharmacologic intervention be harmful under certain conditions? Does drug treatment accelerate recovery of function, induce recovery when none is expected, or both? Does physical or cognitive rehabilitation enhance the effectiveness of drug treatment? Can the models of neural plasticity described at the beginning of this chapter help us to understand behavioral recovery? Behavioral studies can answer these questions best.

Recovery of Function After Brain Damage

An explosion of research has provided critical data on potential treatment strategies for recovery from brain injury in the last ten years. Much of this research has focused on the events that follow the damage and continue for hours, days, or weeks causing neurodegeneration outside the area of initial injury. This "secondary damage" is caused by the excessive release of neurotransmitter, the disintegration of cell membranes by free-radicals, swelling of the brain (i.e., edema), and disruptions in the integrity of the blood-brain barrier. Because these degenerative events persist for so long after the initial trauma, there is a "window of opportunity" within which neurons can be rescued through pharmacological treatment with "neuroprotective drugs." Although it is reasonable to assume that under most circumstances rescuing these neurons will enhance recovery of function, I do not believe that this is always the case. Indeed, Schallert, Jones & Lindner (1990) demonstrated that rescuing neurons actually had detrimental effects on behavioral recovery! Nonetheless, much research effort has focused on understanding the biochemical mechanisms and the resultant anatomical effects of neuroprotective drugs. In contrast, researchers have done very little work to establish their effects on behavioral function following brain injury. For example, one of the neurotransmitters released in excess after brain injury is glutamate,one of the most abundant excitatory neurotransmitters in the central nervous system. In this case, neuroprotective drugs would inhibit the action of glutamate and would be called glutamate antagonists. In a recent survey of the literature since 1985, less than 50 studies could be found that investigated the effects of glutamate antagonists on recovery of behavioral function following brain damage. This number hardly reflects the "explosion" of research reports on the potential use of glutamate antagonists for treating brain injury (Ginsberg, 1995). Behavioral measurements are not redundant to demonstrations of anatomical sparing; some of the few studies that reported both an anatomical and behavioral measure have found that although glutamate antagonists may provide anatomical sparing, researchers do not always observe a concurrent improvement in behavioral function (Grotta et al., 1990; Shapira, Yadid, Cotev, Niska, & Shohami, 1990). Although the demonstration of anatomical sparing and control of secondary factors (i.e., edema) by glutamate antagonists is a fundamental step in the development of pharmacological therapies for brain injuries, it is essential to combine the results of such studies with a detailed behavioral assessment.



The Search for a Magic Pill is Clouded by Methodological Issues

Although many glutamate antagonists have been synthesized as candidates for the treatment of brain injury and stroke, the existing body of literature does not provide a clear picture as to which of these agents is most effective in facilitating recovery of function. However, MK-801, a drug very similar in neurochemical action to phencyclidine (PCP or }angel dust"), is perhaps the most widely used glutamate antagonist in experimental studies. The lack of a candidate drug is largely due to the lack of consistent methodology among the various reports. Factors such as the onset and duration of drug administration vary widely among studies. Behavioral methodologies also differ, especially along the lines of the postoperative observation period, the number of tests given during that time, and the onset of postoperative testing. Other problems with behavioral methodology include the need for quantification of behavioral deficits and the unfortunate practice of combining the results of several behavioral measures together in an attempt to form an index of overall neurological function (i.e., neuroscore or neurological severity score).

The postoperative observation period and the number of tests within that time may be important considerations for recovery of function experiments. In our laboratory, postoperative recovery on some sensorimotor tests is dependent on the number of test trials rather than the time since the brain injury (Barbay & Barth, 1993), whereas for other tasks the reverse appears to be true (Schallert & Whishaw, 1984). These two variables may have played a role in the negative results with glutamate antagonists reported by several laboratories (DeGraba, Ostrow, Hanson, & Grotta, 1994; Follis et al., 1994; Holtz & Gerdin, 1991; Lanier et al., 1990). For example, Follis et al. (1994) reported that two glutamate antagonists, MK-801 and magnesium sulfate, failed to reduce the severity of paraplegia (paralysis on both sides of the body) 24 hr after rats received a stroke in the spinal cord. However, the authors note that with repeated testing over a 4-day period, both treatment groups showed more recovery than saline control animals. Only the magnesium sulfate group was significantly different from the saline group on the fourth day of testing. The authors point out, "Without a doubt a longer period of observation, 4 weeks for example, would have provided more definitive data and perhaps showed a beneficial effect also for the MK group" (p 231). Follis et al. also suggest that in many of the reports attempting to study neuroprotective effects, final observations were made between 2 hours and 7 days (Boast et al., 1988; Kochar, Zivin, Lyden, & Mazzarella, 1988; Yum & Faden, 1990). Although the immediate effects of the drugs are undoubtedly important, it may be the case that on certain behavioral tasks extended postoperative testing will be required to demonstrate that significant neuroprotection was observed. One standard that researchers should entertain is a postoperative testing time that allows the vehicle control group to return and maintain preinjury levels of performance. In this case, researchers can establish any potential benefit of the drug treatment. However, in some cases where the behavioral impairments are chronic or permanent, researchers should determine some reasonable cut-off should be established that would include at least 4 weeks of testing. In our laboratory that restoration of function by a drug treatment in a chronic deficit model (following electrolytic cortical lesions) is established within this time frame, but admittedly the declaration of a 4-week test period is arbitrary and may not generalize to other models of brain injury.

Combining the results on several tests in the form of a neuroscore has both advantages and disadvantages. On the one hand, the single score may give an estimate of overall neurological function in animals receiving neurotrauma or ischemia. Presentation of this type of data allows for a quick assessment of the sensorimotor capacity of brain or spinal cord damaged animals and easy comparison between drug and untreated groups. Moreover, it takes into account performance on a range of behaviors rather than focusing on the results of a single test. However, one advantage of using multiple behavioral tests is to determine the limits of any drug effect on recovery of function. That is, there is evidence to suggest that glutamate antagonists may accelerate recovery on some behavioral tasks but not others. By exclusively using combined neurological scores, the possible behavioral limitations of glutamate antagonists will remain largely undetermined. Moreover, by combining the results on several tasks there is a risk that the magnitude of any drug effect will be misleading. For example, if there is a small effect of the drug on several tasks, combining the results across tests will inflate the effectiveness of the agent. On the other hand, if there is a large drug effect on one or two tests and only a slight or nonsignificant effect on others, the combined score may reveal a nonsignificant treatment effect or only marginally significant results. In this case, although overall neurological function is only slightly impaired, the specific behavioral effect of the drug treatment may be lost.

Another issue concerning the behavioral evaluation of brain-damaged subjects is the need for quantification of the deficits. Researchers often use subjective rating scales to assess sensorimotor behaviors. These rating scales appear to have a high degree of interrater reliability and for this reason are acceptable measures of behavior. However, the use of these scales without any additional quantification of the impairment limits the types of statistical analyses that may be performed. In most cases, the behavioral measure is an ordinal scale and therefore requires a nonparametric statistic. There is no adequate nonparametric statistic that will allow for statements to be made about differences in the rate of recovery between groups. In contrast, an analysis of variance, where repeated testing over time may be measured as a within groups variable, allows for a treatment x test day (or hour) interaction and a comparison of the rates of recovery between groups. Differences in the rate of recovery between groups becomes an important issue if two groups of animals (e.g., treated and nontreated) fail to show a reliable difference on the first few test days but show significant differences thereafter. Such results have been shown in rats with lesions of the rat cortex and treatment with MK-801 beginning 16 hours after the brain injury (Barth, Grant, & Schallert, 1990; Barbay & Barth, 1993).

A Behavioral Research Program Using MK-801: Timing is Everything

We have studied the effects of MK-801 on the recovery and maintenance of function after lesions including the forelimb representation in the primary somatosensory and motor cortex (SMC) of the rat. MK-801 is known to reduce the amount of brain damage and edema as well as improve behavioral recovery in at least some cases following experimentally induced stroke, trauma, or cortical lesions.

The first step we chose to take in investigating the potential behavioral effects of MK-801 was to determine if it facilitated recovery on several sensorimotor tasks that evaluate functions of the forelimb. The SMC lesion produces a syndrome that includes impairments in tactile placing reflexes, placement of the forelimbs during locomotion, and removal of adhesive patches placed on the forelimbs. We create the lesion in one cerebral hemisphere (i.e., a unilateral lesion) so all sensorimotor deficits are seen only with the limb opposite to the side of the lesion (often called contralateral deficits). If we place the lesion in the left hemisphere, then we will observe sensorimotor deficits on the right forelimb. Depending on the extent of the lesion, these impairments typically recover in 1-4 weeks if postoperative tests begin 1 or 2 days following the injury, and are administered on a schedule of approximately 2-4 tests per week. Initial studies suggested that if the first administration of MK-801 is given 16 hours after the lesion, then drug effects would be seen only on the adhesive patch test (Barth et al., 1990). However, in this study recovery on the placing tests occurred in 10 days. Most recovery of function studies with glutamate antagonists begin injections 15 min - 1 hr after the injury. This relatively fast rate of recovery, along with the initial injection occurring at 16 hours after surgery, left open the possibility that MK-801 might have an effect on a wider range of deficits if the duration of the behavioral deficit could be extended in untreated rats with SMC lesions. When the duration of the deficit was extended to 24-35 days (in untreated rats) by increasing the size of the SMC lesion, MK-801 given at 16 hours facilitated recovery of forelimb tactile placing but still had no effect on locomotor placing (Barbay et al., 1992). This limitation on the effects of MK-801 could be removed if treatment began sooner after the lesion; hence, Hoane et al. (1997) reported that MK-801 significantly facilitated recovery on all of the sensorimotor tests if it was administered 15 min after the larger cortical lesion. It is important to realize that the recovery pattern (defined as the time taken to reach preoperative baseline performance) for saline treated rats was around 24 days. Thus, increasing the size of the lesion extended the time to recovery and a facilitative effect for MK-801 is now shown for all sensorimotor tests examined if treatment begins soon after the brain damage. These data suggest that there are no apparent limitations of MK-801 on recovery from sensorimotor deficits if the drug is administered soon (i.e., 15 min) after the brain injury. Moreover, these data may indicate different windows of opportunity for the various sensorimotor tests.

Previous studies have suggested that there is a window of opportunity following brain damage within which neuroprotective drugs may have their beneficial effects. Treatment with the neuroprotective agent outside this window will have either no effect or may even be detrimental to recovery and maintenance of sensorimotor functions. In our next study (Saponjic, 1994), we began to define this window of opportunity for MK-801. We gave a single injection of MK-801 at 15 min, 2 hours and 48 hours after the unilateral SMC lesion and tested the rats on the same battery of tests mentioned earlier. When a single injection is given at 15 min, rats treated with MK-801 showed a significant sparing of function on the first postoperative test day when compared to a group of saline-treated controls rats (performance on postoperative day 1 is better in the MK-801 treated rats). If MK-801 treatment is delayed until 2 hours after surgery, the sparing is no longer observed, however, there is a clear facilitation of recovery over time when compared to the saline-treated lesion control rats. This difference in the rate of recovery is supported by a significant treatment x days interaction. In this case, the repeated testing over numerous postoperative test days was an extremely important factor necessary to see the effect of MK-801. Finally, if MK-801 administration is delayed for 48 hours, the effect of the drug on sparing and recovery of function is lost. If we combine these data with those of previous work that showed a drug effect at 16 hours after the lesion, we may conclude that at least for some behaviors the "treatment window" for MK-801 extends up to 16 hours with there being no effect at 48 hours These data suggest a much longer window than those reported by others that suggest MK-801 may be effective only up to about 1 hr after the lesion (Shapira et al., 1990). This difference may be due to the type of behavioral tests, quantification of the behavioral deficit, or the duration of postoperative testing.

Up to this point we have discussed the effects of MK-801 on the restoration of functions that would otherwise still recover even if no treatment was given (albeit at a slower rate). Although acceleration of recovery by MK-801 is a significant finding, it is questionable whether such an effect would generalize to cases where there is little or no expected recovery. We have found that if the electrolytic lesion was enlarged, forelimb placing deficits appear to be permanent. Rats with these large lesions showed no signs of recovery of forelimb placing during a 6-month postoperative testing period. This more severe deficit may reflect a more complete destruction of corticospinal neurons that innervate the forelimb spinal cord. We tested the effects of MK-801 given 16 hours after the lesion and found no significant improvement in recovery of forelimb placing. However, in a more recent study (Hoane et al., 1995) we found that MK-801 "induces" a significant, yet still incomplete, restoration of forelimb placing if administered 15 min after the large SMC lesion. These data are important because they suggest that at least partial recovery is possible after this larger lesion, and that the window of opportunity may be different depending on the extent of the brain injury. An important question for future studies will be to determine the area or areas that are mediating the forelimb placing in these animals with large SMC lesions.

Although MK-801 appears to have a beneficial effect on recovery after brain damage, it also produces adverse anatomical and behavioral effects. For example, MK-801 produces transient structural changes in cortical neurons of intact rats including the expression of heat shock protein 70 which is a characteristic of injured neurons (Auer & Coulter, 1994; Olney, Labruyere, & Price, 1989; Sharp, Kinouchi, & Koistinaho, 1993). Moreover, behavioral studies have shown that MK-801 may disrupt learning and memory (Whishaw & Auer, 1989; Morris et al., 1989) and cortical plasticity during development (Rauschecker & Hahn, 1987).

MK-801 also appears to interfere with the maintenance of recovered functions. Barth et al. (1990) showed that a single injection of MK-801, given after behavioral recovery from very small unilateral SMC lesions, reinstated the function in the contralateral forelimb (i.e., the forelimb on the side of the body opposite to the hemisphere containing the brain damage). This recovery placed deficits for up to 7 days after the injection (i.e., reinstatement effect). MK-801 did not affect placing with the forelimb ipsilateral to the lesion (i.e., the forelimb on the same side of the body as the hemisphere containing the brain damage), nor did it affect placing reactions in intact control rats. In a more recent study, the SMC lesions were slightly extended in order to produce a longer time to recovery. In this study, the saline-treated rats recovered from the placing deficits in about 35 days. They were then given a single postrecovery injection of MK-801. As expected, MK-801 reinstated the forelimb placing deficits. However, in this case the reinstated deficits lasted for approximately 30-35 days. Thus, postrecovery injections of MK-801 appear to trigger behavioral deficits for a time period similar to that observed after the cortical lesion. These data suggest that although there is recovery following the cortical lesion, the maintenance of this recovery is fragile and potentially vulnerable to later drug treatments. This issue of the maintenance of function is especially important given the duration of the reinstated deficits.

A next question might be whether or not there is a way to stabilize the recovered functions such that they are not vulnerable to postrecovery injections of MK-801. We hypothesized that the reinstatement effect might occur because the neural circuits that maintain the restored functions are insufficient to withstand the drug challenge. The neural circuits likely would include subcortical as well as cortical areas remote from the cortical damage. If this were the case, then treatment with MK-801 beginning soon after the cortical lesion might block the reinstatement effect by keeping the appropriate remote circuits intact. Previous experiments have shown that both the striatum and substantia nigra pars reticulata are affected by the cortical lesion and that these anatomical effects could be prevented or at least reduced by MK-801 given up to 16 hours after the brain injury. For example, following a SMC lesion there is a concomitant atrophy of the posterior striatum and a loss of neurons in the substantia nigra. Both of these remote events are blocked by early treatment with MK-801 (Barth et al., 1990). It may be the case that the presence of this subcortical deterioration is a contributing factor in the inability of the rats to maintain the recovered behavior; likewise, the preservation of these sites may block the reinstatement effect.

In another study, rats received unilateral SMC lesions and either saline or MK-801, 16 hours after surgery. The animals were tested on forelimb placing tests until they returned to preoperative baseline levels of performance on two consecutive test days. After recovery appeared to be complete, the rats were then given an injection of either MK-801 or saline. Thus, the experiment consisted of four groups (early treatment/late treatment): saline/saline; saline/MK-801; MK-801/saline; MK-801/MK-801. We expected that the saline/MK-801 group would show the reinstatement effect and the saline/saline and MK-801/saline groups would fail to show any reappearance of the forelimb placing symptoms. The important question was whether the MK-801/MK-801 group would show the reinstatement effect. These rats show a sparing of neurons in subcortical areas due to the neuroprotective effects of an early injection of MK-801, and therefore might be resistant to the reinstatement effect. The MK-801/MK-801 group failed to show a reinstatement of forelimb placing deficits following the postrecovery injection of MK-801. Subsequent studies have shown that the lack of reinstatement effect in these animals is probably not due to repeated exposure to MK-801 (Barbay et al., 1992). These data support the view that the cortical lesion and concomitant subcortical degeneration leaves the animals vulnerable to a reappearance of forelimb placing deficits after recovery. However, the preservation of subcortical neurons with early treatment of the neuroprotective agent MK-801 appears to be important for the maintenance of recovered functions. Thus, early treatment with MK-801 not only facilitates recovery of sensorimotor function, it also allows for a stable maintenance of those recovered functions.

Behavioral studies have shown the potential for glutamate antagonists to facilitate recovery of function after cortical or spinal cord damage. These behavioral studies also suggest that the duration of glutamate antagonist treatment is an important factor to consider when designing human clinical trials, because late administration of MK-801 may be harmful to recovery of function. Many questions that are best addressed through behavioral studies remain largely unanswered. Most importantly, the effects of glutamate antagonists on permanent deficits and whether those recovered functions can be maintained are questions that should be addressed. Ultimately it will be important to identify those neural circuits that allow for recovery and maintenance of function. In the case of cortical injury, we have alluded to the possibility that these answers may be found in the pattern of secondary degeneration in subcortical structures associated with the primary injury. Preventing or limiting the amount of subcortical degeneration may lead to a restoration of function and a stable maintenance of those recovered functions. If these subcortical systems are critical for recovery, we must ask whether their integrity allows for the restoration of the function lost or whether they represent a parallel system that encourages the development of alternative behavioral strategies. Only through extensive behavioral analyses can these questions be answered.



Recovery of Function Studies in the 21st Century

Can we attain the goal of developing a pharmacological treatment for stroke and closed-head injury? Although the end of the 20th century gave us a deeper understanding of the events that occur around the time of the brain damage, we still do not have an obvious candidate that can be safely and effectively used as a treatment. I expect that it is going to become clear that an important part of that search will be to find an agent that can be given at time periods long after the injury occurred. It seems unrealistic that treatments whose effectiveness is limited to the time period soon after the brain injury (i.e., 15 minutes) will be of much value in the long run. Ideally, a treatment should be safe regardless of when it is given and even be effective at promoting restoration of functions long after the injury occurred. The focus of research in the 21st century should be on affecting chronic deficits. This approach might involve rehabilitative strategies, both pharmacological and behavioral, that encourage the development of alternate behavioral strategies that allow for compensation of the lost function. This approach might have as a neural basis those models of plasticity discussed at the beginning of this chapter.

Magnesium: A Possible Safe and Effective Treatment for Brain Injury

One of the events that follows an injury to the brain is a depletion of magnesium in the brain and spinal cord. We are just beginning to understand the importance of this occurrence. Magnesium is a critical element for neural transmission and basic cellular processes in the brain. It is essential for protein and RNA synthesis and the stabilization of cell membranes. Magnesium serves as a modulator of activity at some glutamate receptors. Magnesium blocks the activity of glutamate by directly binding to a receptor site within the calcium channel. When glutamate binds to it's receptor, calcium will enter the neuron and cause a depolarization. However, magnesium blocks the entry of calcium and therefore inhibits the activity of glutamate. Thus, magnesium serves as a glutamate antagonist and a neuroprotective agent.

Treatment with magnesium has been used in experimental models of stroke and head trauma. These studies have shown that treatment with magnesium reduce the amount of brain damage and accelerate the rate of behavioral recovery (Hoane, Raad & Barth, 1997; Izumi, Rousel, Pinard, & Selyaz, 1991; McIntosh, 1993; Vacanti & Ames, 1984 ). Because magnesium is relatively safe, it becomes an attractive option for treatment following brain injury. Moreover, magnesium has unique qualities that may make it useful beyond the time immediately following brain injury. Specifically, magnesium may be useful as a preventative treatment and long after the injury in cases where there are chronic deficits. In the latter case, magnesium may be effective in promoting neural and behavioral plasticity by indirectly affecting certain neurotransmitter systems.

Researchers have used magnesium treatment as a preventative treatment for several medical conditions, such as coronary heart disease and postoperative pain management (Bashir et al., 1993; Lassere, Spoerri, Moullet, & Theubet, 1994; Sjostrom & Weiner, 1996). Treatment in these cases suggests that magnesium supplements can elevate and maintain plasma levels for a prolonged period of time. Although there is little evidence pertaining to the long-term elevation of magnesium levels through the use of supplements, our data suggests that daily treatment with magnesium may lead to beneficial effects in the case of experimentally induced brain injury. We administered magnesium chloride to rats for 2 or 5 days with the last treatment ending 24 hours prior to a unilateral lesion in the SMC (Hoane, Irish, Marks, & Barth, 1998). When compared to saline-treated control rats, magnesium-treated animals showed less severe behavioral impairments, accelerated rates of recovery, and a reduction in the amount of atrophy in structures connected to but remote from the SMC. We believe that these data have far reaching implications for the preventative treatment of brain injury in high risk populations. For example, these data may be particularly important for individuals with a history of stroke or those participating in high contact sports like football or boxing. Could it be that daily magnesium supplements will "inoculate" these individuals against some of the secondary effects of brain injury?

A second potentially novel use of magnesium may be in the treatment of chronic deficits that occur following brain injury. As stated previously, although it is important to develop treatments that prevent the extent of brain injury through administration of agents around the time of the damage, it is equally important to develop treatments that can be used long after the initial trauma or stroke. The population of individuals with chronic neurological deficits due to trauma or stroke is getting larger and there is currently no effective treatment for these individuals. Is it possible that there is some type of intervention that can be used to help restore function long after the injury? In a pilot study, we produced chronic sensorimotor deficits in rats by making very large unilateral SMC lesions. As stated previously, this large SMC lesion produces impairments that do not recover for at least 6 months. In six rats with these large lesions we administered a daily regimen of magnesium chloride beginning 2 weeks after the lesion was created (Mishalanie, Stuntz, & Barth, 1997). Daily injections were given over a 2-week period. By the end of the injection period the treated rats were showing a partial restoration of forelimb placing behavior. However, after treatment was discontinued, the performance of the magnesium treated rats slowly worsened until they were as impaired as rats given no treatment. Several weeks later, we resumed magnesium chloride treatment and the rats once again showed a partial restoration of function that could only be maintained for a short time after the treatment was discontinued. These data suggest that the severity of chronic sensorimotor deficits associated with brain damage can be reduced, at least temporarily.

There are several possibilities for the mechanism of magnesium's effect on chronic deficits. A first possibility is that following brain damage there may be a population of neurons remote from the site of damage that becomes inactive. In the early 1900s, von Monakow introduced this idea in his theory of diaschisis. According to von Monakow, behavioral impairments following brain injury are due to the actual tissue lost, and to the metabolic depression of areas proximal and remote to the brain injury. Von Monakow called this metabolic depression, "neural shock" or diaschisis. Does magnesium somehow bring these neurons back from diaschisis? If so, what has made these neurons inactive and how does magnesium have its beneficial effect? If we take this idea to its logical conclusion, we may suggest that in people with chronic behavioral deficits due to brain injury, there are silent neurons that have the potential to become active again. This is an exciting possibility, because it suggests that the basic "hardware" is available, we just have to find a way to activate it.

Magnesium has the potential to affect the nervous system in a variety of ways. However, an understanding of the neurobiology of magnesium would not reveal its true potential as an effective treatment for brain injury. This potential is realized as we combine the neuroanatomical, neurophysiological, and neuropharmacological data with neurobehavioral studies of magnesium treatment.

Neuroplasticity and Recovery of Function

How do the neuroplastic events mentioned at the beginning of this chapter help us to understand recovery of function after brain damage? If we assume that these models are the basis for learning and memory, we find ourselves at the doorstep of an important concept in the study of recovery of function. This concept is behavioral compensation. Behavioral compensation is the idea that following brain damage the improvement in performance that we often label as a restoration of function is actually the development of an alternate behavioral strategy. Thus, the behavioral process following brain-damage is better characterized as the learning of a compensatory behavior rather than a restoration of a function.



If recovery after brain injury is due to learning a new motor skill or cognitive strategy to compensate for the lost function, then models like LTP become relevant. For example, if a unilateral brain lesion in the motor cortex of the rat produces contralateral sensorimotor deficits, then "recovery" may include the development of new motor skills and LTP-like phenomenon in other cortical areas. A solid research program would need to include both very sophisticated behavioral analyses to describe the alternate or compensatory behavior and physiological measurement to show the development of LTP. If a strong correlation in the time course of these behavioral and physiological phenomena can be demonstrated, then we may conclude that effective treatments would include those procedures that encourage the learning of new behaviors and the development of LTP. Moreover, researchers could support and strengthen the hypothesis that LTP is a mechanism of behavioral compensation if it can be shown that pharmacological manipulations affecting the time course of one, also affects the timing of the other. Experiments aimed at challenging the correlations between the behavioral and neurophysiological events would be most important for both understanding the process of recovery after brain damage and the development of effective treatments.

The second model of neural plasticity we have considered includes the experience-induced increase in dendritic branching and the possibility that behavior can drive morphological and neurophysiological changes in the brain. Jones and Schallert (1992; 1994) investigated this issue in regard to recovery of function after brain injury. They showed that rats with unilateral lesions in the SMC exhibited sensorimotor deficits contralateral to the brain injury. They also showed a hyperreliance of the forelimb ipsilateral to brain damage. If the SMC in the left hemisphere is damaged, then there are sensorimotor deficits with the right forelimb and a hyperreliance on the left forelimb). This hyperreliance appeared to be correlated with an increase in dendritic branching in the SMC of the intact cortex (which controls the unimpaired limb). This increase in dendritic branching was maximal 2-3 weeks after the injury, and was actually "pruned back" at later time points. The time course of dendritic changes appeared to correlate with the relative use of the corresponding unimpaired forelimb. The authors concluded that the overuse of the unimpaired limbs might be driving the reported structural changes. This hypothesis was challenged in the next series of experiments. Jones and Schallert decided to restrict the use of the unimpaired limb by placing a one-sleeved cast on rats immediately after the SMC lesion. In this case, it was impossible for the rats to use the unimpaired limb, so if the before-mentioned dendritic changes failed to occur it could be concluded that, in fact, the hyper-reliance on the unimpaired limb was a necessary factor to induce the neuroplasticity. Moreover, if casted nonlesioned animals showed the same dendritic changes, then the neuroplastic event could be specifically related to the behavioral experience. The results were that casted lesioned rats failed to show the increase in dendritic branching, but casted nonlesioned rats also failed to exhibit the effect. These results lead the authors to conclude that the behavioral experience produced the dendritic changes only if there was a cortical lesion present. These data suggested that following a brain lesion, intact areas of the brain may have a greater potential for neuroplastic changes. One question for future research will be to determine the factors or events that follow brain injury and allow for greater neuroplasticity. Is some substance that encourages neuroplasticity released following a trauma? Could changes in electrical gradients be responsible for the enhanced neuroplasticity? There are many candidates (i.e., neurotrophic factors) that once isolated, could be used to induce neuroplasticity. The discovery of the neuroplastic triggers or enhancers may be a very important event in the treatment of people with chronic brain damage, if we consider they are probably only available for a relatively short time after the trauma. Jones and Schallert report that the increase in dendritic branching is maximal at 2-3 weeks and thereafter there is a pruning back of dendrites. The pruning back may be due to behavioral recovery, but also could be due to the lack of these neuroplastic triggers. Moreover, it may be the case that the neuroplastic enhancer will also have a beneficial effect on neurodegenerative diseases like Alzheimer's or Parkinson's.

The final model we discussed was cortical reorganization. The malleability of cortical fields is undoubtedly dependent on behavior. In an attempt to integrate this model to the question of recovery after brain damage, we should ask the question, "What are the behavioral parameters that best produce the neuroplastic change? For example, do our current physical rehabilitation plans optimize the potential for change in cortical field physiology? Does the frequency and vigor of treatment lead to the best behavioral recovery, and is this correlated with changes in the cortex? Researchers can best answer these questions with animal models of brain damage and plasticity.



Some Advice for Researchers in the 21st Century

To answer the questions put forth in the preceding sections, neuroscience researchers must continue to receive interdisciplinary training represented as the four legs of neuroscience. However, unlike the past, the future will place much more emphasis on behavioral analysis. This shift in emphasis will mean that training in experimental design and statistics will become more important. The renewed interest in physiological psychology integrated with }cutting edge" technology may very well turn the steady pace of progress into a gallop.



Conclusions

The 21st century will be an exciting time for neuroscience and physiological psychology; there will be extensive examination of the dynamic brain and its relationship to changes in behavior. Researchers must continually challenge the correlations between the changes in brain structure, chemistry, physiology, and behavior because there will likely be numerous dynamic events to consider. An important topic for investigation will be how behavior drives neuroplastic events. Once this idea becomes more accepted in the neuroscience community, the true marriage between neuroscience and behavioral science will be realized. This realization will undoubtedly lead to a better understanding of brain function. The application of this new understanding will be new and more effective behavioral and pharmacological treatments for brain injury, stroke, and neurodegenerative disease. Thus, scientists will take another major step in achieving the goals set in the Decade of the Brain.



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Dr. Timothy M. Barth, Chairman and Associate Professor of Psychology and the Director of the Neuroscience Program, received his Ph.D. from the University of Texas at Austin. His main research interest is in recovery after brain injury. He was recently voted the most distinguished member of the Psychology Department. He has taught classes in Neuroscience, Human Neuropsychology, Psychopharmacology, Psychology in Cinema and Parapsychology. He has published articles in the Journal of Neurotrauma, Brain Research Bulletin, and the journal, Magnesium. His work on NutraSweet (aspartame) recently appeared in Psychology Today.

The author may be reached at T.Barth@tcu.edu





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