Research Summary

I.  Introduction
Our laboratory is integrative of two fields of neural plasticity research:  the neurobiology of learning and memory and neural plasticity after brain damage, including stroke and traumatic brain injury.  Our research on the effects of focal damage to the sensorimotor cortex (SMC) in adult rats indicates that neural and glial responses to brain damage are dependent upon post-injury behavioral changes.  This work supports that degenerative effects of brain damage can create a fertile environment for neuronal growth and synaptogenesis.  However, this environment must be driven by appropriate behavioral pressures to influence outcome in a beneficial way.

Learning in healthy brains occurs via neuronal plasticity.  Learning that occurs shortly after brain damage interacts with the plastic brain changes induced by the damage.  This is important to consider given that an animal surviving brain injury typical undergoes many new learning experiences as it attempts to compensate for behavioral impairments.  Some compensatory strategies are among the most significant behavioral changes of an animal's adult life.  For example, a right-handed human that sustains a left hemisphere stroke may learn to perform most manual tasks, such as writing and eating, by relying on the left hand.  Thus, understanding brain adaptation to injury requires understanding its interactions with behavioral experience.  Such knowledge has the potential to be central to endeavors to promote adaptive plasticity and to enhance functional outcome.  We are pursuing such an understanding in two major lines of research:

II. Neural Mechanisms of Compensating for Brain Damage
This research uses a model of brain damage which has produced strong evidence that lesion-induced neural plasticity is influenced by post-injury behavioral experience, including spontaneous (presumably self-taught) compensatory behaviors.  Rats with focal ischemic or electrolytic damage to the SMC (Fig. 1) have sensorimotor impairments in the forelimb opposite the lesion.  The lesions also change the use of the forelimb ipsilateral to the lesion, the "good" forelimb.  Rats begin to use this forelimb more and in different ways to compensate for their impairments. 

In the motor cortex opposite the lesions, we have found a sequence of cellular and structural changes including astrocytic reactivity, expression of trophic (growth and survival promoting) factors, dendritic growth, synaptogenesis and alterations in the configuration of synaptic connections, as detected using various sensitive quantitative methods for light- and electron-microscopy (Fig. 2).  These changes are linked to increased reliance the good forelimb, but the behavioral changes alone are not sufficient to reproduce the effects found after the lesions.  Peripheral manipulations, producing similar behavioral asymmetries, fail to reproduce, in time-course and/or magnitude, many of the changes linked to forelimb asymmetries after the lesions.

The motor cortex of either hemisphere in rats is interconnected via transcallosal connections.  We hypothesized that the degeneration of these connections after unilateral lesions triggers reactive growth-promoting cellular changes that induce an exceptionally permissive environment for behaviorally-induced change.  This facilitation of neural plasticity, in turn, should enhance the development of compensatory behaviors with the good body side (Fig. 3).  Several of our findings are consistent with this general hypothesis: (1) Major neuronal growth responses in the SMC occur in animals with damage to the corpus callosum  (creating degeneration of transcallosal connections) that are also forced to rely on one forelimb.  If degeneration and behavioral asymmetries are uncoupled in time (by damaging callosum well before giving SMC lesions), rats have little neuronal growth response.  (2) Motor skill acquisition with the forelimbs results in greater synapse addition in the motor cortex contralateral to SMC lesions than it does in intact animals. (3) Unilateral SMC lesions enhance the ability to acquire new skills with the good forelimb.  Rats with SMC lesions acquire a skilled reaching task with the good forelimb better than intact rats learning the same task.  This effect is reproducible using corpus callosum transections in place of the SMC lesion.  However, it requires that the animals learn the task after the lesion.  If rats are tested on a pre-existing skill with the good forelimb, there is either no effect (after small lesions) or there are subtle impairments.  These findings suggest that the transcallosal degenerative effects of unilateral damage can simultaneously disrupt pre-existing motor engrams and facilitate the acquisition of new ones.

Compensation with the good forelimb can be considered an adaptive response to unilateral brain damage because it enables animals to return to daily activities that enable survival.  In humans surviving brain damage, early behavioral interventions typically focus on using the good body side to accomplish activities of daily living.  However, we have recently discovered that skill acquisition with the good limb may come at a major cost.  Even a brief period of training focused on the good forelimb in rats greatly worsens function of the impaired forelimb and prolongs its disuse.  Furthermore, it decreases the ability to activate neurons in remaining motor cortex of the damaged hemisphere, a region that appears to be a critical contributor to functional recovery of the impaired body side (Fig. 4).  It has long been proposed that animals learn to disuse the impaired body side and that this disuse limits the opportunity for functional improvements.  Our findings suggest that it is not just disuse of impaired extremities, but learning with the good body side, that exacerbates impairments.  We hypothesize that learning new skills with the good forelimb disrupts neuroplastic changes in the injured hemisphere that might otherwise mediate better recovery of the impaired body side.  Understanding the neural mechanisms of this phenomenon is a major future direction.  This finding has also further spurred our interest in better understanding how restorative neural plasticity can be optimized in a stroke-affected hemisphere.

II. Neural and Behavioral Effects of Motor Rehabilitation
In the chronic period after brain damage, manipulations of behavioral experience are likely to be the foundation of endeavors to improve function.  The reason for this is that, at this point, we are far from understanding the nervous system well enough to put new synapses (and neurons) in just the right places to improve function.  The easiest way to do this is to capitalize upon the way brains have evolved to reorganize functional connectivity, i.e., via learning.  This research direction focuses on 2 topics:  (1) neural and behavioral changes induced by motor rehabilitation after cortical injury and (2) the efficacy of combining rehabilitative training with other therapies. 

In our first experiment using motor rehabilitation, we used the Acrobatic Task, a complex task requiring the development of whole-body coordinated movements (Fig. 5) because, at the time of onset of this experiment, this was the only task that had been found to result in synapse addition in the motor cortex of intact adult animals.  Acrobatic training for 28 days after unilateral SMC lesions enhanced synaptic changes in the motor cortex opposite the lesions compared with lesion-exercised controls and in comparison to intact animals receiving the training.  However, the training more effectively improved function of the good forelimb than the impaired forelimb.  Furthermore, it induced only subtle neuronal structural changes in peri-lesion cortex.  In retrospect, it seems that this training primarily capitalized upon enhanced sensitivity of the good hemisphere to behavioral change.  We needed a motor rehabilitative training task that more specifically targeted function of the impaired forelimb. 
 
Other laboratories have discovered that unilateral skilled reach training has major effects on neural activity patterns and synapses of the motor cortex of intact rats.  We have found that training rats with the impaired forelimb on such skilled reaching tasks (Fig. 6) after unilateral SMC lesions improves forelimb function and this is linked with synaptic plasticity in the remaining motor cortex of the damaged hemisphere.  Five weeks of rehabilitative training in skilled reaching greatly improves function in the impaired forelimb and increases synaptic density and the appearance of presumed efficacious synapse subtypes (perforated and multiple synapses) in remaining motor cortex.  We are currently investigating whether this synaptic plasticity is necessary for the behavioral improvements and how the synaptic changes are linked with functional activation patterns in the motor cortex.

Most research on the neural effects of rehabilitation has focused on treatment of stroke. We are beginning to investigate motor rehabilitation effects after traumatic brain injury in collaboration with Dr. Dorothy Kozlowski (DePaul University). Traumatic brain injury and stroke instigate different post-injury neuronal reactions to damage. Since manipulations of experience interact with post-injury neural responses, we suspect that rehabilitation needs will differ between stroke and traumatic brain injury, even when there are initial behavioral deficits in common.

An issue with rehabilitative training is that, besides being very labor intensive, it can be insufficient to normalize function.  There is much room to positively modulate the effects of experience.  We have begun, in collaboration with other laboratories, to examine the efficacy of combining rehabilitative training with another therapy, motor cortical electrical stimulation (CS).  In this approach, an electrode is implanted over remaining regions of the motor cortex adjacent to unilateral ischemic SMC lesions such that passage of current evokes forelimb movements.  CS is then delivered continuously at ~ 50% of the movement threshold during each session of a 2-3 week course of rehabilitative training on a skilled reaching task.  We do not yet know why CS works, but we hypothesize that it helps to sufficiently activate partially denervated neurons in remaining motor cortex so that they can participate in the training-induced activity-dependent remodeling of synaptic connectivity that supports improved function.  We have found that combining CS with rehabilitative training in skilled reaching tasks motor function and increases the density of dendrites and synapses in stimulated cortex compared to unstimulated controls receiving the same training.   This includes the presumed efficacious synapse subtypes (perforated and multipsynaptic boutons, Fig. 7). Furthermore, the improvements resulting from CS are far more persistent than those resulting from rehabilitative training alone, as assessed 9-10 months after the end of the treatment (a significant portion of a rat's 2-3 year life span).  Collaborating laboratories, including those of Drs. Randolph Nudo and Erik Plautz (Kansas University Medical Center), Jeffrey Kleim (University of Florida) and G. Cambell Teskey (University of Calagary) have found that the treatment results in the re-appearance of movement representations in peri-lesion cortex of rats and monkeys as assessed using microstimulation mapping.  These findings have influenced clinical trials and we believe that they are also likely to be relevant to non-invasive stimulation approaches in humans, which rely on transcranial magnetic stimulation and direct current stimulation to influence activity in remaining cortex.  Our future research on this topic is aimed at better understanding the neural effects mediating the improved behavioral function, so that we can learn how to optimize it and reproduce its effects using other approaches.