Abstract
Background: Converging lines of evidence indicate the utility of medications for enhancing functional recovery after brain injury.
Methods: Laboratory studies using rats and cats suggest that drugs augmenting noradrenergic function may facilitate recovery after cortical injury, when combined with appropriate environmental experience. This short-term noradrenergic strategy can be initiated months after injury and enhance recovery to a higher ultimate outcome level. Additional support for a central role of noradrenaline on recovery of function is that administration of drugs reducing noradrenergic function has the opposite effect, slowing functional recovery. Importantly these include several commonly prescribed medications such as alpha 2-adrenergic agonists, alpha 1-adrenergic blockers, and GABAergic agents that can retard recovery. The role for other medication such as those that affect acetylcholine requires further investigation.
Conclusions: There is a need for controlled clinical trials investigating effects on functional recovery after brain injury addressing basic pharmacological issues of efficacy, safety, and interaction with the rehabilitation environment. Rehabilitation research centers capable of integrating laboratory and clinical research efforts need to be established. This will be a slow and costly endeavor, but certainly less expensive than not developing a scientific basis for rehabilitation medicine.
TRAUMATIC BRAIN INJURY (TBI) is a major public health problem in the United States. It is responsible for 500,000 hospitalizations and 17,000 deaths annually. 1 Because TBI primarily occurs in children and young adults, the impact is immense. In the split second it takes to cause a brain injury, careers are ruined, families fractured, and future dreams forgotten. Indeed, TBI is a destroyer of worlds.
Despite significant advances in prevention and acute medical management of TBI, we can only hope to limit the progressing damage as there is still no accepted therapy available. Decades of research have yet to alter our traditional methods for treating brain injury. Securing adequate airways, stopping bleeding, reducing swelling, and managing medical complications remain standard protocol for limiting some progressive events initiated by TBI. Helicopter transport helps start treatment sooner, but still, life-long sequelae can be expected for many victims. Rehabilitation therapies have been the cornerstone of treatment, helping patients adapt to new deficits through physical therapy, occupational therapy, and speech and language therapy. But underlying deficits often remain, and functional recovery is incomplete. New scientifically based treatment approaches are desperately needed for what the CDC has termed a "silent epidemic." 2
Until quite recently, it was widely assumed that functional recovery simply did not occur after brain injury. This pessimism began to change about two decades ago, when it was recognized that some neuronal death takes place over time, not just at the moment of impact. This suggested a new treatment approach, one of limiting injury by salvaging damaged neurons before cell death occurred-so called neuronal rescue or neuroprotection. Unfortunately, although preclinical work with neuroprotective agents has shown tremendous potential, clinical studies have been disappointing in both TBI 3 and in stroke. 4
An alternative treatment strategy is rehabilitation pharmacology. Rather than simply trying to limit injury, this approach focuses on functional recovery, representing an entirely new way of thinking about brain injury treatment. The target of therapy is symptom reduction through pharmacological enhancement of rehabilitation-therapy is not directed towards reducing the acute neuropathology. Functional improvement is felt to occur through mechanisms such as dendritic growth, enhanced synaptic efficacy, synaptogenesis, and reducing neuronal dysfunction. The goal of rehabilitation pharmacology is to produce an enduring effect through these mechanisms that persist after drug treatment has ceased. Laboratory work suggests that an important factor in pharmacologic-enhanced recovery is the timing of medication and its interaction with the rehabilitation environment. Only recently has it been accepted that late intervention, perhaps even years after brain injury, can still be helpful. This review will summarize data from laboratory and clinical studies for some of the neuroactive agents considered important for facilitating neuronal recovery after brain injury.
For convenience this brief review is organized by neurotransmitters with a focus on the monoamines. This is not to suggest, however, that there is a simple one-drug, one-neurotransmitter relationship. Most drugs affect multiple neurotransmitter systems, in various parts of the nervous system. For example, serotonin receptor agonists are known to increase locomotor activity in rats. It is not a primary effect of the serotonin that causes this, but rather a secondary effect of increased extracellular norepinephrine (NE). 5 Also, some neurotransmitters modulate (eg, either potentiate or dampen other synaptic input)-NE can enhance response of cortical neurons to subthreshold levels of acetylcholine (ACh) in vitro. 6 In this way NE acts in the central nervous system (CNS) as a neuromodulator more than a neurotransmitter, dampening or (as in this case) enhancing the effect of other neurotransmitters. Furthermore, the action of a single neurotransmitter may differ between brain regions, depending on differences in the effects mediated by receptor subtypes. Hasselmo et al. 7,8 showed that in a dose-dependent fashion, NE and ACh suppress synaptic potentials in layer Ib of the rat cortex much more than in layer Ia. Other variables may influence a drug's action such as dose, frequency of administration, concurrent medications, receptor subtype being affected, subject age and gender, the timing of drug therapy in relationship to brain injury, and environmental experience during the time of drug activity. Still, despite these many complications, it is convenient to use such a traditional neurotransmitter categorization as clinical decisions are often made this way; choosing drugs with a single neurotransmitter effect in mind.
Although this review focuses on rehabilitation pharmacology for traumatic brain injury, more work has been done in models of ischemic brain injury (stroke), and these data will also be included. Indeed there are similarities in the pathophysiology of stroke and TBI, particularly in the chronic phase beginning weeks to months after injury; therefore, in many cases, pharmacologic rehabilitation is relevant for both types of injury.