Therapeutics in cognitive and behavioral neurology

The past decade has seen dramatic changes in the field of neurology, making it a very different field of medicine and of research than that of our mentors. Three major components have fueled this change: molecular biology, whereby the neurological phenotypes characterized previously are now correlated with specific genotypes; neuroimaging, whereby the neurological signs previously elucidated and elaborated can now be localized to specific regions or circuits in the brain; and neurological therapeutics, whereby many heretofore untreatable diseases can be treated with increasing effectiveness. Although molecular genetics and neuroimaging have led to many significant advances in cognitive and behavioral neurology as they have in other neurological disciplines, the same cannot be said for neurological therapeutics. Over the past decade, we have novel treatments for previously untreatable diseases, including acute stroke. This decade of the brain has not been as kind to cognitive and behavioral neurological therapeutics, particularly related to chronic stroke and its cognitive sequelae such as aphasia. Whereas we have focused considerable attention on acute stroke therapeutics, the success of this enterprise has left us with a larger number of stroke survivors, many of whom have serious problems with motor function, language, memory and attention, and other cognitive deficits. Current approaches to motor and language therapy, the two basic deficits for which there are formally instantiated treatment mechanisms (ie, physical and occupational therapy for motor dysfunction, and speech pathology for language dysfunction), are not generally based on physiological principles and resemble more classroom education than medical therapy. The approach to care of these patients has so little relationship to neurology that neurologists have abdicated responsibility for them, leaving them in the hands of specialists in rehabilitation. The current approach to the treatment of cognitive deficits is compensatory, that is, learning to get around the problem. Thus, if a patient has a problem with short-term memory, he or she is taught to make better notes. If there is a problem writing with the right hand, he or she is taught to write with the left hand. The “functional outcome” based approaches have been fostered partly by the perceived lack of efficacy of remediative cognitive therapies and partly by the financial concerns of third-party payers. What is the alternative? I would argue that we need more lofty goals than to achieve small gains to compensate for the impaired function. Why don’t we take the same approach in cognitive neurology that we take in other fields of medicine, that is, remediation rather than compensation, with an ultimate goal of cure? But is this approach an impossible dream, or worse yet, a fantastic quixotic quest that will give patients false hopes of functionality that they could never have? I believe that such a dream is not at all preposterous, and that it is high time that cognitive neurology began to play catch-up with the rest of medicine. To do this will require a significant commitment of research activity aimed at restoration of higher cortical function in patients with cognitive dysfunction. Aside from the memory disorder of Alzheimer’s disease, and the disorder of selective attention in attention deficit hyperactivity disorder (ADHD), pharmacological treatment of cognitive disorders has been disappointing. Perhaps the most frustrating pharmacological results have been in the realm of stroke neurorehabilitation. A large number of agents have been used in cognitive and motor therapy after stroke, particularly drugs that increase transmission of the catecholamines noepinephrine and dopamine. Other approaches have included monoaminergic agents, such as the selective serotonin uptake inhibitors, cholinergic agents, and the nootropic drug piracetam. In the older literature, experiments were conducted with hyperbaric oxygen, benzodiazepines, barbiturates, and others. There is no high-grade evidence that any of these agents are effective in remediating cognitive or motor disorders after stroke; yet, several agents that affect catecholaminergic transmission are commonly used by neurologists and physiatrists in the community. Those in highest use are (1) methylphenidate and dextroamphetamine, which nonselectively block reuptake of both dopamine and norepinephrine; and (2) L-dopa, the dopamine precursor, and bromocriptine, the dopamine (D2) receptor agonist. 26 The use of these drugs is based on a few reports suggesting that increasing dopamine and/or norepinephrine might have some utility as an adjunct to speech, physical, or occupational therapy in the treatment of cognitive disorders after stroke. An article that appears in this issue of the Annals has attempted for the first time to understand the mechanism whereby these drugs affect improvements in cognitive function when accompanied by therapy but not when administered by themselves. Collaborators from the Departments of Neurology and Psychology at the University of Münster have demonstrated that the implicit learning of auditory-visual pairings improved significantly in normal subjects who took L-dopa compared with those who did not. Their experiment was very creatively designed, and EDITORIALS