Cosmetic neurology: The controversy over enhancing movement, mentation, and mood

 

By Anjan Chatterjee, MD

Department of Neurology & the Center for Cognitive Neuroscience, University of Pennsylvania

 

From Neurology 2004;63:968 –974

 

Abstract—Advances in cognitive neuroscience and neuropharmacology are yielding exciting treatments for neurologic diseases. Many of these treatments are also likely to have uses for people without disease. Here, I review the ways in which medicine might make bodies and brains function better by modulating motor, cognitive, and affective systems. These potential “quality of life” interventions raise ethical concerns, some related to the individual and others related to society. Despite these concerns, I argue that major restraints on the development of cosmetic neurology are not likely. Neurologists and other clinicians are likely to encounter patient-consumers who view physicians as gatekeepers in their own pursuit of happiness.

 

Are better brains better? Advances in basic neuroscience and neuropharmacology are beginning to yield therapies for cognitive disorders. While we eagerly anticipate treatments for dementing illnesses, stroke, traumatic brain injury, and developmental abnormalities, these very treatments raise uncomfortable questions. If we can improve cognitive systems in disease, can we also do so in health? Should we?

The possibility of “better brains” has captured the attention of the press, policy pundits, and ethicists.1–10 With few exceptions,11 neurologists have not contributed to these discussions, despite the fact that clinicians would be centrally involved as this drama unfolds. In this paper, I review the landscape of cosmetic neurology and offer preliminary speculations about its future. While cosmetic neurology certainly includes the use of botulinum toxin to brush away wrinkles, the focus here runs deeper. I start by considering the purpose of medicine to frame the ethical dilemmas of cosmetic neurology. Then, I review three ways in which bodies and brains might be made better. This is followed by an outline of four main ethical concerns raised and my opinion on why these concerns are unlikely to serve as a restraint. The goal is not to evaluate the correctness of cosmetic neurology. Rather, the goal is to alert neurologists to the shape that cosmetic neurology might take and to consider our possible role.

 

Framing the issue: The purpose of medicine. The strength of allopathic medicine is its focus on mechanisms of disease. Understanding the biologic basis for malfunction provides insight into how to fix that malfunction. Despite the successes of this approach, it has limits. Most notably, patients’ impressions of the quality of their lives do not always correspond directly to bio-markers and symptoms of disease. The cardinal symptoms of Parkinson disease (PD) most responsive to dopamine agonists are not necessarily those that bother patients most.12 Measures of disease activity may not be the best indicator of the impact of multiple sclerosis (MS) on patients.13 Recognizing the limits of clinical and pathologic indices, quality of life assessments of patients have become a standard practice in therapeutic trials. Such assessments seem eminently reasonable, if one believes that the point of treating a disease is to improve patients’ quality of life. However, if improving quality of life is an explicit goal for physicians, and quality of life does not always correspond directly with clinical-pathologic indices, then why not consider biologic interventions for the quality of individuals’ lives whether or not they have a disease?

 

This distinction between treating disease and improving quality of life is echoed in discussions of therapy vs. enhancement.6 Therapy is treating disease, whereas enhancement is improving normal abilities. Most people would probably agree that therapy is desirable. By contrast, enhancing normal abilities gives pause to many. Fukayama14 opines that “the original purpose of medicine is to heal the sick, not turn healthy people into gods.” He suggests that public policy should restrict research for enhancement.

 

On scrutiny, the distinction between therapy and enhancement can be vague particularly when the notion of “disease” lacks clear boundaries. For example, if individuals of short stature can be “treated” with growth hormone,15 does it matter if they are short because of a growth hormone deficiency or because of other reasons?16 Additionally, the idea of promoting research for therapy and restricting it for enhancement misses the point that research in one often applies to the other. Distinguishing between therapy and enhancement may avoid tackling what is perhaps a more difficult question. If one purpose of medicine is to improve the quality of life of individuals who happen to be sick, then should medical knowledge be applied to those who happen to be healthy?

 

Better bodies and brains. The prospects for better bodies and brains fall into three general categories: improvement of motor systems, attention, learning and memory, and mood and affect. With the current and future impact of aging in our society, these prospects are particularly germane. Some interventions like alcohol, tobacco, and caffeine have been available for a long time. Many others are on the horizon. For novel medications, the effects in clinical populations are often not known and their efficacy and safety in healthy individuals are now unexplored. However, for purposes of this discussion, we can anticipate that such interventions will eventually be available, relatively efficacious, and safe.

Movement. Medicine can make people stronger, swifter, and more enduring. While some of these interventions might not be considered “neurologic” as narrowly conceived, I mention them because neurologists treat muscle disorders, and innovative interventions for these diseases may generalize to the normal state.

 

Professional athletes use anabolic steroids to improve their strength and quickness. Beyond steroids, new ways of improving motor performances are being developed. Insulin-like growth factor (IGF) produced by the liver may improve the quality of life of people without disease. IGF given to men over the age of 60 for 6 months increased their muscle mass, decreased body fat, and improved skin elasticity.17 In mice, injection of recombinant viruses containing the IFG-1 gene directly into muscle also increased muscle mass and strength and prevented declines observed in untreated old mice.18

 

Maximizing blood oxygenation optimizes muscle activity and enhances athletic performance. In the 1970s and 1980s, athletes trained at high altitudes and used autologous blood transfusions to increase their oxygen carrying capacities.19 Since the 1980s, human erythropoietin (EPO) has been produced to treat anemia. EPO has become a new form of athletic “doping.”19,20 Similarly, new transfusion methods, motivated by blood supply shortages and contaminants, may have implications for performance when endurance is critical.19

 

Finally, the acquisition of motor skills may be improved by medications developed to enhance neural plasticity. For example, amphetamines in small doses promote plasticity and accelerate motor learning.21,22 Their effects are most pronounced when paired with training as seen in patients with weakness following stroke. Could amphetamines also be used in normal subjects at the time of skilled motor learning, such as learning to swim, ski, or play the piano?

 

Mentation. We now have unprecedented therapeutic options for degenerative and developmental cognitive disorders, with more on the way. Currently available treatments most often modulate catecholamine and cholinergic systems.

 

The effects of amphetamines on plasticity in motor systems may generalize to cognitive systems. Amphetamines improve the effects of speech therapy in aphasic patients.23 Might similar effects occur in normal subjects? Modafinil improves arousal and ameliorates deficits of sustained attention associated with sleep deprivation.24,25 Methylphenidate is used widely to improve attention, concentration, spatial working memory, and planning.26,27 Students commonly use amphetamines despite the fact that it may also impair previously established performance.28,29 Newer non-addictive drugs such as atomoxetine are likely to increase off-label use of such medications.

 

Cholinesterase inhibitors also improve attention and memory. These medications are used widely in AD, and their use in older individuals is on the rise. The reticence for enhancement and enthusiasm for therapy is reflected in the recasting of diagnostic designations of “age-associated memory impairment” to “mild cognitive impairment.” The effects of cholinesterase inhibitors on normal subjects are not well studied. However, one intriguing report suggests an effect in the setting of highly skilled performance. Yesavage et al.30 reported that commercial pilots taking 5 mg of donepezil for 1 month performed better than pilots on placebo on demanding Cessna 172 flight simulation tasks, particularly when responding to emergencies.

 

Two new classes of drugs for memory, ampakines and cyclic AMP response element binding protein (CREB) modulators, are on the horizon.31 These drugs capitalize on recent advances in understanding of the intracellular events that contribute to structural neural changes associated with the acquisition of long-term memory.

 

Facilitation of glutamatergic transmission promotes long-term potentiation, presumed to foster synaptic plasticity and memory formation. Ampakines augment AMPA-type glutamate receptors by depolarizing postsynaptic membranes in response to glutamate. Because NMDA receptors crucial to induction of long-term potentiation32 are sensitive to this depolarization, ampakines are thought to facilitate the acquisition and consolidation of new memories (see for review).33 Early studies show that ampakines improve memory in rats34,35 and normal humans.36 The NMDA receptors themselves may ultimately be a target of genetic modification. Mice genetically altered to overexpress NMDA receptors have superior learning and memory abilities.37

 

Neurogenetic studies suggest that CREB is a critical molecular “switch” in forming long-term memories.38 Gene expression is promoted by activation of CREB, which itself is dependent on NMDA receptor activation. Specific protein kinases activate CREB. CREB then sets off a transcription cascade, which produces specific structural changes at the synapse. Drosophila genetically altered to overexpress CREB demonstrate long-term conditioning to odor-shock pairings after only one exposure, a conditioning that normally takes 10 trials.39 Similar effects are seen in mammals.40 Mice given rolipram, a phosphodiesterase inhibitor, which enhances CREB, form long-term memories in fewer than half the trials needed by untreated mice.38

 

Mood and affect. The aisles of almost any local drug store testify to the public’s appetite for mood regulators, such as St. John’s Wort, kava kava, and valerian. Anti-depressants, most notably selective serotonin reuptake inhibitors (SSRIs), are used widely for depression, but also for anxiety, obsessive compulsive, and oppositional behaviors. Some estimate between 9.5 and 20% of Americans are depressed.41 Kramer42 drew attention to the use of antidepressants in normal people. SSRIs may selectively dampen negative and not positive affect,43 and they seem to increase affiliative behavior in social settings.44 If SSRIs improve a general sense of well being, regardless of illness or health, might more than 20% of Americans wish to take them?

 

New approaches to treating affective illnesses will undoubtedly expand our therapeutic options.45,46 Blocking glucocorticoids may be of benefit in a subset of depressed patients. Corticotropin releasing factor (CRF) seems to mediate long-term stress effects through the stria terminalis, a structure related to the amygdala.47,48 Blocking CRF may selectively blunt stress effects.45 In addition to CRF, other neuropeptides seem to play a role in depression and anxiety. These include substance P, vasopressin, neuropeptide Y, and galanin. Clinical trials of neuropeptide agonists and antagonists that cross the blood-brain barrier are just beginning.46 The efficacy and safety of these novel treatments remain to be seen, but almost certainly new ways to alter mood and affect will be available.

 

Besides pharmacological interventions, other interventions, such as repetitive transcranial magnetic stimulation (rTMS), can have a therapeutic effect on depression.49 Some patients respond to frontal rTMS that are otherwise unresponsive to medications.50 Would TMS improve mood in normal people that are not clinically depressed, but simply have off days?

 

Pharmacologic agents can also modulate the way emotional events are remembered.51 In animals, consolidation of emotional memories are strengthened by epinephrine and dampened by beta blockers injected within the amygdala. Similar effects occur in normal people. Subjects given propranolol recall emotionally arousing stories as if they were emotionally neutral.52 Propranolol also enhances the memory of events surrounding emotionally charged events that are otherwise suppressed.53 In one pilot study, patients in an emergency room given propranolol after a traumatic event suffered fewer post-traumatic stress disorder symptoms when assessed 1 month later.54 Intriguingly, CREB inhibitors may have selective effects on negatively charged memories. Most would agree with treating post-traumatic stress disorder to help individuals that are paralyzed by their disturbing memories. However, these studies suggest that less disturbing memories might also be clipped, if we so desired.

 

Ethical dilemmas. Cosmetic neurology raises deep ethical dilemmas. These dilemmas coalesce around four concerns, two focused on the individual and two on society. While the present context for these concerns is novel, the ethical issues themselves are not without precedent. Our responses to these concerns in other settings may predict how we will deal with cosmetic cognitive neurology.

Safety. Virtually all medications have potential side effects that range from minor inconveniences to severe disability or death. In disease states one weighs risks against potential benefits. Thus a patient with glioblastoma multi-forme might be willing to endure toxic chemotherapies because the alternative is so grim. In healthy states any risk seems harder to accept because the alternative is normal health. For some interventions the risks are known or suspected. EPO improves endurance but increases the risk of stroke. Modafinil enhances alertness on some tasks but may compromise performance on others.25 Genetically modified mice may have terrific memories37 but are more sensitive<