According to the eighteenth-century French philosopher Voltaire, “The art of medicine consists in amusing the patient while nature cures the disease.” Even as late as the beginning of the early twentieth century, the great Oxford physician Sir William Osler wrote, “One of the first duties of the physician is to educate the masses not to take medicine.”

The subsequent years of the twentieth century saw a transformation of these pessimistic views. The discovery of penicillin was the most dramatic example of a “magic bullet” for acute, life-threatening infectious disease. However, although the stories are less well known, neurology paved the way for effective drug therapies for chronic disease. Success in alleviating the symptoms of neurological conditions has come in the use of drugs for treatment of epilepsy, Parkinson’s disease, migraine, pain, multiple sclerosis, amyotrophic lateral sclerosis, and even Alzheimer’s disease. With effective treatments to offer, neurologists have become more than simply spectators to the disorders of brain and mind. They are able to intervene with a scientifically informed expectation that the course of a disease can be changed.

But more than half a century since the modern age of pharmaceuticals was ushered in with the “magic bullet” of penicillin, no major affliction of the brain and mind has a cure. Many, such as dementia, depression, schizophrenia, and stroke, remain without satisfactory treatment. As our population ages, the burden of disorders of later life, frequently neurological, becomes ever greater. At least one in four of us will develop Alzheimer’s disease if we live to the age of 85. Stroke is the third leading cause of death and the major cause of chronic later-life disability in the United States. As our population grows overall, the cost to society in lost work days and lost human potential will increase.

What is keeping us from finding powerful new drugs to relieve patients with these major disorders?  Most people in the pharmaceutical industry now estimate that typically $1 billion or more must be spent to develop a compound, test it in the laboratory and then in clinical trials, and finally obtain approval for it as a new drug.  Development of a new drug typically takes fifteen or more years from identification of a promising target to approval and sale of the drug. (To learn more about this arduous process, read The Long, Sometimes Bumpy Road of Drug Development.)  The number of hurdles that must be met is so great that, in recent history, only one out of ten compounds that entered initial human trials make it to market. For molecules targeting diseases of the brain, the record with conventional approaches has been even less encouraging, with perhaps only one out of 100 chemicals proposed as potential drugs receiving approval for sale. Moreover, many of the diseases for which treatments are now being sought have chronic courses too long to fit into conventional drug development timelines. Many are complex disorders involving interactions between several genetic, developmental, and environmental factors, so that drugs targeting any one process may be expected to have only a partial effect on the overall course of the disease. 

The Potential of Brain Imaging

To help experimental medicine drive the development of drugs in humans faster and with greater confidence, one especially promising area for innovation lies in the use of new technology. Brain imaging methods that allow scientists to watch the living brain in action, non-invasively, are among the most promising of the new technologies. Used in exploratory ways, new imaging methods can better track the activity of diseases, providing more-sensitive measures of patient characteristics than is possible with usual clinical observations. Researchers can directly probe molecular interactions by using imaging to observe responses in patients’ brains, which will permit better selection of the right dose of experimental drugs. Information can be enhanced, and the effect of the drug being studied can begin to be predicted by measuring drug effects on brain functions that are relevant to the disease.

Modern imaging that allows scientists to watch the functioning brain now relies primarily on two approaches. Magnetic resonance imaging (MRI) uses harmless magnetic fields and radio waves to map brain structures and brain physiology. Positron emission tomography (PET) uses safe, tracer doses of radioactive materials to follow the fate of individual molecules as they travel in the human body. These techniques promise to change the way drugs are developed. Future drug development will spend less time studying “models” of disease in animals and move quickly to more-informative experimental medicine in humans. The benefits of using neuroimaging in this way can already be glimpsed in six aspects of drug testing: time and cost, confidence in targets, integration of information, dosage, drug combination, and understanding of the placebo effect. The FDA and other regulatory agencies are encouraging efforts to develop and validate these kinds of approaches. 

1. Alexander GE, Chen K, Pietrini P, Rapoport SI, and Reiman EM. Longitudinal PET Evaluation of Cerebral Metabolic Decline in Dementia: A Potential Outcome Measure in Alzheimer's Disease Treatment Studies. American Journal of Psychiatry 2002; 159(5): 738-745. 

2. Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, and Hardy J. Correlations Between Apolipoprotein Epsilon4 Gene Dose and Brain-Imaging Measurements of Regional Hypometabolism. Proceedings of the National Academy of Science 2005; 102(23): 8299-8302. 

3. Schott JM, Price SL, Frost C, Whitwell JL, Rossor MN, and Fox NC. Measuring Atrophy in Alzheimer Disease: A Serial MRI Study Over 6 and 12 Months. Neurology 2005; 65(1): 119-124. 

4. Matthews, PM, Honey, GD, and Bullmore, ET. Applications of fMRI in Translational Medicine and Clinical Practice. Nature Reviews Neuroscience 2006; 7: 733-744. 

5. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, and Weinberger DR. Catechol O-methyltransferase val158-met Genotype and Individual Variation in the Brain Response to Amphetamine. Proceedings of the National Academy of Science 2003; 100(10): 6186-6191. 

6. Heinz A, Siessmeier T, Wrase J, Hermann D, Klein S, Grusser SM, Flor H, Braus DF, Buchholz HG, Grunder G, Schreckenberger M, Smolka MN, Rosch F, Mann K, and Bartenstein P. Correlation Between Dopamine D(2) Receptors in the Ventral Striatum and Central Processing of Alcohol Cues and Craving. American Journal of Psychiatry 2004; 161(10): 1783-1789. 

7. Paulus MP, Feinstein JS, Castillo G, Simmons AN, and Stein MB. Dose-Dependent Decrease of Activation in Bilateral Amygdala and Insula by Lorazepam During Emotion Processing. Archives of General Psychiatry 2005; 62(3): 282-288. 

8. Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS, Matthews PM, and Rawlins JN. Dissociating Pain from Its Anticipation in the Human Brain. Science 1999; 284(5422): 1979-1981. 

9. Wise RG, Rogers R, Painter D, Bantick S, Ploghaus A, Williams P, Rapeport G, and Tracey I. Combining fMRI with a Pharmacokinetic Model to Determine Which Brain Areas Activated by Painful Stimulation Are Specifically Modulated by Remifentanil. Neuroimage 2002; 16(4): 999-1014. 

10. Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K, and Ingvar M. Placebo in Emotional Processing–Induced Expectations of Anxiety Relief Activate a Generalized Modulatory Network. Neuron 2005; 46(6): 957-969. 

11. Trip SA, Schlottmann PG, Jones SJ, Li WY, Garway-Heath DF, Thompson AJ,Plant GT, and Miller DH. Optic Nerve Atrophy and Retinal Nerve Fibre Layer Thinning Following Optic Neuritis: Evidence That Axonal Loss Is a Substrate of MRI-Detected Atrophy. Neuroimage 2006; 31(1): 286-293.