Another explanation, which we favor, is that we do not know enough yet to translate basic neurobiology into the new diagnostics and therapeutics that will transform public health outcomes. EX 527 Let’s look at both of these possibilities. Although clinical progress is usually measured in breakthrough therapies, progress in improving diagnostics,

elucidating disease pathogenesis, and generating biomarkers can be as important and may be a prerequisite for better treatments. Since 1988, there has been considerable scientific progress on brain disorders. In the past 25 years, genetic mutations underlying a myriad of inherited neurologic disorders have been identified. These discoveries now enable rapid and accurate diagnosis, reducing or even eliminating the diagnostic odyssey, and in some cases even allow for presymptomatic diagnosis. Whole-exome sequencing of families with affected individuals promises to uncover genetic causes of scores of diseases and

already has identified de novo mutations for a number of the childhood epilepsies (Allen et al., 2013). For neurodegenerative disorders, rare disease-causing mutations in common conditions such as Alzheimer’s disease (APP, presenilin) and Parkinson’s disease (synuclein, Parkin, Pink1, LRRK2) and rare diseases like ALS (superoxide dismutase, C9orf72) are shedding light on causative molecular pathways ( Bertram and Tanzi, 2005). These pathways in turn may lead to “druggable targets” for potential disease-modifying therapy. In the near term, projects like the RO4929097 cell line Alzheimer’s Disease Neuroimaging Initiative are yielding biomarkers to track of disease progression in patients. For Alzheimer’s disease, it is possible to image sentinel molecules, like tau- and β-amyloid, and to measure them in cerebrospinal fluid, as well as track hippocampal atrophy ( Toledo et al., 2013). Similar efforts are underway in Parkinson’s

disease. The impact of these kinds of biomarkers can be seen in multiple sclerosis, where the prevention of gadolinium-enhancing MRI lesions has accelerated the development of treatments ( Bermel et al., 2013). While we still lack biomarkers for mental disorders, the tools of basic science are now beginning to change how we approach diagnosis. The discovery of shared genetics, often implicating genes critical for brain development, has supported a new formulation of mental disorders as neurodevelopmental disorders (Smoller et al., 2013). With functional MR and PET imaging, specific circuits have been implicated in depression, obsessive-compulsive disorder, and posttraumatic stress disorder (Insel, 2010). A new approach to classification of psychiatric disorders, called the Research Domain Criteria (RDoC) project, is based on cognitive domains and circuitry (Cuthbert and Insel, 2013).