Returning to basic principles to develop more effective treatments for central nervous system disorders.

Development of new treatments for diseases of the central nervous system (CNS) is stalled. Of candidate drugs developed through costly preclinical research, 93% fail clinical trials. Hoped-for improvements in diagnosis or treatment from decades of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) imaging have yet to materialize. To understand what we are doing wrong, I begin with recognition that all aspects of life, including the brain and mind, are physical phenomena consistent with processes described by physicists. Two processes, emergence and entropy, are of particular relevance in complex arrangements of matter that constitute life in general and the brain in particular. The human brain functions through dynamically reconfiguring and hierarchically organized neural functional systems with emergent properties of cognition, emotion, and conscious experience. These systems are shaped and maintained by negentropic environmental input transformed by sensory receptors into neural signals that trigger epigenetic neuroplastic processes. CNS diseases produce clinical disorders by disrupting these systems. As researchers seek appropriate levels of system organization at which to characterize and treat illness, focus has been on medications that impact processes at lower levels or transcranial electric or magnetic stimulation that impact broad contiguous swaths of tissue. Neither align with the brain's neurosystem organization and therefore lack specificity necessary to be effective and to limit side effects. Digital neurotherapies (DNTs), in contrast, align with neurosystem organization and achieve the needed specificity using the same input pathways and neuroplastic processes that created the neural systems organization to repair it. The omission of DNTs from major systems-based initiatives represents powerful residua of dualist thinking. Interventions based on perceptual and cognitive processes are not thought of as being as physical as drugs or electric or magnetic stimulation through the skull. In fact, they are examples of the most basic processes that create and support life itself.