Friday, April 26, 2024
4/26/2024
SUMMARY/ABSTRACT Mental illnesses are the largest source of healthcare utilization costs in the US, and the costliest of non- communicable diseases worldwide – estimated to result in $6 Trillion in annual societal burden by 2030. The way in which we have defined psychiatric diagnoses (i.e. based only on symptom clusters) and identified treatments (i.e. capitalizing on serendipity), has failed to substantially mitigate the disabling burden of these diseases, which typically appear early in life and persist. Not surprisingly, individual psychiatric diagnoses are highly clinically and biologically heterogeneous, with as much or greater variability within a diagnosis as between diagnoses. The number of mechanistically distinct psychiatric drug targets has also not grown in decades, and typically only half of patients respond well in clinical trials. Public stigma towards psychiatric disorders remains palpable, as lay understanding of the brain bases of these conditions contrasts with the growing excitement amongst scientists for the potential of grounding diagnosis and treatment directly in neurobiology. Neuroimaging, as the dominant tool in human neuroscience, however, has been used largely for comparing these arbitrarily-defined diagnoses against healthy individuals not for robustly characterizing individual patients in objective biological terms. Imaging is also a purely observational method, and thus cannot by itself provide the causal understanding of circuitry that is necessary for transitioning from a descriptive to a circuit-based mechanistic understanding of mental illness that can directly guide novel interventions. Here, I propose a new diagnostic and treatment development framework that transcends the arbitrariness and heterogeneity of traditional diagnoses, the limitations of group-level imaging analyses and current trial-and- error approaches to treatment planning. Rather, this “Circuits-First” platform focuses on understanding causality in the brain circuits of individual patients as a means for personalized diagnosis and treatment using individually-tailored plasticity-inducing neurostimulation, establishing direct linkage between circuits and clinical outcome. Successful implementation of this “Circuits-First” approach will establish a platform for rapid translation to other psychiatric disorders, and beyond to specific neurological disorders (e.g. stroke, Parkinson’s) where circuit perturbations are prominent. Importantly, despite its novelty, my approach will create a readily scalable platform that, with simple modifications, can have the potential to transform clinical practice in the near term. This is facilitated by the use of broadly-applicable, already FDA-approved tools (e.g. transcranial magnetic stimulation (TMS) and electroencephalography (EEG)), and the fact that it can be performed in the office-based settings of the clinical practitioner, thus not restricted to specialized research labs.
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