Circuits and Circuit Disorders: Approaches to Neuromodulation.

Thisthemeissueon“CircuitsandCircuitDisorders:Approaches to Neuromodulation” is the result of a symposium held at the annual meeting of the American Neurological Association in Chicago, Illinois, on September 26, 2015, and cosponsored by JAMA Neurology and the Annals of Neurology. The speakers wereMahlonDeLong,MD,EmoryUniversity (KeynoteSpeaker), Philip Starr, MD, University of California, San Francisco, Jonathan Mink, MD, PhD, University of Rochester, Helen Mayberg, MD, Emory University, and Bryan Roth, MD, PhD, University of North Carolina. The symposium also honored DeLong,who received the2014LaskerDeBakeyClinicalMedical Research Award with Alim-Louis Benabid, MD, Universite JosephFourier, for developingdeepbrain stimulation (DBS) of the subthalamic nucleus as effective therapy for patientswith Parkinson disease. It is estimated that more than 100 000 Parkinsondiseasepatientshavebeen treatedwithDBSwith reduction inbradykinesia and tremorsandwithoverall improvement inmotor function. Deep brain stimulation is credited as being the most important therapeutic advance for Parkinson disease since the introduction of L-dopa in the 1960s. In this issue of JAMA Neurology, DeLong and Wichmann examine in their review1 the scientific foundations and rationale for the use of ablation and DBS for the treatment of neurologic and psychiatric diseases, using Parkinson disease as the primary example. They provide evidence in support of the view that signs and symptoms of movement disorders result from signature abnormalities in one of several parallel and largely segregated basal ganglia thalamocortical circuits forming the “motor circuit.” Recently, they are exploring the pedunculopontine nucleus to study gait disorders responding poorly to levodopa and conventional DBS targets. Miocinovicandcoauthors2emphasizethat isolateddystonia andParkinsondiseasearedisordersofthebasalganglia-thalamocorticalnetwork.Theyviewisolateddystoniaasassociatedwith elevatedcorticalneuronal synchronizationsimilar toParkinson disease.Deepbrainstimulation, theyshow, iseffectivetoreduce cortical synchronization, thusprovidingabasis for their similar therapeutic responses to basal ganglia stimulation. Choi andcoauthors3 provideevidence thatDBSof the subcallosal cingulate in an acute intraoperative setting alters behaviors. Structural connectivity showed that “best” responses had a pattern of connections to bilateral ventromedial frontal cortexandcingulate cortex.Theseare remarkable findings that support their concept of defining the “Depression Switch.” English and Roth4 review the exciting, new, and rapidly expanding fieldofDesignerReceptorsExclusivelyActivatedby Designer Drugs (DREADS) and present evidence of its potential as a powerful tool to augment neuronal and glial signaling and activity with both basic and translational applications. Jonathan Mink, a speaker in the symposium, anticipates making a contribution to another JAMA Neurology theme issue on this subject. Circuits andcircuit disorders arenowshowntobe the fundamental basis for several neurological and psychiatric diseases including Alzheimer disease, Parkinson disease, isolated dystonia, amyotrophic lateral sclerosis, frontotemporal lobar degenerations, depression, Tourette disease, andobsessive-compulsive disorder. Modulation of the circuit abnormalities in thesedisorderswithDBS leading to effective therapieswas emphasized in the symposium and in this collection of articles. They create scientific insights and optimism supporting the view that rapid advances are expected, providing clinical benefit to many patients.