Circuit-based neurosurgery Surgical modalities that can precisely target particular regions of focal and well-localized dysconnectivity in the brain are currently being tested as a more circuit-specific approach to precision medicine in schizophrenia. Deep brain stimulation (DBS) has been a well-established targeted therapeutic approach that has been used to improve the treatment-resistant symptoms of Parkinson's disease, obsessive-compulsive disorder and treatment refractory depression (199–202). Neurosurgical DBS strategies are also now being considered to be used in ultra-resistant schizophrenia to target those relevant brain hubs that may improve the interconnectivity of relevant neuronal circuits. The implantation of electrodes into accessible anatomical nodes can be targeted to normalize or reset abnormal patterns of cortical network GBO activity that disrupt neural circuits. The stimulation settings of the electrodes can be titrated to tune the neurons to specific frequencies and recalibrate neuronal asynchrony. There is current interest in targeting several important network hubs using DBS in ultra-resistant schizophrenia involved in basal ganglia-thalamocortical and DLPFC brain circuits. Hubs identified include the hippocampus, ventral and associated striatum, medial and DLPFC, substantia nigra, nucleus accumbens and the mediodorsal nucleus of the thalamus (203–205). These hubs have been chosen primarily based on known pathological findings in schizophrenia and/or their interconnectedness to other brain hubs that are circuit-specific and related to the excessive and mistimed dopamine release in the striatum. Hippocampal dysfunction that drives downstream dopamine release in the striatum contributing to persistent positive symptoms is one of the clinical hallmarks for treatment-resistant disease (206). Currently there are two phase I DBS trials investigating this approach in ultra-resistant schizophrenia that are recruiting patients. The first trial at Hospital Santa Creu i Sant Pau in Barcelona (Clinicaltrials.gov Identifier: NCT02377505) is targeting electrode placement in either the nucleus accumbens or the subgenual ACC. The participants will be randomized to receive stimulation to either of these neuroanatomical sites with the stimulation remaining on until a full 6 months of stabilization is achieved. Those patients who are responsive will then be crossed-over to stimulation-on or stimulation-off groups for 3 months. The principal investigator, Dr. Iluminada Corripio has recently reported positive findings in the first subject who participated in this clinical trial. The patient had a long history of ultra-resistant schizophrenia-positive symptom domain refractory symptoms including manifestations of persecutory, control and delusions of reference. Her referential delusions had become so pronounced that she was unable to leave her home. The patient had a long treatment history typical of ultra-resistant schizophrenia including many trials with a number of different antipsychotic medications, including the use of clozapine (600 mg/day) with little benefit. The patient underwent bilateral electrode implantation in the nucleus accumbens and left-sided unilateral stimulation. Improvement was achieved in both positive and negative symptoms measured 4 weeks post-implantation and after 11 months of open treatment, the patient experienced over a 60% reduction in positive symptoms as measured by the positive symptoms subscale of the PANSS as well as a 33% reduction in negative symptoms, 50% reduction in the PANSS disorganization factor, 33% reduction in PANSS excited factor and 16.7% increase in the depressed factor. The patient continues to do well and is now able to leave her home and has made significant improvements to her overall functioning. For this patient with ultra-resistant schizophrenia, this DBS treatment option was of substantial benefit to otherwise untreatable refractory symptoms (207). The second DBS trial in ultra-resistant schizophrenia is out of Johns Hopkins University where the study team led by Dr. William Anderson will be recruiting three ultra-refractory patients and will be targeting the local inhibition of the substantia nigra pars reticulata (SNr), a major outflow nucleus of the basal ganglia with the intention of disinhibition and driving the activity of the mediodorsal nucleus of the thalamus (Clinicaltrials.gov Identifier: NCT02361554). The structure and hypofunction of the mediodorsal nucleus of the thalamus has been investigated in several imaging and post-mortem studies in schizophrenia (208). All of the DBS studies in ultra-resistant schizophrenia are only recruiting those patients who have exhausted all other therapeutic alternatives and continue to have severe and disabling clinical symptoms and poor functioning.