Patients with schizophrenia (SCZ) have a high rate of tobacco smoking and pharmacotherapies have shown limited benefit so far. This is of great concern, considering the high mortality and morbidity in this population. Deep repetitive transcranial magnetic stimulation (rTMS) of insular and prefrontal cortices at high frequency, using the H4 coil - termed also the H-ADD coil, has shown benefit in a study in healthy smokers in reducing smoking and achieving abstinence. Within this R21/R33 mechanism we propose to test high frequency stimulation of the insula in the treatment of tobacco smoking in patients with SCZ. In the R21 phase we will test the effects of 3 weeks of daily rTMS stimulation (versus sham) to the insula and other cortical regions on the choice to self-administer tobacco in 30 patients with schizophrenia who are also heavy smokers, using a laboratory model of tobacco choice to detect a therapeutic effect. We will also assess target engagement of the insula by examining treatment induced changes in insula cerebral blood flow (CBF) measured with arterial spin labeled (ASL) MRI imaging from pre to post treatment. In addition, we will measure the resting state functional connectivity (rsFC) of the insula before and after treatment, to search for a potential circuitry based biomarker as a correlate of the therapeutic effect. The overall hypothesis is that deep rTMS with the H-ADD coil will engage the insula (target engagement measured with decrease in CBF) and that 3 weeks of high frequency rTMS administration will reduce the choice to self-administer tobacco. We further propose that this therapeutic effect could be mediated by a change in the FC of the insula. If we measure significant changes in ASL and in choice of cigarettes in active vs sham stimulation groups, we will proceed to phase 2 (R33) of the project. In the R33 phase 30 patients will receive active deep rTMS and thirty will receive sham. We will test the effects of deep rTMS on tobacco abstinence at 6 months and test whether insula rsFC change induced by rTMS predicts therapeutic response.
Patients with schizophrenia have a high rate of tobacco smoking, which is detrimental to their health. Here we will test in two stages the potential benefit of deep neurostimulation targeting the insula to reduce smoking in patients with schizophrenia. First we will evaluate behavioral effects using a cigarette selfadministration laboratory model and show that treatment targets the insula using MRI imaging of insula blood flow and, if successful, then we will test efficacy in reaching tobacco abstinence.
