Rakshathi Basavaraju1, Dhruva Ithal1, Milind Vijay Thanki1, Arvinda Hanumanthapura Ramalingaiah2, Jagadisha Thirthalli3, Rajakumari P Reddy4, Roscoe O Brady5, Mark A Halko6, Nicolas R Bolo7, Matcheri S Keshavan8, Alvaro Pascual-Leone9, Urvakhsh Meherwan Mehta10, Muralidharan Kesavan11. 1. Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, India. 2. Department of Neuro Imaging and Interventional Radiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, India. 3. Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, Karnataka, India. 4. Department of Clinical Psychology, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, Karnataka, India. 5. Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. Electronic address: robrady@bidmc.harvard.edu. 6. Department of Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA, USA. Electronic address: MHALKO@mclean.harvard.edu. 7. Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. Electronic address: nbolo@bidmc.harvard.edu. 8. Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. Electronic address: mkeshava@bidmc.harvard.edu. 9. Hinda and Arthur Marcus Institute for Aging Research and Center for Memory Health, Hebrew Senior Life, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Guttmann Brain Health Institut, Institut Guttmann, Universitat Autonoma Barcelona, Spain. Electronic address: apleone@hsl.harvard.edu. 10. Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore 560029, Karnataka, India. Electronic address: urvakhsh@gmail.com. 11. Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore 560029, Karnataka, India. Electronic address: drmuralidk@gmail.com.
Abstract
OBJECTIVE: Negative symptoms of schizophrenia are substantially disabling and treatment resistant. Novel treatments like repetitive transcranial magnetic stimulation (TMS) need to be examined for the same using the experimental medicine approach that incorporates tests of mechanism of action in addition to clinical efficacy in trials. METHODS: Study was a double-blind, parallel, randomized, sham-controlled trial recruiting schizophrenia with at least a moderate severity of negative symptoms. Participants were randomized to real or sham intermittent theta burst stimulation (iTBS) under MRI-guided neuro-navigation, targeting the cerebellar vermis area VII-B, at a stimulus intensity of 100% active motor threshold, two sessions/day for five days (total = 6000 pulses). Assessments were conducted at baseline (T0), day-6 (T1) and week-6 (T2) after initiation of intervention. Main outcomes were, a) Scale for the Assessment of Negative Symptoms (SANS) score (T0, T1, T2), b) fronto-cerebellar resting state functional connectivity (RSFC) (T0, T1). RESULTS: Thirty participants were recruited in each arm. Negative symptoms improved in both arms (p < 0.001) but was not significantly different between the two arms (p = 0.602). RSFC significantly increased between the cerebellar vermis and the right inferior frontal gyrus (pcluster-FWER = 0.033), right pallidum (pcluster-FWER = 0.042) and right frontal pole (pcluster-FWER = 0.047) in the real arm with no change in the sham arm. CONCLUSION: Cerebellar vermal iTBS engaged a target belonging to the class of cerebello-subcortical-cortical networks, implicated in negative symptoms of schizophrenia. However, this did not translate to a superior clinical efficacy. Future trials should employ enhanced midline cerebellar TMS stimulation parameters for longer durations that can potentiate and translate biological changes into clinical effects.
OBJECTIVE: Negative symptoms of schizophrenia are substantially disabling and treatment resistant. Novel treatments like repetitive transcranial magnetic stimulation (TMS) need to be examined for the same using the experimental medicine approach that incorporates tests of mechanism of action in addition to clinical efficacy in trials. METHODS: Study was a double-blind, parallel, randomized, sham-controlled trial recruiting schizophrenia with at least a moderate severity of negative symptoms. Participants were randomized to real or sham intermittent theta burst stimulation (iTBS) under MRI-guided neuro-navigation, targeting the cerebellar vermis area VII-B, at a stimulus intensity of 100% active motor threshold, two sessions/day for five days (total = 6000 pulses). Assessments were conducted at baseline (T0), day-6 (T1) and week-6 (T2) after initiation of intervention. Main outcomes were, a) Scale for the Assessment of Negative Symptoms (SANS) score (T0, T1, T2), b) fronto-cerebellar resting state functional connectivity (RSFC) (T0, T1). RESULTS: Thirty participants were recruited in each arm. Negative symptoms improved in both arms (p < 0.001) but was not significantly different between the two arms (p = 0.602). RSFC significantly increased between the cerebellar vermis and the right inferior frontal gyrus (pcluster-FWER = 0.033), right pallidum (pcluster-FWER = 0.042) and right frontal pole (pcluster-FWER = 0.047) in the real arm with no change in the sham arm. CONCLUSION: Cerebellar vermal iTBS engaged a target belonging to the class of cerebello-subcortical-cortical networks, implicated in negative symptoms of schizophrenia. However, this did not translate to a superior clinical efficacy. Future trials should employ enhanced midline cerebellar TMS stimulation parameters for longer durations that can potentiate and translate biological changes into clinical effects.
Authors: Alvaro Pascual-Leone; Catarina Freitas; Lindsay Oberman; Jared C Horvath; Mark Halko; Mark Eldaief; Shahid Bashir; Marine Vernet; Mouhshin Shafi; Brandon Westover; Andrew M Vahabzadeh-Hagh; Alexander Rotenberg Journal: Brain Topogr Date: 2011-08-14 Impact factor: 3.020
Authors: N C Andreasen; D S O'Leary; T Cizadlo; S Arndt; K Rezai; L L Ponto; G L Watkins; R D Hichwa Journal: Proc Natl Acad Sci U S A Date: 1996-09-03 Impact factor: 11.205
Authors: Aristotle N Voineskos; George Foussias; Jason Lerch; Daniel Felsky; Gary Remington; Tarek K Rajji; Nancy Lobaugh; Bruce G Pollock; Benoit H Mulsant Journal: JAMA Psychiatry Date: 2013-05 Impact factor: 21.596