Studies suggest that speech processing areas of the brain play an important role in producing auditory hallucinations (AHs). The PI has reported that delivering 1-Hertz repetitive transcranial magnetic stimulation (rTMS) to the left temporoparietal cortex - a brain region underlying speech perception - produces statistically significant improvements in AHs relative to sham simulation. In a follow-up study, the PI used individualized fMRI maps of abnormal speech processing neurocircuitry to position rTMS in multiple cortical sites, and has found that targeting Wernicke's region and a homologous right-sided region in the superior temporal gyrus (STG) optimized clinical improvement of AHs. The proposed study will enroll 90 patients with a diagnosis of schizophrenia and medication-resistant AHs in a more extended, double- masked rTMS trial. Stimulation will be positioned using structural MRI over the left Wernicke's site and right-sided STG site previously found to have optimized clinical response.
Specific Aim #1 is to demonstrate that MRI-positioned 1-Hz rTMS, delivered to the Wernicke's and right STG sites, each for 5 sessions in randomized order, results in greater clinical improvement in AHs compared to sham stimulation.
Specific Aim #2 is to determine if alterations in cerebral laterality predict optimal hemisphere of stimulation in reducing AHs, and the degree of improvement elicited by rTMS at each of the two sites.
Specific Aim #3 is to demonstrate that a third 5-session series of active rTMS directed to the left/right site found to optimize clinical improvement in the first 10 sessions produces greater improvements in AHs compared to sham stimulation positioned according to the same algorithm.
Specific Aim #4 is to demonstrate prospectively that a higher level of hallucination frequency at baseline is a statistical moderator of 1-Hz rTMS in reducing AHs. This study will provide critical information regarding positioning strategies that optimize rTMS for AHs, as well as new insights regarding underlying pathophysiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH073673-05
Application #
7755391
Study Section
Special Emphasis Panel (ZMH1-ERB-D (06))
Program Officer
Hillefors, MI
Project Start
2006-02-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$292,474
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Ford, Judith M; Morris, Sarah E; Hoffman, Ralph E et al. (2014) Studying hallucinations within the NIMH RDoC framework. Schizophr Bull 40 Suppl 4:S295-304
Hoffman, Ralph E; Wu, Kun; Pittman, Brian et al. (2013) Transcranial magnetic stimulation of Wernicke's and Right homologous sites to curtail ""voices"": a randomized trial. Biol Psychiatry 73:1008-14
Allen, Paul; Modinos, Gemma; Hubl, Daniela et al. (2012) Neuroimaging auditory hallucinations in schizophrenia: from neuroanatomy to neurochemistry and beyond. Schizophr Bull 38:695-703
Hoffman, Ralph E; Pittman, Brian; Constable, R Todd et al. (2011) Time course of regional brain activity accompanying auditory verbal hallucinations in schizophrenia. Br J Psychiatry 198:277-83
Hoffman, Ralph E; Fernandez, Thomas; Pittman, Brian et al. (2011) Elevated functional connectivity along a corticostriatal loop and the mechanism of auditory/verbal hallucinations in patients with schizophrenia. Biol Psychiatry 69:407-14
Hoffman, Ralph E; Hampson, Michelle (2011) Functional connectivity studies of patients with auditory verbal hallucinations. Front Hum Neurosci 6:6
Hoffman, Ralph E (2010) Revisiting Arieti's ""listening attitude"" and hallucinated voices. Schizophr Bull 36:440-2
Kennedy, J Phillip; Bridges, Thomas M; Gentry, Patrick R et al. (2009) Synthesis and structure-activity relationships of allosteric potentiators of the m(4) muscarinic acetylcholine receptor. ChemMedChem 4:1600-7
Bridges, Thomas M; Marlo, Joy E; Niswender, Colleen M et al. (2009) Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins. J Med Chem 52:3445-8
Hoffman, Ralph E (2007) A social deafferentation hypothesis for induction of active schizophrenia. Schizophr Bull 33:1066-70