Background: Prefrontal abnormalities in schizophrenia have consistently emerged from resting state and cognitive neuroimaging studies. However, these correlative findings require causal verification via combined imaging/stimulation approaches. To date, no interleaved transcranial magnetic stimulation and functional magnetic resonance imaging study (TMS fMRI) has probed putative prefrontal cortex abnormalities in schizophrenia. Objective: /Hypothesis: We hypothesized that subjects with schizophrenia would show significant hyperexcitability at the site of stimulation (BA9) and decreased interhemispheric functional connectivity. Methods: We enrolled 19 unmedicated subjects with schizophrenia and 22 controls. All subjects underwent brain imaging using a 3T MRI scanner with a SENSE coil. They also underwent a single TMS fMRI session involving motor threshold (rMT) determination, structural imaging, and a parametric TMS fMRI protocol with 10 Hz triplet pulses at 0, 80, 100 and 120% rMT. Scanning involved a surface MR coil optimized for bilateral prefrontal cortex image acquisition. Results: Of the original 41 enrolled subjects, 8 subjects with schizophrenia and 11 controls met full criteria for final data analyses. At equal TMS intensity, subjects with schizophrenia showed hyperexcitability in left BA9 (p = 0.0157; max z-score = 4.7) and neighboring BA46 (p = 0.019; max z-score = 4.47). Controls showed more contralateral functional connectivity between left BA9 and right BA9 through increased activation in right BA9 (p = 0.02; max z-score = 3.4). GM density in subjects with schizophrenia positively correlated with normalized prefrontal to motor cortex ratio of the corresponding distance from skull to cortex ratio (S-BA9/S-MC) (r = 0.83, p = 0.004). Conclusions: Subjects with schizophrenia showed hyperexcitability in left BA9 and impaired interhemispheric functional connectivity compared to controls. Interleaved TMS fMRI is a promising tool to investigate prefrontal dysfunction in schizophrenia.
Bibliographical noteFunding Information:
On the day of scanning, subjects were not allowed to smoke for at least 1 h before image acquisition. This study was funded by the NIMH (R21- MH065630-01A1) and approved by the Medical University of South Carolina Institutional Review Board.We conducted 4 s-level unpaired t-tests with ROIs for bilateral BA9 and 46. Our primary hypothesis outlined in our R21-NIMH grant proposal was to compare BOLD signal in left BA9 (area stimulated with TMS) between unmedicated subjects with schizophrenia and healthy controls. Secondary analyses investigated differences in activation in adjacent cortical regions (ipsilateral BA46) and contralateral BA9 and BA46.Study funded by NIMH MH065630-01A1 (ZN). The authors would like to thank Drs. Scott Christie and Patricia Nnadi and their clinical teams; Crisis Ministries Homeless Shelter, Charleston, SC; and the South Carolina Department of Mental Health for their assistance in recruiting subjects. The investigators would also like to thank Mr. Dave Ramsey, Mr. John Walker and Dr. Jejo Koola for their technical support.
Study funded by NIMH MH065630-01A1 (ZN) . The authors would like to thank Drs. Scott Christie and Patricia Nnadi and their clinical teams; Crisis Ministries Homeless Shelter, Charleston, SC; and the South Carolina Department of Mental Health for their assistance in recruiting subjects. The investigators would also like to thank Mr. Dave Ramsey, Mr. John Walker and Dr. Jejo Koola for their technical support.
- Functional connectivity
- Interleaved TMS fMRI
- Prefrontal cortex