Decreased interhemispheric connectivity and increased cortical excitability in unmedicated schizophrenia: A prefrontal interleaved TMS fMRI study

Abstract

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 ¼ 0.0157; max z-score ¼ 4.7) and neighboring BA46 (p ¼ 0.019; max z-score ¼ 4.47). Controls showed more contralateral functional connectivity between left BA9 and right BA9 through increased activation in right BA9 (p ¼ 0.02; max z-score ¼ 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 ¼ 0.83, p ¼ 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.

Effects of Brain Atlases and Machine Learning Methods on the Discrimination of Schizophrenia Patients: A Multimodal MRI Study

“…The abnormalities in brain regions between SZ patients and NCs were primarily in the bilateral prefrontal cortex, right limbic system, left temporal cortex and left motor strip. While the findings on the prefrontal cortex (Janousova et al, 2015;Ou et al, 2015;Zhuang et al, 2019;Webler et al, 2020), limbic system (Shon et al, 2018;Abdolalizadeh et al, 2020;Falakshahi et al, 2020), and temporal cortex (Shu et al, 2012;Ehrlich et al, 2014;Schnack et al, 2014;Koch et al, 2018;Chatterjee et al, 2020) are aligned with previous studies, the discovery of differences in the motor strip has rarely been reported. The motor strip is imperative as the neural hub that participates in perception, action and anticipation in relation to the environment (Schroeder et al, 1994).…”

A Review of Studies Leveraging Multimodal TMS-fMRI Applications in the Pathophysiology and Treatment of Schizophrenia

“…A recent case-control study by Webler et al (2020) assessed for prefrontal excitability and interhemispheric functional connectivity using concurrent TMS/fMRI in schizophrenia patients and compared them with healthy controls. In both groups, resting motor threshold (RMT) was estimated at baseline and the left-sided DLPFC (Brodmann area 9) was then stimulated using 35 triplet TMS pulses at 100 ms apart (10Hz) at 0, 80, 100, and 120% of RMT in a randomized order.…”

“…The study found that schizophrenia patients showed hyperexcitability in left-sided BA9 and BA46 compared to healthy controls for equal TMS intensity. Also, on stimulating the left BA9, healthy controls showed increased right-sided BA9 activity compared to schizophrenia patients, thereby demonstrating impaired interhemispheric connectivity in the patients ( Webler et al, 2020 ).…”

“…While conducting studies that explore pathophysiology of schizophrenia, there are obvious difficulties in recruiting patients who are unmedicated and in acute phase of psychosis. It is not surprising that subjects in all studies in the current review barring one (Webler et al, 2020) were on antipsychotics at the time of assessment. Some of these studies excluded those on mood stabilizers and benzodiazepines at the time of assessment, while others had subjects who were on stable doses of benzodiazepines, mood stabilizers and antidepressants at the time of assessment.…”

Implementation of a TMS-fMRI system: A primer

“…Concurrent TMS-fMRI was first performed by (Bohning et al, 1997), and experiments have been on the rise in both healthy (Bohning et al, 1997; Nahas et al, 2001; Denslow et al, 2005; Bestmann et al, 2008b; de Vries et al, 2009; Moisa et al, 2009, 2010; Li et al, 2011; Ricci et al, 2012; Hanlon et al, 2013; Schintu et al, 2021; Oathes et al, 2021) and clinical populations (Li et al, 2004; Bestmann et al, 2006; de Vries et al, 2012; Webler et al, 2020). This is not surprising given that this multimodal approach allows to, not only examine the altered brain connectivity patterns of neurological and psychiatric patients but, also to investigate how local stimulation of focal brain regions can alter those same connectivity patterns, in vivo .…”