Cingulum bundle connectivity in treatment-refractory compared to treatment-responsive patients with bipolar disorder and healthy controls: a tractography and surgical targeting analysis

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  • 1 Department of Neurosurgery, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine;
  • | 2 Department of Psychiatry, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine;
  • | 3 Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine; and
  • | 4 Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio
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OBJECTIVE

The clinical response of patients with bipolar disorder to medical treatment is variable. A better understanding of the underlying neural circuitry involved in bipolar treatment responsivity subtypes may provide insight into treatment resistance and aid in identifying an effective surgical target for deep brain stimulation (DBS) specific to the disorder. Despite considerable imaging research related to the disease, a paucity of comparative imaging analyses of treatment responsiveness exists. There are also no DBS targets designed expressly for patients with bipolar disorder. Therefore, the authors analyzed cingulum bundle axonal connectivity in relation to cortico-striatal-thalamo-cortical (CSTC) loops implicated in bipolar disorder across subjects who are responsive to treatment (RSP) and those who are refractory to therapy (REF), compared to healthy controls (HCs).

METHODS

Twenty-five subjects with bipolar disorder (13 RSP and 12 REF), diagnosed using the Mini International Neuropsychiatric Interview and classified with standardized rating scales, and 14 HCs underwent MRI with diffusion sequences for probabilistic diffusion-weighted tractography analysis. Image processing and tractography were performed using MRTrix. Region of interest (ROI) masks were created manually for 10 anterior cingulum bundle subregions, including surgical targets previously evaluated for the treatment of bipolar disorder (cingulotomy and subgenual cingulate DBS targets). Cortical and subcortical ROIs of brain areas thought to be associated with bipolar disorder and described in animal tract-tracing models were created via FreeSurfer. The number of axonal projections from the cingulum bundle subregion ROIs to cortical/subcortical ROIs for each group was compared.

RESULTS

Significant differences were found across groups involving cingulum bundle and CSTC loops. Subjects in the RSP group had increased connections from rostral cingulum bundle to medial orbitofrontal cortex, which is part of the limbic CSTC loop, whereas subjects in the REF group had increased connectivity from rostral cingulum bundle to thalamus. Additionally, compared to HCs, both RSP and REF subjects had decreased cingulum bundle dorsal connectivity (dorsal anterior/posterior cingulate, dorsomedial/lateral frontal cortex) and increased cingulum bundle ventral connectivity (subgenual cingulate, frontal pole, lateral orbitofrontal cortex) involving limbic and associative CSTC loops.

CONCLUSIONS

Findings demonstrate that bipolar treatment responsivity may be associated with significant differences in cingulum bundle connectivity in relation to CSTC loops, which may help identify a surgical target for bipolar disorder treatment via DBS in the future.

ABBREVIATIONS

ACC = anterior cingulate cortex; CGI-S-BD = Clinical Global Impressions–Severity for bipolar disorder; CSTC = cortico-striatal-thalamo-cortical; dACC = dorsal anterior cingulate cortex; DBS = deep brain stimulation; dmFC = dorsomedial frontal cortex; DSM = Diagnostic and Statistical Manual of Mental Disorders; DWI = diffusion-weighted imaging; FP = frontal pole; HC = healthy control; lOFC = lateral orbitofrontal cortex; MADRS = Montgomery-Asberg Depression Rating Scale; mcOFC = medial/central orbitofrontal cortex; MINI = Mini International Neuropsychiatric Interview; OFC = orbitofrontal cortex; OLS = ordinary least squares; PCC = posterior cingulate cortex; REF = refractory to therapy; ROI = region of interest; RSP = responsive to therapy; sACC = subgenual anterior cingulate cortex; SDS = Sheehan Disability Scale; YMRS = Young Mania Rating Scale.

Schematics of transseptal interforniceal resection of a superiorly recessed colloid cyst. ©Mark Souweidane, published with permission. See the article by Tosi et al. (pp 813–819).

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