An advanced version¹ of the Gradient Echo Plural Contrast Imaging technique² is used to measure tissue-specific (R2*_t) and hemodynamic BOLD contributions to the gradient recalled echo (GRE) signal to detect changes in brain baseline hemodynamic activity and underlying tissue pathophysiology of subjects with bipolar disorder and schizophrenia.

The study was approved by Washington University's Institutional Review Board. Participant groups included: 17 healthy controls (CON); 17 bipolar disorder (BPD); 16 schizophrenia (SCZ) and 12 siblings (SIB) of individuals with SCZ who did not have a diagnosis of SCZ or BPD or any other DSM-IV psychotic disorder. Psychopathology was assessed using the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS)³. Specific subscale scores were summed to derive measures of positive symptoms (i.e. hallucination and delusion subscales), disorganization (i.e. formal thought disorder, bizarre behavior and attention subscales), and negative symptoms (i.e. flat affect, alogia, anhedonia and amotivation subscales). All scanning occurred on a 3 T TRIO Scanner (SIEMENS, Erlanger, Germany). GEPCI data were obtained using a 3D version of the multi-gradient echo sequence with a resolution = 1 × 1 × 3 mm³, FOV = 256 × 192 × 120 mm³, and 11 gradient echoes (min TE = 4 ms; ΔTE = 4 ms; TR = 50 ms; bandwidth = 510 Hz/Pixel; FA = 30°) was used, with a total acquisition time of 6.4 min. Additional phase stabilization echo (the navigator data) was collected for each line in k-space to correct for image artifacts due to the physiological fluctuations⁴. Effects of field inhomogeneities were removed using the voxel spread function (VSF) approach⁵. The data were then analyzed on a voxel-by-voxel basis using the following model¹:

$$S(TE)=A_{0}\cdot exp(-R2_C^*\cdot TE)\cdot F_{BOLD}\cdot F(TE)$$

$$F_{BOLD}(TE)=1-\frac{\zeta}{1-\zeta}\cdot f_{s}(\delta\omega\cdot TE)+\frac{\zeta}{1-\zeta}\cdot f_{s}(\zeta\cdot\delta\omega\cdot TE)$$

$$C_{DEOXY}=\zeta\cdot n_{Hb}\cdot Hct\cdot (1-Y)=\frac{3}{4}\cdot \frac{\zeta\cdot\delta\omega\cdot n_{Hb}}{\gamma\cdot\pi\cdot\triangle \chi_{0}\cdot B_{0}}$$

where TE is the gradient echo time, R2*_t = 1/T2*_t is the tissue transverse relaxation rate constant (describing GRE signal decay in the absence of BOLD effect), function F_BOLD(TE)⁶ describes GRE signal decay due to the presence of blood vessel network with deoxygenated blood (veins and adjacent to them part of capillaries), and function F(TE) describes the effects of macroscopic magnetic field inhomogeneities. We used the voxel spread function (VSF) method⁴ for calculating F(TE). ζ is the deoxygenated cerebral blood volume fraction (dCBV) and δω is the characteristic frequency determined by the susceptibility difference between deoxygenated blood and surrounding tissue. In the equation, Δχ₀=0.27 ppm⁷ is the susceptibility difference between fully oxygenated and fully deoxygenated blood, Y is the blood oxygenation level (with Y = 0 being fully deoxygenated, and Y = 1 being fully oxygenated), Hct is the blood hematocrit, and γ is the gyromagnetic ratio. Herein we describe BOLD effect in terms of integrated parameter C_DEOXY - tissue concentration of deoxyhemoglobin. Standard clinical MP-RAGE images and FreeSurfer (Martinos Center for Biomedical Imaging, Harvard) were used to get brain segmentation. R2*_t and C_DEOXY values for each ROI were defined as the median values within that ROI.

R2*_t values of the total white matter and cortical gray matter were not statistically significant (p= 0.3) for different groups. C_DEOXY median values used as dependent variables in an age corrected MANCOVA showed significant omnibus group effects. Mean C_DEOXY showed a tendency towards increased values in all three non-control groups. The percentage of ROIs with increased mean C_DEOXY compared to CON was 92.1% for SCZ, 71.1% for BPD and 81.6% for SIB. Increased superior temporal cortex C_DEOXY was found in SCZ (p=0.01), BPD (p=0.01) and SIB (p=0.02), with bilateral effects in SCZ and only left hemisphere effects in BPD and SIB. Thalamic C_DEOXY abnormalities were observed in SCZ (p = 0.003), BPD (p = 0.03) and SIB (p = 0.02). R2*_t and C_DEOXY group z-score means (SD) of the 32 gray matter ROIs parcellated using FreeSurfer are represented on the cortical surface in Fig. 1.In this study, we found increased C_DEOXY in the majority of ROIs of non-control participants, but most notably in the superior temporal cortex and thalamus. These findings could indicate that hyperactivity in these regions is part of the pathophysiology of schizophrenia and bipolar disorder. Developments in GEPCI and related relaxometric methodologies will likely provide more precise distinctions between underlying brain neuropathologies. Results of such studies could be valuable for selecting treatment and identifying those at risk for developing illness.