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Three-Compartment IVIM Model Applied to Psychotic Spectrum Disorders

Faye McKenna¹, Yu Veronica Sui¹, Hillary Bertisch¹, Donald Goff¹, and Mariana Lazar¹
¹New York University School of Medicine, New York, NY, United States

Synopsis

We applied a three compartment intravoxel incoherent motion (IVIM) technique that estimated the perfusion fraction (PF), free water (FW), and anisotropic diffusion of tissue (FAt) to detect microvascular and microstructural changes in a cohort of 54 psychotic spectrum disorder (PSD) patients compared to 35 healthy controls (HC). We found significantly increased PF, FW and FAt in PSD and PSD subtypes compared to HC, primarily in the frontal and temporal lobes and cingulate and insular cortices at multiple comparisons correction level. In patients, IVIM metrics were found to be associated with the duration of psychosis and performance on several cognitive tests.

Background

Previous research has suggested both perfusion and free water (FW) alterations in Psychotic Spectrum Disorders (PSD)^1–4, assessed independently of each other. An excess in FW, in particular, is established in PSD literature, and appears to change with disease progression^5,6. Perfusion abnormalities were also reported based on DSC or ASL imaging^7,8. However, the intravoxel incoherent motion (IVIM) method is a promising noninvasive technique that has been successfully applied to capture brain perfusion pathologies in several brain disorders and can be further modelled to include a FW and an anisotropic diffusion tissue compartment^9,10. The three compartment IVIM-FWI model is especially promising as it disentangles FW diffusion and perfusion. The estimation of each of these two metrics may be affected when the effects of the other are not taken into consideration¹⁰. Previous histological studies have suggested an array of microvascular and microstructural deficits likely to impact perfusion and FW in PSD, including increased inflammation, morphological differences in capillaries, and disruptions in the neurovascular unit cells and the blood brain barrier¹¹. The aim of this research is to evaluate, for the first time, if the three compartment IVIM-FWI model can describe microvascular and microstructural changes in PSD in both gray (GM) and white matter (WM). Additionally, we examined the relationships between the IVIM-FWI derived measures of perfusion fraction (PF), FW, and fractional anisotropy of tissue (FAt) and psychosis duration and cognition, which may inform upon the biological bases of PSD neuropathology and ultimately contribute to development of targeted treatment approaches.

Methods

Anatomical and diffusion MRI data were acquired for 54 PSD patients (16 schizophrenia, 20 schizoaffective, 18 bipolar with psychotic features), and 35 healthy comparison controls (HC) (men and women, 18-31 years old) using a 3T Prisma MRI scanner. A three-compartment IVIM-FWI model was implemented using DMIPY software⁸ to obtain FW, PF, and FAt metrics (Figure 1)^10,12. Mean gray and white matter FW, PF, and FAt were subsequently calculated bilaterally for the 4 cerebral GM lobes, sub-cortical WM lobes, and 34 cortical regions of interest (ROI) delineated by the Desikan-Killiany atlas¹. Independent t-test analyses and analyses of covariance that accounted for age, sex, pre-morbid IQ and cortical thickness were used to evaluate differences in IVIM-FWI metrics between PSD, PSD subtypes and HC participants in each ROI. Further analyses used Pearson’s and Spearman’s correlations to test whether IVIM metrics relate to the duration from psychosis onset and cognitive function, which was assessed using a battery of working and episodic memory and processing speed neuropsychological tests. The Benjamini-Hochberg (BH) procedure was employed in each analysis to correct for multiple comparisons and decrease the false discovery rate (FDR)¹⁴. Differences were considered significant for q < .05 BH FDR and at trend-level for p < .05.

Results

Controlling for age, sex, pre-morbid IQ and cortical thickness had no effect on group differences and therefore t-test results are presented here. Significant between-group differences were observed with: 1) significantly increased PF and FAt in GM lobar regions in PSD and PSD subtypes, and 2) significantly increased PF, FAt and FW in a number of GM and WM sub-cortical ROIs situated primarily in the frontal and temporal lobes and insular cortices in PSD and PSD subtypes (Figures 2 and 3). Significant positive relationships between PF and FAt with the duration of psychosis and significant negative relationships between FW and duration of psychosis were found in the schizophrenia spectrum disorder (SZA and SZ) subgroup in overlapping ROIs located primarily in the frontal and temporal lobes and insular and cingulate cortices (Figure 4). Furthermore, in patients but not in HC, increased PF in GM and WM and increased FAt in GM were significantly related to poor performance on several cognitive tests of memory and processing speed in the PSD group (Figure 5).

Discussion

Prior IVIM studies have documented the ability of this technique to quantify brain perfusion pathologies in neurological and neurovascular diseases, but until now IVIM has not been applied in PSD populations⁹. Results presented here suggest that a three compartment IVIM-FWI model, which disentangles the perfusion effects from free water, can be applied to quantify both perfusion and microstructural abnormalities in PSD. In addition, these microstructural and microvascular changes appear to progress with the duration of psychosis and be implicated in healthy memory and processing speed functions. The increased PF and FW in PSD and PSD subtypes may be due to alterations in neurovascular unit cells (microglia, astrocytes, pericytes and endothelial cells), increased inflammation, morphological differences in capillaries, and degeneration of the blood brain barrier¹¹. The increased FAt in PSD, specifically in GM, may be associated with increased glial proteins, which were noted to underlie increased FA in GM in other disorders¹⁵.

Conclusion

We demonstrate, for the first time, to the best of our knowledge, that the three compartment IVIM-FWI model can be applied to PSD to quantify abnormalities in perfusion, free water and anisotropy of tissue, and that these changes appear to progress with the duration of psychosis over the first decade from onset and affect healthy memory and processing speed. IVIM-FWI metrics may provide useful biomarkers of abnormal vasculature and microstructure and help elucidate neuropathology in psychiatric and neurological disorders.

Acknowledgements

This work was supported by the R01 MH108962 National Institute of Mental Health award. We greatly thank all of our participants for their help with this study and Researchmatch for supporting our recruitment efforts

References

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Figures

Figure 1. The three-compartmental IVIM-FWI model includes: 1) a compartment that represents the diffusion of brain tissue as a tensor (Dt), 2) a free-water compartment set to Dw = 3mm²/ms, and 3) a fast diffusivity blood compartment set to Df = 7mm²/ms¹⁰.

Figure 2. Group differences in IVIM a) PF, and b) FAt metrics in the left temporal lobe gray and white matter. T-tests were conducted between HC and PSD subtypes: SZA, SZ and BPF. Group differences that reached significance at the FDR BH q < .05 correction-level are noted with an asterisk (*). Plot a) illustrates that, in-line with previous research, PF of in gray matter is about twice as high as white matter therefore supporting the metrics’ validity¹⁶. There were no significant group differences in free water in the left temporal lobe.

Figure 3. Group differences between healthy controls and the PSD schizoaffective subtype in gray matter cortical areas in a) perfusion fraction (PF), b) free water (FW) and (c) fractional anisotropy of tissue (FAt) measures. Green indicates ROIs with significant differences at q < .05 FDR BH corrected, blue indicates ROIs with differences noted at p < .05.

Figure 4. Significant Pearson’s correlations between IVIM metrics (PF, FW and FAt) and the duration of psychosis in the PSD schizoaffective and schizophrenia subtypes in gray and white matter ROIs. All plots reached significance at the FDR BH q < .05 correction-level.

Figure 5. Gray and white matter regions that show significantly increased IVIM perfusion fraction (PF) and fractional anisotropy of tissue (FAt) in PSD relates to poor working memory (Spatial Span) and processing speed (Symbol Coding). Pearson’s r and Spearman’s rho are included on each plot. Significant correlations at q < .05 FDR BH corrected are noted with an asterisk (*).

Proc. Intl. Soc. Mag. Reson. Med. 29 (2021)

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