Bipolar disorder: an association between body mass index and cingulate gyrus fractional anisotropy not mediated by systemic inflammation

Abstract Objective To investigate associations between body mass index (BMI), white matter fractional anisotropy (FA), and C-reactive protein (CRP) in a group of individuals with bipolar disorder (BD) during euthymia and compare them with a control group of healthy subjects (CTR). Methods The sample consisted of 101 individuals (BD n = 35 and CTR n = 66). Regions of interest (ROI) were defined using a machine learning approach. For each ROI, a regression model tested the association between FA and BMI, controlling for covariates. Peripheral CRP levels were assayed, correlated with BMI, and included in a mediation analysis. Results BMI predicted the FA of the right cingulate gyrus in BD (AdjR2 = 0.312 F(3) = 5.537 p = 0.004; β = -0.340 p = 0.034), while there was no association in CTR. There was an interaction effect between BMI and BD diagnosis (F(5) = 3.5857 p = 0.012; Fchange = 0.227 AdjR2 = 0.093; β = -1.093, p = 0.048). Furthermore, there was a positive correlation between BMI and CRP in both groups (AdjR2 = 0.170 F(3) = 7.337 p < 0.001; β = 0.364 p = 0.001), but it did not act as a mediator of the effect on FA. Conclusion Higher BMI is associated with right cingulate microstructure in BD, but not in CTR, and this effect could not be explained by inflammatory mediation alone.


Introduction
Obesity is disquietingly common among individuals living with bipolar disorder (BD). 1,2 Higher body mass index (BMI) is not only associated with increased cardiovascular risk, 3 but is also associated with illness severity, with worse global functioning status, and with cognitive impairment, 4,5 possibly through damage to neural substrates. 6 Compromised white matter (WM) integrity estimated by fiber fractional anisotropy (FA) could be a candidate pathway for such deficits. 7,8 The association between BMI and FA has been previously explored in the context of mood episodes in BD. 9,10 During depression, BMI is associated with structural connectivity in cortico-limbic networks. 9 Following the first episode of mania, the main findings are disruptions in right parietal, temporal, and occipital regions of overweight and obese patients. 10 To our knowledge, there are no studies in euthymic patients. Although abnormalities during euthymia are less pronounced, they seem to reflect long-term and possibly irreversible structural damage and act as more stable markers in BD. 11 Although the association between BMI and WM microstructure has been described previously, 9,10 the neurobiological pathway linking this association with conditions remains unclear. The authors discussed a possible inflammatory process, but no inflammatory markers were actually assayed. 9,10 C-reactive protein (CRP) is a sensitive marker of peripheral inflammation that has been extensively reported in obesity. 12 Also, it has already been associated with WM microstructural damage in severe mental illness, 13 so it constitutes a promising candidate to test the hypothesis of inflammatory damage in obese bipolar patients.
We hypothesize that obese individuals with BD in a euthymic phase present WM microstructural damage related to BMI, as a possible consequence of an unbalanced allostatic and pro-inflammatory profile. 4 Therefore, this is a proof-of-concept study that aims to: 1) investigate associations between BMI and FA in individuals with BD during euthymia in comparison with a control group of healthy individuals (CTR) and 2) test whether any possible association is mediated by inflammation measured by CRP.

Results
The sample groups did not differ in age, smoking status, or years of education, as summarized in Table 1.

Discussion
The results of this study point to an association between BMI and decreased FA in the right cingulate gyrus of individuals with BD, but not in CTR. This association could indicate WM microstructural damage in this region. 18 Decreased cingulate FA is one of the most consistent findings in BD. 18,19 Loss of integrity in this structure is highly deleterious considering its central role of connection in the limbic system. 18 Its posterior portion subserves an integrative network of cognitive tasks, top-down attentional control, visual processing, and memory systems for recognition, 20 while the anterior portion is fundamental for the processing of executive functions related to emotional and visceromotor stimuli. 21 Indeed, the cingulum links together regions critical for these processes, including the cingulate cortex, the ventral visual stream, and the hippocampal complex. 20 In sum, decreased FA in association fibers such as the cingulate gyrus provide evidence of WM dysconnectivity in BD, 17  One possible explanation for the lack of mediation effect of CRP on the FA of cingulate fibers is that our BD sample was out of episode during the assessment, when inflammation may decrease. 8,11 Our hypothesis was that even in recovery obese patients would present higher inflammatory status, which was not confirmed.
We also found a positive association between BMI and the left corticospinal tract among both BD and CTR.
In contrast to right cingulate fibers, corticospinal tracts are reported to have higher FA in BD than in the general population. 22 Higher FA in this essentially motor tract could perpetuate deficits in motor inhibition, 17 which in turn can contribute to behavioral features observed in obese BD as they struggle with inhibition of exaggerated physical and emotional responses. 23 There are important limitations to address in the present study. The lack of association with BMI in CTR should be interpreted with caution, because of limited variability of BMI among this CTR sample. Compromised WM has been described in larger obese non-psychiatric populations. 7 The cross-sectional design of this study does not allow inferences about causality and this limitation cannot be adequately mitigated without a longitudinal follow-up. The sample size was modest, which limited the possibility of including more covariates and performing sensitivity analyses. Also, patients were on continuous use of medications that might influence the integrity of the neural bundles, 24 such as anticonvulsants and antipsychotics, which we could not control for because of the small sample size.
Nonetheless, we were able to control for lithium use.
In summary, we found that BMI was associated with WM microstructure in euthymic bipolar patients.