Correlations between peripheral levels of inflammatory mediators and frontolimbic structures in bipolar disorder: an exploratory analysis

Abstract

Background Altered peripheral immune/inflammatory system and brain volumetric changes have been implicated in the pathophysiology of bipolar disorder (BD). This study aimed to evaluate how peripheral levels of cytokines are related to volumetric brain changes in euthymic patients with BD. Methods Euthymic patients with BD (n = 21) and healthy controls (n = 22) were enrolled in this exploratory study. Blood samples were collected on the same day of clinical assessment and neuroimaging. Cytokines were measured through cytometric bead array method. Neuroimaging data were acquired using a sagittal three-dimensional magnetic resonance imaging T1-weighted fast field echo sequence and was processed using FreeSurfer. Results Compared to controls, BD patients had significantly lower volumes in the cingulate, medial-orbitofrontal (MOF) and parahippocampal regions. We found a negative correlation between right MOF volume and interferon-gamma levels (β = −0.431, P = .049) and a positive correlation between interleukin-10 levels and left posterior cingulate volume (β = 0.457, P = .048). Conclusion Our results support the involvement of inflammatory pathways in structural brain changes in BD.

Structural and functional MRI correlates of inflammation in bipolar disorder: a systematic review

“…However, reviewing the studies on structural MRI, we qualitatively observe a tendency toward proinflammatory markers being more often associated with reduced volumes in several brain regions involved, for instance, in emotion regulation and somatomotor processing (Andreou et al, 2021;Bai et al, 2020;Chen et al, 2019;Mohite et al, 2021;Poletti et al, 2019;Tu et al, 2017), while anti-inflammatory ones were sometimes associated with larger volumes in different brain regions regulating affective processing (Mohite et al, 2021;Savitz et al, 2015). These findings might support the hypothesis of the neurotoxic effects of inflammation (Baharikhoob and Kolla, 2020;Benedetti et al, 2020;Giorgi et al, 2020Giorgi et al, , 2019Kim and Won, 2017;Saccaro et al, 2022), both peripheral and central (Felger, 2018), which may impact the volume of certain brain regions during development, or in adults, since, for instance, hippocampal adult neurogenesis may be affected by inflammation in animal models (Chesnokova et al, 2016;Haarman et al, 2016;Zonis et al, 2015) and in adult patients with schizophrenia, as suggested by indirect evidence on neurogenesis and inflammatory markers (Chesnokova et al, 2016;North et al, 2021).…”

“…It should be noted that the samples of around 70 BD patients recruited in these two studies (Bai et al, 2020;Tu et al, 2017) are likely to be highly overlapping, although they are not identical. Another study on 21 BD patients identified a weakly significant (p=0.049) negative correlation between IFN-γ (a pro-inflammatory cytokine) and the volume of the right medialorbito-frontal cortex (OFC) (Mohite et al, 2021). Similarly, Chen et al (Chen et al, 2019) report a negative correlation between sIL-6R levels and OFC volume (as well as the volumes of lingual gyrus, inferior frontal cortex, middle frontal cortex, and planum polare).…”

“…On the contrary, one study showed a weakly significant positive correlation between indices of neuroprotective kynurenine metabolites and hippocampal (p = 0.048) or amygdala volume (not significant after controlling for covariates) in 63 BD patients (Savitz et al, 2015). Another study identified a weakly significant (p=0.048) positive correlation between the anti-inflammatory cytokine IL-10 and left Posterior-Cingulate cortex volume in 21 BD patients (Mohite et al, 2021).…”

“…17 studies (Andreou et al, 2021;Bai et al, 2020;Bond et al, 2020;Chen et al, 2019;M. H. Chen et al, 2020;Chung et al, 2013;Hoseth et al, 2016;Lesh et al, 2018;Mansur et al, 2020;Mohite et al, 2021;Papiol et al, 2008;Poletti et al, 2019;Quidé et al, 2021;Savitz et al, 2015;Shonibare et al, 2020;Strenn et al, 2021;Tu et al, 2017) focused on the link between immune and inflammatory traits or markers, and structural MRI abnormalities in BD patients, contributing data from 1060 BD patients (985 plus 75 from the only study on both MRI techniques (Tu et al, 2017)). The majority of these studies present results on positive or negative correlations of pro-or anti-inflammatory markers with cortical thickness, white or gray matter (WM or GM) volumes of different brain regions.…”

“…Of note, numerous studies reported the absence of correlations between brain regions volumes and levels of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) (Lesh et al, 2018;Mohite et al, 2021;Quidé et al, 2021) Regarding negative correlations between anti-inflammatory markers and brain regions volumes (i.e. lower brain regions volumes associated with higher levels of anti-inflammatory markers), a recent study found a negative correlation between sTNF-R1 (an immunoregulatory cytokine) levels and GM volume in 10 areas (right: cerebellum, putamen, superior frontal gyrus, fusiform gyrus, pre-cuneus; left: putamen, lingual gyrus, precentral gyrus, calcarine and, inferior temporal gyrus) in 75 BD patients, compared with Major Depressive Disorder patients (p<0.05) (Bai et al, 2020).…”