Exploring brain temperature and free water as markers of neuroinflammation in major depression

462 

Abstract Submission 

Ben Moloney¹, Anna Forsyth¹, Rachael Sumner¹, Nicholas Hoeh¹, Frederick Sundram¹, Suresh Muthukumaraswamy¹, Joanne Lin¹

¹University of Auckland, Auckland, New Zealand

Ben Moloney  
University of Auckland
Auckland, New Zealand

Anna Forsyth  
University of Auckland
Auckland, New Zealand

Rachael Sumner  
University of Auckland
Auckland, New Zealand

Nicholas Hoeh  
University of Auckland
Auckland, New Zealand

Frederick Sundram  
University of Auckland
Auckland, New Zealand

Suresh Muthukumaraswamy  
University of Auckland
Auckland, New Zealand

Joanne Lin  
University of Auckland
Auckland, New Zealand

Major depressive disorder (MDD) is a psychiatric condition affecting over 300 million people worldwide (World Health Organization, 2017). MDD is characterized by persistently low mood and motivation, loss of interest in activities, and, in severe cases, suicidality. Inflammation is thought to play a role in worsening depressive symptoms and inhibiting response to antidepressant medications through direct effects on the brain (Miller & Raison, 2016). However, current methods for measuring inflammation inside the brain, like lumbar puncture and positron emission tomography (PET) imaging, are invasive and not clinically feasible. Measuring neuroinflammation in vivo may allow for the a precise diagnosis and treatment of MDD cases with an inflammatory component than would otherwise be achievable by measuring peripheral inflammation. Regional brain temperature and metabolite concentrations measured using magnetic resonance spectroscopy (MRS) and diffusion metrics derived from neurite orientation density and dispersion index imaging (NODDI), such as free water, are sensitive to neuroinflammation and so may be clinically useful in identifying and monitoring it in MDD (Oestreich & O'Sullivan, 2022; Plank et al., 2022). This exploratory study aims to determine if there is a difference between these markers in the anterior cingulate cortex (ACC) and right insula in MDD compared to controls and whether this is associated with chronic low-grade peripheral inflammation.

Participants with MDD (n=25) who were moderately depressed and receiving pharmacological antidepressant therapy and healthy controls (n=13) were recruited. Participants with MDD were stratified into low and high peripheral inflammation subgroups based on their serum high-sensitivity C-reactive protein (hs-CRP) being consistently ≤ 1 mg/L or ≥ 3mg/L, respectively. MRS and diffusion-weighted imaging data were collected on a 3T Siemens Vida Fit scanner for each participant. Local temperature and N-acetyl aspartate, myoinositol, and choline levels relative to total creatine were measured in voxels placed in the dorsal anterior cingulate cortex (dACC) and right anterior insula. NODDI metrics, including the cerebrospinal fluid (CSF) volume fraction, a measure of free water, were extracted from the anterior cingulate gyrus and the right insula using masks derived from the Harvard-Oxford cortical structural atlas (Desikan et al., 2006). Metrics between MDD and control groups were compared using two-tailed independent sample t-tests. For metrics that differed significantly between groups, post-hoc comparisons were carried out between low and high peripheral inflammation MDD subgroups.

Data from 23 participants in the MDD group and 12 participants in the control group were included in MRS analyses, and data from all participants were included in NODDI analyses. Participants in the MDD group (M=38.45, SD=0.43) exhibited significantly higher temperature in the dACC than the control group (M = 38.09, SD = 0.31), t(29) = -2.78, p=0.009. The CSF volume fraction was also significantly higher in the anterior cingulate gyrus of the MDD group (M = 0.036, SD = 0.011) than the control group (M=0.026, SD=0.008), t(32) = -3.19, p = 0.003. No significant difference between these markers in the low and high peripheral inflammation MDD subgroups was identified.

These results indicate that neuroinflammation may be occurring in the ACC in MDD, and that this may not be reflected by consistently elevated serum hs-CRP. This finding is consistent with post-mortem and positron emission tomography studies identifying neuroinflammation in the ACC in MDD (Enache et al., 2019). To further investigate ACC temperature and free water as markers of neuroinflammation in MDD, longitudinal research is required that tests them in relation to the effects of central nervous system anti-inflammatories and elucidates relationships with symptom profiles and outcomes for patients.

Psychiatric (eg. Depression, Anxiety, Schizophrenia) ¹

Diffusion MRI Modeling and Analysis ²

Diffusion MRI

MR Spectroscopy

Affective Disorders

Cerebro Spinal Fluid (CSF)

DISORDERS

Magnetic Resonance Spectroscopy (MRS)

MR SPECTROSCOPY

MRI

Psychiatric

Psychiatric Disorders

STRUCTURAL MRI

Other - Major depressive disorder; Diffusion weighted imaging; Inflammation