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Structural correlates of trait anxiety: Volume reduction in hypothalamus1NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (INMAS), Delhi, India
Synopsis
Trait anxiety affects brain functioning and cognition as suggested by various neuroimaging and behavioural studies. It is also a a prone phenotype for the development of psychiatric disorders. Therefore, in order to identify individuals that are at risk for the development of clinical anxiety disorders and depression, identifying hallmarks of trait anxiety becomes important, to fascilitate timely preventive interventions. We investigated the structural correlates of trait anxiety in healthy participants using high resolution structural MRI. Results suggest that a reduction in the gray matter volumes of the hypothalamus may be putative imaging marker for trait anxiety.
Introduction
According to the reports of Anxiety and Depression Association of America, anxiety disorders are the most common mental illness in the US affecting around 18% of the population costing almost one-third of the country’s medical bill (approx. $42 billion a year).Trait anxiety (as measured by Spielberger's State-Trait Anxiety Inventory (STAI)), an individual's disposition to experience anxiety-relevant feelings or thoughts, is particularly a prone phenotype for the development of psychiatric disorders (Spielberger, 1983;Sandi and Richter-Levin, 2009; Greening and Mitchell, 2015). Studying the neural underpinnings of trait anxiety may help in identifying a putative biomarker for trait anxiety. In this study, we investigated the structural correlates of trait anxiety in healthy participants.Materials and Methods
High resolution structural images were acquired from 76 right-handed healthy participants using 3T whole-body MRI system (Magnetom Skyra, Siemens) with a 20-channel head and neck coil and 45 mT/ m actively-shielded gradient system. Data were preprocessed using statistical parametric mapping (SPM8) . All the steps were carried out as suggested by Ashburner, 2010 (www.fil.ion.ucl.ac.uk/~john/misc/VBMclass10.pdf). Gray matter (GM) volumes were extracted from a priori regions of interest (ROIs) that were earlier implicated in anxiety like behaviour (i.e., hippocampus, amygdala, anterior cingulate cortex (ACC), thalamus, hypothalamus, dorsolateral prefrontal cortex (DLPFC), rostrolateral prefrontal cortex (RLPFC) and ventrolateral prefrontal cortex (VLPFC)) using the WFU Pickatlas. The extracted GM volumes were normalized by dividing them with total intracranial volumes of the individual subjects. An index of the adjusted volume for each ROI was obtained by multiplying the normalized volumes with 100. Partial correlation analysis was carried out between the normalized adjusted GM values from various ROIs and the trait anxiety scores of the subjects, with age, sex, and Beck Depression Inventory (BDI) score of each subject as covariates of no interest. Hierarchical multiple regression analysis was conducted with the normalized adjusted GM volumes of all the ROIs as predictors and trait anxiety scores as predicted variable. Controlling for the effects of age, sex, sub-clinical depression (BDI scores), anxiety group (median split on the basis of trait anxiety score) (high anxiety group (N = 41, trait anxiety score = 38-57) vs lower anxiety group (N = 35, trait anxiety score = 21-37)) and normalized adjusted GM volumes of all the ROIs were analyzed with Multivariate Analysis of COVAriance (MANCOVA) using general linear model .Results
Descriptive statistics for self-report measures are as: Trait anxiety score (STAI-Y2) = 38.18 + 8.22 (range 21 - 57); BDI = 6.92 + 3.37 (range 0 - 12). Trait anxiety was found to be negatively correlated with the GM volume of hypothalamus (N = 76; r = -0.336, p = 0.004; 2-tailed). BDI score (p=0.000), age (p=0.037), sex (p=0.013) and GM volume of hypothalamus (p=0.012) were found to be significant predictors of trait anxiety using hierarchical regression analysis. MANCOVA showed that the group (high/low trait anxiety) had a partially significant effect on GM volumes of the ROIs (Wilk’s Lambda = 0.814, F (8, 64) = 1.825, p= 0.089, partial h2 = 0.186). The univariate results showed that the GM volume in hippocampus and hypothalamus was lower in high trait anxiety group (N = 41) as compared to low trait anxiety group (N=35) (hippocamous: F = 5.245, p = 0.025; hypothalamus: F = 5.388, p = 0.023).Discussion
To the best of our knowledge, the current study is the first to link higher levels of trait anxiety in healthy young adults to smaller GM volumes in the hypothalamus. The finding is in lines with the findings in an earlier study in patients with generalized anxiety disorders (GAD) (Terlevic et al., 2013). According to the authors the patients with GAD are subjected to a higher cumulative dose of cortisol that might be associated with worrying thoughts and an abnormal hypothalamic pituitary axis (HPA) axis activation. Hypothalamic corticotropin-releasing hormone (CRH) has been known to regulate neuroendocrine functions such as adrenal glucocorticoid release (Zhang et al., 2017). Authors speculated that the increased levels of circulating glucocorticoids (GCs) in the paraventricular nucleus of the hypothalamus might result in a reduction in the hypothalamic volumes through the action on glucocorticoid receptors and finally leading to neuronal atrophy, neurotoxicity and neuroendangerment. The similarity between the findings obtained in the current study on healthy individuals and previous findings obtained in GAD patients suggests that subclinical and clinical populations might share the mechanisms linking anxiety and hypothalamic brain volumes. Thus, studying the healthy population that is at risk of developing affective disorders can further inform our understanding of the etiology of these disorders (Montag et al., 2013) and may help in designing strategies to mitigate them.Acknowledgements
The work was supported by R&D Project No. INM 311 of Defence R&D Organisation, Ministry of Defence, India.References
1. Spielberger CD, 1983. Manual for the state-trait anxiety inventory. Palo Alto, CA: Consulting Psychologists Press.
2. Sandi C, Richter-Levin G, 2009. From high anxiety trait to depression: a neurocognitive hypothesis. Trends in Neuroscience 32 (6), 312-320.
3.Greening SG, Mitchell DGV, 2015. A Network of Amygdala Connections Predict Individual Differences in Trait Anxiety. Human Brain Mapping 36,4819–4830.
4. Terlevic R, Isola M, Ragogna M, Meduri M, Canalaz F, Perini L, Rambaldelli G, Travan L, Crivellato E, Tognin S, Como G, Zuiani C, Bazzocchi M, Balestrieri M, Brambilla P, 2013. Decreased hypothalamus volumes in generalized anxiety disorder but not in panic disorder. Journal of Affective Disorders 146(3), 390-4.
5. Zhang R , Asai M, Mahoney CE , Joachim M, Shen Y, Gunner G, Majzoub JA , 2017. Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice. Molecular Psychiatry 22, 733-744.
6. Montag C, Reuter M, Jurkiewicz M, Markett S, Panksepp J, 2013. Imaging the structure of the humananxious brain: a review of findings from neuroscientificpersonality psychology. Reviews in Neuroscience 24,167–190.
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