Neuroimaging Biomarkers in Generalised Anxiety Disorder, and Associated Modulations Following an Anxiolytic Intervention

Abstract

Introduction and Aims Generalised anxiety disorder (GAD) comprises a debilitating cluster of psychological and physiological symptoms that markedly impairs quality of life. GAD is characterised by hallmark cognitions of persistent worry and anticipatory anxiety. Evidence exists for dysregulation in excitatory/inhibitory neurobiological pathways in prefrontal and limbic brain regions, with the dorsal anterior cingulate cortex an area of particular interest. However, limited research exists assessing regional activations and the role of metabolites such as gamma-aminobutyric acid in these regions, nor modulations as a function of treatment. The aim of the thesis was to investigate the functional and metabolic features of this region, and to assess the role of neuroimaging biomarkers of anxiolytic treatment response. Methods Two investigations were conducted utilising structural features of the region of interest: task-based functional magnetic resonance blood oxygen level-dependant signal activation and GABA levels via magnetic resonance spectroscopy together with relevant psychometric and psychiatric measures. The first study was a cross-sectional investigation undertaken to compare neuroimaging biomarkers in 41 participants with GAD with 35 healthy control participants. The second study was an 8-week RCT sub-study involving 41 participants randomised to either daily 240mg of kavalactones Piper methysticum (Kava) extract or a matching placebo. This proof-of-concept study assessed the aforementioned outcomes and whether these markers signal the plant’s anxiolytic activity. Results The results of the first investigation did not reveal group differences in GABA level (p = .302). The relationship between GABA and anxiety severity was different for each group; a significant positive correlation in GAD (e.g., HAM-A, p = .018) and a negative correlation in healthy controls (e.g., trait anxiety, p = .019). The functional task was successful in eliciting regional BOLD signal differences between valent congruency conditions. Two regions exhibited significant group differences (at p < .05), showing hyperactivation in GAD and reduced activation in healthy controls. In both groups BOLD signal significantly predicted severity of state anxiety (GAD p = .027; HC p = .041). Gender, age, and comorbidity in the GAD group also influenced the biomarker-anxiety relationships. The results of the second study showed that Kava treatment was associated with a reduction to GABA levels at eight weeks (p = .049). The treatment was not associated with anxiety symptom, nor fMRI signal change, measured at eight weeks. Discussion This research investigated regional brain properties in GAD for biomarker utility, before testing them in a ‘proof of concept’ study using the purported anxiolytic agent, Kava. Metabolic and functional data were successful in producing differences in the dorsal ACC that could be (if replicated in a larger study) be utilised as biomarkers to aid in the management of GAD symptoms. Limitations of the studies were small sample sizes, GABA signal quality and equivocal toolbox results. The neurobiological effects of Kava have not been directly studied using MRI imaging in humans. The findings of a reduction to GABA levels after treatment may potentially reflect a normalising of the GABA system similar to healthy control data observed in the first study. GAD is a prevalent psychiatric disorder that is under-diagnosed and under-treated. While a great deal of work is inherent in establishing biomarkers for clinical benefit, this research contributes MRI evidence of biological differences, and insight into the mechanisms of Kava, together with a translational rationale for the study of novel anxiolytics as potential GAD treatments. The outcomes and findings of this research fit well with the current affective disorder literature and exceed contemporary work in the field of GAD biomarker and treatment research.