Development of a theoretically-derived human anxiety syndrome biomarker

Abstract

"Anxiety disorders" are extremely common; and are a major source of health costs and lost work days. Their diagnosis is currently based on clinical symptom check lists and there are no biological markers to diagnose speci c syndromal causes. This paper describes: 1) a detailed theory of the brain systems controlling anxiolytic-insensitive threat-avoidance and anxiolytic-sensitive threat-approach -where, in specific brain structures, activity generates specific normal behaviours, hyperactivity generates abnormal behaviours, and hyper-reactivity (hypersensitivity to input) generates specific clinical syndromes; 2) a rodent model of systemic anxiolytic action (rhythmical slow activity), linked to the theory, that over a period of 40 years has shown predictive validity with no false positives or false negatives -and which is likely to assay the sensitivity of endogenous systems that control anxiety; and, 3) derivation from this rodent-based theory of a specific non-invasive biomarker (goal-conflict-specific rhythmicity) for the threat-approach system in humans. This new biomarker should allow division of untreated "anxiety" patients, with superficially similar clusters of symptoms, into distinct high scoring (syndromal) and low scoring groups with different treatment-responses. This would be the first theoretically-derived biomarker for any mental disorder and should: 1) predict treatment efficacy better than current symptom-based diagnoses; 2) provide a human single dose test of novel anxiolytics; 3) provide a starting point for developing biomarkers for other "anxiety" syndromes; and so, 4) greatly improve treatment outcomes and cost-effectiveness.

The Oscillatory Profile Induced by the Anxiogenic Drug FG-7142 in the Amygdala–Hippocampal Network Is Reversed by Infralimbic Deep Brain Stimulation: Relevance for Mood Disorders

“…In specific behaviors involving decisions related to conflict, hippocampal theta oscillations have been proposed as anxiety biomarkers by McNaughton and colleagues [106,158,159]. In addition, drugs with anxiolytic effects reduce reticular elicited hippocampal rhythms [158,160].…”

Neuroimaging Insights: Kava’s (Piper methysticum) Effect on Dorsal Anterior Cingulate Cortex GABA in Generalized Anxiety Disorder

“…This current study serves to address this shortfall. Biomarker treatment approaches assert that biological patterns may not fit with current diagnostic categories, signalling a vital need for research that clarifies neurobiological marker roles in symptom maintenance and response patterns with treatment [115][116][117][118]. These markers also have potential to identify disorders before the onset of anxiety symptoms and to identify variants or clinically meaningful subsets [18,119,120].…”

Mechanisms of comorbidity, continuity, and discontinuity in anxiety-related disorders

“…As yet, there are no proven biomarkers of this type for any psychiatric disorder. However, the strong neuropsychological basis of the theory of the BIS has allowed development of a putative biomarker for BIS reactivity as a whole (McNaughton, 2014) that we are currently testing for its capacity to be the substrate of a clinical disorder. The key aspects of this biomarker are as follows: (a) it is a rhythmic EEG signal in the same frequency band (Shadli, McIntosh, Glue, & McNaughton, 2015) as the rat hippocampal theta rhythm that acts as the most reliable current assay of antianxiety drug action (McNaughton et al, 2007); (b) it correlates with the shared variance of “neuroticism” and “trait anxiety” personality measures (Neo et al, 2011); and (c) it is sensitive to benzodiazepines, buspirone (McNaughton et al, 2013), and pregabalin (Shadli et al, 2015), that is, all the known classes of antianxiety drug that lack either antipanic or antidepressant action.…”

“…FFFS, fight–flight–freeze system; BIS, behavioral inhibition system; 5-HT, 5-hydroxytryptamine/serotonin; 5-HT 1A , 5-HT 1A receptors; BDZ, benzodiazepine receptors; NA, noradrenaline; OCD, obsessive–compulsive disorder; PAG, periaqueductal gray; PFC, prefrontal cortex. Figure and legend adapted from “Development of a Theoretically-Derived Human Anxiety Syndrome Biomarker,” by N. McNaughton, 2014, Translational Neuroscience, 5 , 137–146. Copyright 2014 by De Gruyter.…”