A formal model of anxiety disorders based on the neural circuit dynamics of the fear and extinction circuits

Abstract

The pathophysiology of anxiety disorders is the outcome of an imbalance of the fear-anxiety circuit and the extinction circuit. We present a formal model using nonlinear dynamics and network theory, which captures the dynamic interactions of the key nodes of the anxiety and extinction networks. This rudimentary model can be modified by newer data. These core nodes consist of the cells of the paraventricular nucleus of the thalamus coding negative valence, the neurons of the basal-lateral amygdala coding negative valence (Rspo2+), the anterior cingulate cortex, the ventral hippocampus neurons coding fear memories, the somatostatin expressing cells of the lateral segment of the central amygdala, the medial segment of the central nucleus of the amygdala-bed nucleus of the stria terminalis and their target nodes. The extinction network consists primarily of the paraventricular thalamic cells coding positive valence, (Ppp1r1b+) cells of the basolateral amygdala coding positive valence, the ventromedial prefrontal cortex, the PKC{delta} cells of the lateral segment of the central amygdala, and the intercalated cells. Human and non-human animal genetic and epigenetic studies point to deficiencies in brain-derived neurotrophic factor and neurotrophic receptor kinase tyrosine 2 production in key nodes causing reduced plasticity extinction network plasticity and leading to a weakened extinction response. We rely primarily on the neurophysiological studies of non-human animal models since nodes generating fear/anxiety and extinction responses are highly conserved across species and equivalent nodes are present within analogous circuits of the human brain. The results are confirmed, where possible by human functional magnetic resonance imaging studies. We believe this simplified model is of heurist value and can lead to a more consistent focus on physiologically based pathophysiology. This would lead to treatments to reverse the pathologic physiology produced by genetic and epigenetic abnormalities, and greater efforts to directly correct pathologic circuit activity through direct interventions such as transcranial magnetic stimulation. SignificanceWe believe this simplified model is of heurist value and can lead to a more consistent focus on physiologically based pathophysiology. This would lead to treatments to reverse the pathologic physiology produced by genetic and epigenetic abnormalities, and greater efforts to directly correct pathologic circuit activity through direct interventions such as transcranial magnetic stimulation.