Pathogenesis of Obsessive-Compulsive Disorder (OCD): Two Conflicting Prediction Errors, Homeostatic Set Points, and Norepinephrine

Patients with OCD exhibit severe deficits in cognitive flexibility, yet its underlying pathogenesis remains unclear. As a person with OCD, I have conducted self-experiments over the past decade guided by Exposure and Response Prevention (ERP) therapy, while meticulously documenting my emotional and behavioral responses to each intervention. 1) I have found that the Prediction Error (PE) theory is the theoretical model that best aligns with human emotional and behavioral responses. Human brain cognition mainly consists of six processes: perceptual inference, cognitive reasoning, downregulating homeostatic set points, planning motor sequences, planning compensatory motor sequences, and shifting attention. Among these, the first five are major mechanisms for eliminating prediction errors, whereas the last only reduces the generation of prediction errors and cannot eliminate already formed prediction errors. These cognitive activities constitute the neural basis of cognitive flexibility. 2) the brain may contain a neural circuit induced by cognitive reasoning. The basolateral amygdala (BLA) and nucleus accumbens (NAc) may be regions where prediction errors are computed. Activation in the ventromedial prefrontal cortex (vmPFC, including the subgenual anterior cingulate cortex (sgACC)) may encode the homeostatic set point of this circuit. Phasic firing of dopamine (DA) neurons in the ventral tegmental area (VTA)–vmPFC pathway may mediate the real-time upregulation of homeostatic set points induced by reward cues. The rostral anterior cingulate cortex (rACC), periaqueductal gray (PAG), and von Economo neurons (VENs) may mediate the downregulation of homeostatic set points. The dorsal anterior cingulate cortex (dACC) may mediate the planning and storage of compensatory motor sequences. The neural mechanism of mindfulness involves the real-time downregulation of homeostatic set points mediated by the rACC. In addition, there may exist a neural circuit induced by actual stimuli, Activation of the limbic thalamic nuclei may encode the homeostatic set point of this circuit, and the dorsal anterior insula (dAI) may be the region where prediction errors are computed. 3) The initial onset of OCD is triggered by the emergence of two mutually conflicting prediction errors (PEs) that cannot be effectively eliminated through the six cognitive processes mentioned above. A high level of norepinephrine (NE) is also an important factor in the onset and maintenance of OCD. The "perfectionism" exhibited by OCD patients results from the disruption of the real-time downregulation of homeostatic set points mediated by the rACC caused by norepinephrine. Therapeutic approaches based on these six cognitive processes are highly consistent with normal human cognitive patterns.