Transition of Neural Activity From the Chaotic Bipolar-Disorder State to the Periodic Healthy State Using External Feedback Signals.

Chronotherapy is a treatment for mood disorders, including major depressive disorder, mania, and bipolar disorder (BD). Neurotransmitters associated with the pathology of mood disorders exhibit circadian rhythms. A functional deficit in the neural circuits related to mood disorders disturbs the circadian rhythm; chronotherapy is an intervention that helps resynchronize the patient's biological clock with the periodic daily cycle, leading to amelioration of symptoms. In previous reports, Hadaeghi et al. proposed a non-linear dynamic model composed of the frontal and sensory cortical neural networks and the hypothalamus to explain the relationship between deficits in neural function in the frontal cortex and the disturbed circadian rhythm/mood transitions in BD (hereinafter referred to as the Hadaeghi model). In this model, neural activity in the frontal and sensory lobes exhibits periodic behavior in the healthy state; while in BD, this neural activity is in a state of chaos-chaos intermittency; this temporal departure from the healthy periodic state disturbs the circadian pacemaker in the hypothalamus. In this study, we propose an intervention based on a feedback method called the "reduced region of orbit" (RRO) method to facilitate the transition of the disturbed frontal cortical neural activity underlying BD to healthy periodic activity. Our simulation was based on the Hadaeghi model. We used an RRO feedback signal based on the return-map structure of the simulated frontal and sensory lobes to induce synchronization with a relatively weak periodic signal corresponding to the healthy condition by applying feedback of appropriate strength. The RRO feedback signal induces chaotic resonance, which facilitates the transition to healthy, periodic frontal neural activity, although this synchronization is restricted to a relatively low frequency of the periodic input signal. Additionally, applying an appropriate strength of the RRO feedback signal lowered the amplitude of the periodic input signal required to induce a synchronous state compared with the periodic signal applied alone. In conclusion, through a chaotic-resonance effect induced by the RRO feedback method, the state of the disturbed frontal neural activity characteristic of BD was transformed into a state close to healthy periodic activity by relatively weak periodic perturbations. Thus, RRO feedback-modulated chronotherapy might be an innovative new type of minimally invasive chronotherapy.