No abstract

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.

Chaotic resonance is a phenomenon that can replace the fluctuation source in stochastic resonance from additive noise to chaos. We previously developed a method to control the chaotic state for suitably generating chaotic resonance by external feedback even when the external adjustment of chaos is difficult, establishing a method named reduced region of orbit (RRO) feedback. However, a feedback signal was utilized only for dividing the merged attractor. In addition, the signal sensitivity in chaotic resonance induced by feedback signals and that of stochastic resonance by additive noise have not been compared. To merge the separated attractor, we propose a negative strength of the RRO feedback signal in a discrete neural system which is composed of excitatory and inhibitory neurons. We evaluate the features of chaotic resonance and compare it to stochastic resonance. The RRO feedback signal with negative strength can merge the separated attractor and induce chaotic resonance. We also confirm that additive noise induces stochastic resonance through attractor merging. The comparison of these resonance modalities verifies that chaotic resonance provides more applicability than stochastic resonance given its capability to handle attractor separation and merging.