AUTHOR=Doho Hirotaka , Nobukawa Sou , Nishimura Haruhiko , Wagatsuma Nobuhiko , Takahashi Tetsuya 

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

JOURNAL=Frontiers in Computational Neuroscience

VOLUME=Volume 14 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/computational-neuroscience/articles/10.3389/fncom.2020.00076

DOI=10.3389/fncom.2020.00076

ISSN=1662-5188

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.  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 of neural function in the frontal cortex and disturbed circadian rhythms/mood transitions in BD (hereinafter referred to as the Hadaeghi model). In this model, neural activity in the frontal and sensory lobes exhibit 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 appropriate feedback strength. The RRO feedback signal induces chaotic resonance, which facilitates the transition to healthy, periodic frontal neural activity, although this synchronization is restricted under the condition with relatively slow frequency of the input periodic signal. Additionally, an appropriate strength of the RRO feedback signal lowered the input periodic signal required for inducing a synchronous state, as compared to the periodic signal applied alone. In conclusion, through the chaotic resonance effect induced by the RRO feedback method, the state of disturbed frontal neural activity characteristic of BD was transformed to 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.