Insomnia is the most common sleep disorder. Due to the increase of social pressure and aging population, the prevalence of insomnia will continue to increase . A recent meta-analysis of the prevalence of insomnia disorder (ID) in the general population in China showed that the prevalence rate of ID is 15.0%. The long-term existence of insomnia may be the cause of the huge social and economic burden of this disease, and can lead to cognitive dysfunction, psychological abnormalities and increased suicide tendency. Therefore, early identification and early effective therapies of ID patients are especially important.
At present, the first line therapies for insomnia recommended by sleep guidelines is cognitive behavioral therapy and hypnotic medication. However, many insomniac have poor compliance with cognitive behavioral therapy in clinical practice and long-term use of hypnotic medication also have side effects and increase suicide risks. In recent years, there has been an increasing number of novel physical methods to treat insomnia, such as repetitive transcranial magnetic stimulation (rTMS), which has emerged as a new option due to its low side effects.
As a neuromodulation technique, the common therapeutic target of rTMS is the dorsolateral prefrontal cortex (DLPFC). Many studies [5–7] applied rTMS (on right DLPFC, 1Hz) for insomniacs and the results indicated that rTMS can improve the sleep quality of insomniacs and the effect is better than hypnotic medication without side effects. These results suggest that rTMS is safe and effective for primary insomnia.
Huang et al choose the posterior parietal lobe as stimulated position for insomnia patients with generalized anxiety. They showed that the anxiety and insomnia symptoms were improved significantly. However, some studies suggest that rTMS does not significantly improve insomnia symptoms in Parkinson's disease. A recent meta-analysis suggested that rTMS was effective in ID patients, while placebo effect of sham stimulation was significant.
Aforementioned studies are focus on the right DLPFC or posterior parietal cortex with low frequency rTMS. Although rTMS display a certain effect, but there are still some patients cannot benefit from it. The current studies have not take involved abnormal brain network of insomnia patients as stimulation target, then in this study, we will explore the therapeutic effects and neural basis of another new stimulated target.
Insomnia is an abnormal sleep pattern. Two important neurotransmitter receptors (dopamine receptors and adenosine receptors) involved in sleep arousal are expressed in the nucleus accumbens(NAc)[11, 12]. In addition, the glutamate neurons of thalamus paraventricular nucleus and the ventral tegmental area can control awakening by regulating the NAc[13, 14]. Therefore, the NAc may play an important role in regulating sleep and awakening. Lazarus et al proposed a network model of sleep-wake regulation, suggesting that adenosine and dopamine receptors in NAc regulate sleep-wake behavior through cortical activation, mainly involving the excitatory neural projection from the medial prefrontal cortex (mPFC) to NAc. In addition, mPFC can directly project excitatory neurons downward to the sleep-wake regulatory system such as tuberopapillary nucleus of hypothalamus, lateral hypothalamus and locus blueleus).These results suggest that mPFC may be involved in the regulation of sleep and awakening at the cortical level, and may serve as a potential target of rTMS in the treatment of chronic insomnia.
Two recent neuroimaging studies used functional Magnetic Resonance Imaging (fMRI) to analyse resting state functional connection (RSFC) of NAc in ID patients and revealed abnormal RSFC between NAc and mPFC which suggest the brain related to the severity of insomnia[16, 17]. Shao et al proposed abnormal NAC- mPFC circuit in ID. In addition, the hypothalamus, a central role in sleep-wake regulation was recently used as the seed for functional connection by fMRI and the results showed that the bilateral hypothalamus and bilateral mPFC resting state functional connection were enhanced in ID patients, and were positively correlated with sleep quality. Moreover, neuroimaging revealed reduced gray matter density[19, 20], abnormal regional homogeneity (ReHo), amplitude of low frequency fluctuations (ALFF) and reduced activation of mpfc[23, 24]. These studies suggest that mPFC may play an important role in the pathophysiological mechanism of insomnia.
Therefore, we hypothesized that 1Hz rTMS stimulation over mPFC would improve insomnia symptoms of ID patients by altering mPFC -seed functional connectivity in the group receiving real mPFC -rTMS group compared with the sham mPFC -rTMS group.