Hyperarousal and Beyond: New Insights to the Pathophysiology of Insomnia Disorder through Functional Neuroimaging Studies

Abstract

Neuroimaging studies have produced seemingly contradictory findings in regards to the pathophysiology of insomnia. Although most study results are interpreted from the perspective of a "hyperarousal" model, the aggregate findings from neuroimaging studies suggest a more complex model is needed. We provide a review of the major findings from neuroimaging studies, then discuss them in relation to a heuristic model of sleep-wake states that involves three major factors: wake drive, sleep drive, and level of conscious awareness. We propose that insomnia involves dysregulation in these factors, resulting in subtle dysregulation of sleep-wake states throughout the 24 h light/dark cycle.

Keywords: heuristic model; hyperarousal; insomnia; neuroimaging.

Figure 1

Group differences in relative glucose metabolism during wakefulness. We assessed relative regional cerebral metabolic rate for glucose (rCMR_glc) in a sample of 44 patients with primary insomnia (PI) and 40 good sleeper controls (GS) during morning wakefulness. Patients with PI had lower relative rCMR_glc in four clusters spanning the neocortex and brainstem. Patients with PI also had higher relative rCMR_glc than GS in the right cerebellum. All clusters were significant at p_{3DC_corrected} < 0.05. A full list of brain regions involving these clusters is presented in Table 1. The color bar represents t values; blue indicates regions where patients with PI had lower relative rCMR_glc than GS and orange indicates regions where patients with PI had higher relative rCMR_glc than GS during wakefulness. This figure was originally published in the journal Sleep [52]. Used with permission. Note: L indicates the left side of the brain, R indicates the right side of the brain, and 3DC_corrected indicates that familywise error (FWE) correction and clusterwise extent thresholds were determined using 3dClustSim [53].

Figure 2

Group differences in relative glucose metabolism during non-rapid eye movement (NREM) sleep. We assessed relative regional cerebral metabolic rate for glucose (rCMR_glc) in a sample of 44 patients with primary insomnia (PI) and 40 good sleeper controls (GS) during NREM sleep. Patients with PI had lower relative rCMR_glc in three clusters centered on the anterior cingulate, right medial temporal lobe, and right precuneus/posterior cingulate; p_{3DC_corrected} < 0.05 for all clusters. A full list of brain regions involving these clusters is presented in Table 1. The color bar represents t values; blue indicates regions where PI had lower relative rCMR_glc than GS during NREM sleep. This figure was originally published in the journal Sleep in 2016 [52]. Used with permission. Note: L indicates the left side of the brain, R indicates the right side of the brain, and 3DC_corrected indicates that familywise error (FWE) correction and clusterwise extent thresholds were determined using 3dClustSim [53].

Figure 3

A heuristic model of sleep-wake states. In this model global states are represented in 2-dimensional space based on three major factors: sleep drive, wake drive, and level of conscious awareness. The black arrow pointing toward the top of the circle represents greater wake drive. The black arrow pointing toward the right of the circle represents greater sleep drive. The two blue-lined arrows pointing to the left side of the circle represent higher conscious awareness. To help visualize the conscious awareness factor in relation to the other two factors in the model, the + symbols represent sectors where conscious awareness is higher and the − symbols represent sectors where conscious awareness is lower. Healthy states are indicated by the blue boxes. Healthy active wakefulness (AW) occurs in sector 1 and healthy quiet wakefulness (QW) occurs in sector 2. Healthy rapid-eye movement (REM) sleep occurs in sectors 3 and healthy non-rapid eye-movement (NREM) sleep occurs in sector 4. States experienced by patients with primary insomnia (PI) are indicated by the red boxes. The green arrows represent the hypothesized state shifts experienced by patients with PI relative to good sleepers. Patients with PI may have altered states across sleep-wake states due to reduced activation in brain regions involved in conscious awareness during the wake states and heightened brain activation in these regions during sleep.