TABLE 2 ] .
Evidence for the Pathophysiology of Insomnia at Each Unit of Analysis
| Unit of Analysis | Evidence for This Perspective in Pathophysiology of Insomnia |
| Genes | Elevated family risk for insomnia |
| Elevated genetic risk in twin studies | |
| Insomnia phenotype in drosophila related to mutations in 755 genes with human homologs | |
| Candidate gene studies support association between aspects of insomnia and Apoε4, PER34/4, HLA DQB1*0602, 3111C/C Clock, short (s-) allele of the 5-HTTLPR | |
| Numerous SNPs identified in human genomewide association study studies | |
| Molecules | Mixed findings regarding the role of wake- and sleep-promoting molecules in insomnia; no consistent pattern for a specific type of molecule has emerged |
| Unlikely that all cases of insomnia can be explained by alterations in any single molecule type | |
| See Table 1 for links between various molecules and insomnia | |
| Cells | Simultaneous localized Fos activation in both sleep-promoting and wake-promoting regions during global sleep in rats. Individual cortical columns show sleep-like activity while other parts of the brain show wake-like activity |
| Neuronal use results in modulation of gene expression in sleep regulatory substance, which acts locally in the brain to promote sleep | |
| Circuits | In animals, lesions of the anterior ventral and the dorsomedial thalamus, raphe nucleus, or paramedial preoptic area results in insomnia |
| Less robust slow wave activity following sleep deprivation among subjects with insomnia than control subjects (process S); delayed and advanced core body temperature rhythms and heightened nocturnal core body temperature linked to insomnia (process C) | |
| Those reporting greater subjective-objective sleep discrepancy demonstrate sleep-related behaviors consistent with rapid switching between sleep and wake states | |
| Reduced gray matter volume in left ventromedial prefrontal cortex, precuneus, and temporal cortices in patients with insomnia | |
| Patients with insomnia have smaller reductions in brain activity during NREM sleep relative to resting wake | |
| Higher β activity in left frontal and frontal midline regions during W and N1, higher levels of temporal coupling linking the frontal, parietal, and posterior midline regions during the sleep onset period in insomnia as compared with control subjects | |
| Physiology | Diminished δ and increased high-frequency NREM EEG power among patients with insomnia |
| Association between high-frequency EEG activity and subjective sleep complaints | |
| High-frequency waking EEG activity correlates with high-frequency EEG activity during NREM, and with self-reported hyperarousal symptoms | |
| Arousals and awakenings during REM sleep more precisely distinguished subjects with insomnia from good sleepers than the NREM parameters | |
| Insomnia associated with increased body temperature, vasoconstrictions, body movements, skin resistance, 24-h metabolic rate, 24-h ACTH, cortisol levels | |
| Continuous sympathetic hyperactivation among subjects with insomnia during sleep onset | |
| Behavior | Some efficacious treatments for insomnia focus on resolving the behavioral and cognitive factors contributing to and exacerbating insomnia. These include: |
| Increasing the association between the bed and being asleep | |
| Reestablishing a consistent sleep-wake schedule | |
| Restricting time in bed to increase sleep drive and, subsequently, sleep efficiency | |
| Reducing somatic tension or intrusive thoughts that are antithetical to sleep | |
| Psychotherapy targeting maladaptive beliefs about sleep | |
| Self-reports | Self-report measures discriminate subjects with insomnia from good sleepers |
| Presleep mentation among subjects with insomnia focuses on rehearsal/planning, sleep and its consequences, and autonomic experiences | |
| The areas of energy/motivation, performance at work, cognitive functioning, and emotion regulation are the most commonly reported sleep-related impairments in insomnia | |
| Underestimation of sleep duration is prevalent among those with a subjective complaint of insomnia but objectively normal sleep duration | |
| The magnitude of discrepancy between self-reported and objectively measured sleep may itself constitute a high risk factor for insomnia. |
ACTH = adrenocorticotropic hormone; NREM = non-rapid eye movement; SNP = single-nucleotide polymorphism.