The Pathophysiology of Insomnia

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Historically, insomnia has been subdivided into two different types: primary and secondary. If insomnia could be traced to another condition or disease that resulted in sleep disturbance as a symptom or side effect, it was called “secondary insomnia“.  Primary insomnia occurred when there was no obvious or apparent cause.

This definition changed following 2015 revisions to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). At that time, the terms ‘primary’ and ‘secondary’ insomnia were eliminated in favor of a broader ‘insomnia’ term. DSM editors reasoned that a singular term would stress the importance of seeking treatment for insomnia, whether the symptoms arose independently or occurred a a result of other factors. The chronic insomnia diagnosis was also changed during the 2015 revision. Currently, insomnia is considered chronic by some when it lasts three months. The previous benchmark set for this diagnosis was one month.

However, the terms ‘primary’ and ‘secondary insomnia’ are still widely used, and those who have not seen a doctor since 2015 may still have a primary or secondary insomnia diagnosis.

If the ability to fall and stay asleep is the product of a struggle between arousal and sleepiness, maybe the problem with some insomniacs is not insufficient sleepiness, but too much arousal.  There is scientific evidence for this idea, although it is still unclear. Studies of the brains of depressed people show they don’t shift down as much during sleep as healthy persons’ brains do (as measured by glucose use in the frontal lobe.)

What does it mean to have elevated arousal, at the biochemical level? The levels of glucose in the frontal lobe may be part of it, and the hormone system is part of it, too.  The hypothalamic-pituitary-adrenal-gonadotropic (HPA) axis refers to a complex of interactions among the adrenal gland, the pituitary, and the hypothalamus.  It’s also implicated in metabolic syndrome.

Levels of stress hormones (such as cortisol and corticotropin releasing factor) are also elevated in many insomniacs (which could be the cause or the effect of the insomnia) and the overall metabolic rate is higher even during the daytime in people with insomnia.

Research focused on the pathophysiology of insomnia caused much of the change in thinking about insomnia. Patients with chronic insomnia are now considered to be in a state of hyperarousal, which occurs happens throughout the day. In addition to having trouble sleeping, they may be anxious. They are more alert than good sleepers and have higher levels of the stress hormone cortisol. Adrenocorticotropic hormone levels are also higher than normal, especially in the evening and first half of the night.

In one study, brain metabolisms of patients with insomnia and healthy controls were evaluated using a type of positron emission tomography (PET scan) during both wake and non-REM sleep. The researchers observed increased metabolic activity in the frontal lobes of patients with insomnia while they were awake. During non-REM sleep they had increased whole-brain metabolic activity. Researchers also noted increased metabolic activity in the midbrain and brainstem of patients with insomnia during sleep.

There is evidence that there is a physiologic basis for the hyperarousal. Some of the measurable indicators of hyper-arousal found in patients with insomnia include increased basal metabolic rate, central nervous system metabolic rate and body temperature. High levels of catecholamines — hormones released due to stress — are present as is increased brain wave activity measured by electroencephalography. People with insomnia tend to be more alert, on edge, than people without. Physiologists have also shown insomniacs on average have higher metabolic activity in the brain during both waking and sleeping. This isn’t to say we don’t want to be alert when we are awake — indeed that is one of the prime benefits of sleep — but it suggests hyperarousal and an inability to “turn off” are what drives insomnia.

Investigators trying to understand the pathophysiology of sleep continue to focus on hyperarousal. In major depressive disorders, there is abnormal regulation of corticotropin-releasing factor CRF). Altered regulation of CRF, hyperarousal and sleep disturbances occur both in patients with insomnia and depressed patients.  High cortisol levels correlate with nocturnal wakenings. Increased HPA axis activity fragments sleep, but sleep fragmentation also increases cortisol levels.

Current thinking about the main cause of hyper-arousal in insomniacs focuses on neuroendocrine dysfunction, including increased CRF activity. Researchers have found evidence that there is overactivity of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis may cause elevated levels of CRF, which then causes the pituitary to release adreno-corticotropic hormone (ACTH). This causes the adrenal glands to secrete excessive amounts of cortisol. Increased cortisol and ACTH levels have been found in patients with chronic insomnia. There seems to be a strong correlation between cortisol levels and sleep disruption or fragmentation. Some researchers think that chemical events in the brain associated with the HPA access also cause release of norepinephrine, which may also be disrupting sleep.

Other investigators have found that patients with chronic insomnia have lower nocturnal levels of melatonin. Melatonin, a hormone produced in the pineal gland, is part of the regulation of circadian rhythm. When melatonin levels increase, sleepiness occurs. Not only do patients with insomnia have lower melatonin levels, the levels are more disturbed the longer the patients have trouble sleeping.

Research is ongoing in these areas,. Clinical trials have been suggested to investigate whether an antiglucocorticoid agent might counteract the increased cortisol, and be useful in treatment of insomnia. Other researchers think that it is the CRH and its actions in the brain that need to be suppressed.

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