Can’t sleep? How neurocircuitry may help.

CDC sleep map

age-adjusted percentage of adults who reported 30 days of insufficient rest or sleep during the preceding 30 days (Source: CDC).

While I love my work at NeuroScience, I also love a three day weekend, especially for that additional bit of sleep I gain before getting back to the fast pace of the work week. Did you know that sleep disorders affect an estimated 10-40% of American adults, and according to the CDC, 25-39% of us get less than 7 hours a night of sleep, including yours truly? Chronic sleep disturbances can lead to impaired concentration, cognition, memory, and coordination, as well as a host of chronic health issues.

Frustratingly, there is no “magic bullet” that brings relief to all sufferers. If you think about the neurocircuitry of sleep, this shouldn’t be a surprise – there are many points in this circuitry when things can go out of balance. Here’s a quick review.

During wakefulness, the brain is kept active and alert by the actions of neurotransmitters that include acetylcholine, norepinephrine, serotonin, dopamine, and histamine. Norepinephrine contributes to elevated energy, mood, and vigilance. Histamine promotes wakefulness and arousal. In the absence of light, the brain’s wake-promoting centers are inhibited when sleep-promoting regions of the brain release gamma amino-butyric acid (GABA) as well as melatonin, resulting in a sleep-state.

Sleep is characterized by stages of non-rapid eye movement (NREM) and rapid eye movement (REM). Here too, neurotransmitters play a role in the transition between these stages; particularly the reciprocal actions of norepinephrine and serotonin (enhancing NREM sleep) and acetylcholine (which is involved in inducing REM sleep).

In recent years, researchers have made great strides toward understanding the neurocircuitry that controls sleep-wake states. As we’ve discussed previously in this space, neurocircuitry has helped us understand some of the possible causes of sleep difficulties, for example:

  • Excess release of norepinephrine and histamine results in a state of wakefulness .
  • Perturbations in neurotransmitter signaling can interfere with REM/NREM oscillations, leading to impaired sleep.
Circuit Board Butterfly #16

Circuit Board Butterfly #16 by Truda Glatz.

Understanding the neurocircuitry of sleep has allowed researchers to identify biomarkers that can be measured in urine. These biomarkers can help characterize patients’ individual biochemical imbalances, as well as help healthcare practitioners select and monitor therapeutic interventions. Several correlations between central brain activity and peripheral biomarkers have been reported, such as:

  • Overactivity of certain wake centers in the brain can trigger the release of norepinephrine which is reflected in urinary norepinephrine levels. Therapeutic strategies that successfully regulate norepinephrine output may help promote sleep.
  • Exercise-induced increase in epinephrine correlates with a delay in REM sleep onset (Netzer, 2001), and total REM sleep is lower following exercise. Accordingly, exercise has been shown to stimulate an increase in urinary epinephrine.

Data suggests that neurotransmitter imbalances that have been associated with neuropsychological disorders, such as insufficient serotonin and elevated glutamate, norepinephrine, dopamine, and epinephrine may also contribute to sleep disturbances.  Depression has been reported to be one of the strongest risk factors for current insomnia, but it has also been suggested that current insomnia is a risk factor for future depression.

Analysis of peripheral biomarkers may also help predict who will respond to various sleep medications, thereby simplifying the therapeutic protocol. For example, in a study of a sleep-inducing benzodiazepine, patients who had a favorable antidepressant response had significantly higher pretreatment urinary epinephrine and norepinephrine levels than control subjects, while no such difference was found among nonresponders.

Overall, it’s become clear that individuals with sleep disorders may exhibit a spectrum of different biochemical imbalances. Using neurocircuitry to define clinically relevant peripheral neurotransmitter and hormone biomarkers, we are beginning to characterize individual patients’ imbalances, thus customizing sleep aids for better likelihood of efficacy.

Frequent readers of this blog will notice the unusual absence of references in this post! That’s because it was adapted from the white paper we wrote earlier this year about the neurocircuitry of sleep. You can get a copy – and see all the references – by contacting me in the Comments section below. Thanks for your interest!

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3 Responses to Can’t sleep? How neurocircuitry may help.

  1. Erica says:

    I have a question I have not been able to get answered: Proponents of urinary NT testing, such as NS Labs, say that urinary measures are accurate, useful indicators; indeed, I know many people who have used the tests to guide their treatment plans and then feel much better.

    On the other side, there are those who say that the body fluids are compartmentalized enough, and the barriers between compartments tight enough (except in cases of pathology), that what you find in the urine, in no way reflects what is available in the CNS, which is where we’re (usually) the most interested in modulating them. Could you please respond to this criticism?

    I can come up with hypothesis on how both could be true, but I’d rather stop theorizing and just hear it from someone who would have an intelligent response. Thanks.

    • Erica, great question and I’m sorry I didn’t answer you sooner… It was on my to-do list and then got missed until I stumbled across it this past weekend.

      Let me start by reframing your question. What NeuroScience aims to do is assess AUTONOMIC nervous system function by measuring peripheral neurotransmitters – we never claimed to be measuring CNS function, though peripheral imbalances doubtlessly are due to central control mechanisms gone awry.

      I can perhaps best elaborate by suggesting you take a look at our recent blog entry about the autonomic nervous system (ANS), that part of our nervous system that pervades our entire peripheral physiology, and manages all the things our bodies do without conscious thought – like gland function, sleeping, heart rate, blood pressure, digestion, etc. etc. Neurotransmitters are the biochemical signals that help make these processes happen – and when the ANS goes wonky (yes, that’s a clinical term) you will see it in the peripheral neurotransmitters. When we talk about intervening, however, it makes sense address from the “top down”, that is, to go after the control mechanisms in the brainstem that govern the ANS. Centers like, for example, the locus ceruleus that determines the balance between sympathetic vs. adrenal dominance. (We’ll discuss the role of brain centers in adrenal fatigue in a later blog, FTI).

      So, urinary neurotransmitter testing can tell us about a patient’s nervous system and, by extension, overall health. They are biomarkers of nervous system function, with over 5 decades of clinical research to back this up (look up this comprehensive review by D.T. Marc and colleagues ( As biomarkers, NT’s are in some ways no different than C-reactive protein (CRP), cholesterol, and HbA1c are markers that healthcare practitioners use to assess our cardiovascular, immune, and metabolic health. Are NT’s be-all end-all diagnostic markers? No more so than some of those other, more well-established markers I just listed. But they can provide pointers as to what may be going on with the patient, more so than the, dare I say it, medieval approach of merely assessing patients’ symptoms and prescribing accordingly.

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