Microglia And Sleep Disorders: Explained For Clinicians

For tonight’s Deep Dive we’ll explore how the body’s largest gland – and indeed possibly the most important single organ – is your brain, specifically how your brain’s immune cells known as microglia are intricately involved with sleep and wakefulness. Understanding how the body’s native guardians of health and disease maintain homeostasis in these two states will provide great insight into why sleep disturbance can have such far reaching effects on the entire body that so much extend beyond the realm of basic fatigue. Importantly, prolonged sleep disruption results in a change in the biology of microglia, whereby these cells shift from monitoring for injury and disease to a reactive state, thereby significantly altering the patterns of both inflammation and synaptic plasticity and furthermore, greatly impairing the brain’s ability to repair itself. This neuro-immune state can lead to a host of unpleasant symptoms such as fatigue, mood alterations, decreased cognitive function, an impaired ability to recover from illness and even potentially contribute to the development of certain neurodegenerative diseases in vulnerable individuals.

Why It Matters

Sleep problems are perhaps the most common health complaint in the world today, and sleep disorders have real consequences for safety, for function, and for health. Every day clinicians treat for drowsy driving, and for sleepiness at work. Patients with sleep problems often complain of problems with attention, with accidents and falls, and with worsening of their symptoms of depression and anxiety. Even over the long-term, sleep problems have been associated with an increased risk for a variety of negative outcomes related to cardiometabolic health, including weight gain, insulin resistance, and hypertension. In contrast to previous views of sleep problems as solely behavioral problems, or problems related to brain wave activity, increasingly we are recognizing the association of sleep problems with neuro-immune stress.

Microglia matter because they are the defenders of the brain and cone at the nexus of inflammation, synaptic health, and repair. When microglia are actively patrolling, clearing out dead and sticky material, they are supporting healthy synaptic plasticity and proper neural communication. When they become persistently reactive, however, they can produce proteins that hinder healthy neuronal function and synaptic balance, causing symptoms such as slow processing speed, emotional dysregulation, hypersensitivity, and wakeful, unrestorative sleep.

A practical clinical reframe

Two patients, both insomniacs with the same sleep complaints (e.g. poor sleep quality, wake time after sleep onset), may have very different daytime symptoms and different sleep recovery trajectories. While the first patient is wakeful and refreshed in the daytime and sleeps well at night, the second patient reports pronounced daytime fatigue, reduced memory and concentration, and decreased energy, motivation, and stress tolerance, and experiences low mood. Many factors likely interact to explain these different phenomena. From a neuro-immune perspective, the reactive state of microglia may contribute to persistent daytime sleep symptoms resulting from insomnia, and affect the course of recovery, possibly in interaction with other comorbid factors, such as chronic pain, depression, systemic low-grade inflammation, or sleep apnea.

Examining sleep problems through the lens of cognitive protection offers potential for early intervention. Untreated sleep problems may enhance processes that increase risk for cognitive decline in vulnerable individuals. While problematic sleep is known to have immediate effects on concentration and mood, evidence suggests that it also may pose increased long-term risk for brain health by maintaining pro-inflammatory cytokines and otherwise disrupting synapse homeostasis. While not all individuals with insomnia are at risk for dementia, viewing sleep problems through the lens of cognitive protection supports a very serious view of sleep as a potentially modifiable health risk.

How microglia relate to normal sleep

Sleep facilitates brain recovery from wakefulness, enabling synaptic strengthening and weakening, metabolic clearing of waste products, and consolidation of memories. To achieve this, microglia respond to chemical signals within the brain that fluctuate over diurnal and nocturnal cycles. The optimal function of microglia during sleep involves a dynamic equilibrium of synaptic pruning and plasticity with efficient debris removal, and is critical to avoid excessive pro-inflammatory gene expression.

Circadian rhythmicity exerts significant control over many aspects of immune function, and microglia, the brain’s resident macrophages, are likely no exception. Many individuals, however, do not follow a traditional nocturnal-to-diurnal sleep/wake schedule, particularly shift workers who experience so-called “circadian disruption” due to forced wakefulness at times when their bodies would be naturally sleeping. Time zone transitions, or jet lag, are another form of temporary circadian desynchronization that many individuals experience after traveling to a foreign location. As individuals attempt to readjust to their new locale, sleep inefficacy due to circadian misalignment is likely to alter immune signaling. These changes are supported by patient reports of fatigue, irritability, and decreased mental clarity not explained by reduced total sleep time.

What changes during sleep loss or fragmentation

Sleep stressors can lead to sleep-inertia-induced activation of pro-inflammatory gene expression following acute sleep deprivation and can also push the microglia in patients with chronic sleep disruptions into a state of sustained activation. In patients who experience sleep stressors, clinicians may observe symptoms of hyperarousal including feeling revved up and tired at the same time, having low patience, and poor attention and working memory. Clinicians often need to educate their patients as to the degree of stress their brain is under due to fragmented sleep. This is often surprising to the patient who is sleeping 10 hours per night. However, it is not uncommon for patients who have sleep apnea, pain, acid reflux, nocturia, or environmental noise at night to only have sleep continuity of 4-5 hours per night. As a clinician, it is sometimes helpful to provide patients with sleep promoting medications to determine their true sleep needs, prior to developing sleep habits that promote sleep continuity.

Sleep-disordered breathing, which includes obstructive sleep apnea (OSA), periodic breathing, and sleep-related hypoapneic hemoglobin desaturation, results in intermittent hypoxia and repeated arousals/stirings from sleep. As a result, neuro-immune activation is increased dramatically. The stress induced by the arousal and hypoxia can have profound effects on the vasculature and on a variety of different inflammatory pathways. Obstructive sleep apnea (OSA) is commonly presented to the primary care physician by patients complaining of depression, anxiety, cognitive dysfunction, morning headache, insomnia, fatigue, and decreased stress tolerance, and they report snoring and daytime sleepiness.

Therapeutic implications and real-world caution

The study of the mechanisms of microglia has focussed considerable attention on the potential therapeutic benefits of anti-inflammatory or immune-modulating treatments. Modulating the brain’s immune response may reduce detrimental inflammation in a number of clinical scenarios. However, decreasing brain immune function could have negative consequences, most notably, it would eliminate any protective immune response and could alter mood or neuroplasticic processes. For now, the best way to manage immune activation in ME/CFS may be to decrease stimuli for immune activation by treating sleep disorders and other potential contributing medical conditions aggressively.

After we have matched patients up with the best over the counter or prescription sleep treatments to help sleep continuity and reduce sleep pathophysiology driven stress (which just so happens to reduce neuro-immune drive for many insomnia complaints) we can move on to CBT for insomnia, sleep apnea and SDB, and circadian treatments. Not to be forgotten is the best treatment for mood and pain complaints that negatively affect sleep architecture. Most effective answers to sleep and neuro-immune complaints start with treatments which decrease sleep disturbance and improves sleep quality and wakefulness.

Health system implications

As sleep disorders are recognized to have a neuro-immune component, sleep specialists anticipate that sleep disorders with “sleep plus cognitive symptoms” will require the health system and payers to support longer diagnostic pathways and more complex multidisciplinary care. Providers will need to evaluate and/or screen for sleep and cognitive symptoms and follow patients over time to assess for worsening of either or both sets of symptoms. Additionally, patients will need more behavioral sleep therapy, sleep studies and coordinated care with their PCP, psychiatry, neurology and sleep medicine.

Sleep problems need early treatment to save money and prevent increased healthcare costs. If sleep problems are not treated, children and their families may return repeatedly for symptoms of fatigue, headaches, mood disturbance, and poor concentration. If left untreated, sleep problems can increase the risk of children developing vascular and metabolic diseases leading to increased health care costs in the long run. However, an integrated model of care can identify and treat children with sleep disorders early in the course of their illness even before neuro-immune testing becomes a common practice in pediatrics.

Who It Affects

A number of sleep disorders could be influenced by microglia. Several forms of sleep disturbance including chronic insomnia and fragmented sleep, as well as inadequate sleep, can increase fatigue, alter neuro-immune signaling pathways, and decrease cognitive clarity and mood. Sleep-disordered breathing, such as obstructive sleep apnea, characterised by recurrent episodes of upper airway obstruction during sleep leading to episodic hypoxaemias and arousals, places the body intermittently on “alert status”. This state can induce activation of microglia and contribute to sleep pathology either initiating or perpetuating disease. The hypersomnias and the REM sleep behavior disorder, especially when associated with neurodegenerative disease, may also involve microglia.

Research on brain sleep and wakefulness mechanisms specific to the older adult and person with early cognitive decline is of special significance. Microglia change with age and could impair sleep, thereby contributing to decreased memory, poorer executive function, and increased gait problems among the aging population. Patients with chronic multisystem diseases such as chronic fatigue syndrome and chronic inflammatory diseases typically exhibit a spectrum of often overlapping symptoms that are mediated by sleep problems and by neuro-immune dysregulation which in turn promote each other.

This book will be of interest to a variety of clinicians in many medical disciplines including sleep medicine. Sleep medicine specialists (including sleep medicine physicians and neurologists) need to understand immune-mediated processes which can lead to sleep disturbances in patients presenting with symptoms of cognitive dysfunction or a movement disorder. Sleep disturbed patients are often first evaluated by primary care physicians and/or psychiatrists and this book will provide straightforward practical guidelines to determine which patients need further evaluation. Health systems, payers and health care policy makers will be needed to decide whether to reimburse for an extended evaluation and to cover the costs of multi-disciplinary clinics and clinician training programs to address sleep disturbances.

What Changes

• Assessment should broaden: incorporate questions about cognitive change, mood, systemic inflammation, and the trajectory of sleep problems — not just sleep duration and timing — and consider neuro-immune contributors when symptoms are refractory to standard approaches.
• Treatment planning must weigh immunologic trade-offs: while anti-inflammatory or immune-targeting strategies are an emerging possibility, conservative measures — optimizing sleep architecture, treating sleep-disordered breathing, and addressing comorbid mood or pain conditions — remain first-line and often reduce neuro-immune stressors.
• Systems of care should become more multidisciplinary: integrate sleep specialists, neurologists, and behavioral health clinicians, and create referral pathways for patients with combined sleep and cognitive complaints to ensure coordinated diagnostic evaluation and follow-up.
• Policy and reimbursement should adapt: support for extended diagnostic pathways, access to specialty care, and clinician education will be necessary if neuro-immune approaches enter routine practice.

Future cases in sleep medicine will require more nuanced clinical decision making. The patient with decades of insomnia who suddenly develops complaints of memory problems will require a differential diagnosis that includes potential neuro-immune causes in addition to more traditional psychiatric and behavioral primary sleep causes. Yet not every case will require sophisticated and expensive advanced diagnostic tests. The clinician will need to use several clinical clues (such as whether or not there has been a change in the patient’s cognitive symptoms over time, whether the patient is experiencing daytime symptoms of inflammation, and whether or not the patient has received a poor outcome from behavioral and/or pharmacologic treatments targeted to sleep and/or cognitive complaints) to make a decision about whether or not to pursue further investigation into a patient’s set of symptoms. The clinician will also need to present an accurate vision for the state of the field to the patient and family members, and give them an accurate sense of the evidence-based and experimental treatments that are available for treatment of sleep and cognitive complaints.

In the practical realm there are several important things to keep in mind when caring for a patient with a neurodegenerative disease. First, it is crucial that patients receive evidence-based sleep treatments that reduce pathophysiological sleep drive and decrease sources of sleep-related physiological stress that increase waking microglial activation (e.g., aid adherence to CPAP for obstructive sleep apnea, treat psychiatric and pain symptoms that disrupt sleep, and promote regular sleep times and sleep promoting sleep hygiene). Secondly, patients and their families should be monitored for sleep disturbances throughout the disease trajectory, particularly if sleep disturbances are associated with worsening of cognitive or motor decline and warrant a referral back to their respective specialty for evaluation and management. Lastly, patients and families should be thoroughly screened for potential, reversible contributors to increased waking brain inflammation, including sleep promoting medications (e.g., sedatives/hypnotics), sleep- disordered breathing, substance use, and systemic inflammatory conditions.

Interventions that target brain immune activity pose certain levels of risk to patients. Dampening detrimental levels of inflammation, while enhancing beneficial aspects of immune function and promoting neural plasticity, may prove to be a particularly elusive goal. Clinicians should be aware of both what is known and unknown about these drugs and their interactions with other conditions (e.g., infections, psychiatric disorders). Off-label or experimental use of these agents should occur with at least as much vigilance as is afforded to studies conducted under controlled clinical protocols and with informed consent of patients and their families.

Future directions for research in practice: are there better biomarkers for neuro-immune activity that will allow clinicians to identify patients that require different treatment approaches? Digital sleep monitoring and remote symptom tracking will be useful for monitoring sleep continuity and related daytime effects over time and linking to neurocognitive outcomes. Modulation of microglial activity and downstream effects on inflammatory pathways could lead to the development of effective new treatments for sleep that affects cognition or is intractable.

Education and policy need to catch up. Insurance coverage for diagnosis and treatment of sleep disorders also needs to catch up. Health systems need to develop interdisciplinary programs and clinics in sleep medicine staffed by neurologists and behavioral health professionals. Training programs for clinicians need to have a basic understanding of the neuro-immune system to make appropriate referrals and provide informed counseling to their patients regarding sleep treatment. For researchers and funders, the next step will be to conduct studies in sleep and wakefulness that define which patients are most likely to benefit from this emerging neuro-immune based approach to treatment and to determine long term safety.

The take-home message for the clinician is that sleep disturbances trigger microglial activation in the brain, and the most important thing to do for patients with these symptoms is to control the modifiable causes. A multi-disciplinary, longitudinal approach to these patients who have complex symptoms which are persistent or progressive is most helpful. As the field continues to grow, one can anticipate the development of better diagnostic tools and more therapeutic options, which should be considered for benefit against unknown long-term risks. However, the issues of access and cost cannot be ignored.

References:

https://pubmed.ncbi.nlm.nih.gov/39207702/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067066/