Science: the interrelated causes and consequences of sleep in the brain

Sleep is crucial to brain function , Its action mode is various , It's amazing . In the short term , Lack of sleep can lead to impaired memory and attention ; In the long run , It can lead to neurological dysfunction and even death . I will discuss the latest advances in understanding how sleep maintains the physiological health of the brain through a system of interconnected neuronal activity and fluid flow . The neurodynamics that occur during sleep are essentially related to its effect on blood flow 、 Cerebrospinal fluid dynamics is associated with the effects of waste removal . Recognize these interrelated causes and consequences of sleep , It gives people a new understanding of why sleep is so important to these different aspects of brain function .

Our nighttime sleep is crucial for many brain functions . Just miss a night's sleep , The memory of the next day 、 Emotions and attention are impaired ; Sleep disruption throughout life is associated with neurodegeneration . These heterogeneous effects of sleep have led to a mystery in neuroscience : Why does this brain state play a unique role in supporting these seemingly different aspects of brain function ?

Decades of research have shown that , Sleep contains unique neurodynamics related to cognition , For example, in non rapid eye movement (NREM) A slow wave of neural activity that occurs during sleep . Recent findings show that , Sleep is also an improved state of removing substances from the brain . Metabolic waste passes through interstitial fluid (ISF) And cerebrospinal fluid (CSF) Transport from brain tissue , Sleep plays a key role in waste regulation and cerebrospinal fluid flow , This is critical to maintaining neuronal health . These beneficial effects may explain why we spend so much time sleeping every day , Because the role of sleep in the basic management of the brain involves a wide range of neural functions . But why sleep is associated with different hydrodynamics , Why does sleep play such an important role in maintaining brain function .

1 A control loop that manages sleep
Sleep is controlled by a large-scale arousal regulation system , It can quickly induce sleep or wakefulness . A number of loop based studies have documented and manipulated individual brain regions and cell types , To determine their various roles in the behavior . This method is very effective , It recognizes the hypothalamus 、 brainstem 、 Multiple regions in the basal forebrain and other subcortical nuclei that control sleep . Key interaction circuits include noradrenergic 、 Dopaminergic 、 Cholinergic and orexin systems , They can induce sleep - The transformation of awakening . However , These findings also raise a new question : Why do so many different nuclei play a decisive role in whether an animal is asleep or awake ?

One possibility is , This system is usually redundant ; Sleep is so important , So that the brain contains multiple switches to induce sleep . However , The second and more likely possibility is , These loops represent the interacting components of a larger system , The system triggers many different sleep characteristics , Including behavior change 、 Oscillatory neurodynamics 、 Regulate respiratory and vascular physiology and clearance . It is worth noting that , The circuits that regulate sleep are all over the forebrain , They also influence each other , Therefore, activities within one system inevitably affect other systems . Besides , Neuromodulators, such as norepinephrine and acetylcholine, that alter neuronal arousal also have direct effects on blood vessels .

2 Low frequency neurodynamics during sleep
In sleep , Large scale neural activity reorganizes into a unique oscillation pattern , It reflects the thalamus that produces EEG oscillations - A wide range of arousal regulatory circuits in the cortical network . For a long time , These patterns are thought to define different stages of sleep , Distinguish between non rapid eye movements and rapid eye movements . As sleep enters rapid eye movement , There are many different EEG patterns , Including spindles (~11 - 14hz) And slow waves , It is obviously related to memory and cognition . The increase in low-frequency power is called slow wave activity , This is a general term , Corresponding 0.5 - 4hz Of EEG power , It can reflect several low-frequency dynamics ( chart 1A). These include separate k complex ( Every few minutes ),δ wave (1 To 4Hz), And slowly (0.1 To 1Hz) Oscillate , Combine and coordinate higher frequency rhythms .k The complex corresponds to a duration of hundreds of milliseconds ( Under the state of ) A wide range of neural activity inhibition cycles , It usually runs through a large area of the cortex . In the deeper NREM In sleep , Slow waves become continuous and rhythmic , Alternate between the lower state and the upper state . by comparison ,REM Sleep is associated with asynchronous deep sleep, rapid eye movement and muscle tone inhibition . Although there is ample evidence that , During sleep , Brain activity changes , The slow wave may be the activity of the whole cerebral cortex , But this does not mean that sleep is a unity of the whole brain 、 A homogeneous state . Even in the conscious mind , Slow waves similar to sleep also appear in local areas of the cerebral cortex ( chart 1B), It is called partial sleep . One possibility is , The brain reacts so strongly to slow waves , So that after a lack of sleep , Although slow waves can have harmful consequences for behavior , But it still appears in the conscious mind . During non REM sleep , Slow waves originally thought to represent coherent global activity have also been found to exhibit local dynamics . Slow wave activity is less obvious during REM sleep , But it can occur in the superficial cortex or frontal lobe .

chart 1 Low frequency neural activity during sleep
3 Sleep brain waste removal and CSF flow
Decades of research have contributed to our understanding of the above slow wave phenomena . Recent studies have found the role of sleep in waste removal : Mice clear molecular chains in the brain during sleep ( Such as amyloid ) Is much faster than waking up . This solute removal is achieved by ISF And cerebrospinal fluid flowing along blood vessels ; However , Precise mechanisms are still a controversial topic , The debate about the force driving the flow and the exit route of the solute . This observation provides a new perspective on the importance of sleep ： Sleep maintains the basic physiological health of neurons by removing potentially harmful metabolic wastes from neurons . An important consideration is , The rate of waste production varies in different awakening states , Rodents and humans are awake tau The production of protein and amyloid is higher . therefore , Sleep can serve as a pause in the waste generation process , Allow the removal system time to remove the waste accumulated in the awake state . The relative balance between these two procedures , In addition to generating waste , Or a period of intensive cleaning , Further research is needed . Human imaging studies have recently supported the link between sleep and brain waste regulation . Lack of sleep increases amyloid in the brains of healthy young people . Besides , After injection of contrast agent, it was found that , The clearance rate of brain tissue was higher when subjects slept than when they stayed awake . This ability to remove waste is evident after a night of sleep deprivation , This is an amazing observation , Because this is not a rare behavior for many people .

Why sleep can increase brain clearance ? One factor is the expansion of extracellular volume during sleep , This will increase the speed of molecular transport . secondly , When using narcotics , Rodents have a higher clearance rate , Induce high trigonal wave power , It is suggested that the neurodynamics of sleep is related to clearance rate . Another factor is changes in fluid flow patterns during sleep . People have long known , The cerebrospinal fluid flow when a person is awake keeps beating with the heart and respiratory cycle , But cerebrospinal fluid flow during sleep has only recently been studied . A recent study of human imaging has re used functional magnetic resonance imaging (fMRI) The classic blood flow related enhancement signal is used to simultaneously measure EEG during sleep 、 Blood oxygenation and cerebrospinal fluid flow . This image shows NREM Large waves of cerebrospinal fluid flow during sleep . A few seconds before cerebrospinal fluid wave appears, nerve slow wave activity , It is negatively correlated with hemodynamic signals . This time coupling is consistent with a model , The model suggests that neural activity drives cerebrospinal fluid flow by affecting blood volume , To replace cerebrospinal fluid ( chart 1).2) This mechanism may explain how the intrinsic neurodynamics of sleep is associated with fluid flow .

4 CSF Contribution of flow to neurovascular physiology
What specific vascular mechanisms might achieve this observed coupling of the neural slow waves and cerebrospinal fluid flow ? This question highlights the continuing challenges of sleep research as a whole : Many features of brain physiology have undergone relevant changes . say concretely , Nerve slow wave and glial activity 、 The cognitive process 、 Autonomic state is related to vascular dynamics . Some of these processes may lead to the coupling of neural and cerebrospinal fluid flow waves . First , Nerve activity causes local blood volume changes through neurovascular coupling ; This relationship is the most fmri Basis of research . Low frequency (~0.1 Hz) The regulation of nerve activity can also restrict the movement of arterioles , Cause blood volume fluctuation . Because EEG slow wave corresponds to extensive cortical discharge inhibition , These neuronal changes lead to decreased blood volume and increased cerebrospinal fluid flow . Besides , During non REM sleep , Neurovascular coupling is enhanced , Support this mechanism .

second , Slow waves in sleep not only reflect local nerve activity , And it is often associated with systemic changes in vasoconstriction caused by neuromodulation and autonomic state changes , Especially when slow waves occur as isolated events , be called k compound . This systemic vasoconstriction is also associated with global cerebral hemodynamic changes and human cerebrospinal fluid flow . Besides , Individual slow waves are locked to slow oscillations (1hz), This is related to the autonomic regulation of blood flow . in fact , This pathway may not be completely decoupled from neurovascular coupling ; Systemic vasoconstriction may partly reflect the need for global cerebral hemodynamic regulation , Consistent with the dramatic changes in neuronal activity . Neuromodulatory substances related to sleep can also have a direct effect on vasodilation ; for example , The adrenergic system regulates slow sleep oscillation and vascular diameter . Its effect may depend on whether the release is tetanic or periodic , This is different in different sleep stages , And will affect the subsequent cerebrospinal fluid flow . Low frequency oscillation of blood vessels (~0.1 Hz, namely ;( Every time 10 One second ) It also appears at a lower level when awake . Consistent with the vessel based model ( chart 2), These low-frequency hemodynamics are also coupled to cerebrospinal fluid flow when awake , But the amplitude is lower than that of sleep . Again , Regulate breathing ( Affect vasodilation ) It also affects cerebrospinal fluid flow when awake . therefore , In this framework , The time characteristic of the vascular system is the key factor to determine the liquid flow time , therefore , Coherent low-frequency neural activity during sleep is a particularly effective driver of fluid flow .

A key prediction of the model proposed in this paper is , The neural activity that most effectively guides vascular changes will drive the largest CSF Traffic ( chart 2B). Low frequency EEG dynamics during sleep show many different patterns ( chart 1; The model predicts , Any of these slow dynamics can drive the blood flow , If it is associated with extensive changes in vasodilation . for example , Due to slow vascular response , An isolated slow wave is predicted to drive CSF flow more effectively than a continuous slow wave ( chart 2B). Besides , Low frequency oscillation ( for example , Slow oscillation ) Expected higher frequency oscillation ( for example ,δ wave ) More effective . Besides , Slow oscillation and high frequency dynamics ( Like a spindle ) The amplitude of . Studies of total sleep deprivation have failed to identify the role of different neural rhythms , Further studies are needed to test whether different oscillations have different associations with cardiac flow . Considering that vascular mechanics may be a key factor in controlling fluid flow and clearance , It may be induced by a variety of types of coherent neural activity or slow vasodilator . Recent studies in mice support this view : Low frequency (0.05 Hz, Or every 20 second ) Visual stimulation can cause arteriole dilatation and enhance paravascular clearance .

5 Mesoscale neural and hydrodynamics
The macroscopic and microscopic scales of fluid dynamics observed during sleep . Rodent studies have established clearance by monitoring solute transport in long containers . Human sleep studies have observed macroscopic cerebrospinal fluid flow in the ventricles and protein accumulation in the brain . A major problem is how these scales are linked : How cerebrospinal fluid flow in the ventricles affects tissue clearance , And is neurovascular coupling a viable mechanism for transporting solutes out of the brain ? Although mesoscale experimental research is challenging , But computational models have clarified these issues . The model shows , The slow time scale and large amplitude of neurovascular coupling make it an effective mechanism to drive solute transport along arterioles .

Studies measuring macroscopic cerebrospinal fluid flow in humans have not yet clearly defined ventricles CSF The flow rate is related to the clearance rate . Intuition , Use high speed during sleep CSFflow The idea of waves may increase the gap , It's like the difference between a stagnant bathtub and constantly mixing and refreshing water . However , This has not been proved by experience , Future studies also need to determine the precise relationship between large-scale cerebrospinal fluid flow and solute transport outside the brain tissue .

6 Close the loop ： Results of fluid physiology and neural function
A curious question is , Whether the influence of neural activity on cerebrospinal fluid flow forms part of a two-way feedback loop , Each of them can affect the other . Some research shows that , The liquid contents can regulate excitement through specific ways .ISF The ionic component of can regulate neuronal discharge , Induce wakefulness or sleep . Amyloid and inflammatory cytokines also affect the state of neural arousal . By adjusting the ISF and CSF The local environment of molecular composition , Clearance may therefore affect sleep .

Besides , And aquaporins -4 Genotypic individuals associated with low expression ( Aquaporin -4 It is part of the gelatinous lymphatic pathway ) Show a higher EEG Slow wave activity . This observation was interpreted as an increase in EEG slow wave activity to compensate for lower clearance , Although it is not clear how this compensatory feedback may be achieved . Besides , The long-term consequences of clearance or lack of clearance may have more fundamental consequences for neuronal health , Causes inflammation or neurodegeneration in areas that lack adequate clearance . If clearing obstacles affects the wakefulness regulatory circuit that induces sleep , This will further reduce sleep . Besides , As mentioned above , Lucidity is not only associated with lower clearance rates , And first of all, it is related to the high waste generation rate . This vicious cycle hypothesis can explain why sleep disruption is associated with the development of neurodegenerative diseases .

The related nervous and vascular systems are also doubly vulnerable in the aging process . With age , The length and depth of sleep will decrease . Although some sleep loss is typical of healthy aging , But more severe sleep deprivation can predict subsequent Alzheimer's disease pathology . EEG slow wave is especially related to this : Patients with reduced slow wave activity showed lower memory scores and higher gray matter atrophy . The reduction of slow waves in sleep (< 1hz) It indicates the accumulation of amyloid protein after several years . Although causal evidence has not yet been established , But the connection between EEG slow wave and fluid dynamics shows that , Slow wave loss , Especially in the lowest frequency band , May damage removal .

In addition to the decline of sleep nerve signals during aging , Neurovascular physiology is also disrupted . Vascular dysfunction may be an early cause of Alzheimer's disease , Because cerebral blood flow drops a few years before symptoms appear ; This decline can also lead to sleep deprivation , Unable to drive effective cleanup , Because vasodilation drives CSF Traffic . To support this view , Cerebrospinal fluid flow imaging was recently applied to a database of patients with mild cognitive impairment . Interestingly , The coupling between hemodynamics and cerebrospinal fluid flow is weak in patients with this injury , This suggests that the vascular mechanisms that drive cerebrospinal fluid flow may indeed be impaired in the early stages of neurodegeneration .

7 Fluid physiology at different sleep stages
Last , It is not clear how different sleep stages contribute to fluid flow . Of course , The mechanism discussed here solves part of the problem , To determine how neurodynamics and fluid dynamics are linked in non REM sleep , Especially in N2 Sleep phase , Slow wave is obvious , But the time is irregular . Human NREM Sleep most of the time in N2 period , Due to slow vessel filtering , The low frequency slow wave time in this state may be particularly effective in driving cerebrospinal fluid flow ( chart 2). However , In the conscious mind , Local slow waves and systemic vasodilation may occur ; therefore , During waking and light sleep , Cerebrospinal fluid flow waves similar to sleep also appear less . What complicates these problems is , Of rodents NREM There is no clear correspondence between sleep stage and human sleep stage , And the time of neural oscillation and neurovascular coupling may be different . Although these species-specific differences may pose challenges to translation , But they are also anatomical NREM The different neuro - and physiologically dynamic regulatory clearance systems provide opportunities .

contrary , During REM sleep , How clearance and cerebrospinal fluid dynamics change remains unknown . Recently, whole brain hyperemia patterns have been observed during REM sleep in rodents , The arterioles show an unusually large dilation . These large fluctuations in blood volume may also drive cerebrospinal fluid flow , But this possibility has not been tested . Because slow wave is not significant in REM sleep , Therefore, there may be a unique mechanism to drive fluid dynamics in REM sleep . One may be the direct effect of rapid eye movement related neuromodulators on blood vessels ; for example , The cholinergic system, which is highly active during rapid eye movement, can also have a direct vasodilator effect . Besides , The circadian cycle also affects clearance ( chart 2C). therefore , Neural activity alone cannot explain all the clearing in sleep , More needs to be done to understand how these mechanisms work together .

chart 2 Coupled nerves in sleep 、 Blood vessels and CSF Different time scales of dynamics
8 Outlook and open questions
Sleep has different effects on the brain ; Changes in neural activity and cognition , Changes in the system and autonomic physiology , Key management processes support neuronal health . These processes are usually studied separately , But they are intrinsically linked through their mechanical origins and physiological consequences . In turn, , The neurodynamics that occur during sleep form blood vessels and cerebrospinal fluid flow , These flows feed back to these neurodynamics . These convergence results point to some key open issues . First , What are the neural circuits that control gaps and fluid flow during sleep ? Although the above work emphasizes the role of neural activity , However, how the specific neural characteristics and the diversity of sleep stages regulate fluid dynamics has not been well understood . Given the amazing number of neural circuits that control sleep , Future work should determine that their interactions will not only affect neural activity , It also affects vascular dynamics 、 Cerebrospinal fluid flow and clearance . Recently developed technologies increasingly make this whole brain multimodal imaging possible . The ability to record on a large scale in animal models enables the study of joints , Sleep is formed spontaneously and dynamically through circuits . In human neuroscience , Recently fMRI The impressive progress made in the resolution of spatiotemporal holes has also made many of these problems within reach . With these new technologies , This field is expected to make significant progress in studying how these distributed dynamics interact to produce sleep states .

The second key challenge is to understand the mechanistic connections between these interacting neuronal and non neuronal systems , This poses a challenge to experimental research . Considering that many characteristics of sleep are strongly correlated , It is difficult to analyze causality , And many traditional methods include the assumption that these links are excluded from discovery . Functional magnetic resonance imaging (fMRI) Research usually returns only one feature , Like breathing , But this assumes that the physiological dynamics of these systems is a pure confounding factor ; in fact , In sleep , Neural state is usually collinear with system physiology , And drive system physiology . Systems neuroscience methods often manipulate a circuit to state causality , But you may miss the cascade of follow-up activities caused by the focusing operation , Moreover, direct regulation of neural activity sometimes produces different effects than spontaneous . In addition to the neural and fluid dynamics outlined here , Sleep also provides many other functions for the brain , Such as synaptic homeostasis 、 Glial function 、 Memories and dreams . By simultaneously capturing different aspects of sleep in a multimodal study , Think of brain physiology during sleep as an interconnected dynamic system , This is a promising perspective for understanding how these processes interact .

The results of these studies are crucial to explain the link between sleep and neurological and psychiatric disorders . Sleep loss in neurodegenerative diseases has now been clearly demonstrated , This highlights the need to determine the exact impact of sleep on brain health . Because sleep disorder is one of the characteristics of several mental diseases , therefore , The relationship between lucidity and mental disorders is an area that needs further study . Understanding the mechanism of sleep requires not only exploring and predicting the neural functions related to sleep , There is also a need to identify possible goals for sleep based interventions to improve brain health and clinical outcomes .

Final , Many factors work together to produce sleep effects , Including coherent neural activity 、 Vascular dynamics 、 Cerebrospinal fluid and ISF flow . Although these interacting components make it challenging to explore individual mechanisms through experiments , But considering these dynamics as a whole can reveal their biophysical connections . Sleep is a powerful regulator of these interconnected brain systems , It provides a wide range of effects for maintaining cognitive ability and healthy brain function .

reference ：The interconnected causes and consequences of sleep in the brain