NAME: SAIFUL BAHARI BIN BAKHTIAR
YEAR: THIRD YEAR , FACULTY OF MEDICINE, ALEXANDRIA UNIVERSITY, EGYPT.
TITLE: PHYSIOLOGICAL CROSS-TALK BETWEEN SLEEP AND MEMORY CONSOLIDATION
ABSTRACT
This article aims to provide a better understanding between the correlation between sleep and memory consolidation. The explanation of the physiology of each sleep stages occurring throughout the night and the general function of sleep such as saving energy, restoration of energy resources, immunologic function and etc. Memory will also be explained especially the scope of short term memory and long term memory in the brain. Then from the understanding of sleep and memory, we will try to uncover the process of how sleep help in memory consolidation with the dependant of few hypothesizes that may cement a concrete correlation between both aspect. Finally, we will try to put theory into application by discussing about obstructive sleep apnea (OSA) that may damage the hippocampus impairing the process of memory consolidation.
KEYWORDS: REM sleep, long-term memory, consolidation of memory, hippocampus, obstructive sleep apnea
1.0 INTRODUCTION
Function of sleep remains largely unknown although researchers have been experimenting for decades, yet there are still more to be discovered. Sleep has been associated with multiple functions but its role in consolidation of memory is very important as it helps in producing long term memory in the brain and help generating consciousness during wakefulness. Hence, this review targets to provide a better understanding on how sleep helps in consolidation of memory. Brief explanation on the concept of the definition of sleep and memory itself before going into further details into the electrical activities and few main hypothesis in assisting plasticity of memory in sleep.
2.0 SLEEP
Sleep is defined as physiological natural periodic state of rest for the mind and body, in which the eyes usually close and consciousness is completely or partially lost, so that there is a decrease in bodily movement and responsiveness to external stimuli.1 Sleep occurs in regular intervals daily and homeostatically regulated. However this occurrence happen in all vertebrae such as birds, fishes, reptiles and sleeplike states are similarly observes in invertebrates like flies, bees and cockroaches.2 The sleep cycle in the human body is divided into 2 separate stages; slow-wave sleep (SWS) and rapid eye movement (REM) sleep mainly. In each sleep cycle, these 2 main stages occur alternating between each other. The SWS stage is further subdivided into 4 stages (Refer figure 1):

 Stage 1: It is the lightest of the 4 stages and resembles wakefulness. This is further characterized with short Theta wave (4-7 Hz) via electroencephalogram (EEG).
 Stage 2: It is characterized with the appearance of sleep spindle waves which are rhythmic burst of 12-15 Hz activity in the EEG. The waves slowly increase and decrease the amplitude giving its spindle like characteristic.
 Stage 3: It is quite similar with stage 2 with difference of very low frequency delta waves (12-15 Hz) which is quite large in frequency.
 Stage 4: Similar with stage 3 but more extensive delta waves activity. It is the deepest stage of slow-wave sleep, in which arousal is most difficult.3

Figure 1: The physiological sleep stages.4

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Next, REM stage of sleep is predominant at the later stage of sleep cycle. It begins with Ponto-geniculo-occipital (PGO) wave which is a sharp electrical spike that starts from the pons, continue to the lateral geniculate nucleus and reaching the occipital cortex. This stage received its name solely due to the rapid movement of the eye that really takes place during sleep. REM sleep wave is similar to the wakefulness condition of our body but with few differences especially towards cardiac acceleration and increase of blood pressure due to phasic activity of the autonomic nervous system, increase breathing rate and inhibition activity of the muscle such as back, legs and necks. Only minute movement do occur which is called twitches at the extraocular muscle and flexor muscle of the finger and toes.

Hence, with a very complex physiological activity that takes place in sleep, question do remains on the actual function of sleep? Mammals do need sufficient hours of sleep to avoid any side effects of sleeping disorder. Generally, sleep has been discovered to save energy, restoration of energy resources and repairing cell tissues, thermoregulation, metabolic regulation and adaptation of immune functions.5,6 Then further studies have further improve our understanding on sleep by the discovery how sleep may help detoxification of radicals from the brain and glycogen replacement in which have shown relation in memory plasticity.7,8 These 2 major functions are exclusively occur during sleep cycle by which during wakefulness may not occur or it is less effective. Under this basis of sleep physiology, we can further discuss and understand how consolidation of memory during sleep at the latter function.
3.0 MEMORY
Memory is the term given to the structures and processes involved in the storage and subsequent retrieval of information.9 The memory is separated into short-term memory (STM) and long-term memory (LTM). Short term memory is also known as working memory, which is only for a short periods of time with very limited amounts. STM act in allowing human to provide continuity of life performing life essential function. This type of memory has been proposed that it has limited capacity of workspace. This idea is further supported by 2 different subsystems; phonological loop and visuospatial sketchpad. Phonological loop comprise of memory from verbal information that can only be remember in a short period by is reinforce by rehearsal and repetition. The brain however is limited to 6 or 7 items at one time. Example: remembering telephone numbers. Next is the visuospatial sketchpad, information that is obtained from visually related information.

Next, it is the long-term memory (LTM). LTM differ from the STM in such they can encode unlimited amount of memory. This is a very stable memory that cannot disappear from the brain even by unconsciousness and coma because it involves the changes of structure in
the nervous system, instead of dynamic patterns of a group of neuronal interactions only. Changing STM to LTM consist of 3 separate processes of encoding, consolidation and recall. Encoding is interacting with something and performing an action to the extent that they will become a representation of the brain. Then it will further proceed to consolidation process which is define as a process of not only stabilizing memory but also a process increasing resistance from disturbing factors without any practise through the passage of time .10 This process plays a vital role in contributing towards the formations of LTM. Reconsolidation consists of different waves of stabilizing sequence at different time. Most of these processes take place in Hippocampus of the brain (Refer figure 2). Since time act as a key factor in it, strongest effect have been applied immediately after learning.11,12 It is reclassified into 2 further types of reconsolidation which are synaptic reconsolidation and systemic reconsolidation. Both of these types lead to remodelling of the synapses and spines of neuronal connection causing higher endurance of efficacy in each synapse. Lastly, the process is known as recall that may strengthen the old memories without causing it to disappear every time we are learning new things in our daily lives. This will further enhance the stability of consolidation of memory.

Figure 2: The Hippocampus of the brain, main site for consolidation of memory.
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In our daily lives, we learn new things in every days which some of that are irrelevant to be stored as long term memory. Hence, a hypothesis was suggested that and accepted as a resolution of this problems, the standards two stage model of memory. It was suggested that the brain has 2 types of storages; fast storage that hold information temporarily in the hippoccampus and slow storage that holds information in a long periods in the neocortex. The new information will be encoded by the brain and gradually repeatedly reactivated during the periods of consolidations. The fast learning memory is encoded rapidly yet unstable making it very vulnerable to disappear upon new information. The slow storage takes longer time for consolidation of memory but it is more stable. All of these are possible due to repetitive activations of causing the brain to reorganised the informations and strengthen them. Every reactivation of new and old memories, temporary memory may adapt to the long term memory network making them permanent. Once present as a long term memory, the brain has the ability to eliminate any irrelevant and unwanted informations from the new memories. This process is best perform during sleep because there will be less interference during that moments of offline periods.13
4.0 CONSOLIDATION OF MEMORY & SLEEP
The standard two-stage model of memory has been taken as a basis for conceptualizing the function of sleep for memory as a process supporting active system consolidation.14,15 Based on multiples research findings, efforts have been put in to integrate all of them to provide a better understanding on this occurrence. The relation between both sleep and memory may be further explained through these hypotheses:
 Dual Process Hypothesis
 Sequential Hypothesis
 Active System Consolidation Hypothesis

Dual process hypothesis explained how different sleep stages help with different types of memories consolidation. This hypothesis shows that SWS sleep helps consolidation in declarative memory while REM sleep helps with non-declarative memories which were supported by a theory of the ‘night half paradigm’. Based on a study done by Yarush et. Al., he concluded that with SWS-rich sleep provide a positive increase in declarative memory with retention occurring during REM- rich sleep.16 Although declarative memory is highly useful in that stage, emotional memory is otherwise different in which it is enhance during REM stage. Hence, this shows memories such as procedural, implicit and emotional will be profitable in REM-rich sleep.

The second hypothesis, Sequential hypothesis explained the importance of successive cycle of REM and SWS sleep stages in the natural occurrence of sleep by saying that during SWS sleep non adaptive memories were weakened and adaptive response were strengthen but during REM sleep, adaptive memory further adapted into the existing memory networks. Further study provided proof towards this mechanism by concluding that any increase of SWS sleep followed by REM sleep cycle, enhance brain memory consolidation via global depontetiation of synaptic connection due to slow waves capacity by the EEG which will be supported by REM stage, increasing hippocampal-theta waves that enhance synaptic connection in the brain.17 Research have also been tested among humans, how naps in between studies, show increase production of same task only if they sleep more than 90 minutes consisting SWS and REM sleeps rather than short sleep below 60 minutes as it is only include with SWS sleep.18

The third hypothesis, Active System Consolidation Hypothesis is the combination of both, dual process and sequential hypothesis (Refer figure 3). The SWS stage will take the upper hand in this process that causes memory consolidation during sleep with repetitive reactivation of newly encoded information. During SWS stage, the brain tries to help adaptation of STM to LTM by repetitive reactivations of the sharp wave ripple in the hippocampus together with thalamo-cortical spindle wave that may help in brain memory plasticity if the waves are able to be change into slow oscillation wave mimicking the wave in the neocortex, center for long term memory. REM sleep will act as a support system for SWS sleep as every memory activation and consolidation happening, it will stabilize the synaptic consolidation process. This process plays a major role in providing understanding in sleep dependant memory consolidation but with a few drawbacks:

Figure 3: The process of Active System Consolidation Hypothesis.19
3 Reorganization of procedural and declarative memories during sleep
Studies have shown that in sleep dependant consolidation will not cover all type of skills but training of perceptual and motor skills will have major improvements.20,21 The debate on procedural memory even up to the point that memory consolidation will not even take place as for procedural memory if the circadian rhythm and homeostatic is influenced and controlled. Networking between procedural memory and declarative memory, study has shown that reorganisation did take place especially towards memories from the learned materials involving abstraction, inference and insight. This statement is supported from studies that consolidation of newly learn vocabulary into existing knowledge networking through lexical competition method that will increase spindle activity denoting reactivation of the hippocompal short term memory.22 Via sleep, it has also concluded that it may help in training of insight and with the aid of high SWS-rich sleep, increase spindle activity was noticed. A study using Serial Reaction Time Task (SRTT) help in developing of explicit sequence knowledge found that, although with training, subject cannot called out the SRTT sequence except if they received sleep after training.23 This is more prominent in children because of its slow wave oscillation in the brain after training.
 Selectivity of memory consolidation during sleep
This factor is another important point to understand as in active system consolidation, offline consolidation enhance memory traces and synaptic connection holistically because it can cause overflow of information which are not needed by the subject. The selectivity in sleep is influenced by several factors; firstly, sleep dependant gains are higher when explicit learning is used rather than implicit learning. Second, initial memory strength might affect consolidation in sleep although the data are not consistent. This will help propose a new founding in a study by Stickgold, saying that sleep will only benefit memory at an intermediate strength because consolidation of memory is different and also difference of initial encoding.24 Moreover, encoding of information will be stronger with emotional association. Third, sleep may enhance encoding of memory depending on future prospect of the subject. The future prospect can be further understood by any sort of motivational factors and specifically strengthen those memories for our future goals and behaviours. The mechanism upon this process is not well understood until today but it has said that prefrontal cortex, which is responsible for the anticipatory behaviour will collaborate with the hippocampus to regulate implementation of anticipated memory retrieval as well as allocation of expectance to a memory.25 Theta wave produce by the prefrontal cortex in the prefrontal-hippocompal circuit act as memory tagger these memories which will receive specialty to undergo memory consolidation during sleep.
5.0 SLEEP DIORDERS AFFECTING MEMORY
Obstructive Sleep Apnea(OSA)
Obstructive Sleep Apnea(OSA) is a syndrome present usually among mid-aged adults with an occurance rate of 2-4% among the general population.26 It is manifested with obstruction or closure through the upper airway respiratory pathway; nasopharynx, oropharynx and laryngopharynx in our body affecting our daily physiological sleep cycle. This syndrome is different in comparison with obstructive hypopnea and upper airway resistance in such way that OSA is the temporary cessation of airflow during sleep for 10 seconds or more despite continuing ventilatory effort.27 Further clarification of between obstructive sleep apnea, obstructive sleep hypopnea and upper airway resistance can be seen through (Table 1). OSA may also occur in children, women and obese persons in which all of them usually develop snoring during sleep. The pathogenesis of OSA mainly involves underlying neuromuscular tone, upper-airway muscle synchrony, and the stage of sleep that may contribute towards the patency of the upper airway respiratory tracts preventing sleep fragmentation which may cause implication to the autonomic nervous system, heart and respiratory system.28 In this part, stress upon how stages of sleep may play a key role in disrupting the patency of pathway during sleep will be explained in order to get a proper correlation between sleep and memory.

Table 1: Manifestations of Upper-Airway Closure during Sleep.29
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The occurrence of OSA in sleep differs between SWS and REM stage especially in the point in breathing patterns in each specific stage physiologically. REM stage cause variety of changes towards breathing rate but to a small extent of the tidal volume in the pulmonary ventilation. Hence, we can see the body compensation through regular interval of tachypnea through this stage. SWS stage however affects breathing rate differently in each stages from stage one to stage four. Physiologically during stage 4, it is much more stable, deep and regular patterns in comparison with stage 1 and 2 which has variety of patterns because wakeful stimulus present periodically throughout the SWS stage. The present of wakeful stimulus cause excitation of sleep and the reversed take place in the absence of the stimulus that caused the sleep to be deepen and produce much more stabilize breathing. This is known as Cheyne-Stockes breathing.30 The occurrence of OSA may take place in certain stages of human sleep cycle causing wakefulness in certain period. Apnea in this condition affects the brain through the deficiency of oxygen supply producing hypoxic stage. Hypoxia to the brain multiple times and for a long duration affects mainly the hippocampus, anterior cingulate, cerebellum, and the frontal, parietal, and temporal lobes in patients with OSA.31 Study by Citra Lal via various neuroimaging techniques, shown significant damage towards these areas in OSA patients by reduction of grey matter of each specific area. Extensive damage of the hippocampus area especially results in impairment of memory consolidation that may lead to anterograde and retrograde amnesia towards the patient.

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ACKNOWLEDGEMENT:
I am grateful towards Dr. Adham, Professor of Physiology Department, Faculty of medicine, Alexandria University for his support and guidance throughout this article writing process.
DISCLOSURE OF INTEREST
None.
Figure 4: Neuroimaging of affected parts of the brains in OSA patients.32
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Prepared by,
…………………………………………………
SAIFUL BAHARI BIN BAKHTIAR
MEDICAL STUDENT,
ALEXANDRIA UNIVERSITY, EGYPT.
Approved by,
……………………………………………………
DR. ADHAM RASHED, MD,
PROFFESOR OF PHYSIOLOGY,
FACULTY OF MEDICINE,
ALEXANDRIA UNIVERSITY, EGYPT.

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