Sleep and Addiction

One of the major problems that I treat in people with significant substance use disorders is insomnia of all types.  I see people who have had insomnia since childhood.  A significant number have had insomnia and nightmares since childhood.  In that case the insomnia often precedes the development of any associated psychiatric diagnoses – it is a primary problem. In many cases, it is one of the reasons that people develop a substance use problem.  Alcohol, sedative hypnotics (often benzodiazepine type drugs), opioids, and cannabis are commonly taken for sleep and typically lead to many secondary problems.  Alcohol for example, will often lead to faster sleep onset, but as tolerance develops, the person will start to make up at 2 or 3 in the morning.  With increasing tolerance, a decision about taking more drinks at that time or toughing it out until the morning will need to be made. Some people can get to the point that they ingest large enough quantities of alcohol that they sleep the entire night and wake up with elevated blood alcohol levels.  Some do not realize the problem until they are arrested driving into work the next morning for intoxicated driving.

The available medications for treating insomnia in patients with addiction are limited.  We can currently treat a significant number of patients with sleep problems but there are still many that have very difficult to treat insomnia.

Medication	Probable Sleep Mechanism of Action
Trazodone	H-1 antagonist, NE antagonist, 5-HT2 antagonist
Doxepin	H-1 antagonist, NE antagonist, Ach antagonist
Mirtazapine	H-1 antagonist, 5-HT2 antagonist
Hydroxyzine	H-1 inverse agonist, Ach antagonist
Quetiapine	H-1 antagonist, NE antagonist, Ach antagonist, 5-HT2 antagonist, DA antagonist
Ramelteon	MT-1/MT-2 agonist  MT-1> MT-2
Melatonin	MT-1/MT-2 agonist  MT-1>MT-2
Prazosin	α1- adrenergic antagonist
Gabapentin	inhibition of the alpha 2-delta subunit of voltage-gated calcium channels
Benzodiazepines (detox only)	GABAA receptor agonist
Opioids (detox, MAT)	MOR agonist

 

The general strategy of using these medications is apparent from the purported mechanisms. For example, brain histamine (H) and acetylcholine (Ach) are alerting and arousing neurotransmitter systems so that antagonists/inverse agonists would be expected to decrease arousal and facilitate sleep.  Noradrenergic (NE) systems are wake promoting so NE antagonists would be expected to decrease this function.  The compounds in the above table work the best in addictive states when a person is abstinent from intoxicants and chronic use of intoxicants and after they have been detoxed.  Benzodiazepines and opioids are in the table for that purpose.  Although I have seen detox protocols that include many of the medications listed in the table as needed for insomnia and anxiety it is unlikely that they will work until detoxification has occurred.  In many cases, the expected duration of detox is much longer than anticipated and sleep problems are a prominent reason.    

That brings me to the primary focus of this post and that is a recent paper entitled “Drugs, Sleep, and the Addicted brain.” I generally don’t get too excited about research papers these days, but after reading this brief paper by Valentino and Volkow – I was fairly excited.  In this paper the authors main goal is to demonstrate how the biological substrates that regulate sleep interact with the reward system and how they can be direct targets for substance use. 

The first system they look at is the locus ceruleus (LC)-norepinephrine (NE) system that is involved in arousal. LC-NE neurons do not fire during REM sleep.  Activation of the LC results in firing of noradrenergic neurons that activate the cortex. Corticotropin-releasing factor (CRF) leads to LC activation and heightened arousal.  Endogenous opioids lead to damped excitation and decreased arousal.  Tolerance to exogenous opioids would lead to an expected inability to dampen the LC-NE system and increased activation and arousal during opioid withdrawal.

The serotonin (5-HT) dorsal raphe nuclei (DRN) system is also a system implicated in both sleep and arousal.   5-HT neurons are active during waking and do not fire during REM sleep. 

Histaminergic (H) neurons in the tuberomammillary nucleus (TMN) have an arousal function on cortical neurons.  They are active in the awake state.

Midbrain dopaminergic neurons (DA) in the ventral tegmental are (VTA) specifically those projecting to the nucleus accumbens (NAc) increase wakefulness upon activation but activation of the other major set of DA neurons in the substantia nigra has no effect.  This is a critical circuit in substance use because this system determines the value function of stimuli in the environment including addictive compounds and affects arousal.

Cannabinoids promote sleep, sleep onset, slow wave sleep, and sleep duration.  They decrease REM sleep.  CB1 agonists and antagonists respond in the expected manner.  The effects of CB1 agonism may be mediated by adenosine which increases in response to the stimulation of this pathway.  Caffeine is an adenosine antagonist and that may be the reason is promotes wakefulness.  Endocannabinoids also inhibit orexin neurons (arousal promoting) in the lateral hypothalamus and increase the activity of melanin neurons.  These combined effects of cannabinoids on the endogenous cannabinoid system explain the expected insomnia when these compounds are stopped for any reason.

The orexin system in the lateral hypothalamus and dorsal medical hypothalamus/perifornical area is activated during wakening and silent during sleep.  It is the system that is disrupted in narcolepsy.  It is also the system that coordinates the activity of the other arousal centers in the brain including the TMN-HA, LC-NE, DRN-5-HT, VTA-DA, and cholinergic neurons in the Nucleus Basalis of Meynert (NBM-Ach).  This relationship is depicted in the following graphic from the paper and detailed in reference 3.

Orexin A and Orexin B are wake  promoting neuropeptides the general structure of which is given below.  These peptides bind to Ox1R and Ox2R G-protein coupled receptors.  Orexin A has equal binding affinity to both receptor but Orexin B preferentially binds to the Ox2R receptor.  Detailed information is available from PubChem.

Human Orexin A

The orexin system may be critical not just in arousal but also in reward.  Patients with narcolepsy have orexin deficiency and generally do not overuse opioids and are less likely to overuse stimulants even though many have been prescribed very high doses.  Opioid users have increased orexin neurons in the lateral hypothalamus.  This increase in orexin signaling may lead to profound insomnia and the associated arousal state after prolonged exposure to opioids and makes this insomnia very difficult to treat.  Orexin can directly potentiate reward in some models.  Orexin is implicated in states where a high level of motivation to acquire the target substance is required or where there are external stimuli like stress, and specific cues for drug use that lead to increased motivational states.  The authors in reference 2 refer to orexin's ability to affect the approach toward a reinforcing stimulus or active withdrawal from an aversive stimulus as motivational activation.

Suvorexant is an interesting compound in that it antagonizes Orexin A and Orexin B wake-promoting neuropeptides and prevents them from binding to Ox1R and OXxR receptors decreasing wakefulness.  It is currently FDA approved as a treatment for insomnia, but the authors propose that it is a compound of interest in that it can potentially counter the arousal and reward potentiation associated with drug seeking states.  If that is the case it could be a useful treatment for both insomnia and the primary addictive disorders.

When I look at possible treatments for insomnia in addiction, a central question is whether or not they will potentially worsen the addictive state.  That is why there are no specific benzodiazepine related sleep compounds in the table at the top of this post.  The benzodiazepines listed there are all basically used on a short term basis for detox and then tapered and discontinued.  In the case of mu-opioid receptors (MOR), medication assisted treatment with both buprenorphine and methadone are possible on an ongoing basis. The package insert for suvorexant suggests possible problems in that subjects with recreational polydrug use rated their "liking" of the drug as being similar to zolpidem 15 and 30 mg doses.  Zolpidem is a standard sedative hypnotic that can be used to treat insomnia.  It definitely has abuse potential and in some cases patients can end up taking very high doses per day until they can be detoxified.  That is not reassuring in terms of safety for persons with substance use problems but I would not take it as proof that it cannot be safely used.  According to the DEA, suvorexant is currently a Schedule IV drug or low potential for abuse or dependence. Some articles on insomnia suggest that despite what appears to be a comprehensive mechanism, the short term efficacy of suvorexant is no greater than zolpidem but at a much greater cost.

I am currently looking at the medicinal chemistry and clinical trials literature to assist me decision making on orexin receptor antagonists and just how much of withdrawal related insomnia is due to orexins. The other important question is whether it will also decrease drug seeking states and withdrawal avoidance.   

George Dawson, MD, DFAPA

References:

All full text and all excellent

1: Valentino RJ, Volkow ND. Drugs, sleep, and the addicted brain. Neuropsychopharmacology. 2020;45(1):3–5. doi:10.1038/s41386-019-0465-x

2: James MH, Mahler SV, Moorman DE, Aston-Jones G. A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?. Curr Top Behav Neurosci. 2017;33:247–281. doi:10.1007/7854_2016_57

3: Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18(23):9996–10015. doi:10.1523/JNEUROSCI.18-23-09996.1998

Graphics Credit:

The brain graphic is from reference 1 and is used here without modification per the Creative Commons Attribution 4.0 License.

Disclaimer:

This post may change significantly over the next two weeks.  I had to put it up to see what it looks like and plan to elaborate the behavioral pharmacology of orexin and the pharmacology of suvorexant.

Relief For the Sleep Deprived?

Sleep is a major problem for the majority of people who I see in clinical practice.  It is both a diagnostic feature and a primary disorder.  It is not uncommon for me to see people in their 30s or 40s who have had consistent sleep problems since childhood.  Environmental, medical problems, and alcohol/substance use are also common causes of insomnia.  After cessation of opioids, cannabis, or alcohol there can be disrupted sleep that lasts for months or longer. The treatment of insomnia is partially effective.  Behavioral methods like sleep hygiene measures and CBTi are useful for some people.  Medications can be helpful but they are a mixed bag for practitioners.  Sleep medications that are typically recommended have significant side effects including tolerance to the sedative effects that can lead to dose escalation and addiction.  The non-FDA approved medications like trazodone are widely used but routinely criticized in the literature for not having enough of an evidence base.  Physicians often face patients who are not sleeping well and ask for practical ways on catching up.  The news media lately has a lot of stories about the dangers of sleep deprivation creating some desperation in the sleep deprived population.  A common question is: "Can a sleep deprived person make up for lost sleep?" 

There was a very interesting study released by a research group this month on sleep and whether or not the sleep deprived can make up for lost sleep on the weekends.  The study looked at 38,015 participants in the Swedish National March Study who returned a general health questionnaire on medical history and lifestyle in 1997.  There were two questions about sleep:

How many hours  approximately, do you sleep during a workday/weekday night?

How many hours approximately, do you sleep per night on days off? 

The authors considered short sleep < 5 hours per night and long sleep > 9 hours per night.  The considered days off to be the equivalent of weekend sleep and simplified the response categories to reduce cells with low numbers of subjects.  The reference category was considered to be 7 hours.  The formed the following 6 categories based on that sleep classification and the pattern over the weekday/weekend (S=short, M=medium, L=-long):  SS, MM, LL, SML, ML, and LS.  Patient were following to the endpoints of death, emigration or study termination on December 31, 2010.

The authors used a Cox proportional hazards model with attained age to estimate mortality hazard ratios and 95% confidence intervals for each group adjusted for a number of variables including sex, BMI, smoking status,  physical activity, alcohol intake, educational level, shift work, and a weighted index based on an inpatient register.

The main finding with the correlations of mortality with short weekend sleep.  For subjects less that the age of 65, short weekend sleep was associated with a hazard ratio (HR) or 1.52 95% CI 1.15-2.02.  In other words subjects with short weekend sleep had a 52% greater mortality rate.  There was no different in mortality for short weekend sleep in subjects older than 65 years of age.  Forest plots were provided to look at adjusted and unadjusted HR across 5 sleep categories (≤ 5 hrs, 6 hrs, 7 hours, 8 hrs, ≥ 9 hrs).  A weekend sleep duration of ≤ 5 hours in subjects less than 65 clearly had the highest mortality ratio. In other analyses short sleep on both the weekdays and weekends and consistently long sleep were also associated with higher mortality.

Interestingly from a psychiatric perspective self reported sleep medication use did not alter the outcomes.  Sleep medication use was reported in every sleep category by 9.5 to 28% of the subjects in those categories (the short sleepers reporting more medication use).  Snoring, napping, restorative sleep, general health and high work demand did not affect results.  The initial model also corrected for shift work.

This is very interesting research because it suggests that there is a way to catch up on sleep debt at least on a short term basis.  Chronic sleep debt like the kind that physicians endure in medical school and residency training is probably gone forever.  But in clinical practice, it is theoretically possible to sleep in on the weekends after getting 5 hour blocks during the week and erase that debt - at least from  mortality standpoint.  Even though the authors seem to be doing a lot of analysis from 12 data points on a survey - the  structure of that data allowed them to look at sleep from a different perspective than it is typically analyzed from.  In their introductory section, they discuss the typical analysis focuses on typical sleep patterns and there are no distinctions between weekday and weekend hours.  Analyzing that data typically results in a J-shaped mortality curve with the highest mortality for too little sleep or a U-shaped mortality curve with highest mortality for too little and too much sleep.

The authors discuss the strength of their study (large N, good follow-up) and the potential weaknesses (misinterpretation of the questions by some subjects). From their exclusion process they did a good job of cleaning up the sample.  Their recommendation for closer follow-up studies on a longitudinal basis with more frequent data points is a good one.  From a clinical perspective, it would be useful to know what the time frame is that would allow for the cancellation of sleep debt.  Does it all have to happen in the space of a week or can you sleep very long at the end of two or three weeks and get back on track?  There may be some insights from people with prolonged insomnia from substance use (cannabis, methamphetamine, opioids, alcohol) and how they recover.


George Dawson, MD, DFAPA

References:

1:  Åkerstedt T, Ghilotti F, Grotta A, Zhao H, Adami HO, Trolle-Lagerros Y, Bellocco R. Sleep duration and mortality - Does weekend sleep matter? J Sleep Res. 2018 May 22:e12712. doi: 10.1111/jsr.12712. [Epub ahead of print] PubMed PMID: 29790200.



Graphic:

Sleep duration on successive nights from the smartphone of a person who is off work on the 19th and the 24th and works 20-23 - showing total hours of sleep as 8.19, 5.15, 5.51, 5.45, 5.49, 8.17.  This is a workday/weekend pattern described by the authors in the study.

Waiting List Mortality? - An Example of Nocturnal Panic Attacks

Any PubMed search on waiting list mortality will produce a long list of articles on mortality that occurs on transplantation waiting lists and all of the associated ethical and logistic problems.  I could not locate any work done on waiting lists to get in to see psychiatrists, primary care physicians, or specialists.  To an extent, waiting list mortality is expected and some of the risk factors (increasing age, significant chronic medical illnesses, high  risk medications) is undoubtedly predictive.  But what about the person who calls in and describes a clear cut problem that is misclassified and the error is potentially life threatening.  I have picked up a few of these problems in psychiatric clinics where the ultimate emergency diagnosis was unrelated to the reason for the appointment.  Seeing a patient who is white as a ghost, complaining of coffee ground emesis, and determining the hemoglobin to be 7 is one of many examples.  Anxiety was the reason for that appointment.  I have found a number of acutely anemic patients due to blood loss with complaints about anxiety, shortness of breath, and panic attacks  who really needed blood transfusions.

I have a more concrete recent example that is much more common in psychiatric practice, especially if a significant number of patients with alcohol and benzodiazepine problems are being seen.  That is the problem of nocturnal anxiety with panic attacks.  To make it a little more interesting, let's say our hypothetical patient is 55 years old, has a history of paroxysmal atrial fibrillation (2 brief episodes), does not take an anticoagulant, and takes flecainide to prevent atrial fibrillation and metroprolol to prevent palpitations.  He has obstructive sleep apnea and is on APAP.  His AHI is 3.5 or less on any given night.  He has never has an electrophysiological study. Stress test and echocardiogram were both negative.  He has had to taper the metoprolol over a period of about 5 years from 25 mg BID to 3.125 mg daily due to lower and lower BP.  Suddenly the patient is noticing palpitations at night.  They seem to occur at the end of REM type dreams and do not seem to correlate with the emotional content of the dream.  The awakenings with palpitations typically occur at 4AM.  He has not had a panic attacks in 35 years.  He does not drink or use benzodiazepines.  To terminate the palpitations he gets up and drinks a large glass of water or walks around and they resolve in about 10 - 20 seconds.  He gets a small single lead ECG device that reads one aberrant beat as "occasional PVC".

He gets in to see his primary care MD in a couple of days.  His exam is normal and he is in sinus rhythm.  No aberrant heart beats are noted by his internist.  Electrolytes and magnesium level are normal.  He goes home that night and the palpitations continue.  He calls his sleep medicine physicians who tells him to start with his Cardiologist.  He calls the Cardiologist who concludes that "these are beats that originate in the lower chambers of the heart and there is nothing to be concerned about." Despite the acute change in symptoms that is waking him up on a nightly basis - no further testing, examination. or diagnosis is offered.  Frustrated - he calls a referral center and schedules a sleep study in about 2 1/2 months.

Is there something else that could have happened in this case? If you happen to be this man's psychiatrist - like I am in many of these cases of sleep related symptoms what is the differential diagnosis and what else can be done.  A reasonable differential diagnosis of these palpitations might consider the following list of conditions.

 

Night time palpitations – differential diagnosis:
1.	Sleep  terrors
2.	Nightmares
3.	Nocturnal panic attacks
4.	Alcohol or sedative hypnotic withdrawal
5.	Stimulant or hallucinogen intoxication
6.	Cardiac arrhythmia Tachyarrhythmias Ventricular arrhythmias Supraventricular arrhythmias Conduction delay arrhythmias

In considering the list. there are some useful clinical features.  Sleep terrors are rare in adults.  They typically occur in the first half of the night.  The patient suddenly arouses from sleep.  They may  scream.  They have intense sympathetic output including diaphoresis, flushing, tachycardia, tachypnea,and mydriasis.  They may appear to be disoriented.  Nightmares are typically dreams with negative emotional content that occur with awakening from non-REM sleep.  Sympathetic arousal is not as prominent.  Nocturnal panic attacks (NP) can occur in people with daytime panic attacks (DP) or as a separate entity.  People with combined DP/NP had more symptom severity. Palpitations are a feature of panic attacks.  In a recent study (2) the authors also rule out associated disorders  like substance use problems and obstructive sleep apnea by exclusion and testing.  The pure NP group were predominately male, had a childhood history of sleep terrors, and were more likely to have respiratory symptoms (choking sensations) despite a lower overall symptom severity score than the DP/NP group suggesting a more common mechanism with night terrors.  Because of the similarity between nocturnal panic attacks, sleep terrors, dream anxiety attacks and nocturnal seizures some authors encourage "extreme caution" in making the diagnosis (3).

The alcohol and substance intoxication and withdrawal states may be less obvious outside of treatment setting specializing in these disorders.  Patients with these problems may not disclose the full extent of use.  In the proper context, discontinuation of both cannabis and hallucinogens like LSD occurs due to increasing anxiety and panic attacks.  Alcohol and sedative hypnotic withdrawal can cause prominent sympathetic symptoms including night sweats, tachycardia, and panic attacks.  Those symptoms typically resolve with treatment of the underlying withdrawal syndrome.  In some cases the anxiety and panic attacks persist and require additional treatment.

Pure cardiac symptoms associated with sleep can be confusing.  The patient is aroused and may notice the arrhythmia.  The question becomes is the arrhythmia secondary to anxiety and sympathetic arousal or is the anxiety secondary to the chest sensation?  In the case of a patient with known sleep apnea and atrial fibrillation here are several possible causes including breakthrough atrial fibrillation at the time of the awakening.  In this case there was a crude monopolar tracing that showed a ventricular premature beat (VPB).  VPBs are commonly associated with anxiety, but is it enough to count on the patient capturing the event by getting up out of bed and holding an inexpensive device to his chest?  Patient with sleep disordered breathing are at increased risk from nocturnal death (midnight to 6AM) and one of the mechanisms may be arrhythmia from the cardiac effects of sleep disordered breathing. 

The patient in this case is very much alive and functioning at a high level.  He still has the nocturnal palpitations but is less anxious about them because they are now intermittent and always seem to resolve in a short period of time. If he thinks about it for nay length of time the question that comes up is: "Why now?"  He hopes that the referral center will have the answer to that question.

  I don't have any outcome or ready solutions to this problem. In many ways it highlights a potential quality problem in the high tech American healthcare system.  Here we have a patient who is fairly compulsive about his own health care.  He has a primary care physician who he saw and contacted both his specialists.  When there was no answer, he contacted a referral center and set up an appointment 2 1/2 months out into the future.  What will happen while he is on that waiting list is a probability statement with a series of unknown probabilities.  What is disappointing from my perspective as a physician trained in the 1980s is that at some point - the rigorous intellectual approach to patients problems has fallen by the wayside in favor of rationing.  We are no longer in pursuit of a diagnosis that might make a difference.  We are satisfied with saying "I checked off all of the boxes and I didn't see anything".  It's a 21st century variation of the old joke: "The operation was a success but unfortunately the patient died."

I am very interested in what the cost of this approach is in terms of human life and additional comorbidity.  I think that what happens to people on these waiting lists (compared to controls) is where the emphasis should be place and not on how fast patients should be discharged and not readmitted to hospitals.  Despite all of the press about unnecessary tests and the risks associated with those tests, the commonest errors I see that result in patient injury is missing the obvious diagnosis and not doing the appropriate tests.     

There is something wrong with a health care system when a psychiatrist cares more about these problems than the physicians running the system.               


George Dawson, MD, DFAPA


References:

1:  Selim BJ, Koo BB, Qin L, et al. The Association between Nocturnal Cardiac Arrhythmias and Sleep-Disordered Breathing: The DREAM Study. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine. 2016;12(6):829-837. doi:10.5664/jcsm.5880.

2: Nakamura M, Sugiura T, Nishida S, Komada Y, Inoue Y. Is nocturnal panic adistinct disease category? Comparison of clinical characteristics among patients with primary nocturnal panic, daytime panic, and coexistence of nocturnal and daytime panic. J Clin Sleep Med. 2013 May 15;9(5):461-7. doi: 10.5664/jcsm.2666. PubMed PMID: 23674937.

3: Shouse M, Mahowald MW.  Epilepsy, sleep, and sleep disorders.  in: Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. 5th ed. St. Louis, Missouri. Elsevier Sanders, 2011: 1048-1063.










       

Sleeping Cleans Your Brain

Why we need sleep and what happens during that process is an area of great interest for both the basic and clinical neurosciences. I recall listening to a lecture by Giulio Tononi at the 75th Anniversary of the University of Wisconsin's Department of Psychiatry on a theory of how synapses were processed during sleep in order to renew the brain's learning capacity for the next day.

I encountered a fascinating paper in this week's Science magazine on a possible sleep function that I have never seen described before - flushing toxins out of the brain.  The lead author hails from the Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical School.  That probably says a lot about the focus of the paper and that is the movement of interstitial fluid (ISF) as it circulates through the interstitial spaces around neurons and removes toxic waste products including β-amyloid (Aβ)  Since the brain lacks a lymphatic system convective exchange between CSF and ISF controls this turnover.  One author named the system the glymphatic system since the system is dependent on astrocytic aquaporin-4 (APQ-4) channels for establishing the  convective movement of ISF and this is homologous to peripheral lymphatic movement and removal of toxic byproducts from peripheral tissue by the lymphatic system.  The authors also note that the observation that (Aβ)  protein has been observed to be at a higher concentration in the daytime as opposed to during sleep.  To explain this one hypothesis was that production was greater in the daytime.  They tested the alternate hypothesis that glymphatic clearance is greater at night.

The basic experiment for the paper involved teaching mice to sleep on a two-photon microscope.  That allows imaging of dye moving through living tissue.  The researcher would inject mice with  green dye at sleep onset and red dye upon awakening.  They could determine that during sleep a much higher volume or CSF flowed through the brain.  They also injected labelled (Aβ)  protein and showed that the brain of a sleeping mouse cleared these proteins twice as fast.  The art below shows the experiment and the 60% increase in channels carrying CSF during sleep.  I would encourage anyone interested to read the original in color as Science has outstanding graphics.  To download my original PowerPoint slide use this link.

The authors went on to demonstrate that the increase in interstitial space was a sleep related phenomenon because it could be induced by natural sleep and anesthesia but not circadian rhythm.  In looking for a mechanism they postulated that adrenergic mechanisms associated with arousal like locus ceruleus derived noradrenergic signaling was involved.  They demonstrated that adrenergic antagonists could induce the expected increase in tracer influx and interstitial volume so that it was similar to what was seen in the sleep state. 

Implications for psychiatry?  To some extent, those of us interested in neuroscience and not forgetting what we learned in PChem will always be interested in article at the interface between the biochemical and the biophysical.  Despite having this elegant system coupled with our arousal state and metabolic state none of this information was around during the recent Decade of the Brain.  The authors discuss the sensitivity of neurons to various toxic products and proteins and the implications for neurodegenerative diseases.  I can start with insomnia and build from there.  People with addictions can have sustained insomnia and associated impairment in cognition the next day.  Delirium also affects the sleep-wake cycle and some experts have suggested that two different types of delirium can be distinguished based on EEG spectra.  The obvious questions are is the insomnia associated with these states literally toxic to the patient by restricting ISF clearance?    Another key correlate mentioned by the authors is the decrease in ISF with age.  Does that account for the predisposition to delirium and protracted delirium as people age?  And finally what about the toxicity of medication?  We are used to receptor based explanations of why certain medications have sustained or unexpected toxicity.  How much of that is due to a collapsed ISF and restricted clearance to the CSF?

Brain energetics is also an interesting question specifically the AQP-4 channels.  Most psychiatrists are familiar with the renal aquaporin channels when considering renal water metabolism.  The fact that you have these channels on astrocytes and that removing them reduces (Aβ)  clearance by 65% is fascinating and seems like another potential intervention point for brain disease.  What needs to happen to keep these AQP-4 channels healthy and what happens when they are not? 

There are many more questions that come to mind based on the mechanism these authors have elucidated.  I hope that papers like these are translated into both clinical research and our thinking about newer and more innovative ways to think about whole brain function and think about all of the mechanisms instead of just the usual receptors.

George Dawson, MD, DFAPA

Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. doi: 10.1126/science.1241224. PubMed PMID: 24136970

Footnote:  I decided to update (12/13/2013) this post by adding this interesting piece of news.  According to Altmetric, this paper received the 4th highest rating of online interest in scientific papers.  For the Top 100 papers click on the link.

Dream recall endophenotypes?

Dreams are important part of psychiatric practice.  A discussion of dreams comes up in a number of contexts ranging from diagnoses like Post Traumatic Stress Disorder to primary sleep problems like Nightmare Disorder.   Dreams can be affected by substance abuse and medications.  Some people are still interested in what a dream might mean or they have their own interpretation that they want to discuss.  Sleep is often a source of stress to people who come in to see psychiatrists and questions about dreams frequently come up in discussion about too much sleep or too little sleep.  As a result, I have done a lot of reading and study about sleep and dreams.  I have the last 5 editions of Kryger, Roth and Dement's Principles and Practice of Sleep Medicine and additional texts and journals.  Since I worked in a residential settings, I see people who have their sleep observed and can tell me if they have apneic episodes or behavioral problems associated with sleep and refer them for polysomnography.  Whenever I ask about sleep there are a significant number of people who tell me: "I never dream."

Is it possible that a person is not dreaming at night?  Since the discovery of REM sleep it is well known that this biological process and dreaming are inextricably linked.  Dream researchers have determined that dream recall is influenced by a number of factors including the setting, whether a person is awakened slowly or rapidly and the sleep stage that they are awakened from.  For example, awakenings form REM sleep can result in 4 or 5 dream narratives per night.  Writing dreams recalled the next morning is not likely to produce that amount of content.

When an article suggesting a marker for differences in dream recall showed up on my Facebook feed I was naturally interested.  The authors in this case had a pool of 1,000 people who completed questionnaires indicating an interest in the study.  They were contacted by phone and asked the question: "on the average, how many mornings in the week do you wake up with a dream in mind?"  That is an important distinction from the people I talk with because they usually say: "I dream a lot." or "I don't dream at all."  For the purpose of this study the authors defined high recallers (HR) as those who recalled dream narratives or images on three mornings per week(4.42 ± 0.25 SEM dream recalls/week).  Low recallers (LR) recalled narratives or images per month (0.25  ± 0.02).   The subjects underwent standard polysomnography and an experimental paradigm that involved presenting a recorded voice saying first names through headphones in the alert and REM state.  Event related potentials (ERPs) and alpha frequency (8-12 Hz) responses to the auditory hallucinations were recorded.        

The authors summarize their data using the above graphics.  The top graphic is a little confusing at first if you are used to seeing similar graphics from QEEG analysis.  It is only alpha spectrum and the white lines represent occurrences of the auditory stimulus.  The bottom row shows the HR - LR power and the significant difference at the Pz electrode.  The black and white graphics at the bottom show ERPs and alpha power in response to first names for HR, LR, and HR-LR.  In general the alpha power decreases during wakefulness and increases during  REM sleep on all graphics.  The HR group had a more sustained decrease in alpha power to first names at 1000 to 1200 ms during wakefulness.

The authors go on to discuss the implications of these findings including the theory that increased alpha power during REM sleep could imply microarousals without awakenings.  A second hypothesis is that increased alpha power during REM sleep implies cortical deactivation rather than microarousal that would lead to decreased processing and less likelihood of awakening.  The authors interpret the greater reactivity in ERPs and alpha activation in the HR state as indicating that alpha is associated with activation in sleep.  They point out that the increased intrasleep wakefulness being great in HR is consistent with that observation.  They go on to point out that this trait may be central to a personality organization and cognitive substrate within the brain.  They pose a larger question about moving from one phenotype to the other.  They make the important observation that a hippocampus needs to be in the loop for dream recall and that there may be a point where functional imaging will be able to provide that level of detail.

I could not help but wonder if dream recall is a possible endophenotype.  What would happen if families were studied on their ability to recall dreams?  Would there be characteristic findings on polysomnography?  What would the pattern of heritability be and what would lead to transitions between phenotypes?  Sleep medicine is one of the areas of psychiatry where there are clear and valid biomarkers and it would be interesting to look at those differences.  In the meantime, it appears that what I have been saying to people about possible REM related dreams seems to be true based on this study.  Microarousals - probably from a number of possible etiologies will probably increase dream recall of characteristic REM type dreams and you may not actually experience interrupted sleep.  There is also the interesting consideration of dreaming without the hippocampus being engaged and have no dream recall on that basis.

George Dawson, MD, DFAPA

Ruby PM, Blochet C, Eichenlaub J-B, Bertrand O, Morlet D, Bidet-Caulet A (2013) Alpha reactivity to first names differs in subjects with high and low dream recall frequency. Frontiers in Psychology 4.

All of the figures in this post are from the above reference and are produced here via Creative Commons license.  Please see the original article for all of the details.