Year: 2023
Type: article
Abstract: This paper is part of the Living Legends in Sleep Research series, which is sponsored by Idorsia Pharmaceuticals and Jazz Pharmaceuticals. This paper is respectfully submitted in response to an invitation from the Editors of SLEEP Advances. From the several options offered to me, I chose to give a personal perspective that begins with my studies at Michigan State University and continues with my sleep research at Stanford University, Stony Brook University/Long Island Research Institute and The Scripps Clinic and Research Foundation. I was also asked to summarize some of the most significant aspects of my government work pertaining to sleep disorders at the National Institutes of Health in Washington. Since the overall timeframe is a bit over 55 years, readers must excuse a few gaps in the chronology. Also excluded from this narrative is my work from 2016 to the present as Scientific Consultant with The Commonwealth Health Research Board, an agency which provides financial support by means of competitive grants for human health research in the Commonwealth of Virginia [https://www.chrb.org/about.shtml]. I trained as a developmental psychologist. An emphasis in my training was the measurement of change over developmental time in behaviors and abilities. One lesson from my training that I will not forget is that an investigator must always inspect data in an unprocessed state to look for errors and unanticipated patterns. Then the investigator must proceed with the preplanned statistical analyses. However, the investigator is free to perform post hoc analyses including those that may be suggested from inspection of data. One central idea of inspection is that the human eye can detect patterns and trends that often are missed by number crunching processes. This lesson has proven to be crucial in my career. Being in Developmental Psychology, as I was, I got hooked on sleep research by a 1966 paper in Science, “Ontogenetic development of the human sleep-dream cycle” [1]. Here, Roffwarg et al. proposed that CNS development in young animals was aided by endogenous sensory stimulation during REM sleep. The more immature the animal is, the less the animal can obtain sensory stimulation from interacting with its environment. The general idea is that an immature CNS needs more endogenous stimulation than a mature CNS, hence more REM sleep. This notion fit with findings in the literature of more REM sleep in premature human infants than in full-term infants. The idea also fit with data from various species that varied in CNS maturity at the time of birth. I was told that Danielle Jouvet-Mounier in Michel Jouvet’s laboratory in Lyon, France was developing methods of surgically implanting recording electrodes in newborn and pre-born rodents to track sleep stages in early development [2, 3]. In 1968, on the advice of my doctoral thesis advisor, Ralph Levine, I travelled to Lyon to visit and learn. The Jouvets were extremely helpful, and I eventually became immersed in the field. After completing my PhD at Michigan State University, the most important career choice I made was on the advice of Michel Jouvet and Allan Rechtschaffen to accept a post-doctoral fellowship with William C. Dement (Bill) at Stanford University Medical School. I arrived at Stanford in 1970. Here, I joined a diverse group of physicians, neuroscientists, graduate students, and undergraduate students working with Bill on multiple independent projects involving sleep and sleep disorders. As mentioned earlier, quantitative characterization of signs and symptoms in children and experimental animals was a key aspect of my training. That training proved useful as this era of sleep medicine unfolded. At Stanford, Bill had just founded the first sleep disorders clinic based on a fee-for-service medical model. The Stanford Sleep Clinic began diagnosing and treating numerous patients with symptoms of excessive sleepiness severe enough to interfere with their livelihoods. Prominent among such patients were those found to have narcolepsy. The derangement of REM sleep mechanisms in narcolepsy suggested to us that brainstem cholinergic systems were inappropriately activated during sleep attacks and cataplexy. With the encouragement of Barry Jacobs, then a postdoctoral fellow at Stanford, Bill and I revisited the earlier studies of Hernandez-Peon’s group and others on cholinergic stimulation to the brain. We began experiments with microinjections of the cholinomimetic agent, carbachol, into pontine sites of cats surgically instrumented for polysomnography. Indeed, cataplectic-like episodes could be triggered with such microinjections [4]. Figure 1 comprises four excerpts of polygraph data from a cat after microinjection of carbachol in the pontine reticular formation. Our studies with cholinergic drugs at Stanford stimulated renewed interest for a number of sleep researchers using refined methods and nanogram doses at various points in the cholinergic pathways involved in REM sleep [5]. Effects of bilateral micro-injections of carbachol (reprinted from [4] with permission) These 30-second tracings represent the effects of bilateral micro-injections of carbachol 5 micrograms of carbamylcholine chloride in the pontine reticular formation of chronically implanted cats. a: baseline; b: early response to injection; c: representative episode of atonia 7 hours post-injection; d: representative episode of atonia 15 hours post injection. Note the eye movement and PGO activity during atonic periods. In 1973, while our studies with cholinergic drugs continued, Bill Dement continued to develop the sleep clinic at Stanford and to identify patients with narcolepsy. Bill, in his book, The Promise of Sleep [6], related the story of how he acquired for study a famous dog that displayed clinical signs of narcolepsy. The story is exciting, and reminiscent of an adventure movie. It should be read in Bill’s own prose. For the purposes of this paper, here, I include only key elements. In 1972, at the convention of the American Medical Association, Bill showed a couple of film clips of cataplectic attacks in patients from the Stanford clinic. A neurologist approached him and told him that he knew of a dog that had similar attacks. Bill was able to contact the dog’s veterinarian and learned that the affected dog had been euthanized because of then supposed “epileptic seizures,” a film was made of the dog having the attacks. Interestingly, during this time, a number of veterinarians and breeders were describing somewhat similar postural collapses in other animals including a miniature horse [7, 8]. It appeared that these other animals were often euthanized by their owners or breeders because of clinical care expense or the breeder’s concerns about reputation or other economic reasons. Bill took serious note of the euthanized dog’s case. The next year at the American Academy of Neurology, Bill showed a film of human cataplexy and the film of the dog’s attacks. A neurologist at that meeting told Bill of a French poodle in Saskatoon, Canada that had similar symptoms. Bill was able to contact a veterinarian practicing in Saskatoon, Saskatchewan named Byron Boysen. Dr. Boysen had a case of a young female French poodle that presented to the University of Saskatchewan Veterinary Clinic in November 1972. He, along with several other veterinarians in the Saskatoon area, saw the dog clinically. It appeared to them that she was in good health except for clinical signs suggesting narcolepsy‐cataplexy. The most prominent feature was reversible, hypotonic postural collapses triggered by excitement. With the help of Bill’s Congressman and the president of the airline, restrictions against the transport of “sick animals” was overcome. The little dog, Monique, was flown out of Canada to Stanford for further study and possible breeding. During 41 hours of continuous EEG, EOG, and EMG monitoring in conjunction with behavioral observation, the dog exhibited normal polygraphically determined wakefulness, slow-wave sleep, and REM sleep. Unambiguous sleep onset REM periods and cataplectic attacks were also documented polygraphically. These pathological manifestations were judged to be analogous to those that characterize human narcolepsy. The diagnosis of canine narcolepsy was further confirmed by two negative trials with neostigmine (ruling out myasthenia) and two positive trials with imipramine (cataplexy in human narcolepsy responds to imipramine treatment). Early publications of Monique’s case prompted referral of other dogs from various veterinary practices in North America. Thus began the Stanford narcoleptic dog colony [9]. The following years saw numerous important contributions pertaining to our narcoleptic dogs. Only a few highlights can be mentioned here. Although the phenotypes of canine narcolepsy varied in terms of symptom severity and heritability from breed to breed, these dogs appeared to have similarities in symptoms and proved to be informative subjects for studies of drugs that could point to underlying neurochemical defects. An objective measurement was devised to measure cataplexy and changes in cataplexy after a drug, such as imipramine, was introduced. Objective measurement of fluctuations in cataplexy was achieved with the so-called Food Elicited Cataplexy Test (FECT). Once this ad hoc test was designed, we had become familiar with these animals’ behavior and symptom triggers. The FECT entails presentation of 10, 1 cm cubes of cheese or other desired food spaced 30.5 cm apart in a row. Normal and cataplectic dogs are easily trained to eat the bits of food one after the other, while the experimenter sits at the end of the row, recording both how long it takes the dog to eat all 10 pieces, and how many full and partial cataplectic attacks occur before the last piece of food is swallowed. Normal dogs consume all the bits of food within a few seconds. Dogs with cataplexy may require several minutes and experience dozens of cataplectic episodes. Number of cataplectic episodes and elapsed time were the metrics extracted from each FECT to measure the severity of the symptom of cataplexy. Serial FECTs reflected the onset, and of a and one of the first studies using the FECT to breed dogs with narcolepsy a heritability affected not miniature were by at animal sleep laboratory sleep researchers at the Stanford colony and laboratory including and and studies continued and were at underlying canine narcolepsy. From to a of animals of various were were A of the Stanford appeared in One study an that was with the canine narcolepsy In group the for canine narcolepsy. 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This of to the development of research and clinical of the Sleep Test The key the two is that in the research sleep were as as the was to be by sleep This was for in sleep because sleep not sleep to of sleep In the clinical sleep were a of the This time for sleep onset REM periods to With to normal sleep for to offered at at 5 subjects sleep of and For patients sleep of and Figure is a that several studies that for at to sleep offered hours at or or or or and or Figure that for each to sleep, narcoleptic patients more than Sleep in narcoleptic patients and (reprinted from with permission) sleep for and narcoleptic For each to sleep, more than In a study of REM sleep periods during we the of REM sleep episodes in narcoleptic patients each a Sleep Test with to sleep hours at 10 The of number of REM sleep episodes patients presented REM sleep 5 presented presented and presented The number of REM sleep episodes was of subjects presented REM sleep episodes on the Sleep A a significant of time on sleep that reflected the in sleep These and to be among the first to objective of sleep and to sleep onset REM periods in the study of patients with narcolepsy With and clinical a of for of the that an sleep on the of 5 minutes a found to be with and episodes of sleep in patients and in The that a of or more REM episodes in a of 5 sleep a is with a diagnosis of narcolepsy. 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The in the National and The of at that time was Dr. a prominent had been in and government for many of with of the sleep research and the was that all Institutes and could be The that a many projects were at and having the in was an important for sleep disorders it became that a more work was to sleep disorders research a among The of sleep disorders research had become more with more for and the The of the not it for sleep researchers to their with other was, as An important piece of advice the sleep research was from had other and was to more sleep disorders more competitive and with the of the I that the and the this advice and to work in these In I was to the National Institute on and at the in Washington. The is the that most of my research for many I to have the and research experience for the I was in on was achieved by the formation of the National on Sleep and I for I the from the to the to be exciting, also that I on to others my at Scripps of on government grants and was to the of others and the of an for research I became immersed in of grants and I was one of of in the development of research in various of I had sleep medicine as a of medical I to help others in the government to this I at within the for about and a years to at was to grants and pertaining to and These sleep and often involved to sleep researchers grants the National was in and and not in some other such as or Medical always an easily by the end of my government I that it was to that the sleep and including the notion of changes in symptom and to had become the government and medicine The Sleep Research for by the National on Sleep Research to for Sleep and Health and and of Sleep and of Sleep and Research Sleep and and Health Sleep and Research For me, to as significant in the of the of sleep disorders One is the in to and for their of mechanisms underlying of work was by The work of these over a of years in the and our present of the the and This over years with the of numerous to the sleep research including such as and The important for the and the last I will on here, was the of the in to and for their independent on in the of narcolepsy. in part by grants from in narcoleptic dogs that their sleep was to a that to a for a that was as and Dr. at the University of had been working on in that these were the out the in and found that the to in REM sleep, symptoms of narcolepsy. found the were and displayed sleep attacks at A of data to the present that and were both with the of this by some and by narcolepsy. often to the as that narcolepsy is by an that CNS that This with mentioned work by group in the of narcolepsy. I that will be his own paper for this and I both time I my few will not the for his I also that I to an end to the present paper, In I to the of SLEEP for this to look and my It has been an and a I that for of I could not the from the many prominent in the various or over the these just to a were Michel Allan and I that many on this with those are and to the Editors of SLEEP for this to look and I these not to sleep. sleep researchers that can to such a while not it the of a sleep
Source: SLEEP Advances
Author: Merrill M Mitler
Institution: Commonwealth Health Research Board
Language: English
Topic: Sleep and related disorders
Subfield: Experimental and Cognitive Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: gold
Estimated APC paid: $1,881
OpenAlex ID: W4379744229