The Neurophysiology of Pain During REM Sleep

In the last post, we learned about The Phenomenology of Pain During REM Sleep. Real life pain can intrude into dreams, as was shown for experimentally induced pain (Nielsen et al., 1993) and in hospitalized burn patients (Raymond et al., 2002). In this post we'll hear about a fascinating experiment that recorded laser evoked potentials directly from the brains of epilepsy patients who were being surgically monitored for seizures (Bastuji et al. 2011). Only under rare circumstances can intracranial electrodes be placed in the brains of humans, and the current study had the unique opportunity to record from three major pain regions simultaneously: the posterior insula (Brodmann area 13), the parietal operculum (somatosensory area S2), and the mid-anterior cingulate cortex (BA 24). These areas comprise the so-called "Pain Matrix"¹ (PM), or

network of cortical structures that respond consistently to noxious mechanical or thermal stimuli. The lateral structures of the PM (posterior insula and suprasylvian operculum) are thought to subserve intensity coding and localization of pain inputs, while the medial PM system (anterior and mid-cingulate cortex) is linked to the attentional (orienting and arousing) components of pain.

In the present study, Bastuji et al. (2011) recorded laser evoked potentials (LEPs) from these brain regions during different stages of sleep, as well as while the patients were awake. LEPs are a specific type of EEG response time-locked to the application of painful laser heat stimuli. When recorded from the scalp, a sequence of three LEPs is generated in rapid succession, within the first 400 milliseconds after laser stimulation. As described in a review by Plaghki and Mouraux (2005),

Laser heat stimulators selectively activate Aδ and C-nociceptors ["pain receptors"] in the superficial layers of the skin. Their high power output produces steep heating ramps, which improve synchronization of afferent volleys and therefore allow the recording of time-locked events, such as laser-evoked brain potentials. Study of the electrical brain activity evoked by Aδ- and C-nociceptor afferent volleys revealed the existence of an extensive, sequentially activated, cortical network.

The advantage of recording intracranial LEPs is that you know precisely when the pain-related activity occurred, as well as where the brain response was located (unlike with standard EEG). Two major components were observed: Component 1 (C1), peaking at ~200 ms post-stimulus and Component 2 (C2), peaking at ~300 ms. Because the components were of varying polarities depending on brain region, they weren't labelled according to the customary N2/P2 as seen on the scalp. Of primary interest was what happened to these components during Stage 2 sleep and REM sleep (see Fig. 3A below).


Figure 3A (modified from Bastuji et al. 2011). Grand average LEPs in referential recording mode during wakefulness, sleep stage 2, and paradoxical sleep in the operculum (bottom), the insula (middle), and the mid-anterior cingulate (top). Traces recorded by the electrode contact yielding the largest amplitudes are superimposed on those from the adjacent contact. On the left part of the figure, for each structure, the coordinates of the contacts where the maximal amplitudes of the C1–C2 components were recorded are indicated on mean sagittal MRIs.


Typically, painful stimuli at the nociceptive threshold will cause awakening ~30% of the time. In this study, the stimulus intensity of the laser² was set individually in each participant to be slightly above pain threshold. C1 and C2 decreased in amplitude in all three brain regions during Stage 2 sleep, relative to wakefulness. During REM sleep, however, both components remained stable in amplitude (relative to Stage 2) in the operculum and insula, but they decreased dramatically in the cingulate. Recall that the medial mid-anterior cingulate cortex (ACC) is associated with the attentional and affective components of pain, while the lateral opercular and insular cortices are more related to the sensory aspects of pain. The authors suggest that this dissociation between the lateral and medial pain systems is what allows the experience of pain in dreams without being alerted enough to wake up. The fact that larger mid-ACC LEPs can predict when motor responses to pain will occur supports this interpretation.


CODA (Notes from an Actual Pain Dream)

Lately I've had a painful orthopedic issue (in real life). I also have a cat who is fond of laying on my legs at night, which is not comfortable at all under the circumstances. Yesterday morning, I had a terrible nightmare in which my real life leg pain was projected onto someone else in an exceptionally gruesome way. I was driving along an unknown neighborhood street when suddenly a man appeared in front of my car. It wasn't clear if he was on the hood or on the trunk of the car ahead of me or suspended in the air in a dream-like way. At any rate, if that wasn't bad enough, he pulled up the body of a man who had fallen under my car and had both his legs amputated from being run over -- one leg was amputated below the knee, the other was at the hip. The gravely injured man was still alive. I was absolutely horrified. All I could do is say "oh my god oh my god oh my god" over and over. At some point my car rolled backward down a steep hill and the other motorists behind me were exclaiming "oh my god oh my god" as well.

It was an awful nightmare, and in the dream I was quite traumatized by the entire experience. Did I feel excruciating pain when I woke up? No, not really, just the usual ache.


Further Reading

LEPs and pain perception can be reduced while looking at one's own hand or at beautiful artwork:

It Hurts Less When I Can See It

Pain & Paintings: Beholding Beauty Reduces Pain Perception and Laser Evoked Potentials

Footnotes

¹ "So-called" because the Pain Matrix might not be that specific to nociception after all (Iannetti & Mouraux, 2010).

² Laser pulses were delivered to the back of the hand opposite to the hemisphere with the implanted electrodes.

References

Bastuji, H., Mazza, S., Perchet, C., Frot, M., Mauguière, F., Magnin, M., & Garcia-Larrea, L. (2011). Filtering the reality: Functional dissociation of lateral and medial pain systems during sleep in humans. Human Brain Mapping DOI: 10.1002/hbm.21390

Iannetti GD, Mouraux A. (2010). From the neuromatrix to the pain matrix (and back). Exp Brain Res. 205:1-12.

Nielsen TA, McGregor DL, Zadra A, Ilnicki D, & Ouellet L (1993). Pain in dreams. Sleep 16:490-8.

Plaghki L, Mouraux A. (2005). EEG and laser stimulation as tools for pain research. Curr Opin Investig Drugs 6:58-64. PDF

Raymond I, Nielsen TA, Lavigne G, Choinière M. (2002). Incorporation of pain in dreams of hospitalized burn victims. Sleep 25:765-70.

The Phenomenology of Pain During REM Sleep

Coarse — Pain in Dreams

Have you ever felt pain in dreams? I have. Once I dreamed I was lying on my stomach, getting a tattoo on my calf against my will. Because it was a particularly malevolent tattoo studio, I cried out in the dream. When I woke up, I felt no pain at all. It was false, a figment of the Pain Matrix. Another time a monkey bit me on the arm. Once again, the pain vanished upon awakening.

I think these examples of what I'll call "fake pain" are unusual. More common are instances when you get a calf cramp or have pins and needles in your arm while sleeping, and this real life pain gets incorporated into dreams about tattoos or monkey bites. But even these possibilities have been discounted as unlikely, because of limitations on which sensory modalities can be represented in dreams (Nielsen et al., 1993):

One possibility is that pain is beyond the representational capability of image formation processes -- that neither pain memories nor pain images are reproducible in the dreaming mode. A second possibility is that the sensory systems that might contribute to the representation of pain imagery are not functional during dreaming. This possibility is consistent with the finding that the high threshold polysynaptic afferent fibers that conduct pain sensations are actively inhibited during REM sleep in cats.

But plenty of people have reported feeling pain in dreams, so why construct hypotheses about why it's impossible? So skeptics Tore A. Nielsen and three fellow psychology graduate students, along with an undergrad art therapy student, conducted experiments on themselves in a 1993 paper. They inflated a blood pressure cuff above the knee of their colleagues 5 min into a bout of REM sleep¹ [to produce ischemia of the leg muscles, i.e. pins and needles or paralysis].

Results indicated that pain sensations occurred in 13 out of 42 stimulation trials with usable dream reports (31%). In contrast, only one of the 21 non-stimulated control dreams contained a reference to pain (4.8%). Many of the dreams were realistic and took place in a sleep lab-like setting. Others were more fantastic; one was set at a rodeo, another at a dance party in a barn [the authors lived in Montreal]. Some were lucid², like the "ugly shoe" dream:

I'm in a small store trying on a pair of ugly shoes. I started walking. Then I staggered forward because I was waking up and not fully conscious. You were laughing at me. I said "come on, its not funny, I'm trying to wake up!" This is the second or third time I've been trying to wake up.

Some of the participants were more likely to experience pain dreams than others. Subject B, who reported pain dreams on 70% of the stimulation trials, had knee surgery a few years prior and still felt numbness or tingling sensations on occasion. Most of the time, the pain sensations occurred in the appropriate leg for all participants. Interestingly, the "crampy pressure", "tingling", or "hurting a bit" sensations felt upon awakening were much less intense than those that occurred during the dream.

When interpreting these subjective reports, one has to consider an expectation or priming effect, since all the students were focused on dream research, with extensive experience in the sleep lab. However, this was not the case in a study of 28 hospitalized burn patients (Raymond et al., 2002). Obviously, the severity of suffering in burn patients is intense and chronic, unlike having temporary "pins and needles" in your leg. Over a period of 5 days, pain dreams comprised 30% of all reported dreams, which is quite comparable to the artificial BP cuff study. The patients who reported pain dreams (39%) had more nightmares, worse sleep quality, and more post-traumatic stress symptoms. The other 61% of the patients did not have any pain dreams. Why?

What sort of neurophysiological activity can account for painful sensations that are experienced during REM sleep? We'll find out in the next post.


Footnotes

¹ It wasn't clear how they monitored for REM, since EEG methods were not described. However, the transcript of one dream suggested that EEG was in fact recorded:

Then I was trying to get comfortable on the bed. All the electrodes but one for the EEG had fallen off; the others were dangling free.

The dream transcript continues:

You said that this was too bad. I had tossed around in bed trying to get comfortable. It was really cold and hurt my backside. There was almost no mattress; I was on a board. I was saying to you that we had hit rock bottom in this bed.

The interesting part about this segment is that there was no BP cuff applied; out of 14 dreams this was the only one without external stimulation (kind of like my "fake pain" dreams).

² The subject was aware they were dreaming and tried to control the action.


References

Nielsen TA, McGregor DL, Zadra A, Ilnicki D, & Ouellet L (1993). Pain in dreams. Sleep, 16 (5), 490-8 PMID: 7690981

Raymond I, Nielsen TA, Lavigne G, Choinière M. (2002). Incorporation of pain in dreams of hospitalized burn victims. Sleep 25:765-70.

Was the "psychosis prevention" drug trial actually approved before it was terminated?

THIS POST WILL BE UPDATED AT A LATER TIME, PENDING OFFICIAL CLARIFICATION ABOUT THE APPROVAL AND TERMINATION OF THE TRIAL.

SORRY FOR THE INCONVENIENCE.

Chronic Ketamine for Depression: An Unethical Case Study?

A year ago, Ketamine for Depression: Yay or Neigh? covered acute administration of the club drug (and dissociative anesthetic) ketamine for rapid (albeit transient) relief of major depression. That post was part of a blog focus on hallucinogenic drugs in medicine and mental health, organized by Nature editor Noah Gray following publication of a review article on The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. At the time, I wrote:

Although the immediate onset of symptom amelioration gives ketamine a substantial advantage over traditional antidepressants (which take 4-6 weeks to work), there are definite limitations (Tsai, 2007). Drawbacks include the possibility of ketamine-induced psychosis (Javitt, 2010), limited duration of effectiveness (aan het Rot et al., 2010), potential long-term deleterious effects such as white matter abnormalities (Liao et al., 2010), and an inability to truly blind the ketamine condition due to obvious dissociative effects in many participants.

At present, what are the most promising uses for ketamine as a fast-acting antidepressant? Given the disadvantages discussed above, short-term use for immediate relief of life-threatening or end-of-life depressive symptoms seem to be the best indications.

For the past few weeks, I've been wanting to do a follow-up post that looks at the ups and downs of the mTOR (mammalian target of rapamycin) protein kinase pathway, which is rapidly activated by ketamine. Although activation of mTOR leads to the beneficial effect of increased synaptogenesis in the medial prefrontal cortex (Li et al., 2010), it can also cause accelerated tumor growth, as recently noted by Yang et al., 2011 ("Be prudent of ketamine in treating resistant depression in patients with cancer"). However, I've been unable to complete this planned post, specifically because the topic of ketamine use in palliative care settings is something I wrote about last year, while watching my father die of cancer.

More recently, an open label study in two hospice patients, each with a prognosis of only weeks or months to live, showed beneficial effects of ketamine in the treatment of anxiety and depression (Irwin & Iglewicz, 2010). A single oral dose produced rapid improvement of symptoms and improved end of life quality.

To be blunt, the possibility of accelerated tumor growth is not an issue in terminal patients.

In terms of medical ethics, it's easier for me to take a different angle and address the unusual case of a grievously and chronically depressed patient (Messer & Haller, 2010). An anonymous reader alerted me to this paper, which isn't indexed in PubMed. The case history is as follows:

In January 2008, a 46-year old female with MDD was hospitalized for a course of electroconvulsive therapy (ECT). Successive interventions over 15 years had included trials of 24 psychotropic medications and 273 ECT treatments, 251 of which were bilateral [which can produce significant amnesia]. No intervention had produced remission but only a short-lived response to treatment...

ECT during this admission was administered with ketamine as the anesthetic at 2 mg/kg given over 60 seconds. Surgical anesthesia occurred ~30 seconds after the end of intravenous injection and lasted ~10 minutes. There was no significant change in depression symptoms with the ketamine used as an anesthetic during the ECT treatment. Alternative treatments were reviewed for potential use. In addition to no significant recovery from her depression, the long-term use of ECT caused problems with memory loss and focused attention. She was unable to remember much of her history over the previous 15 years. Re-learning the information became futile since each course of ECT would eliminate what had been gained.

I'm not going to weigh in here on ECT, beyond saying that it can be beneficial in some intractable patients [with fewer amnestic effects if unilateral]. But here we have an individual with profound ECT-induced amnesia who, although giving informed consent, was then treated with a highly unorthodox regimen of repeated ketamine infusions. The majority of registered clinical trials administer a single dose of ketamine, with one trial administering 5 additional ketamine infusions over a 2-week period. Relapse typically occurs within a week after a single dose.

On the other hand Dr. Messer's clinical trial, Ketamine Frequency Treatment for Major Depressive Disorder, was withdrawn prior to enrollment because pilot study determined the trial would not be feasible. The planned regimen was 6 injections every other day for 12 days. But the actual treatment given to the 46 yr old woman was much more extensive: 22 doses over 4 months, followed by 21 doses over 1 yr (approximately):

The first ketamine treatment led to a dramatic remission of depressive symptoms: the Beck Depression Inventory (BDI) score decreased from 22 to 6 (Figure). Three additional infusions administered every other day over 5 days produced remission lasting 17 days after the last infusion in this series. Three series of six ketamine infusions given every other day except weekends were repeated over the next 16 weeks (Figure). Each infusion sequence produced remission lasting 16, 28, and 16 days, respectively, followed by a relapse. After three remission/relapse cycles and before relapse could occur after the fourth infusion series, a maintenance ketamine regimen was established on August 27, 2008 using 0.5 mg/kg IBW at a 3-week inter-dose interval. The authors’ estimation for the maintenance dosing interval was based on the time frame between remission and relapse for this patient. Relapse to depression was prevented by treating prior to the onset of a relapse.

First, I was struck by the starting BDI score of 22, which falls within the low end of moderate depression, with scores of 29-63 indicating severe depression. I don't want to question Dr. Messer's clinical diagnosis of the patient, but I would guess that a typical BDI II score of 22 might not call for drastic measures. But perhaps the original BDI was used, in which case 19-29 indicates moderate-severe depression (which is still not severe). Second, the number of infusions went well beyond what has been established as safe, particularly in the context of treatment-resistant depression.

- click on image for a larger view -

What were the cognitive effects? We don't really know, because there was no formal testing:

As shown in the Figure, with maintenance infusions the patient has been in remission for >15 months. No concurrent pharmacotherapeutic agents have been administered or required during this time period, no adverse events have emerged, and there has been no cognitive impairment as is typical with ECT, polypharmacy, or from MDD itself.

What we do know is that ketamine is cost-effective relative to ECT:

The cost and personnel needed for a ketamine treatment are far less than that of ECT since no charges associated with anesthesia or operating room use are needed. The data from our institution suggest that the charges associated with one ketamine treatment are ~33% of the charges for one ECT.

But it's caution, and not cost-effectiveness, that should be of the utmost importance in vulnerable, chronically depressed patients who are treatment-resistant.


References

aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ. (2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 67:139-45.

Irwin SA, Iglewicz A. (2010). Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med. 13:903-8.

Javitt DC. (2010). Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci. 47:4-16.

Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959-64.

Liao Y, Tang J, Ma M, Wu Z, Yang M, Wang X, Liu T, Chen X, Fletcher PC, Hao W. (2010). Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study. Brain 133:2115-22.

Messer M, Haller IV (2010). Maintenance Ketamine Treatment Produces Long-term Recovery from Depression. Primary Psychiatry, 17, 48-50.

Tsai GE. (2007). Searching for rational anti N-methyl-D-aspartate treatment for depression. Arch Gen Psychiatry 64:1099-100; author reply 1100-1.

Vollenweider F, Kometer M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders Nature Reviews Neuroscience, 11 (9), 642-651.

Yang C, Zhou ZQ, Yang JJ. (2011). Be prudent of ketamine in treating resistant depression in patients with cancer. J Palliat Med. 14:537.

Dedication:

For my father, who has been deeply missed since September 6, 2010.