Circadian Body Temp Linked to Consciousness After Brain Injury

A new study shows that circadian body temperature rhythms are related to the level of consciousness in patients with a severe brain injury.

The results suggest that circadian rhythm may represent a therapeutic target in patients who have a disorder of consciousness (DOC).

Bright light therapy, which is easy to apply at the bedside and is relatively inexpensive, may be one such therapeutic approach.

"We think clinicians should consider circadian rhythms in the diagnostic process and try to create an environment in the hospital that mimics diurnal light-dark cycles," lead author, Christine Blume, PhD, Laboratory for Sleep, Cognition and Consciousness Research, Centre for Cognitive Neuroscience, University of Salzburg, Austria, told Medscape Medical News

The study was published online April 19 in Neurology.

Many rhythmic processes follow a circadian pattern in that they last about 24 hours and are tightly controlled by a biological master clock located in the suprachiasmatic nuclei of the hypothalamus, the researchers note.

In healthy individuals, consciousness varies rhythmically with the sleep-wake cycle, during which behaviorally detectable consciousness fades and recovers on a diurnal basis.

Body temperature is thought to be crucial in the regulation and stabilization of sleep-wake cycles and thereby also in the stabilization of arousal levels. At the same time, arousal is necessary for consciousness to occur.

In healthy people, misalignment of circadian rhythms, which occurs when the sleep-wake schedule is at odds with the light-dark cycle, can cause considerable stress, have detrimental effects on the immune system, and impair cognitive abilities.

Disordered Consciousness

But very little is known about circadian rhythms in patients diagnosed with a DOC following a severe brain injury. DOC states include the vegetative state (VS), also called unresponsive wakefulness syndrome (UWS), and the minimally conscious state (MCS).

The new study included 18 patients, 14 of them female, ranging in age from 17 to 71 years. Of these, 4 had sustained a traumatic brain injury (TBI) and 14 a nontraumatic brain injury (NTBI).

Researchers studied temperature rhythms for a week in all patients under a habitual light (HL) condition, which mimicked normal light conditions in the hospital environment. They collected temperature data using external skin sensors, two at proximal sites near the collarbone and two at distal sites near the ankles; they pooled data from each of the two sensors.

"We were specifically interested in the interdaily stability…of the rhythm, an index that informs about how well the patient's temperature rhythms were entrained to a 24-hour zeitgeber (i.e., the light-dark cycle)," the authors write.

In addition to interdaily stability, Dr Blume and her colleagues were interested in group differences in period length (the length of one cycle) and normalized power (indexing how pronounced the circadian rhythm was).

They were also keen to investigate the TBI and NTBI subgroups.

Investigators assessed patients by using the Coma Recovery Scale-Revised (CRS-R), a behavioral assessment tool for patients' consciousness levels, which consists of 23 items in six subscales that address auditory, visual, motor, oromotor, communication, and arousal functions. In the arousal subscale, patients are assessed on whether they spontaneously open their eyes during the assessment, whether they consistently respond to the items demonstrating attention, or whether they need repeated stimulation to stay awake, said Dr Blume.

She called the CRS-R the "current gold standard" in behavioral assessment of patients with DOC.

At the end of the HL condition, 3 of the patients were diagnosed with MCS, 2 with MCS_exit (they had regained the ability to communicate or use objects functionally), and 13 with VS/UWS.

Researchers found that circadian variations in body temperature during the HL condition were related to the behavioral state of the patients. They detected circadian rhythms in all patients irrespective of cause or diagnosis.

The relationship between the circadian indexes and the patients' state was especially pronounced for the arousal subscale of the CRS-R.

"We found that the integrity of these temperature variations was related to patients' arousal levels; patients with a temperature rhythm that was more similar to what we would expect in healthy individuals scored higher on the arousal subscale," said Dr Blume.

"This is first time this relationship has been demonstrated."

Light Stimulation

Investigators tested the potential of bright light stimulation (BLS) — about 2000 LUX with blue-enriched light, at eye level — to enhance circadian rhythmicity in a subset of 8 patients. After the HL condition, these patients received BLS three times a day for 1 hour over the course of a week.

Three of these patients were reclassified: from VS/UWS after the HL condition to MCS/MCS_exit after the BLS condition.

Dr Blume noted that in two patients, the BLS condition preceded the HL condition, suggesting that passage of time does not seem to account for the change in diagnosis.

In these patients, the temperature maximum, which occurs at about the same time as the circadian peak in alertness and performance in healthy persons, was shifted — occurring closer to the times when the temperature maximum would be expected in healthy individuals, and closer to the times of the CRS-R assessments in these cases.

Although there was no statistical effect of BLS, the findings suggest that this light therapy may have had a beneficial effect on consciousness levels.

Dr Blume and her colleagues suggest carrying out a proof-of-principle study before drawing conclusions about the usefulness of BLS. Such a study, they said, may also allow for the evaluation for the potential influence of factors such as sex, age, or accompanying medical conditions, on circadian temperature rhythms.

The new results highlight the importance of considering circadian rhythm when diagnosing patients with a DOC, said Dr Blume.

"For example, it may be very important to schedule testing at times when we would expect patients to be more aroused," she said.

In healthy people, cognitive performance tends to peak when the body temperature is at its maximum, which for them is about 4 pm, said Dr Blume.

In patients with DOC, clinicians might assess temperature rhythms and maximum temperature and schedule behavioral testing accordingly. According to Dr Blume, "It's easy and cheap to do this with external skin sensors and you could prespecify the time when you expect performance to peak."

Dr Blume stressed that circadian rhythm could be a promising target for therapeutic approaches. "Our findings make a case for treatment aiming at the promotion and stabilization of circadian rhythms."

A possible limitation of the study was that no MRI data were available to evaluate the extent of the brain injury and potential damage to the hypothalamus and the suprachiasmatic nuclei in particular.

Medscape Medical News invited Professor Stefan Golaszewski, MD, senior physician, Department of Neurology, and medical head, Neuroscience Institute Salzburg, Christian Doppler Clinic, Paracelsus Medical University Salzburg, Austria, to comment on this study. 

The study is "interesting and important," said Dr Golaszewski.

Clinically and behaviorally, there are diagnostic problems in patients remaining in a VS/UWS or MCS state. When patients show no signs of consciousness, for example, when there are no reliable motor responses in UWS and MCS patients, a misdiagnosis between these two conditions (based on the CRS-R) of up to 43% is described in the literature.

"Maybe this high rate of misdiagnosis can be reduced under consideration of the circadian variations in body temperature" said Dr Golaszewski.

Likewise, he added, daily therapeutic interventions can "probably be optimized" in light of the study results because MCS patients often can't be actively treated because of absent arousal.

But no "far-ranging" conclusions can be drawn from the results using bright light stimulation because the data are too few, said Dr Golaszewski.

The study was supported by grants to individual researcher from the Konrad-Adenauer-Stiftung eV, the Austrian Science Fund, and the Doctoral College "Imaging the Mind." The authors have disclosed no relevant financial relationships.

Neurology. Published online April 19, 2017. Abstract

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