Circadian-induced hypothermia of the cerebral cortex in rehabilitation of patients after ischemic stroke

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Introduction

Homeostatic mechanisms in warm-blooded animals and humans normally allow significant deviations of physiological parameters from mean values. A striking example of such events are circadian (approximately 24-hour) rhythms, which are accompanied by pronounced periodic changes in organ and system function during daytime and nighttime and across sleep phases.

The circadian "pacemaker" of endogenous rhythms is located in the suprachiasmatic nucleus of the hypothalamus, which is involved in the central regulation of thermohomeostasis [1, 2]. Throughout the day, body and brain temperature change substantially. The highest values are observed in the morning and daytime hours, and the lowest in the evening and at night. The amplitude of basal temperature fluctuations in healthy adults is 0.7–1.0°C, while cerebral temperature fluctuations reach 1.4–1.7°C, reflecting the relative independence of cerebral temperature from body temperature [3]. The nighttime decrease in brain temperature is more pronounced than that of basal temperature, driven by the brain's internal need for recovery following daytime activity [4, 5].

The main processes underlying the restoration of brain structure and function are associated with periods of endogenous cerebral hypothermia that develop at night and during NREM (non-rapid eye movement) sleep phases. The glymphatic system, which serves the functions of the lymphatic system in the central nervous system, clears metabolites from the brain parenchyma at night and during NREM sleep 80–90% more intensively than during daytime wakefulness [6, 7]. The decrease in brain temperature during NREM phases and the increase during REM (rapid eye movement) sleep generate phase-transition recovery responses in fast synapses [8].

Furthermore, the positive effects of periodic endogenous hypothermia are linked to epigenetic reprogramming of brain cells, driven by the expression of early genes triggered by a significant temperature signal [9]. Gene expression initiates translation and synthesis of various proteins, including fibroblast growth factor, cold shock proteins, uncoupling proteins, irisin, and brain-derived neurotrophic factor, all of which possess pronounced neuroprotective properties [10]. Fluctuations in brain temperature of even 1°C serve as a significant signal for increasing the production of endogenous hypothermia proteins and heat shock proteins during sleep phase transitions [11, 12]. Taken together, biophysical and epigenetically mediated biochemical reactions form the basis of an evolutionarily developed response complex that underpins the restorative and protective functions of periodic endogenous hypothermia [13].

Selective brain hypothermia can be reproduced therapeutically using craniocerebral hypothermia induced by cooling the scalp. Using non-invasive microwave radiothermometry, it has been shown that lowering the skin temperature of the entire craniocerebral region to 5°C for 60–90 minutes reduces cortical temperature by 2.0–2.5°C [14]. Unfortunately, data on temperature changes in deep brain structures during craniocerebral hypothermia (CCH) could not be found in the available literature.

Experience with CCH in patients with severe brain injury has demonstrated improvement in neurological status and level of consciousness [15, 16], while cooling the skin of the forehead or occipital region in the evening and at night has been successfully used for sleep disorders [17–19]. Importantly, brain diseases and injuries disrupt biological rhythms, alter the timing of endogenous hypothermia, and impair sleep architecture, all of which contribute significantly to disease pathogenesis [20–22].

Aim: To investigate the clinical effects of a course of CCH administered between 20:00 and 22:00 as part of comprehensive rehabilitation in patients during the early post-stroke recovery period.

Materials and methods

A single-center, prospective, pilot, open-label, randomized, controlled study with unequal allocation (3:1 ratio) was conducted. Using random digit generation to form the allocation sequence, 95 patients in the early post-stroke recovery period were enrolled. Two groups were identified: the main group A-1 (n = 70) and the comparison group B-1 (n = 25). Both groups were representative in terms of sex, age, and comorbidities. The study was approved by the Local Ethics Committee of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology (Protocol No. 3/19/1 dated September 18, 2019) and was conducted at the Department of Medical Rehabilitation for Patients with Central Nervous System Disorders, Prof. I.V. Pryanikov, Research Institute of Rehabilitation, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology.

Inclusion criteria: patients with a history of IS in the carotid or vertebrobasilar arterial systems, with a disease duration of 3–6 months, a modified Rankin Scale (mRS) score of 3–4, and a National Institutes of Health Stroke Scale (NIHSS) score of 5–15.

Exclusion criteria: severe cognitive impairment preventing effective communication; severe comorbid somatic diseases. Analysis was performed according to the intention-to-treat principle. No patients withdrew from the study.

Patients in both groups were assessed using standard scales: the NIHSS and the mRS for functional status and disability; the Rivermead Mobility Index (RMI); and the Barthel Index (BI) for activities of daily living. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA).

In addition, within the main group (A-1), a subgroup A-2 (n = 22) was randomly selected, and within the comparison group (B-1), subgroup B-2 (n = 10) was randomly selected for sleep structure assessment using the Neuron-Spectr-65/PSG system (Neurosoft). The following parameters were recorded: total sleep time, sleep efficiency index, sleep latency, number of awakenings, total wake time during the night, and duration of NREM sleep stages (N1, N2, N3) and REM sleep.

Patients in all groups received standard pharmacotherapy, physiotherapy (magnetotherapy with an alternating magnetic field applied to the collar zone and functional electrical neurostimulation of paretic muscles, depending on muscle tone), therapeutic exercise, and massage. Patients in group A-1 additionally received a course of CCH in the evening (20:00–22:00) — 10 daily sessions of 90 minutes each.

For CCH, the domestic device ATG-01 (Kalashnikov Concern, Russian Registration Certificate No. FSR 2011/11788 dated December 12, 2017) was used, which maintains the skin temperature of the craniocerebral region at 5 ± 2°C throughout the procedure.

Cortical temperature was measured using non-invasive radiothermometry with the RTM-01-RES radiothermometer (RES, Russia, Russian Registration Certificate No. FSR 2007/01307). Radiothermometry is based on recording the intrinsic electromagnetic radiation of deep tissues in the microwave range.

Outcomes were compared between groups A-1 and B-1 using the scale scores, and between groups A-2 and B-2 using polysomnography data, recorded on day 1 of the study before treatment and on the day after the completion of the treatment course.

The primary endpoint was the change in the NIHSS score after treatment. Secondary endpoints were mRS, RMI, BI, MoCA scores, and sleep parameters.

Statistical analysis was performed using Statistica v. 10 software (Tibco). Intra-group changes were assessed using the Wilcoxon test. Inter-group differences were analyzed using the Mann–Whitney U test. Values were considered statistically significant at p < 0.05.

Results

The results of the scale and index assessments are presented in Table 1. Baseline scores did not differ significantly between the two groups (A-1 and B-1) (p > 0.05).

 

Table 1. Comparative characteristics of scales and indices between groups before and after treatment, Me [Q₁; Q₃]

Scale / Index	Before treatment			After treatment
	А-1	B-1	p	А-1	B-1	p
NIHSS	11.0 [10.0; 11.0]	11.0 [10.0; 11.0]	0.655	5.0 [5.0; 6.0]	7.0 [7.0; 8.0]	< 0.0001
mRS	3.0 [3.0; 4.0]	3.0 [3.0; 4.0]	0.66	2.0 [2.0; 3.0]	3.0 [3.0; 3.0]	0.001
RMI	7.0 [6.0; 8.0]	7.0 [6.0; 8.0]	0.62	12.0 [11.0; 12.0]	10.0 [8.0; 10.0]	< 0.0001
BI	70.0 [60.0; 70.0]	70.0 [60.0; 70.0]	0.86	85.0 [85.0; 85.0]	80.0 [70.0; 85.0]	0.013
MoCA	21.0 [20.0; 22.0]	21.0 [20.0; 22.0]	0.43	25.0 [24.0; 25.0]	23.0 [22.0; 23.0]	< 0.0001

 

Following the comprehensive rehabilitation program, both groups showed statistically significant improvement across all scales, with the exception of the mRS in the comparison group (B-1). At the end of treatment, statistically significant differences (p < 0.05) were observed between the main group and the comparison group for all scale parameters (Table 2).

 

Table 2. Changes in scale scores in the main group and comparison group before and after treatment, Me [Q₁; Q₃]

Group	Scale / Index	Before treatment	After treatment	p
Main group A-1 (n = 70)	NIHSS	11.0 [10.0; 11.0]	5.0 [5.0; 6.0]	< 0.0001
	mRS	3.0 [3.0; 4.0]	2.0 [2.0; 3.0]	0.0001
	RMI	7.0 [6.0; 8.0]	12.0 [11.0; 12.0]	0.0001
	BI	70.0 [60.0; 70.0]	85.0 [85.0; 85.0]	< 0.0001
	MoCA	21.0 [20.0; 22.0]	25.0 [24.0; 25.0]	< 0.0001
Comparison group B-1 (n = 25)	NIHSS	11.0 [10.0; 11.0]	7.0 [7.0; 8.0]	0.0002
	mRS	3.0 [3.0; 4.0]	3.0 [3.0; 3.0]	0.073
	RMI	7.0 [6.0; 8.0]	10.0 [8.0; 10.0]	0.0005
	BI	70.0 [60.0; 70.0]	80.0 [70.0; 85.0]	0.0002
	MoCA	21.0 [20.0; 22.0]	23.0 [22.0; 23.0]	0.0014

 

The main group showed greater improvements compared to the comparison group, including improvements in cognitive and motor functions, increased daily activity, self-care ability, and functional independence. However, interpretation of these differences requires caution due to the limitations of the study design.

Polysomnography data showed no significant differences in sleep parameters between the two groups before treatment (Table 3).

 

Table 3. Sleep parameters in the main group and comparison group before and after treatment, Me [Q₁; Q₃]

Parameter	Before treatment			After treatment
	A-2	B-2	р	A-2	B-2	р
Total sleep time, min	263 [101; 401]	290 [185; 309]	0.722	327 [181; 435]	258 [256; 392]	0.929
Sleep efficiency index, %	51 [18.0; 72.6]	54 [33.4; 55.0]	0.563	62.3 [46.0; 85.3]	53 [48.0; 69.6]	0.448
Wakefulness, %	40 [13; 57]	35.9 [33.0; 44.2]	0.689	34.5 [11; 44]	30.4 [28; 42]	0.422
N2 sleep stage, %	25.6 [15.7; 36.9]	22.6 [19; 24]	0.5	29.0 [22.0; 42.9]	20 [8; 25]	0.007

 

Significant differences between groups were found only for the proportion of N2 sleep stage (p = 0.007), while other parameters (total sleep time, sleep efficiency, wakefulness) did not reach statistical significance (Table 4). In the comparison group B-2, no significant changes in sleep parameters were observed, though there was a trend toward reduced wakefulness time.

 

Table 4. Comparative characteristics of sleep parameters in the main group and comparison group by polysomnography before and after treatment, Me [Q₁; Q₃]

Group	Parameter	Before treatment	After treatment	p
Main group A-2 (n = 22)	Total sleep time, min	263 [101; 401]	327 [181; 435]	0.044
	Sleep efficiency index, %	51 [18.0; 72.6]	62.3 [46; 85.3]	0.003
	Wakefulness, %	40 [13; 57]	34.5 [11; 44]	0.028
	N2 sleep stage, %	25.6 [15.7; 36.9]	29.0 [22; 42.9]	0.011
Comparison group B-2 (n = 10)	Total sleep time, min	290 [185; 309]	258 [256; 392]	0.374
	Sleep efficiency index, %	54 [33.4; 55]	53 [48.0; 69.6]	0.314
	Wakefulness, %	35.9 [33.0; 44.2]	30.4 [28; 42]	0.594
	N2 sleep stage, %	22.6 [19; 24]	20 [8; 25]	0.314

 

The above data indicate improved recovery of neurological status, mobility, daily activity, and cognitive function, along with enhanced sleep quality, in post-stroke patients when CCH (10 daily 90-minute sessions in the evening) was incorporated into the rehabilitation program.

Notably, frontal cortical temperatures measured before treatment in the morning, afternoon, and evening did not differ between the main group A-1 and the comparison group B-1. After the treatment course, no temperature changes were observed in the comparison group, whereas in the CCH group, temperature decreased significantly (p < 0.05) at all measurement time points and was lowest in the evening hours (Figure 1).

 

Fig. 1. Changes in the frontal cortical temperature in the morning, afternoon, and evening in patients of the main group A-1 (A) and comparison group B-1 (B) before and after therapy.

 

Discussion

The clinical improvement observed in patients after IS when CCH is incorporated into the rehabilitation program is presumably attributable to the replication of physiological mechanisms of endogenous periodic brain hypothermia that develops at night and possesses significant neuroprotective potential. The hypothermic period is characterized by reduced neuronal metabolism and free radical production, decreased inflammation, and inhibition of excitotoxicity and apoptosis, driven by biophysical and epigenetic responses that establish a cytoprotective phenotype [23].

By reducing metabolic intensity, CCH decreases lactate production and the severity of acidosis [24]. Hypothermia prevents glutamate accumulation and release [25], reduces neutrophil and activated microglial cell counts in the injury area, and decreases the production of multiple inflammatory mediators [26]. It also inhibits matrix metalloproteinase activation, thereby protecting the blood–brain barrier [27].

Studies of CCH in the acute IS phase have demonstrated a significant reduction in neurological deficit as measured by the NIHSS and improved consciousness levels [28, 29]. CCH has not previously been used in early rehabilitation of patients with cerebral infarction. Given the significant neuroprotective potential of cerebral hypothermia, we hypothesized that its effects could be enhanced by administering it in the evening, before sleep. This approach is considered a chronotherapy method, where interventions are designed to mimic natural circadian physiological fluctuations [30]. A course of daily procedures performed at the same time may help restore and "entrain" the circadian rhythm of physiological parameters, prolonging the protective effects of natural hypothermia that develops without low-temperature induction. This is supported by our finding of a significant decrease in cortical temperature on the day after the CCH course, in the absence of cold exposure.

The more pronounced positive neurological dynamics and improved sleep quality observed when CCH is added to comprehensive rehabilitation are likely related both to the neuroprotective effects of cerebral hypothermia and to the chronotherapeutic nature of the intervention. Sleep disturbances develop in most patients after IS [31], and a strong positive association between circadian rhythm disruption and IS has also been reported [32]. The observed prolongation of NREM sleep, primarily due to increased N2 stage duration, persisting after the CCH course, appears to contribute to the positive clinical outcomes in this patient population. This is further supported by existing evidence that neuroprotective effects are enhanced during slow-wave sleep, which has also been linked to circadian activity of enzymatic antioxidant systems [33, 34].

The above findings highlight the promise of craniocerebral cooling in the early post-stroke recovery period. Administering procedures in the evening, before sleep, improves sleep architecture, as previously shown in several studies [18, 19]. The use of CCH in alignment with physiological biorhythms brings the body closer to its natural functioning. This supports the view of this treatment as a biomimetic approach. No complications or adverse effects were reported during the CCH course.

Conclusion

This clinical-instrumental randomized comparative study supports the feasibility of incorporating CCH into comprehensive rehabilitation programs for post-stroke patients, taking into account the physiological circadian rhythmicity of brain temperature changes. Further large-scale studies are warranted to fully assess the clinical efficacy of this therapeutic hypothermia approach.

About the authors

Oleg A. Shevelev

Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology; Peoples' Friendship University of Russia named after Patrice Lumumba

Email: torshin.dmitrii@rambler.ru
ORCID iD: 0000-0002-6204-1110

Dr. Sci. (Med.), Professor, Principal Researcher, Laboratory of Innovative Rehabilitation Technologies; Professor, Department of General Pathology and Pathological Physiology named after V.A. Frolov, Medical Institute

Russian Federation, Moscow; Moscow

Marina V. Petrova

Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology; Peoples' Friendship University of Russia named after Patrice Lumumba

Email: torshin.dmitrii@rambler.ru
ORCID iD: 0000-0003-4272-0957

Dr. Sci. (Med.), Professor, Deputy Director for Scientific and Clinical Activities; Head, Department of Anesthesiology and Intensive Care Medicine with a Course in Medical Rehabilitation, Medical Institute

Russian Federation, Moscow; Moscow

Anatoly I. Fedin

The Pirogov Russian National Research Medical University

Email: torshin.dmitrii@rambler.ru
ORCID iD: 0000-0002-6996-2828

Dr. Sci. (Med.), Professor, Department of Neurology, Institute of Continuing Professional Education

Russian Federation, Moscow

Dmitry V. Torshin

Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology

Author for correspondence.
Email: torshin.dmitrii@rambler.ru
ORCID iD: 0000-0002-0134-5284

Cand. Sci. (Med.), Deputy Head, Medical Department of the Sanatorium "Uzkoe"

Russian Federation, Moscow

Nadezhda A. Khodorovich

Peoples' Friendship University of Russia named after Patrice Lumumba

Email: torshin.dmitrii@rambler.ru
ORCID iD: 0000-0002-1289-4545

Dr. Sci. (Med.), Professor, Department of General Pathology and Pathological Physiology named after V.A. Frolov, Medical Institute

Russian Federation, Moscow

Elias M. Mengistu

Peoples' Friendship University of Russia named after Patrice Lumumba

Email: torshin.dmitrii@rambler.ru
ORCID iD: 0000-0002-6928-2320

Postgraduate Student, Department of Anesthesiology and Intensive Care Medicine with a Course in Medical Rehabilitation, Medical Institute

Russian Federation, Moscow

Ilya V. Borisov

Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology

Email: torshin.dmitrii@rambler.ru
ORCID iD: 0000-0002-5707-118X

Research Associate, Laboratory of Innovative Rehabilitation Technologies

Russian Federation, Moscow

References

Supplementary files