Does the Heart Fall Asleep?-Diurnal Variations in Heart Rate Variability in Patients with Disorders of Consciousness.

The current study investigated heart rate (HR) and heart rate variability (HRV) across day and night in patients with disorders of consciousness (DOC). We recorded 24-h electrocardiography in 26 patients with DOC (i.e., unresponsive wakefulness syndrome (UWS; n = 16) and (exit) minimally conscious state ((E)MCS; n = 10)). To examine diurnal variations, HR and HRV indices in the time, frequency, and entropy domains were computed for periods of clear day- (forenoon: 8 a.m.-2 p.m.; afternoon: 2 p.m.-8 p.m.) and nighttime (11 p.m.-5 a.m.). The results indicate that patients' interbeat intervals (IBIs) were larger during the night than during the day, indicating HR slowing. The patients in UWS showed larger IBIs compared to the patients in (E)MCS, and the patients with non-traumatic brain injury showed lower HRV entropy than the patients with traumatic brain injury. Additionally, higher HRV entropy was associated with higher EEG entropy during the night. Thus, cardiac activity varies with a diurnal pattern in patients with DOC and can differentiate between patients' diagnoses and etiologies. Moreover, the interaction of heart and brain appears to follow a diurnal rhythm. Thus, HR and HRV seem to mirror the integrity of brain functioning and, consequently, might serve as supplementary measures for improving the validity of assessments in patients with DOC.

From dawn to dusk-mimicking natural daylight exposure improves circadian rhythm entrainment in patients with severe brain injury.

STUDY OBJECTIVES: While light therapy has proven effective in re-entraining circadian rhythms, the potential of such an intervention has not been evaluated systematically in post-comatose patients with disorders of consciousness (DOC), who often have strongly altered circadian rhythms. METHODS: We recorded skin temperature over 7-8 days in patients with DOC in each of two conditions: habitual light (HL), and dynamic daylight (DDL) condition. While patients were in a room with usual clinic lighting in the HL condition, they were in an otherwise comparable room with biodynamic lighting (i.e. higher illuminance and dynamic changes in spectral characteristics during the day) in the DDL condition. To detect rhythmicity in the patients' temperature data, we computed Lomb-Scargle periodograms and analyzed normalized power, and peak period. Furthermore, we computed interdaily stability and intradaily variability, which provide information about rhythm entrainment and fragmentation. RESULTS: We analyzed data from 17 patients with DOC (i.e. unresponsive wakefulness syndrome [n = 15] and minimally conscious state [n = 2]). The period length of the patients' temperature rhythms was closer to 24 h in the DDL as compared to the HL condition (median median deviation from 24 h: DDL = 0.52 h, HL = 3.62 h). Specifically, in 11/17 (65%) patients the period length was closer to 24 h in the DDL condition. Furthermore, the patients' rhythm was more pronounced, more stable, and less variable in the DDL condition. CONCLUSIONS: Our results indicate that DDL stimulation entrains and stabilizes circadian rhythms. This highlights the importance of adequate room lighting as an adjunct therapeutic approach for improving circadian rhythms in severely brain-injured patients. TRIAL REGISTRATION INFORMATION: German Clinical Trials Register (DRKS00016041); registration: 18.01.2019; recording start: 04.06.2019 https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016041.

Dysbiosis, gut barrier dysfunction and inflammation in dementia: a pilot study.

BACKGROUND: Dementia is an increasing public health threat worldwide. The pathogenesis of dementia has not been fully elucidated yet. Inflammatory processes are hypothesized to play an important role as a driver for cognitive decline but the origin of inflammation is not clear. We hypothesize that disturbances in gut microbiome composition, gut barrier dysfunction, bacterial translocation and resulting inflammation are associated with cognitive dysfunction in dementia. METHODS: To test this hypothesis, a cohort of 23 patients with dementia and 18 age and sex matched controls without cognitive impairments were studied. Gut microbiome composition, gut barrier dysfunction, bacterial translocation and inflammation were assessed from stool and serum samples. Malnutrition was assessed by Mini Nutritional Assessment Short Form (MNA-SF), detailed information on drug use was collected. Microbiome composition was assessed by 16S rRNA sequencing, QIIME 2 and Calypso 7.14 tools. RESULTS: Dementia was associated with dysbiosis characterized by differences in beta diversity and changes in taxonomic composition. Gut permeability was increased as evidenced by increased serum diamine oxidase (DAO) levels and systemic inflammation was confirmed by increased soluble cluster of differentiation 14 levels (sCD14). BMI and statin use had the strongest impact on microbiome composition. CONCLUSION: Dementia is associated with changes in gut microbiome composition and increased biomarkers of gut permeability and inflammation. Lachnospiraceae NK4A136 group as potential butyrate producer was reduced in dementia. Malnutrition and drug intake were factors, that impact on microbiome composition. Increasing butyrate producing bacteria and targeting malnutrition may be promising therapeutic targets in dementia. TRIAL REGISTRATION: NCT03167983 .

Effect of a Multispecies Probiotic on Intestinal and Skin Colonization by Multidrug-Resistant Gram-Negative Bacteria in Patients in a Long-Term Care Facility: A Pilot Study.

Residents in long-term care facilities (LTCFs) are frequently colonized by multidrug-resistant Gram-negative bacteria, putting them at risk for subsequent infections. We aimed to evaluate the effect of the multispecies probiotic Omnibiotic10AAD® on the intestinal and inguinal skin colonization of patients by multidrug-resistant Gram-negative bacteria in LTCFs. Patients colonized by multidrug-resistant Gram-negative bacteria received a 12 week oral course of Omnibiotic10AAD®. Inguinal swabs and stool samples were collected during and after treatment for microbiological and microbiome analysis. The median age of patients was 76 years. Twelve patients completed the pilot study. Intestinal colonization was reduced to 42% of patients 8 weeks after the end of treatment, but increased to 66% 24 weeks after the end of probiotic treatment. Colonization of inguinal skin was lowest during probiotic treatment and increased thereafter. Fecal microbiome analysis revealed statistically significant increases of the genus Enterococcus comparing start and end of probiotic treatment. In conclusion, a 12 week course of a multispecies probiotic led to a transient reduction of intestinal colonization 8 weeks after the end of treatment. The findings of our pilot study warrant further research in the area of probiotics and intestinal colonization by multidrug-resistant bacteria.

Actigraphy in brain-injured patients - A valid measurement for assessing circadian rhythms?

BACKGROUND: Actigraphy has received increasing attention in classifying rest-activity cycles. However, in patients with disorders of consciousness (DOC), actigraphy data may be considerably confounded by passive movements, such as nursing activities and therapies. Consequently, this study verified whether circadian rhythmicity is (still) visible in actigraphy data from patients with DOC after correcting for passive movements. METHODS: Wrist actigraphy was recorded over 7-8 consecutive days in patients with DOC (diagnosed with unresponsive wakefulness syndrome [UWS; n = 19] and [exit] minimally conscious state [MCS/EMCS; n = 11]). The presence and actions of clinical and research staff as well as visitors were indicated using a tablet in the patient's room. Following removal and interpolation of passive movements, non-parametric rank-based tests were computed to identify differences between circadian parameters of uncorrected and corrected actigraphy data. RESULTS: Uncorrected actigraphy data overestimated the interdaily stability and intradaily variability of patients' activity and underestimated the deviation from a circadian 24-h rhythm. Only 5/30 (17%) patients deviated more than 1 h from 24 h in the uncorrected data, whereas this was the case for 17/30 (57%) patients in the corrected data. When contrasting diagnoses based on the corrected dataset, stronger circadian rhythms and higher activity levels were observed in MCS/EMCS as compared to UWS patients. Day-to-night differences in activity were evident for both patient groups. CONCLUSION: Our findings indicate that uncorrected actigraphy data overestimates the circadian rhythmicity of patients' activity, as nursing activities, therapies, and visits by relatives follow a circadian pattern itself. Therefore, we suggest correcting actigraphy data from patients with reduced mobility.

Significance of circadian rhythms in severely brain-injured patients: A clue to consciousness?

OBJECTIVE: To investigate the relationship between the presence of a circadian body temperature rhythm and behaviorally assessed consciousness levels in patients with disorders of consciousness (DOC; i.e., vegetative state/unresponsive wakefulness syndrome or minimally conscious state). METHODS: In a cross-sectional study, we investigated the presence of circadian temperature rhythms across 6 to 7 days using external skin temperature sensors in 18 patients with DOC. Beyond this, we examined the relationship between behaviorally assessed consciousness levels and circadian rhythmicity. RESULTS: Analyses with Lomb-Scargle periodograms revealed significant circadian rhythmicity in all patients (range 23.5-26.3 hours). We found that especially scores on the arousal subscale of the Coma Recovery Scale-Revised were closely linked to the integrity of circadian variations in body temperature. Finally, we piloted whether bright light stimulation could boost circadian rhythmicity and found positive evidence in 2 out of 8 patients. CONCLUSION: The study provides evidence for an association between circadian body temperature rhythms and arousal as a necessary precondition for consciousness. Our findings also make a case for circadian rhythms as a target for treatment as well as the application of diagnostic and therapeutic means at times when cognitive performance is expected to peak.