Publications by authors named "Leilah K Grant"

7 Publications

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Endogenous circadian regulation and phase resetting of clinical metabolic biomarkers.

J Pineal Res 2021 Jun 12:e12752. Epub 2021 Jun 12.

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA.

Shiftwork and circadian disruption are associated with adverse metabolic effects. Therefore, we examined whether clinical biomarkers of metabolic health are under endogenous circadian regulation using a 40 hours constant routine protocol (CR; constant environmental and behavioral conditions) and evaluated the impact of typical daily conditions with periodic sleep and meals (baseline; 8 hours sleep at night, four meals during a 16 hour wake episode) on the phase and amplitude of these rhythms. Additionally, we tested whether these circadian rhythms are reset during simulated shiftwork. Under CR (n = 16 males, mean age ± SD = 23.4 ± 2.3 years), we found endogenous circadian rhythms in cholesterol, HDL and LDL, albumin and total protein, and VLDL and triglyceride. The rhythms were masked under baseline conditions except for cholesterol, which had near-identical phases under both conditions. Resetting of the cholesterol rhythm and Dim Light Melatonin Onset (DLMO) was then tested in a study of simulated shiftwork (n = 25, 14 females, 36.3 ± 8.9 years) across four protocols; two with abrupt 8 hour delay shifts and exposure to either blue-enriched or standard white light; and either an abrupt or gradual 8 hour advance (1.6 hours/day over 5 days) both with exposure to blue-enriched white light. In the delay protocols, the cholesterol rhythm shifted later by -3.7 hours and -4.2 hours, respectively, compared to -6.6 hours and -4.7 hours, for DLMO. There was a significant advance in cholesterol in the abrupt (+5.1 hours) but not the gradual (+2.1 hours) protocol, compared to +3.1 hours and +2.8 hours in DLMO, respectively. Exploratory group analysis comparing the phases of all metabolic biomarkers under both studies showed evidence of phase shifts due to simulated shiftwork. These results show that clinical biomarkers of metabolic health are under endogenous circadian regulation but that the expression of these rhythms is substantially influenced by environmental factors. These rhythms can also be reset, which has implications for understanding how both behavioral changes and circadian shifts due to shiftwork may disrupt metabolic function.
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http://dx.doi.org/10.1111/jpi.12752DOI Listing
June 2021

Daytime Exposure to Short Wavelength-Enriched Light Improves Cognitive Performance in Sleep-Restricted College-Aged Adults.

Front Neurol 2021 22;12:624217. Epub 2021 Feb 22.

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, United States.

We tested the effect of daytime indoor light exposure with varying melanopic strength on cognitive performance in college-aged students who maintained an enforced nightly sleep opportunity of 7 h (i.e., nightly sleep duration no longer than 7 h) for 1 week immediately preceding the day of light exposure. Participants ( = 39; mean age ± SD = 24.5 ± 3.2 years; 21 F) were randomized to an 8 h daytime exposure to one of four white light conditions of equal photopic illuminance (~50 lux at eye level in the vertical plane) but different melanopic illuminance [24-45 melanopic-EDI lux (melEDI)] generated by varying correlated color temperatures [3000K (low-melEDI) or 5000K (high-melEDI)] and spectra [conventional or daylight-like]. Accuracy on a 2-min addition task was 5% better in the daylight-like high-melEDI condition (highest melEDI) compared to the conventional low-melEDI condition (lowest melEDI; < 0.01). Performance speed on the motor sequence learning task was 3.2 times faster ( < 0.05) during the daylight-like high-melEDI condition compared to the conventional low-melEDI. Subjective sleepiness was 1.5 times lower in the conventional high-melEDI condition compared to the conventional low-melEDI condition, but levels were similar between conventional low- and daylight-like high-melEDI conditions. These results demonstrate that exposure to high-melanopic (short wavelength-enriched) white light improves processing speed, working memory, and procedural learning on a motor sequence task in modestly sleep restricted young adults, and have important implications for optimizing lighting conditions in schools, colleges, and other built environments.
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http://dx.doi.org/10.3389/fneur.2021.624217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937889PMC
February 2021

Time-of-day and Meal Size Effects on Clinical Lipid Markers.

J Clin Endocrinol Metab 2021 Mar;106(3):e1373-e1379

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, Massachusetts.

Context: Dyslipidemia and cardiovascular disease are common in shift workers and eating at night may contribute to this pathophysiology.

Objective: To examine the effects of eating at different times of day on lipid profiles.

Design: Two 24-hour baseline days with 8 hours of sleep, 3 meals (breakfast, lunch, dinner) and a snack, followed by a 40-hour constant routine (CR) with hourly isocaloric meals.

Setting: Intensive Physiological Monitoring Unit, Brigham and Women's Hospital.

Participants: Twenty-one healthy adults [23.4 ± 2.7 years, 5F].

Intervention: Forty-hour CR.

Main Outcome Measures: A standard clinical lipid panel, consisting of total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), was assayed in blood samples collected 4-hourly across ~4 days.

Results: When participants ate at night, levels of TG were similar to eating during the day, however, these levels at night were reached with consuming approximately half the calories. Additionally, 24-hour levels of TG were 10% higher when meals were consumed hourly across 24 hours compared to consuming a typical 3-meal schedule while awake during the day and sleeping at night. The endogenous circadian rhythms of TG, which peaked at night, were shifted earlier by ~10 hours under baseline conditions, whereas the rhythms in total cholesterol, HDL-C, and LDL-C remained unchanged and peaked in the afternoon.

Conclusions: The time-of-day dependency on postprandial lipid metabolism, which leads to hypersensitivity in TG responses when eating at night, may underlie the dyslipidemia and elevated cardiovascular disease risk observed in shift workers.
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http://dx.doi.org/10.1210/clinem/dgaa739DOI Listing
March 2021

Menstrual phase-dependent differences in neurobehavioral performance: the role of temperature and the progesterone/estradiol ratio.

Sleep 2020 02;43(2)

Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA.

Study Objectives: Women in the luteal phase of the menstrual cycle exhibit better cognitive performance overnight than women in the follicular phase, although the mechanism is unknown. Given the link between core body temperature (CBT) and performance, one potential mechanism is the thermoregulatory role of progesterone (P4), estradiol (E2), and their ratio (P4/E2), which change across the menstrual cycle. We examined the role of P4/E2 in modulating performance during extended wake in premenopausal women. Additionally, we compared the acute effects of nighttime light exposure on performance, CBT, and hormones between the menstrual phases.

Methods: Participants were studied during a 50 h constant routine and a 6.5 h monochromatic nighttime light exposure. Participants were 16 healthy, naturally cycling women (eight follicular; eight luteal). Outcome measures included reaction time, attentional failures, self-reported sleepiness, CBT, melatonin, P4, and E2.

Results: As compared to women in the luteal phase, women in the follicular phase exhibited worse performance overnight. CBT was significantly associated with performance, P4, and P4/E2 but not with other sex hormones. Sex hormones were not directly related to performance. Light exposure that suppressed melatonin improved performance in the follicular phase (n = 4 per group) to levels observed during the luteal phase and increased CBT but without concomitant changes in P4/E2.

Conclusions: Our results underscore the importance of considering menstrual phase when assessing cognitive performance during sleep loss in women and indicate that these changes are driven predominantly by CBT. Furthermore, this study shows that vulnerability to sleep loss during the follicular phase may be resolved by exposure to light.
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http://dx.doi.org/10.1093/sleep/zsz227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457328PMC
February 2020

Endogenous Circadian Regulation of Female Reproductive Hormones.

J Clin Endocrinol Metab 2019 12;104(12):6049-6059

Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Context: Studies suggest that female reproductive hormones are under circadian regulation, although methodological differences have led to inconsistent findings.

Objective: To determine whether circulating levels of reproductive hormones exhibit circadian rhythms.

Design: Blood samples were collected across ∼90 consecutive hours, including 2 baseline days under a standard sleep-wake schedule and ∼50 hours of extended wake under constant routine (CR) conditions.

Setting: Intensive Physiological Monitoring Unit, Brigham and Women's Hospital.

Participants: Seventeen healthy premenopausal women (22.8 ± 2.6 years; nine follicular; eight luteal).

Interventions: Fifty-hour CR.

Main Outcome Measures: Plasma estradiol (E2), progesterone (P4), LH, FSH, SHBG, melatonin, and core body temperature.

Results: All hormones exhibited significant 24-hour rhythms under both standard sleep-wake and CR conditions during the follicular phase (P < 0.05). In contrast, only FSH and SHBG were significantly rhythmic during the luteal phase. Rhythm acrophases and amplitudes were similar between standard sleep-wake and CR conditions. The acrophase occurred in the morning for P4; in the afternoon for FSH, LH, and SHBG; and during the night for E2.

Conclusions: Our results confirm previous reports of ∼24-hour rhythms in many female reproductive hormones in humans under ambulatory conditions but demonstrate that these hormones are under endogenous circadian regulation, defined as persisting in the absence of external time cues. These results may have important implications for the effects of circadian disruption on reproductive function.
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http://dx.doi.org/10.1210/jc.2019-00803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821202PMC
December 2019

Circadian and wake-dependent changes in human plasma polar metabolites during prolonged wakefulness: A preliminary analysis.

Sci Rep 2019 03 14;9(1):4428. Epub 2019 Mar 14.

School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia.

Establishing circadian and wake-dependent changes in the human metabolome are critical for understanding and treating human diseases due to circadian misalignment or extended wake. Here, we assessed endogenous circadian rhythms and wake-dependent changes in plasma metabolites in 13 participants (4 females) studied during 40-hours of wakefulness. Four-hourly plasma samples were analyzed by hydrophilic interaction liquid chromatography (HILIC)-LC-MS for 1,740 metabolite signals. Group-averaged (relative to DLMO) and individual participant metabolite profiles were fitted with a combined cosinor and linear regression model. In group-level analyses, 22% of metabolites were rhythmic and 8% were linear, whereas in individual-level analyses, 14% of profiles were rhythmic and 4% were linear. We observed metabolites that were significant at the group-level but not significant in a single individual, and metabolites that were significant in approximately half of individuals but not group-significant. Of the group-rhythmic and group-linear metabolites, only 7% and 12% were also significantly rhythmic or linear, respectively, in ≥50% of participants. Owing to large inter-individual variation in rhythm timing and the magnitude and direction of linear change, acrophase and slope estimates also differed between group- and individual-level analyses. These preliminary findings have important implications for biomarker development and understanding of sleep and circadian regulation of metabolism.
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http://dx.doi.org/10.1038/s41598-019-40353-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418225PMC
March 2019

Impaired cognitive flexibility during sleep deprivation among carriers of the Brain Derived Neurotrophic Factor (BDNF) Val66Met allele.

Behav Brain Res 2018 02 22;338:51-55. Epub 2017 Sep 22.

Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, Clayton, Victoria 3800, Australia; Sleep Health Institute and Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address:

Accumulating evidence points to a genetic contribution to explain inter-individual vulnerability to sleep deprivation. A functional polymorphism in the BDNF gene, which causes a valine (Val) to methionine (Met) amino acid substitution at Codon 66, has been associated with cognitive impairment, particularly in populations with impaired frontal functioning. We hypothesised that sleep deprivation, which affects frontal function, may lead to cognitive dysfunction in Met allele carriers. To examine this, we investigated, in different BDNF genotypes, the effects of sleep deprivation on cognitive flexibility, as measured by response inhibition using the Stroop Color Naming Task. Thirty healthy, adults of European ancestry, including 12 heterozygous Met allele carriers and 18 Val/Val homozygotes, underwent 30-h of extended wakefulness under constant routine conditions. A computerised Stroop task was administered every 2h. Error rate and reaction times increased with time awake for all individuals. Participants with the Val/Met genotype made more errors on incongruent trials after 20h awake. While Val/Met participants also took significantly longer to respond when inhibiting a prepotent response irrespective of time awake, this was particularly evident during the biological night. Our study shows that carriers of the BDNF Met allele are more vulnerable to the impact of prolonged wakefulness and the biological night on a critical component of executive function, as measured by response inhibition on the Stroop task.
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http://dx.doi.org/10.1016/j.bbr.2017.09.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957758PMC
February 2018
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