Dynamics of Non-visual Responses in Humans: As Fast as Lightning?

The eye drives non-visual (NV) responses to light, including circadian resetting, pupillary reflex and alerting effects. Initially thought to depend on melanopsin-expressing retinal ganglion cells (ipRGCs), classical photopigments play a modulatory role in some of these responses. As most studies have investigated only a limited number of NV functions, generally under conditions of relatively high light levels and long duration of exposure, whether NV functions share similar irradiance sensitivities and response dynamics during light exposure is unknown. We addressed this issue using light exposure paradigms spectrally and spatially tuned to target mainly cones or ipRGCs, and by measuring longitudinally (50 min) several NV responses in 28 men. We demonstrate that the response dynamics of NV functions are faster than previously thought. We find that the brain, the heart, and thermoregulation are activated within 1 to 5 min of light exposure. Further, we show that NV functions do not share the same response sensitivities. While the half-maximum response is only ∼48 s for the tonic pupil diameter, it is ∼12 min for EEG gamma activity. Most NV responses seem to be saturated by low light levels, as low as 90 melanopic lux. Our results also reveal that it is possible to maintain optimal visual performance while modulating NV responses. Our findings have real-life implications. On one hand, light therapy paradigms should be re-evaluated with lower intensities and shorter durations, with the potential of improving patients’ compliance. On the other hand, the significant impact of low intensity and short duration light exposures on NV physiology should make us reconsider the potential health consequences of light exposure before bedtime, in particular on sleep and circadian physiology

Imaging Individual Differences in the Response of the Human Suprachiasmatic Area to Light

Circadian disruption is associated with poor health outcomes, including sleep and mood disorders. The suprachiasmatic nucleus (SCN) of the anterior hypothalamus acts as the master biological clock in mammals, regulating circadian rhythms throughout the body. The clock is synchronized to the day/night cycle via retinal light exposure. The BOLD-fMRI response of the human suprachiasmatic area to light has been shown to be greater in the night than in the day, consistent with the known sensitivity of the clock to light at night. Whether the BOLD-fMRI response of the human suprachiasmatic area to light is related to a functional outcome has not been demonstrated. In a pilot study (n = 10), we investigated suprachiasmatic area activation in response to light in a 30 s block-paradigm of lights on (100 lux) and lights off (< 1 lux) using the BOLD-fMRI response, compared to each participant's melatonin suppression response to moderate indoor light (100 lux). We found a significant correlation between activation in the suprachiasmatic area in response to light in the scanner and melatonin suppression, with increased melatonin suppression being associated with increased suprachiasmatic area activation in response to the same light level. These preliminary findings are a first step toward using imaging techniques to measure individual differences in circadian light sensitivity, a measure that may have clinical relevance in understanding vulnerability in disorders that are influenced by circadian disruption

Mind Wandering in Sensory Cortices

Mind wandering contains rich phenomenology as we experience moment by moment, however, such linkage between our subjective experiences and the underlying neural mechanism has been missing in the literature. Here we report that the sensory contents of mind wandering recruit corresponding sensory cortices, serving as the neural bases of the sensory contents in mind wandering

The effect of bright light on rest-activity rhythms and behavioural and psychological symptoms of dementia

De fleste som lever med demens har også atferdsmessige- og psykologiske symptomer ved demens (APSD) som for eksempel depresjon, angst, agitasjon, og søvnforstyrrelser. APSD påvirker livskvalitet og pleiebehov. Aktivitetsrytmen er ofte endret hos personer med demens. For eksempel kan søvn og våkenhet forekomme uregelmessig, med rastløshet og atferdsforstyrrelser på kvelds- og nattestid, og søvn på dagtid. Forstyrrelser i søvn og våkenhet har negative konsekvenser for daglig fungering, kognisjon, og affekt. I tillegg er det trolig at denne typen problemer gjenspeiler forstyrrelse av den endogene cirkadiane rytmen. APSD, inkludert søvnproblemer, behandles ofte medikamentelt, på tross av at slik behandling har begrenset effekt og kan medføre alvorlige bivirkninger. Lys påvirker den cirkadiane rytmen, og kan i tillegg ha en innvirkning på våkenhet og humør. Disse omtales som ikke-visuelle effekter av lys. Lysterapi er en ikke-medikamentell behandling som ifølge noen tidligere studier kan ha en positiv effekt på affekt, agitasjon, søvnforstyrrelser og aktivitetsrytmer hos personer med demens, men resultatene fra ulike studier har ikke vært entydige. Målet med denne avhandlingen var å undersøke effekten av lysterapi på APSD og aktivitetsrytmer, gjennom en klynge-randomisert placebo-kontrollert studie over 24 uker – DEM.LIGHT studien. Et sekundært mål, og et forarbeid til hovedstudien, var å undersøke lysforholdene ved demensenheter på sykehjem. Artikkel 1 presenterte en undersøkelse av lys på 15 demensenheter i Bergen kommune, gjennomført ved to årstider og med lysmålinger i ulike retninger. Lysmålingene ble sammenlignet med grenseverdier basert på anbefalinger og tidligere forskning. Lysverdiene ble oppgitt i måleenheter som er relevante for ikkevisuelle effekter av lys. Artikkel 2 og 3 rapporterte resultater fra DEM.LIGHTstudien, gjennomført på 8 sykehjem med 69 deltagere. Intervensjonen besto av takmonterte LED-lys i fellesstuen på 4 demensenheter, som gav lys av ulik styrke og fargetemperatur gjennom dagen. Maksimalt nivå for intervensjonen var ~1000 lx og 6000 K, mellom kl. 10:00 og 15:00, målt vertikalt 1.2 m over gulvet. Kontrollgruppen (4 demensenheter) hadde standard innendørsbelysning (~150–300 lx, 3000 K). Data ble innhentet ved baseline, og etter 8, 16 og 24 uker. Artikkel 2 undersøkte effekten av lysbehandlingen på aktivitetsrytmer registrert med aktigrafi, og artikkel 3 undersøkte effekten på proxy-vurderte APSD-mål (Cornell Scale for Depression in Dementia, CSDD og Neuropsychiatric Inventory – Nursing Home Version, NPI-NH). Effekten av behandlingen ble analysert ved bruk av blandede regresjonsmodeller (multilevel models), med demensstadium (Functional Assessment Staging Tool, FAST skåre) ved baseline som en a priori bestemt kovariat. I tillegg ble baselineskårer på utfallsmålene inkludert som kovariater i analysene til artikkel 3. I artikkel 1 fant vi at de fleste målingene av lyset på demensenhetene var under terskelverdiene, uavhengig av årstid og måleretning. I artikkel 2 fant vi ingen forbedring av aktivitetsrytmen etter BLT hos personer med demens når vi korrigerte for multippel testing. Uten slik korreksjon var akrofasen (tidspunktet for aktivitetrytmens makspunkt) signifikant mindre forsinket (med en time) i uke 16 i intervensjonsgruppen sammenlignet med kontrollgruppen. Artikkel 3 rapporterte blandede resultater for effekten av lysintervensjonen på APSD. Det var en signifikant effekt på underskalaer som måler affektive symptomer i uke 16, men ikke i uke 8 eller 24, etter korreksjon for multippel testing. Det var en signifikant effekt på CSDD og NPI-NH total-skårer i uke 16 før, men ikke etter, korreksjon for multippel testing. Det var ingen signifikant effekt på andre underskalaer. Oppsummert peker funnene fra artikkel 1 mot at lyset på demensenheter er utilstrekkelig sett opp mot terskelverdier for ikke-visuelle effekter av lys. Likevel var resultatene fra DEM.LIGHT-studien, som økte belysningen på demensenheter, blandede. Basert på disse resultatene kan vi ikke anbefale takmontert lysterapi ved demensenheter. Det er imidlertid flere metodologiske utfordringer og karakteristikker ved utvalget som begrenser generaliserbarheten til disse funnene.Most people living with dementia have behavioural and psychological symptoms of dementia (BPSD), such as depression, anxiety, agitation, and disturbed sleep, that strongly affect well-being and care needs. The rest-activity rhythm (RAR), i.e., the diurnal pattern of activity, is often altered in individuals with dementia. Sleep and wakefulness may, for instance, occur at irregular intervals, characterised by restlessness and behavioural disturbances at night, and napping during the day. This disruption of the sleep-wake pattern is detrimental to functioning and well-being. It is also thought to reflect deterioration of the endogenous circadian rhythm. Pharmacotherapy is often used to treat BPSD, including sleep disturbances, but has limited efficacy and is associated with severe side effects. Light influences the circadian rhythm, and can also have effects on alertness and mood. These are collectively referred to as non-image forming (NIF) effects of light. Bright light treatment (BLT) is a non-pharmacological intervention that has been found to improve affective symptoms, agitation, sleep disorders, and RARs in people with dementia in some studies, but results have been mixed. The main aim of this thesis was to investigate the effect of BLT on RARs and BPSD in a 24-week cluster randomised controlled trial - the DEM.LIGHT trial (ClinicalTrials.gov identifier: NCT03357328). A secondary aim, and preparation for the trial, was to investigate the illumination in nursing home dementia units. Paper 1 was a field study investigating nursing home illumination in 15 dementia units across seasons and gaze directions. Measured illuminances were compared to thresholds suggested by industry standards and research, and measurement units relevant to NIF effects of light were used. Paper 2 and 3 reported results from the DEM.LIGHT trial, conducted at 8 dementia units, with 69 participants. In the intervention group (4 units), ceiling mounted LED-panels provided ambient light of varying illuminance and correlated colour temperature throughout the day, with a peak of ~1000 lx and 6000 K (measured vertically at 1.2 m) between 10:00 and 15:00. In the control group (4 units), standard indoor light of ~150–300 lx, 3000 K was used. Data were collected at baseline and at 8, 16, and 24 weeks. Paper 2 investigated the effect of the intervention on actigraphy-measured RARs, and paper 3 investigated the effect on proxy-rated BPSD measures: the Cornell Scale for Depression in Dementia (CSDD) and the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH). Treatment effects were analysed using multilevel regression models, with dementia stage (score on the Functional Assessment Staging Tool, FAST) at baseline as a pre-determined covariate. In addition, baseline scores on the outcome measures were included as covariates in the models in paper 3. In paper 1 we found that, regardless of season and gaze direction, nearly all measured illuminances in dementia units fell below the thresholds. In paper 2, we found that there was no effect of BLT on RAR outcomes in people with dementia when controlling for multiple testing. Without controlling for multiple testing, the acrophase (i.e., timing of the activity peak) was significantly less delayed (by one hour) in the intervention group compared to the control group, in week 16. Paper 3 found mixed results for the effect of BLT on BPSD. There was a significant reduction of scores on affective subscales in the intervention group in week 16, but not at other follow-ups, after controlling for multiple testing. There was a significant effect on the NPI-NH and CSDD total scores in week 16 before, but not after, controlling for multiple testing. There were no significant effects on other subscales. In conclusion, the findings in paper 1 suggest that illumination in dementia units is inadequate compared to thresholds suggested for NIF effects of light. However, the results of the DEM.LIGHT trial, which increased the indoor illumination in dementia units, were mixed. Based on our results, we cannot make clear recommendations regarding the use of ambient BLT in dementia units. Several methodological challenges and sample characteristics may limit the generalisability of these results.Doktorgradsavhandlin

Measuring Melanopsin Function In Humans To Understand Photophobia In Migraine

Bright light can be uncomfortable, and sometimes even painful, to look at. Bright light, however, hurts more in numerous clinical contexts, including in people who suffer from migraine headache. This pathology is referred to as photophobia or light sensitivity. Migraineurs tend to not only be light sensitive during headaches, but between headaches as well. Prior work has tentatively linked photophobia to the melanopsin and intrinsically photosensitive retinal ganglion cell (ipRGC) system. In the first chapter, this work describes how we can effectively probe the ipRGC system in healthy human subjects. We highlight the utility of silent substitution to selectively stimulate melanopsin to thereby isolate the ipRGCs from the rest of the retina. We then demonstrate that pupillometry is a stable measure of the response to this selective stimulation, and shows temporal properties consistent with the prolonged signal transduction associated with melanopsin. In the second chapter, we then extend these insights to the study of photophobia in migraine, comparing light-related responses in people with migraine to headache free controls. Through this project, we show that migraineurs find melanopsin-isolating stimuli more uncomfortable than headache free controls, providing some of the strongest evidence to date that variation in ipRGC function relates to clinical pathology in humans. We also show that migraineurs find cone-isolating stimuli more uncomfortable, suggesting that both melanopsin and cone signals contribute to photophobia. Finally, we show that pupil constriction is not similarly enhanced in migraine. By demonstrating this dissociation in light-mediated responses, we reveal a selective amplification of ipRGC signals, in a manner consistent with a post-retinal localization of photophobia