Anne-Marie Gagné

Evidence of a Biological Effect of Light Therapy on the Retina of Patients with Seasonal Affective Disorder

BACKGROUND Retinal sensitivity anomalies have been reported in patients affected by seasonal affective disorder (SAD). We used the electroretinogram (ERG) to assess seasonal change in retinal function in patients with SAD and healthy participants, as well as in patients following 4 weeks of light therapy. METHODS ERG assessments were obtained in 22 SAD patients (2 men, 20 women, mean age 31 +/- 9 years) in the fall/winter season before and after 2 and 4 weeks of light therapy and in summertime. Matched healthy participants (2 men, 14 women; mean age 29 +/- 8 years) were evaluated once in the fall/winter and once in summer. The 29-item Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder version was administered. Standard ERG parameters were derived from the photopic and scotopic luminance response functions. Salivary melatonin concentration during ERG was assessed in both groups but during fall/winter assessments only. RESULTS A significantly lower cone ERG maximal amplitude and lower rod sensitivity was found in SAD patients before light therapy compared with healthy participants. Following 4 weeks of light therapy, a normalization of cone and rod ERG function occurred. ERG parameters in the summer and melatonin concentrations in fall/winter were not significantly different between groups. CONCLUSIONS Depressed patients with SAD demonstrate ERG changes in the winter compared with healthy comparison subjects with lower rod retinal sensitivity and lower cone maximal amplitude. These changes normalized following 4 weeks of light therapy and during the summer, suggesting that ERG changes are state markers for SAD.

Impact of blue vs red light on retinal response of patients with seasonal affective disorder and healthy controls

OBJECTIVES Seasonal affective disorder (SAD) is characterized by a mood lowering in autumn and/or winter followed by spontaneous remission in spring or summer. Bright light (BL) is recognized as the treatment of choice for individuals affected with this disease. It was speculated that BL acts on photosensitive retinal ganglion cells, particularly sensitive to blue light, which led to the emergence of apparatus enriched with blue light. However, blue light is more at risk to cause retinal damage. In addition, we reported using electroretinography (ERG) that a 60 min exposure of BL could reduce rod sensitivity. The goal of the present study was to verify if this decreased in sensitivity could be a consequence of the blue light portion present in the white light therapy lamps. We also wanted to assess the effect of monochromatic blue light vs red light in both healthy controls and patients with SAD. METHOD 10 healthy subjects and 10 patients with SAD were exposed in a random order for 60 min to two different light colors (red or blue) separated by an interval of at least 1 day. Cone and rod ERG luminance-response function was assessed after light exposure. RESULTS A two-way ANOVA indicates that blue light decreases the maximal ERG response (Vmax) in both groups in photopic (p<0.05) and scotopic conditions (p<0.01). CONCLUSION The main finding of this experiment is that blue light reduces photoreceptor responses after only a single administration. This brings important concerns with regard to blue-enriched light therapy lamps used to treat SAD symptoms and other disorders.

Atypical pattern of rod electroretinogram modulation by recent light history: A possible biomarker of seasonal affective disorder

Our goal was to challenge both normal controls and patients with seasonal affective disorders (SAD) to various light histories and then measure their retinal response modulation using the electroretinogram (ERG) in both winter and summer. In winter and summer, 11 normal controls and 12 SAD patients were exposed to three different light conditions for 1 h (10,000, 100 and 5 lux) followed by an ERG. Groups showed similar ERG amplitudes in the 100 lux condition. Compared with the 100-lux condition, in controls, the ERG response was significantly increased in the 5-lux condition; in SAD, it was significantly decreased in the 10,000-lux condition. This pattern was present in both seasons. This is the first time a retinal response modulation anomaly has been observed in SAD patients in both the depressed and euthymic states. Retinal response modulation may represent an interesting biomarker of the disease for future research.

Impact of oral melatonin on the electroretinogram cone response.

Background In the eye, melatonin plays a role in promoting light sensitivity at night and modulating many aspects of circadian retinal physiology. It is also an inhibitor of retinal dopamine, which is a promoter of day vision through the cone system. Consequently, it is possible that oral melatonin (an inhibitor of retinal dopamine) taken to alleviate circadian disorders may affect cone functioning. Our aim was to assess the impact of melatonin on the cone response of the human retina using electroretinography (ERG). Methods Twelve healthy participants aged between 18 to 52 years old were submitted to a placebo-controlled, double-blind, crossover, and counterbalanced-order design. The subjects were tested on 2 sessions beginning first with a baseline ERG, followed by the administration of the placebo or melatonin condition and then, 30 min later, a second ERG to test the effect. Results Following oral melatonin administration, a significant decrease of about 8% of the cone maximal response was observed (mean 6.9 μV ± SEM 2.0; P = 0.0065) along with a prolonged b-wave implicit time of 0.4 ms ± 0.1, 50 minutes after ingestion. Conclusion Oral melatonin appears to reach the eye through the circulation. When it is administered at a time of day when it is not usually present, melatonin appears to reduce input to retinal cones. We believe that the impact of melatonin on retinal function should be taken into consideration when used without supervision in chronic self-medication for sleep or circadian disorder treatment.

Impact of light therapy on rod and cone functions in healthy subjects

Light therapy is an effective treatment for patients with seasonal affective disorders and is commonly used at an intensity of 10,000 lx. The aim of this study was to investigate the direct impact of light therapy on cones and rods photoreceptors using the electroretinogram (ERG) technique. Twelve healthy subjects were exposed for 60 min to three light conditions: 10,000 lx, 100 lx and 5 lx. ERG cone and rod luminance response functions were obtained immediately after exposures. Cone function was not affected by any light conditions. Maximal response achieved by the rods was significantly lower following the 100 lx and 10,000 lx conditions when compared with the 5 lx condition. Retinal rod sensitivity was significantly lower in the 10,000 lx condition when compared with the 12 lx condition. A decrease in rod function can readily be observed at 100 lx, that is, at regular indoor lighting. This decrease could be related to the triggering of retinal dopamine production, which would favour day vision over night vision. The further decrease in light sensitivity observed after 60 min at 10,000 lx may be perceived as a protective mechanism of the rod system against bright light.

Revisiting visual dysfunctions in schizophrenia from the retina to the cortical cells: A manifestation of defective neurodevelopment

This review highlights morphological and functional anomalies found along the entire visual pathway in schizophrenia, from the retina to the cortex. Based on the evidence of widespread anatomical and functional visual abnormalities, we posited that a neurodevelopmental anomaly occurring early in life was likely to explain those. Incidentally, support to the neurodevelopmental theory of schizophrenia is strongly emerging from many neurobiological domains. In vertebrates, the first visual structures migrate toward the orbit position at the end of the fourth week of gestation. A neurodevelopmental defect around that time on these embryonic structures could account for the visual anomalies in schizophrenia. Retinol activity might be involved in the process. Future research in schizophrenia should focus on early visual testing, on trials combining multiple visual anomaly assessments and a closer look to retinol activity during the pregnancy.

A transdisciplinary approach to the decision-making process in extreme prematurity

BackgroundA wide range of dilemmas encountered in the health domain can be addressed more efficiently by a transdisciplinary approach. The complex context of extreme prematurity, which is raising important challenges for caregivers and parents, warrants such an approach.MethodsIn the present work, experts from various disciplinary fields, namely biomedical, epidemiology, psychology, ethics, and law, were enrolled to participate in a reflection. Gathering a group of experts could be very demanding, both in terms of time and resources, so we created a web-based discussion forum to facilitate the exchanges. The participants were mandated to solve two questions: “Which parameters should be considered before delivering survival care to a premature baby born at the threshold of viability?” and “Would it be acceptable to give different information to parents according to the sex of the baby considering that outcome differences exist between sexes?”ResultsThe discussion forum was performed over a period of nine months and went through three phases: unidisciplinary, interdisciplinary and transdisciplinary, which required extensive discussions and the preparation of several written reports. Those steps were successfully achieved and the participants finally developed a consensual point of view regarding the initial questions. This discussion board also led to a concrete knowledge product, the publication of the popularized results as an electronic book.ConclusionsWe propose, with our transdisciplinary analysis, a relevant and innovative complement to existing guidelines regarding the decision-making process for premature infants born at the threshold of viability, with an emphasis on the respective responsabilities of the caregivers and the parents.

T29. ELECTRORETINOGRAPHIC RESPONSE IN YOUTHS AT GENETIC RISK OF SCHIZOPHRENIA AND BIPOLAR DISORDER AND IN NORMAL CONTROLS: TRANSVERSAL AND LONGITUDINAL DIFFERENCES AND IMPLICATIONS FOR THE RISK TRAJECTORY

Abstract Background Visual defects have been widely reported in major psychosis. This includes altered eye tracking, retinal thinning and electrophysiological anomalies.1 One of the most replicated alterations is decreased electroretinographic (ERG) responses that are observed in both bipolar disorder and schizophrenia. Our previous study showed a diminished rod b-wave amplitude in a small sample of children born to an affected parent.2 The fact that an anomaly found in patients would also be observed in children at genetic risk suggests a neurodevelopmental origin and may represent a vulnerability marker. Little data exists on the stability of ERG measures in childhood and adolescence. We wanted to evaluate rod and cone ERG response in larger samples of young offspring of an affected parent (HR) and age and gender balanced controls. By comparing a subsample of 33 offspring to controls, we were able to evaluate the stability and change of ERG over time. Methods ERGs of 71 offspring (mean age of 19 y.o.) and 224 healthy controls (mean age of 20 y.o.) was recorded. From this sample, 33 HR and 26 healthy controls had ERG recordings at 2 different moments (mean interval of 4 years). We then compared the amplitudes obtained at Time 1 and Time 2 in order to assess whether the ERG amplitudes remained stable or varied over time. Results Congruent with our 2010 report, this larger HR sample showed a reduced rod b-wave amplitude (p<.05). Probably due to higher statistical power, two other differences were found: an increased cone b-wave latency (p<.05) as well as a diminished mixed rod/cone ERG amplitude (p <.05). None of the ERG amplitudes of the healthy controls changed over time. In contrast, 12 out of 33 HR participant showed a variation of more than one standard deviation (either increase or decrease) on the rod b-wave amplitude which was significantly more frequent than in healthy controls (2/26; p<.05). Change in offspring occurred in both directions: some of them had an increased ERG amplitude response that was sufficient to end up in the confidence interval of the controls whereas others experienced a decreased of their rod amplitude over time. Discussion These young high-risk offspring displayed three ERG anomalies that we have already reported in adult patients.2 Our finding bolstered the evidence that ERG anomalies observed in patients may have neurodevelopmental or childhood roots. We observed only little variation in the ERG of the healthy controls over time in that early age range and this appears concordant with existing literature. Of particular interest is the finding that rod b-wave amplitudes were diminished in patients and in offspring. The offspring also showed increased variability over time in comparison to controls. Future studies will seek to understand the relationship between the transversal or longitudinal patterns of rod b-wave amplitudes, as an indicator of risk, and the risk endophenotypes previously reported in the children born to an affected parent.3,4 References 1. Gagné et al. Prog Neuropsychopharmacol Biol Psychiatry. 2015 2. Hébert et al. Bill Psychiatry, 2010 3. Maziade, N Eng J Med, 2017 4. Paccalet et al., Schizophr Res, 2016

7.2 ELECTRORETINOGRAPHIC ANOMALIES SEEN IN PATIENTS AFFECTED BY SCHIZOPHRENIA OR BIPOLAR DISORDER ARE DETECTABLE EARLY IN CHILDREN BORN TO AN AFFECTED PARENT: IMPLICATIONS FOR THE STAGING OF RISK STATUS IN CHILDHOOD-ADOLESCENCE

Abstract Background Adult patients having schizophrenia, bipolar disorder or major depression display indicators of brain dysfunctions that may be detectable in healthy children-adolescents at genetic risk, such as those born to an affected parent (Maziade, New Eng J Med 2017; Schizophr Res 2013). For instance, cognitive deficits are displayed by both adult patients and children at risk (Maziade, Schizophr Bull 2011). We had reported that schizophrenia patients present diminished amplitudes and delayed latencies of rod and cone photoreceptor responses (Hébert, Schizophr Res, 2015) and we recently found that bipolar patients have similar ERG anomalies. We had also reported preliminary data in a small sample of 29 children born to an affected parent showing that young offspring had rod diminished amplitudes (Hébert, Biol Psychiatry 2010). The present objectives were i) under the hypothesis that offspring would display many of the ERG anomalies that schizophrenia or mood disorder patients carry (Hébert, Schizophr Res 2015; Prog Neuropsychopharmacol Biol Psychiatry 2017), to look for cone and rod response anomalies in a large sample of young high-risk offspring; ii) to describe the relationship between ERG anomalies and other risk endophenotypes in the offspring; and iii) look at the relationship between ERG anomalies and the risk clusters already shown to predict later transition to illness. Methods The sample consisted of 84 young offspring (aged 6 to 27) of a parent affected by schizophrenia or bipolar disorder, compared to 224 healthy controls balanced for age and sex. Full-field cone and rod ERG was measured in non-dilated eyes for all subjects. In the young offspring, we also collected measures of different cognitive domains, attenuated symptoms of psychosis, non-psychotic DSM diagnosis and/or an episode of poor GAF functioning in childhood-adolescence, childhood trauma, and cannabis use (Paccalet, Schizophr Res 2016). Results In comparison to controls the offspring displayed three ERG anomalies that were observed in adult patients: prolonged cone b-wave latency (p=0.04), diminished rod b-wave amplitude (p=0.04) and prolonged rod b-wave latency (p=0.006). These ERG anomalies were shared by offspring of a parent with schizophrenia or bipolar disorder, an observation of ERG commonality that we had made in adult patients. The three ERG amplitude and latency anomalies tended to aggregate in a child at risk, a trend we also observed in another endophenotype modality such as deficits in different cognitive domains. However, in these high-risk children and adolescents, the patterns of aggregation suggest that ERG anomalies would depict another risk pathway than that marked by cognitive deficits. Discussion First, ERG anomalies in high-risk children have neurobiological implications for future research on the illness neurodevelopment. Second, as found for other modalities of risk endophenotypes in children at genetic risk (Maziade, New Eng J Med 2017), multiple rod and cone ERG anomalies tended to cluster together in a child. Such an aggregation may be compatible with the multifactorial polygenic theory with a threshold. Remarkably, a clustering of risk indicators is also observed in children at risk of metabolic cardiovascular disorders and is presently considered in practice guidelines for these children. The clustering of risk indicators may provide an empirical basis for the staging of the risk status of children at genetic risk and has immediate implications for their longitudinal surveillance in the clinic.

Electroretinographic anomalies in medicated and drug free patients with major depression: Tagging the developmental roots of major psychiatric disorders

ABSTRACT The retina is tagged as an approachable part of the brain due to its common embryonic origin and appears as a promising site of investigation for psychiatric disorders. Retinal function is assessed best with the electroretinogram (ERG), which was obtained in a large sample of patients with major depressive disorder and matched controls. ERG cone and rod luminance response functions were recorded in non‐dilated eyes in 100 major depressive disorder patients (MDD) and 100 controls, (mean age of 42.8 and 40.9 y. o. respectively). Amongst MDD patients, 17 were drug free (mean age 41.2 y. o). In medicated patients, at the cone level, a prolonged b‐wave was observed (p ≤ 0.01). In drug free patients a prolonged b‐wave was discovered only when averaging the implicit time of the 3 highest b‐wave amplitudes of the photopic hill. For the medicated patients, the mixed rods/cones a‐wave was reduced (p = 0.01) whereas a trend (p = 0.06) was observed for the pure rod b‐wave (reduced) and the mixed rods/cones (reduced and prolonged; p = 0.05). In drug free patients, a similar pattern could be observed in terms of effect sizes. Overall, medicated and drug free MDD patients shared some deficits suggesting that some anomalies are present above and beyond the effect of medication. Of interest, the prolonged cone and reduced rod amplitude were reported by our group in schizophrenia patients, suggesting a common neurodevelopmental root of major psychiatric disorders. HIGHLIGHTSElectroretinography (ERG) indicated retinal anomalies in MDD patients at the cone and rod levels.Drug free MDD patients showed similar anomalies to MDD medicated patients suggesting that anomalies are not due to medications.Reduced cone ERG a‐ and b‐ waves amplitudes are present in only drug free patients.Specific deficits of prolonged cone implicit time and reduced rod b‐wave were also observed in schizophrenia suggesting communalities.