Martin K. Madsen

Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder

Cross-sectional neuroimaging studies in non-depressed individuals have demonstrated an inverse relationship between daylight minutes and cerebral serotonin transporter; this relationship is modified by serotonin-transporter-linked polymorphic region short allele carrier status. We here present data from the first longitudinal investigation of seasonal serotonin transporter fluctuations in both patients with seasonal affective disorder and in healthy individuals. Eighty (11)C-DASB positron emission tomography scans were conducted to quantify cerebral serotonin transporter binding; 23 healthy controls with low seasonality scores and 17 patients diagnosed with seasonal affective disorder were scanned in both summer and winter to investigate differences in cerebral serotonin transporter binding across groups and across seasons. The two groups had similar cerebral serotonin transporter binding in the summer but in their symptomatic phase during winter, patients with seasonal affective disorder had higher serotonin transporter than the healthy control subjects (P = 0.01). Compared to the healthy controls, patients with seasonal affective disorder changed their serotonin transporter significantly less between summer and winter (P < 0.001). Further, the change in serotonin transporter was sex- (P = 0.02) and genotype- (P = 0.04) dependent. In the patients with seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom severity, as indexed by Hamilton Rating Scale for Depression - Seasonal Affective Disorder version scores (P = 0.01). Our findings suggest that the development of depressive symptoms in winter is associated with a failure to downregulate serotonin transporter levels appropriately during exposure to the environmental stress of winter, especially in individuals with high predisposition to affective disorders.media-1vid110.1093/brain/aww043_video_abstractaww043_video_abstract.

Three-Week Bright-Light Intervention Has Dose-Related Effects on Threat-Related Corticolimbic Reactivity and Functional Coupling

BACKGROUND Bright-light intervention is reported to successfully treat depression, in particular seasonal affective disorder, but the neural pathways and molecular mechanisms mediating its effects are unclear. An amygdala-prefrontal cortex corticolimbic circuit regulates responses to salient environmental stimuli (e.g., threat) and may underlie these effects. Serotonin signaling modulates this circuit and is implicated in the pathophysiology of seasonal and other affective disorders. METHODS We evaluated the effects of a bright-light intervention protocol on threat-related corticolimbic reactivity and functional coupling, assessed with an emotional faces functional magnetic resonance imaging paradigm at preintervention and postintervention. In a double-blind study conducted in the winter, 30 healthy male subjects received bright-light intervention (dose range between participants: .1-11.0 kilolux) for 30 minutes daily over a period of 3 weeks. Additionally, we considered serotonin transporter-linked polymorphic region (5-HTTLPR) genotype status as a model for differences in serotonin signaling and moderator of intervention effects. RESULTS Bright-light dose significantly negatively affected threat-related amygdala and prefrontal reactivity in a dose-dependent manner. Conversely, amygdala-prefrontal and intraprefrontal functional coupling increased significantly in a dose-dependent manner. Genotype status significantly moderated bright-light intervention effects on intraprefrontal functional coupling. CONCLUSIONS This is the first study to evaluate the effects of clinically relevant bright-light intervention on threat-related brain function. We show that amygdala-prefrontal reactivity and communication are significantly affected by bright-light intervention, an effect partly moderated by genotype. These novel findings support that this threat-related corticolimbic circuit is sensitive to light intervention and may mediate the therapeutic effects of bright-light intervention.

5-HTTLPR differentially predicts brain network responses to emotional faces

The effects of the 5‐HTTLPR polymorphism on neural responses to emotionally salient faces have been studied extensively, focusing on amygdala reactivity and amygdala‐prefrontal interactions. Despite compelling evidence that emotional face paradigms engage a distributed network of brain regions involved in emotion, cognitive and visual processing, less is known about 5‐HTTLPR effects on broader network responses. To address this, we evaluated 5‐HTTLPR differences in the whole‐brain response to an emotional faces paradigm including neutral, angry and fearful faces using functional magnetic resonance imaging in 76 healthy adults. We observed robust increased response to emotional faces in the amygdala, hippocampus, caudate, fusiform gyrus, superior temporal sulcus and lateral prefrontal and occipito‐parietal cortices. We observed dissociation between 5‐HTTLPR groups such that LALA individuals had increased response to only angry faces, relative to neutral ones, but S′ carriers had increased activity for both angry and fearful faces relative to neutral. Additionally, the response to angry faces was significantly greater in LALA individuals compared to S′ carriers and the response to fearful faces was significantly greater in S′ carriers compared to LALA individuals. These findings provide novel evidence for emotion‐specific 5‐HTTLPR effects on the response of a distributed set of brain regions including areas responsive to emotionally salient stimuli and critical components of the face‐processing network. These findings provide additional insight into neurobiological mechanisms through which 5‐HTTLPR genotype may affect personality and related risk for neuropsychiatric illness. Hum Brain Mapp 36:2842–2851, 2015.

Bright-light intervention induces a dose-dependent increase in striatal response to risk in healthy volunteers.

Bright-light interventions have successfully been used to reduce depression symptoms in patients with seasonal affective disorder, a depressive disorder most frequently occurring during seasons with reduced daylight availability. Yet, little is known about how light exposure impacts human brain function, for instance on risk taking, a process affected in depressive disorders. Here we examined the modulatory effects of bright-light exposure on brain activity during a risk-taking task. Thirty-two healthy male volunteers living in the greater Copenhagen area received 3weeks of bright-light intervention during the winter season. Adopting a double-blinded dose-response design, bright-light was applied for 30minutes continuously every morning. The individual dose varied between 100 and 11.000lx. Whole-brain functional MRI was performed before and after bright-light intervention to probe how the intervention modifies risk-taking related neural activity during a two-choice gambling task. We also assessed whether inter-individual differences in the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype influenced the effects of bright-light intervention on risk processing. Bright-light intervention led to a dose-dependent increase in risk-taking in the LA/LA group relative to the non-LA/LA group. Further, bright-light intervention enhanced risk-related activity in ventral striatum and head of caudate nucleus in proportion with the individual bright-light dose. The augmentation effect of light exposure on striatal risk processing was not influenced by the 5-HTTLPR-genotype. This study provides novel evidence that in healthy non-depressive individuals bright-light intervention increases striatal processing to risk in a dose-dependent fashion. The findings provide converging evidence that risk processing is sensitive to bright-light exposure during winter.

P.1.i.037 Patients with seasonal affective disorder show seasonal fluctuations in their cerebral serotonin transporter binding

Objectives: Lack of daylight is a prominent environmental stressor at high latitudes. It is estimated that more than 15a of the Copenhagen inhabitants suffer from Seasonal Affective Disorder (SAD) or sub-syndromal SAD [1]. Cross-sectional neuroimaging studies have demonstrated that in healthy individuals, striatal serotonin transporter (SERT) binding is high at winter solstice and low at summer solstice. These fluctuations are particularly evident in carriers of the short 5-HTTLPR polymorphism (S-allele carriers). The aim of the present study is to do the first longitudinal investigation of seasonal SERT fluctuations in healthy S-allele carriers and in S-allele carriers suffering from SAD. Methods: All participantscompleted the Seasonal Pattern Assessment Questionnaire (SPAQ) to evaluate seasonal variations in sleep, social activity, mood, weight, appetite and energy. The score on each item was summed to obtain a Global Seasonality Score (GSS), which indexes the degree of winter depression (range: 0–24, GSS>10 indicates SAD). Subjects without any seasonality and a GSS equal to or less than 10 entered the study as healthy participants while subject with a GSS score equal to or higher than 11 were interviewed by specialized psychiatrists both in their asymptomatic and their symptomatic (winter) phase to establish the SAD diagnosis. Twenty-three (13 females) healthy S-allele carriers (mean±SD: GSS: 4.8±2 and age: 25±7 years) and 11 (six females) Sallele carrying SAD patients (mean±SD: GSS:13.7±2 and age: 26±8 years) were investigated with a dynamic [ 11 C]DASB HRRT PET scan and a MRI brain scan both summer and winter, in randomized order. Non-displaceable binding potential (BP ND ) was quantified using MRTM2. Summer BP ND s were plotted as a function of winter BP ND s for 17 different brain regions [2]. The slope of the regression line (β) was used as a measure of individual change in global brain SERT changes across seasons. β values were compared between healthy controls and SAD patient using a Mann–Whitney unpaired t-test. A one sample paired t-test was used within groups to investigate significant seasonal SERT changes. Results: We found a significant difference between healthy controls and SAD patients in seasonal SERT changes: median β healthy controls: 1.033, median β SAD: 0.93, U=59, p=0.01. Furthermore we observed a tendency for a winter-summer change in the SAD group (β≠1): t(10)=2.136, meanβ±SD: 0.96±0.07, p=0.058 but not in the healthy control group: t(22)=1.759, mean β±SD: 1.024±0.07, p=0.092. Conclusions: We find that SAD patients experience a significantly larger seasonal SERT fluctuation compared to their healthy counterparts. We were not able to reproduce previous findings of a similar up-regulation during winter in healthy subjects and we speculate that this is due to a careful selection of individuals completely void of season related symptoms. Our data suggests that seasonally provoked depression is linked to seasonal SERT changes.

Sweet taste sensitivity is influenced by 5-HTTLPR genotype and affected in seasonal affective disorder.

(1) 5-HTTLPR study: the stable influence of the 5-HTTLPR (S/L) and rs25531 (A/G) polymorphism in the promoter region of the 5-HT transporter (SERT) gene on basic sweet taste sensitivity in healthy males (n1⁄435). The 5-HTTLPR S-allele is associated with lower levels of SERTmRNA and lower SERT expression (Heils et al., 1996; Willeit and Praschak-Rieder, 2010) compared to the LA-allele. (2) Seasonal affective disorder (SAD) study: the seasonal influence on the sucrose sensitivity in SAD patients (n1⁄412) and in age and gender matched healthy controls (n1⁄417). Serotonin is believed to contribute to the pathology causing SAD (Neumeister et al., 2001). SAD patients were screened using the “Seasonal Pattern Assessment Questionnaire” (SPAQ) (Murray, 2003) and included after psychiatric evaluations by trained consultants using the DSM IV criteria (American Psychiatric Association, 2007), a 29-item SIGHSAD (Williams et al., 1992) and the SCAN interview (Aboraya et al., 1998). All participants in both studies were drug naïve with respect to psychoactive medication and had normal neurological and medical examinations. In addition, all healthy participants in both studies had normal brief psychiatric assessments.

Amygdala response to emotional faces in seasonal affective disorder

BACKGROUND Seasonal affective disorder (SAD) is characterized by seasonally recurring depression. Heightened amygdala activation to aversive stimuli is associated with major depressive disorder but its relation to SAD is unclear. We evaluated seasonal variation in amygdala activation in SAD and healthy controls (HC) using a longitudinal design targeting the asymptomatic/symptomatic phases of SAD. We hypothesized increased amygdala activation to aversive stimuli in the winter in SAD individuals (season-by-group interaction). METHODS Seventeen SAD individuals and 15 HCs completed an implicit emotional faces BOLD-fMRI paradigm during summer and winter. We computed amygdala activation (SPM5) to an aversive contrast (angry & fearful minus neutral) and angry, fearful and neutral faces, separately. Season-by-group and main effects were evaluated using Generalized Least Squares. In SAD individuals, we correlated change in symptom severity, assessed with The Hamilton Rating Scale for Depression - Seasonal Affective Disorder version (SIGH-SAD), with change in amygdala activation. RESULTS We found no season-by-group, season or group effect on our aversive contrast. Independent of season, SAD individuals showed significantly lower amygdala activation to all faces compared to healthy controls, with no evidence for a season-by-group interaction. Seasonal change in amygdala activation was unrelated to change in SIGH-SAD. LIMITATIONS Small sample size, lack of positive valence stimuli. CONCLUSIONS Amygdala activation to aversive faces is not increased in symptomatic SAD individuals. Instead, we observed decreased amygdala activation across faces, independent of season. Our findings suggest that amygdala activation to angry, fearful and neutral faces is altered in SAD individuals, independent of the presence of depressive symptoms.

P.1.030 Three week bright-light intervention has dose-related effects on threat-related corticolimbic reactivity and functional coupling

Conclusions: This is the first study to evaluate the effects of clinically relevant bright-light intervention on threat-related brain function. We show that amygdala-prefrontal reactivity and communication are significantly affected by bright-light intervention, an effect partly moderated by genotype. These novel findings support that this threat-related corticolimbic circuit is sensitive to light intervention and may mediate the therapeutic effects of bright-light intervention.

P.1.i.007 The effect of bright light intervention on cerebral serotonin transporter binding

molecular brain imaging Effect of Bright Light Intervention on Cerebral Serotonin Transporter Binding Brenda Mc Mahon1, Anne Sofie Andersen1, Ling Feng1, Klaus Holst1,2, Martin Korsbak Madsen1, Szabolcs Lehel3, Matthias M. Herth1,3, Pernille Iversen4, Lis Hasholt5, and Gitte Moos Knudsen1. 1) Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging (Cimbi), Rigshospitalet and University of Copenhagen, Denmark, 2) Dept. Biostatistics, University of Copenhagen, Denmark 3) PET and Cyclotron Unit, Rigshospitalet, Copenhagen, Denmark, 4) Cimbi and Danish Research Centre for MR, Hvidovre Hospital, Denmark 5) Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark.