Seasonality-resilient individuals downregulate their cerebral 5-HT transporter binding in winter - A longitudinal combined 11C-DASB and 11C-SB207145 PET study.

We have recently shown that the emergence and severity of seasonal affective disorder (SAD) symptoms in the winter is associated with an increase in cerebral serotonin (5-HT) transporter (SERT) binding. Intriguingly, we also found that individuals resilient to SAD downregulate their cerebral SERT binding in the winter. In the present paper, we provide an analysis of the SERT- and 5-HT dynamics as indexed by 5-HT4 receptor (5-HT4R) binding related to successful stress coping. We included 46 11C-DASB positron emission tomography (PET) scans (N = 23, 13 women, age: 26 ± 6 years) and 14 11C-SB207145 PET scans (7 participants, 3 women, age: 25 ± 3 years) from 23 SAD-resilient Danes. Data was collected longitudinally in summer and winter. We found that compared to the summer, raphe nuclei and global brain SERT binding decreased significantly in the winter (praphe = 0.003 and pglobal = 0.003) and the two measures were positively correlated across seasons (summer: R2 = 0.33, p = .004, winter: R2 = 0.24, p = .018). A voxel-based analysis revealed prominent changes in SERT in clusters covering both angular gyri (0.0005 < pcorrected < 0.0016), prefrontal cortices (0.00087 < pcorrected < 0.0039) and the posterior temporal and adjacent occipital cortices (0.0001 < pcorrected < 0.0066). We did not observe changes in 5-HT4R binding, suggesting that 5-HT levels remained stable across seasons. We conclude that resilience to SAD is associated with a global downregulation of SERT levels in winter which serves to keep 5-HT levels across seasons.

Seasonal pattern in bipolar disorders and cardio-vascular risk factors: A study from the FACE-BD cohort.

Seasonal pattern (SP) and metabolic syndrome (MetS) are major contributors to poor outcome in bipolar disorders (BD). Patients with seasonal bipolar depression present increased appetite, carbohydrate cravings, weight gain, and hypersomnia, which can increase the development of MetS. MetS also appears to be associated with seasonal mood changes in the general population. This study examines whether a SP in BD is associated with an increased risk of MetS and its sub-components. One thousand four hundred and seventy-one outpatients with BD were systematically enrolled from 2009 to 2016. Inclusion required a disease duration of at least 5 years, with 486 (33%) patients with SP (SP+) and 985 (67%) without (SP-) according to the DSM IV-TR criteria. When using continuous measures of metabolic components, SP+ patients, as compared to SP-, suffered from higher levels for systolic blood pressure (p = 0.01), low-density lipoprotein cholesterol (p = 0.009), fasting glucose (p = 0.007), triglycerides levels (p = 0.03), a larger abdominal circumference (p = 0.02), and a higher body mass index (p = 0.07). In the covariance analysis, adjusted for gender, age, and bipolar subtype, as well as the number of depressive and hypomanic episode, SP+ patients had a significantly higher level of fasting glucose and higher systolic blood pressure. The frequency of MetS did not differ between groups (21.2% in SP- versus 23.9% in SP+). When using categorical definitions for abnormal metabolic components (International Diabetes Federation criteria), there were no differences between groups, except that SP+ patients were more overweight/obese as compared to SP- patients (55.03% versus 46.7%, respectively; p = 0.002) and tended to have more frequently high fasting glucose (18.2% versus 14.3%, respectively; p = 0.07). MetS was frequent in patients with BD, however not associated with SP. Patients with SP appeared more vulnerable to overweight/obesity and presented with higher levels of MetS subcomponents although these parameters were mainly in the normal range. All patients with BD should benefit from early screening and targeted management of cardio-vascular risk factors.

Increased Seasonal Variation in Serotonin Transporter Binding in Seasonal Affective Disorder.

Seasonal affective disorder (SAD) is highly prevalent with rates of 1-6% and greater prevalence at more extreme latitudes; however, there are almost no direct brain investigations of this disorder. In health, serotonin transporter binding potential (5-HTT BPND), an index of 5-HTT levels, is greater throughout the brain in fall-winter compared with spring-summer. We hypothesized that in SAD, this seasonal variation would be greater in brain regions containing structures that regulate affect such as the prefrontal and anterior cingulate cortices (PFC and ACC). Furthermore, given the dimensional nature of SAD symptoms, it was hypothesized that seasonal fluctuation of 5-HTT BPND in the PFC and ACC would be greatest in severe SAD. Twenty SAD and twenty healthy participants underwent [(11)C]DASB positron emission tomography scans in summer and winter to measure seasonal variation in [(11)C]DASB 5-HTT BPND. Seasonal increases in [(11)C]DASB 5-HTT BPND were greater in SAD compared with healthy in the PFC and ACC, primarily due to differences between severe SAD and healthy (severe SAD vs healthy; Mann-Whitney U, U=42.5 and 37.0, p=0.005 and 0.003, respectively; greater magnitude in severe SAD of 35.10 and 14.23%, respectively), with similar findings observed in other regions (U=40.0-62.0, p=0.004-0.048; greater magnitude in severe SAD of 13.16-17.49%). To our knowledge, this is the first brain biomarker identified in SAD. This creates a new opportunity for phase 0 studies to target this phenotype and optimize novel prevention/treatment strategies for SAD.

Postcomparison of [(18) F]-fluorodeoxyglucose uptake in the brain after short-term bright light exposure and no intervention.

OBJECTIVE: Bright light therapy is widely used as the treatment of choice for seasonal affective disorder. Nonetheless, our understanding of the mechanisms of bright light is limited and it is important to investigate the mechanisms. The purpose of this study is to examine the hypothesis that bright light exposure may increase [(18) F]-fluorodeoxyglucose (FDG) uptake in olfactory bulb and/or hippocampus which may be associated neurogenesis in the human brain. METHOD: A randomized controlled trial comparing 5-day bright light exposure + environmental light (bright light exposure group) with environmental light alone (no intervention group) was performed for 55 participants in a university hospital. The uptake of [(18) F]FDG in olfactory bulb and hippocampus using FDG positron emission tomography was compared between two groups. RESULTS: There was a significant increase of uptake in both right and left olfactory bulb for bright light exposure group vs. no intervention group. After adjustment of log-transformed illuminance, there remained a significant increase of uptake in the right olfactory bulb. CONCLUSION: The present findings suggest a possibility that 5-day bright light exposure may increase [(18) F]FDG in the right olfactory bulb of the human brain, suggesting a possibility of neurogenesis. Further studies are warranted to directly confirm this possibility.

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.

Imaging of seasonal affective disorder and seasonality effects on serotonin and dopamine function in the human brain.

According to current knowledge, disturbances in brain monoamine transmission play a major role in many psychiatric disorders, and many of the radioligands used for investigating these disorders bind to targets within the brain monoamine systems. However, a phylogenetically ancient and prevailing function of monoamines is to mediate the adaptation of organisms and cells to rhythmical changes in light conditions, and to other environmental rhythms, such as changes in temperature, or the availability of energy resources throughout the seasons. The physiological systems mediating these changes are highly conserved throughout species, including humans. Here we review the literature on seasonal changes in binding of monoaminergic ligands in the human brain. Moreover, we argue for the importance of considering possible effects of season when investigating brain monoamines in healthy subjects and subjects with psychiatric disorders.

Single photon emission computed tomography (SPECT) of anxiety disorders before and after treatment with citalopram.

BACKGROUND: Several studies have now examined the effects of selective serotonin reuptake inhibitor (SSRI) treatment on brain function in a variety of anxiety disorders including obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and social anxiety disorder (social phobia) (SAD). Regional changes in cerebral perfusion following SSRI treatment have been shown for all three disorders. The orbitofrontal cortex (OFC) (OCD), caudate (OCD), medial pre-frontal/cingulate (OCD, SAD, PTSD), temporal (OCD, SAD, PTSD) and, thalamic regions (OCD, SAD) are some of those implicated. Some data also suggests that higher perfusion pre-treatment in the anterior cingulate (PTSD), OFC, caudate (OCD) and antero-lateral temporal region (SAD) predicts subsequent treatment response. This paper further examines the notion of overlap in the neurocircuitry of treatment and indeed treatment response across anxiety disorders with SSRI treatment. METHODS: Single photon emission computed tomography (SPECT) using Tc-99 m HMPAO to assess brain perfusion was performed on subjects with OCD, PTSD, and SAD before and after 8 weeks (SAD) and 12 weeks (OCD and PTSD) treatment with the SSRI citalopram. Statistical parametric mapping (SPM) was used to compare scans (pre- vs post-medication, and responders vs non-responders) in the combined group of subjects. RESULTS: Citalopram treatment resulted in significant deactivation (p = 0.001) for the entire group in the superior (t = 4.78) and anterior (t = 4.04) cingulate, right thalamus (t = 4.66) and left hippocampus (t = 3.96). Deactivation (p = 0.001) within the left precentral (t = 4.26), right mid-frontal (t = 4.03), right inferior frontal (t = 3.99), left prefrontal (3.81) and right precuneus (t= 3.85) was more marked in treatment responders. No pattern of baseline activation distinguished responders from non-responders to subsequent pharmacotherapy. CONCLUSIONS: Although each of the anxiety disorders may be mediated by different neurocircuits, there is some overlap in the functional neuro-anatomy of their response to SSRI treatment. The current data are consistent with previous work demonstrating the importance of limbic circuits in this spectrum of disorders. These play a crucial role in cognitive-affective processing, are innervated by serotonergic neurons, and changes in their activity during serotonergic pharmacotherapy seem crucial.

Regional cerebral blood flow changes after light therapy in seasonal affective disorder.

There is considerable evidence to indicate that depressive disorders may be associated with changes in regional cerebral blood flow (rCBF), and that successful treatment may reverse these changes. We studied patients with seasonal affective disorder (SAD) using 99Tcm-hexamethylpropylene amine oxime (99TCm-HMPAO) single photon emission tomography (SPET) to examine the effect of light therapy on rCBF. Ten depressed patients (8 females, 2 males) with a mean (+/- S.D.) age of 33.5 +/- 11.3 years underwent 99TCm-HMPAO SPET studies before and after light therapy. The treatment response was evaluated using the Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorders Version (SIGH-SAD). A patient was considered responsive to light therapy if the post-treatment SIGH-SAD score was reduced by 60% or more in comparison to the pre-treatment score (responders, n = 5; non-responders, n = 5). Pre- and post-treatment SIGH-SAD scores and SPET data were compared in each patient. An improvement in depressive symptoms after light therapy was associated with an increase in rCBF in the frontal and cingulate regions as well as the thalamus. Such changes were not seen in non-responsive subjects.

Cerebral glucose metabolism in patients with summer seasonal affective disorder.

Positron emission tomography scans of nine patients diagnosed with summer seasonal affective disorder (SSAD) were compared with scans of 45 normal control subjects to investigate differences in brain glucose metabolism. All subjects performed an auditory discrimination task beginning several minutes before injection of F-18-deoxyglucose and continuing for 30 minutes after injection. Regional glucose metabolic rates were extracted from 60 rectangular regions of interest measured in five planes selected as atlas matches from 28 total slices. Statistically significant differences between patients with SSAD and normal control subjects were found in cerebral glucose metabolic rate and also in normalized regional glucose metabolic rates in the orbital frontal cortex and in the left inferior parietal lobule.