The association between brain serotonin transporter binding and impulsivity and aggression in healthy individuals.

The serotonin system plays a critical role in the modulation of impulsive aggression. Although serotonin transporters (SERT) are key in modulating synaptic serotonin levels, few studies have investigated the role of SERT levels in human impulsive aggression. The aim of this study was to investigate whether brain SERT levels are associated with trait impulsive aggression. We included 148 healthy individuals (mean age 29.3 ± 13.0, range 18-80 years, 91 females) who had undergone positron emission positron (PET) examinations with the SERT tracer [11C]DASB and filled in self-report questionnaires of trait aggression, trait impulsivity and state aggression. We evaluated the association between cerebral SERT binding (BPND) and trait impulsive aggression in a latent variable model, with one latent variable (LVSERT) modelled from SERT BPND in frontostriatal and frontolimbic networks implicated in impulsive aggression, and another latent variable (LVIA) modelled from various trait measures of impulsivity and aggression. The LVSERT was not significantly associated with the LVIA (p = 0.8). Post-hoc univariate analyses did not reveal any significant associations between regional SERT levels and trait aggression, trait impulsivity or state aggression, but we found that state aggression at the day of PET scan was significantly lower in LA/LA homozygotes vs S-carriers of the 5-HTTLPR gene (p = 0.008). We conclude that brain SERT binding was not related to variations in trait impulsive aggression or state aggression. Our findings do not support that SERT is involved in mediating the serotonergic effects on aggression and impulsivity, at least not in individuals with non-pathological levels of impulsive aggression.

Measuring endogenous changes in serotonergic neurotransmission with [11C]Cimbi-36 positron emission tomography in humans.

Developing positron emission tomography (PET) radioligands for the detection of endogenous serotonin release will enable the investigation of serotonergic deficits in many neuropsychiatric disorders. The present study investigates how acute challenges that aim to increase or decrease cerebral serotonin levels affect binding of the serotonin 2A receptor (5-HT2AR) agonist radioligand [11C]Cimbi-36. In a randomized, double-blind, placebo-controlled, three-arm design, 23 healthy volunteers were PET scanned twice with [11C]Cimbi-36: at baseline and following double-blind assignment to one of three interventions (1) infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram preceded by oral dosing of the 5-HT1AR antagonist pindolol, (n = 8) (2) acute tryptophan depletion (ATD) (n = 7) and (3) placebo (n = 8). Two-sample t-tests revealed no significant group differences in percent change of neocortical [11C]Cimbi-36 binding from baseline to intervention between placebo and citalopram/pindolol (p = 0.4) or between placebo and ATD (p = 0.5). Notably, there was a significantly larger within-group variation in 5-HT2AR binding after intervention with citalopram/pindolol, as compared with placebo (p = 0.007). These findings suggest that neither ATD nor a combination of citalopram and pindolol elicit acute unidirectional changes in serotonin levels sufficient to be detected with [11C]Cimbi-36 PET in neocortex. We suggest that the large interindividual variation in 5-HT2AR binding after citalopram/pindolol reflects that after an acute SSRI intervention, individuals respond substantially different in terms of their brain serotonin levels. Our observation has a potential impact for the understanding of patient responses to SSRI.

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.

Self-perceived personality characteristics in seasonal affective disorder and their implications for severity of depression.

The personality traits Neuroticism and Extraversion may be involved in the development of seasonal affective disorder (SAD). However, the impact of personality traits on SAD severity and whether such self-reported traits fluctuate with season is unknown. We investigated the association between Neuroticism, as acquired in a symptom-free phase and depression severity in individuals with SAD and seasonal changes in personality traits in individuals with SAD compared to healthy controls. Twenty-nine individuals diagnosed with SAD and thirty demographically matched controls completed the NEO Personality Inventory-Revised and the Major Depression Inventory twice: in summer when individuals with SAD were symptom-free, and in winter when they experienced SAD symptoms. In summer, the groups scored similarly on their personality traits, and the controls did not score any different in winter compared to summer. High scores on Neuroticism in summer was associated with more severe depressive symptoms in winter in SAD individuals. In winter, individuals with SAD scored higher on Neuroticism and lower on Extraversion, both compared to controls and to their own summer scores. Our results support that Neuroticism may represent a vulnerability marker related to SAD, and during a depressive episode Neuroticism and Extraversion may be sensitive markers of SAD pathology.

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.

Season-independent cognitive deficits in seasonal affective disorder and their relation to depressive symptoms.

Although cognitive impairments are common in depressed individuals, it is unclear which aspects of cognition are affected and whether they represent state or trait features of depression. We here exploited a naturalistic model, namely the seasonal fluctuations in depressed status in individuals with Seasonal Affective Disorder (SAD), to study depression-related cognition, longitudinally. Twenty-nine medication-free individuals diagnosed with winter-SAD and 30 demographically matched healthy controls with no seasonality symptoms completed the Letter-number Sequencing task (LNS), the Symbol Digit Modalities Test (SDMT) and the Simple Reaction Time (SRT) twice; in summer and in winter. Compared to controls, SAD individuals showed significant season-independent impairments in tasks measuring working memory (LNS), cognitive processing speed (SDMT) and motor speed (SRT). In SAD individuals, cognitive processing speed was significantly negatively associated with the seasonal change in SAD depressive symptoms. We present novel evidence that in SAD individuals, working memory, cognitive processing- and motor speed is not only impaired in the winter but also in the summer. This suggests that certain cognitive impairments are SAD traits. Furthermore, impairments in cognitive processing speed appear to be related to depressive symptoms in SAD. Reduced processing speed may thus constitute a SAD vulnerability trait marker.

State-dependent alterations in inhibitory control and emotional face identification in seasonal affective disorder.

BACKGROUND: Depressed individuals often exhibit impaired inhibition to negative input and identification of positive stimuli, but it is unclear whether this is a state or trait feature. We here exploited a naturalistic model, namely individuals with seasonal affective disorder (SAD), to study this feature longitudinally. AIM: The goal of this study was to examine seasonal changes in inhibitory control and identification of emotional faces in individuals with SAD. METHOD: Twenty-nine individuals diagnosed with winter-SAD and 30 demographically matched controls with no seasonality symptoms completed an emotional Go/NoGo task, requiring inhibition of prepotent responses to emotional facial expressions and an emotional face identification task twice, in winter and summer. RESULTS: In winter, individuals with SAD showed impaired ability to inhibit responses to angry (p = .0006) and sad faces (p = .011), and decreased identification of happy faces (p = .032) compared with controls. In summer, individuals with SAD and controls performed similarly on these tasks (ps > .24). CONCLUSION: We provide novel evidence that inhibition of angry and sad faces and identification of happy faces are impaired in SAD in the symptomatic phase, but not in the remitted phase. The affective biases in cognitive processing constitute state-dependent features of SAD. Our data show that reinstatement of a normal affective cognition should be possible and would constitute a major goal in psychiatric treatment to improve the quality of life for these patients. (PsycINFO Database Record

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.

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.

High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding.

Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [(11)C]SB207145 for quantification of brain 5-HT4R binding. The Buss-Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT4R binding were associated with high trait aggression in males, but not in females.

Threat-related amygdala functional connectivity is associated with 5-HTTLPR genotype and neuroticism.

Communication between the amygdala and other brain regions critically regulates sensitivity to threat, which has been associated with risk for mood and affective disorders. The extent to which these neural pathways are genetically determined or correlate with risk-related personality measures is not fully understood. Using functional magnetic resonance imaging, we evaluated independent and interactive effects of the 5-HTTLPR genotype and neuroticism on amygdala functional connectivity during an emotional faces paradigm in 76 healthy individuals. Functional connectivity between left amygdala and medial prefrontal cortex (mPFC) and between both amygdalae and a cluster including posterior cingulate cortex, precuneus and visual cortex was significantly increased in 5-HTTLPR S' allele carriers relative to L(A)L(A) individuals. Neuroticism was negatively correlated with functional connectivity between right amygdala and mPFC and visual cortex, and between both amygdalae and left lateral orbitofrontal (lOFC) and ventrolateral prefrontal cortex (vlPFC). Notably, 5-HTTLPR moderated the association between neuroticism and functional connectivity between both amygdalae and left lOFC/vlPFC, such that S' carriers exhibited a more negative association relative to L(A)L(A) individuals. These findings provide novel evidence for both independent and interactive effects of 5-HTTLPR genotype and neuroticism on amygdala communication, which may mediate effects on risk for mood and affective disorders.

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 status predictive of neocortical 5-HT4 binding assessed with [(11)C]SB207145 PET in humans.

Serotonin (5-HT) is a neuromodulator affecting myriad aspects of personality and behavior and has been implicated in the pathophysiology of affective disorders including depression and anxiety. The 5-HTTLPR is a common genetic polymorphism within the promoter region of the gene coding for the serotonin transporter such that the S allele is associated with reduced transcriptional efficacy compared to the L allele, potentially contributing to increased serotonin levels. In humans, this genetic variant has been linked to inter-individual variability in risk for affective disorders, related aspects of personality and brain function including response to threat. However, its effects on aspects of serotonin signaling in humans are not fully understood. Studies in animals suggest that the 5-HT 4 receptor (5-HT(4)) shows a monotonic inverse association with long-term changes in serotonin levels indicating that it may be a useful measure for identifying differences in serotonergic neurotransmission. In 47 healthy adults we evaluated the association between 5-HTTLPR status and in vivo 5-HT(4) receptor binding assessed with [(11)C]SB207145 positron emission tomography (PET). We observed a significant association within the neocortex where [(11)C]SB207145 binding was 9% lower in S carriers compared to LL homozygotes. We did not find evidence for an effect of season or a season-by-5-HTTLPR interaction effect on regional [(11)C]SB207145 binding. Our findings are consistent with a model wherein the 5-HTTLPR S allele is associated with relatively increased serotonin levels. These findings provide novel evidence supporting an effect of 5-HTTLPR status on serotonergic neurotransmission in adult humans. There were no indications of seasonal effects on serotonergic neurotransmission.