Liv V. Hjordt

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.

Serotonin 1B Receptor Binding Is Associated With Trait Anger and Level of Psychopathy in Violent Offenders.

BACKGROUND The involvement of serotonin in aggression has traditionally been attributed to impaired prefrontal serotonergic inhibitory control of emotional reactions to provocations in antisocial individuals. However, it is unclear which specific serotonergic receptors are involved in the effects. A large body of preclinical research supports a specific role of serotonin 1B receptors (5-HT1BRs) in aggression and impulsivity, but this has never been evaluated in humans. METHODS Nineteen incarcerated violent offenders and 24 healthy control nonoffenders were included and examined with positron emission tomography, using the radioligand [11C]AZ10419369 for quantification of cerebral 5-HT1BR binding in three regions of interest: the anterior cingulate cortex, orbitofrontal cortex, and striatum. RESULTS Group status significantly moderated the association between striatal 5-HT1BRs and trait anger (difference in slopes, pcorrected = .04). In the violent offender group, striatal 5-HT1BR binding was positively correlated with self-reported trait anger (p = .0004), trait psychopathy (p = .008), and level of psychopathy according to the Psychopathy Checklist-Revised (p = .02). We found no group differences in 5-HT1BR binding. CONCLUSIONS Our data demonstrate for the first time in humans a specific involvement of 5-HT1BR binding in anger and psychopathy. 5-HT1BRs putatively represent a molecular target for development of pharmacologic antiaggressive treatments.

Personality characteristics in surgery seeking and non-surgery seeking obese individuals compared to non-obese controls.

It is currently unknown what makes some obese individuals opt for bariatric surgery whereas others choose not to. The aim of this study was to examine whether personality characteristics differed between obese individuals signed up for Roux-en-Y gastric bypass (RYGB) (N=30) and obese individuals not seeking RYGB (N=30) compared to non-obese controls (N=30). All participants completed the NEO Personality Inventory-Revised. The obese RYGB group displayed higher levels of Neuroticism and borderline lower levels of Extraversion compared to the obese non-RYGB and the non-obese group, while the two latter groups did not differ in terms of personality. The Neuroticism domain and possibly the Extraversion domain may therefore be worthwhile to consider in future studies investigating the outcome of bariatric surgery.

Violent offenders respond to provocations with high amygdala and striatal reactivity.

Abstract The ability to successfully suppress impulses and angry affect is fundamental to control aggressive reactions following provocations. The aim of this study was to examine neural responses to provocations and aggression using a laboratory model of reactive aggression. We used a novel functional magnetic resonance imaging point-subtraction aggression paradigm in 44 men, of whom 18 were incarcerated violent offenders and 26 were control non-offenders. We measured brain activation following provocations (monetary subtractions), while the subjects had the possibility to behave aggressively or pursue monetary rewards. The violent offenders behaved more aggressively than controls (aggression frequency 150 vs 84, P = 0.03) and showed significantly higher brain reactivity to provocations within the amygdala and striatum, as well as reduced amygdala-prefrontal and striato-prefrontal connectivity. Amygdala reactivity to provocations was positively correlated with task-related behavior in the violent offenders. Across groups, striatal and prefrontal reactivity to provocations was positively associated with trait anger and trait aggression. These results suggest that violent individuals display abnormally high neural sensitivity to social provocations, a sensitivity related to aggressive behavior. These findings provide novel insight into the neural pathways that are sensitive to provocations, which is critical to more effectively shaped interventions that aim to reduce pathological aggressive behavior.

Development and psychometric validation of the verbal affective memory test

ABSTRACT We here present the development and validation of the Verbal Affective Memory Test-24 (VAMT-24). First, we ensured face validity by selecting 24 words reliably perceived as positive, negative or neutral, respectively, according to healthy Danish adults’ valence ratings of 210 common and non-taboo words. Second, we studied the tests psychometric properties in healthy adults. Finally, we investigated whether individuals diagnosed with Seasonal Affective Disorder (SAD) differed from healthy controls on seasonal changes in affective recall. Recall rates were internally consistent and reliable and converged satisfactorily with established non-affective verbal tests. Immediate recall (IMR) for positive words exceeded IMR for negative words in the healthy sample. Relatedly, individuals with SAD showed a significantly larger decrease in positive recall from summer to winter than healthy controls. Furthermore, larger seasonal decreases in positive recall significantly predicted larger increases in depressive symptoms. Retest reliability was satisfactory, rs ≥ .77. In conclusion, VAMT-24 is more thoroughly developed and validated than existing verbal affective memory tests and showed satisfactory psychometric properties. VAMT-24 seems especially sensitive to measuring positive verbal recall bias, perhaps due to the application of common, non-taboo words. Based on the psychometric and clinical results, we recommend VAMT-24 for international translations and studies of affective memory.

Mental distress and personality in women undergoing GnRH agonist versus GnRH antagonist protocols for assisted reproductive technology

STUDY QUESTION Do mental distress and mood fluctuations in women undergoing GnRH agonist and GnRH antagonist protocols for assisted reproductive technology (ART) differ depending on protocol and the personality trait, neuroticism? SUMMARY ANSWER ART treatment did not induce elevated levels of mental distress in either GnRH antagonist or agonist protocols but neuroticism was positively associated with increased mental distress, independent of protocols. WHAT IS KNOWN ALREADY ART treatment may increase mental distress by mechanisms linked to sex hormone fluctuations. General psychological characteristics, such as personality traits indexing negative emotionality, e.g. neuroticism, are likely to affect mental distress during ART treatment. STUDY DESIGN, SIZE, DURATION A total of 83 women undergoing their first ART cycle were consecutively randomized 1:1 to GnRH antagonist (n = 42) or GnRH agonist (n = 41) protocol. The study population was a subgroup of a larger ongoing Danish clinical randomized trial and was established as an add-on in the period 2010-2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Women in the GnRH antagonist protocol received daily injections with recombinant follicle-stimulating hormone, Puregon(®) and subcutaneous injections with GnRH antagonist, Orgalutran(®). Women in the GnRH agonist protocol received nasal administration of the GnRH agonist, Synarela(®) and subcutaneous injections with FSH, Puregon(®). The study design did not allow for a blinding procedure. All women self-reported the Profile of Mood States, the Perceived Stress Scale, the Symptom Checklist-92-Revised, and the Major Depression Inventory questionnaires, at baseline, at ART cycle day 35, on the day of oocyte pick-up, and on the day of hCG testing. Also, a series of Profile of Mood States were reported daily during pharmacological treatment to monitor mood fluctuations. The personality trait Neuroticism was assessed at baseline by the self-reported NEO-PI-R questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE ART did not induce within- or between-protocol changes in any of the applied measures of mental distress. However, the GnRH antagonist protocol was associated with more pronounced median mood fluctuations during the stimulation phase (antagonist, 11.0 SD, [IQR = 21.1-6.1]; agonist, 8.9 SD, [IQR = 11.3-5.7], P = 0.025). This association became non-significant after applying a Bonferroni-Holm correction. Neuroticism was highly positively associated with increased levels of mental distress throughout treatment independent of protocols (all P-values <0.006), and cross-sectional analysis revealed that women with high or low Neuroticism scores at baseline showed a significant trend towards lower chances of a positive pregnancy test (P-value =0.028). LIMITATIONS, REASONS FOR CAUTION Information on prognostic factors such as preceding length of infertility, number of retrieved oocytes and number of prior insemination treatments was not accounted for in the analyses. The stratification of protocols by age in the subgroups of women included in this study was suboptimal. Women with prior or current use of antidepressant medication were excluded from our study. WIDER IMPLICATIONS Our results imply that mental distress emerging during ART treatment is not causally linked to hypogonadism per se or to the choice of protocol. Rather, our data highlight the potential importance of (i) rapid increases in ovarian steroids and (ii) addressing personality traits indexing negative emotionality, i.e. Neuroticism, in women undergoing ART treatment, to optimize both emotional adjustment and, possibly, the chances of obtaining pregnancy. STUDY FUNDING/COMPETING INTERESTS The Danish Research Council for Independent Research and MSD, Denmark kindly supported the study. The authors declare no competing financial interests. TRIAL REGISTRATION NUMBER EudraCT - 2008-005452-24.

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.

Men with high serotonin 1B receptor binding respond to provocations with heightened amygdala reactivity

&NA; Serotonin signalling influences amygdala reactivity to threat‐related emotional facial expressions in healthy adults, but in vivo serotonin signalling has never been investigated in the context of provocative stimuli in aggressive individuals. The aim of this study was to evaluate associations between serotonin 1B receptor (5‐HT1BR) levels and brain reactivity to provocations. We quantified regional 5‐HT1BR binding using [11C]AZ10419369 positron emission tomography (PET) and measured brain activation following provocations with functional magnetic resonance imaging (fMRI) in eighteen violent offenders and 25 healthy control subjects. The point‐subtraction aggression paradigm (PSAP) was used in fMRI to elicit provocations in terms of monetary subtractions from a fictive opponent. We estimated global 5‐HT1BR binding using a linear structural equation model, with a single latent response variable (LV1B) modelling shared correlation between 5‐HT1BR binding across multiple brain regions (neocortex, anterior and posterior cingulate cortex, raphe, amygdala, hippocampus and striatum). We tested whether the LV1B was associated with amygdala, striatal and prefrontal reactivity to provocations, adjusting for age, injected mass and group. Across participants, LV1B was statistically significantly positively associated with amygdala (p = 0.01) but not with striatal (p = 0.2) or prefrontal reactivity to provocations (p = 0.3). These findings provide novel evidence that 5‐HT1BR levels are linked to amygdala reactivity to provocations in a cohort of men displaying a wide range of aggressive behavior. The data suggest that 5‐HT1BR represents an intriguing target for reducing excessive neural reactivity to provocations and thereby putatively violent behavior. HighlightsOur data link serotonin signalling and amygdala reactivity in men.5‐HT1B receptor levels correlate positively with amygdala reactivity to provocations.5‐HT1B receptors may be a target for reducing excessive reactivity to provocations.

Brain serotonin 4 receptor binding is inversely associated with verbal memory recall

We have previously identified an inverse relationship between cerebral serotonin 4 receptor (5‐HT4R) binding and nonaffective episodic memory in healthy individuals. Here, we investigate in a novel sample if the association is related to affective components of memory, by examining the association between cerebral 5‐HT4R binding and affective verbal memory recall.

Sex hormone manipulation slows reaction time and increases labile mood in healthy women

BACKGROUND Women show increased risk of depressive symptoms in life phases where ovarian steroid hormone levels fluctuate or decline rapidly. The risk mechanisms may include changes in mental state and affective cognition possibly mediated by serotonergic neurotransmission. METHODS In a randomized controlled double-blinded trial, 61 healthy women (mean age 24.3±4.9 years) were tested with measures of affective verbal memory, reaction time, mental distress, and serotonin transporter binding at baseline and at follow-up after receiving gonadotropin-releasing hormone agonist (GnRHa) or placebo intervention. Women also reported daily mood profiles during intervention. We tested direct effects of intervention and indirect effects through changes in serotonin transporter binding on verbal affective memory, simple reaction time and self-reported measures of mental distress, and further effects of GnRHa on daily mood. RESULTS GnRHa induced an increase in simple reaction time (p=0.03) and more pronounced fluctuations in daily self-reported mood in a manner dependent on baseline mood (p=0.003). Verbal affective memory recall, overall self-perceived mental distress, and serotonin transporter binding were not affected. CONCLUSIONS In healthy women transient sex-steroid hormone fluctuations decrease speed of information processing and further produce more labile mood only in women with elevated levels of mood disturbances at baseline.