Category: My publications

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No evidence for a role of the serotonin 4 receptor in five-factor personality traits: A positron emission tomography brain study.

PLoS One. 2017;12(9):e0184403

Authors: Stenbæk DS, Dam VH, Fisher PM, Hansen N, Hjordt LV, Frokjaer VG

Abstract
Serotonin (5-HT) brain architecture appears to be implicated in normal personality traits as supported by genetic associations and studies using molecular brain imaging. However, so far, no studies have addressed potential contributions to variation in normal personality traits from in vivo serotonin 4 receptor (5-HT4R) brain availability, which has recently become possible to image with Positron Emission Tomography (PET). This is particularly relevant since availability of 5-HT4R has been shown to adapt to synaptic levels of 5-HT and thus offers information about serotonergic tone in the healthy brain. In 69 healthy participants (18 females), the associations between personality traits assessed with the five-factor NEO Personality Inventory-Revised (NEO PI-R) and regional cerebral 5-HT4R binding in neocortex, amygdala, hippocampus, and anterior cingulate cortex (ACC) were investigated using linear regression models. The associations between each of the five personality traits and a latent variable construct of global 5-HT4R levels were also evaluated using latent variable structural equation models. We found no significant associations between the five NEO personality traits and regional 5-HT4R binding (all p-values > .17) or the latent construct of global 5-HT4R levels (all p-values > .37). Our findings indicate that NEO personality traits and 5-HT4R are not related in healthy participants. Under the assumption that global 5-HT4R levels index 5-HT tone, our data also suggest that 5-HT tone per se is not directly implicated in normal personality traits.

PMID: 28880910 [PubMed – in process]

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Neuroticism associates with cerebral in vivo serotonin transporter binding differently in males and females.

Int J Neuropsychopharmacol. 2017 Aug 07;:

Authors: Tuominen L, Miettunen J, Cannon DM, Drevets WC, Frokjaer VG, Hirvonen J, Ichise M, Jensen PS, Keltikangas-Järvinen L, Klaver JM, Knudsen GM, Takano A, Suhara T, Hietala J

Abstract
Background: Neuroticism is a major risk factor for affective disorders. This personality trait has been hypothesized to associate with synaptic availability of the serotonin transporter (5-HTT), which critically controls serotonergic tone in the brain. However, earlier studies linking neuroticism and 5-HTT have failed to produce converging findings. Because sex affects both the serotonergic system and the risk that neuroticism poses to the individual, sex may modify the association between neuroticism and 5-HTT, but this question has not been investigated by previous studies.
Methods: Here, we combined data from four different positron emission tomography imaging centers to address whether neuroticism is related to 5-HTT binding in vivo. The data set included 5-HTT binding potential (BPND) values from the thalamus and striatum, and personality scores from 91 healthy males and 56 healthy females. We specifically tested if the association between neuroticism and 5-HTT is different in females and males.
Results: We found that neuroticism and thalamic 5-HTT BPND were associated in both males and females, but with opposite directionality. Higher neuroticism associated with higher 5-HTT BPND in males (standardized beta 0.292, p = .008), whereas in females, higher neuroticism associated with lower 5-HTT BPND (standardized beta -0.288, p = .014).
Conclusions: The finding is in agreement with recent studies showing that the serotonergic system is involved in affective disorders differently in males and females and suggests that contribution of thalamic 5-HTT to the risk of affective disorders depends on sex.

PMID: 29020405 [PubMed – as supplied by publisher]

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Testosterone levels in healthy men correlate negatively with serotonin 4 receptor binding.

Psychoneuroendocrinology. 2017 Mar 22;81:22-28

Authors: Perfalk E, Cunha-Bang SD, Holst KK, Keller S, Svarer C, Knudsen GM, Frokjaer VG

Abstract
The serotonergic system integrates sex steroid information and plays a central role in mood and stress regulation, cognition, appetite and sleep. This interplay may be critical for likelihood of developing depressive episodes, at least in a subgroup of sensitive individuals. The serotonin 4 receptor (5-HT4R) indexes central serotonergic tonus, which may be related to endogenous sex-steroid levels in the mentally healthy state even though this remains elusive. Here we evaluate if peripheral levels of estradiol and testosterone are associated with 5-HT4R binding as imaged by [(11)C]SB207145 positron emission tomography in a group of 41 healthy men. We estimated global 5-HT4R binding using a latent variable model framework, which models shared correlation between 5-HT4R across multiple brain regions (hippocampus, amygdala, posterior and anterior cingulate, thalamus, pallidostriatum and neocortex). We tested whether testosterone and estradiol predict global 5-HT4R, adjusting for age. We found that testosterone, but not estradiol, correlated negatively with global 5-HT4R levels (p=0.02) suggesting that men with high levels of testosterone have higher cerebral serotonergic tonus. Our findings corroborate the link between sex hormone levels and serotonin signalling. Future longitudinal studies in clinical relevant populations are needed to elucidate the potential importance of testosterone in the pathophysiology of e.g. major depression and its treatment.

PMID: 28426945 [PubMed – as supplied by publisher]

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

Brain Behav. 2017 Apr;7(4):e00674

Authors: Stenbæk DS, Fisher PM, Ozenne B, Andersen E, Hjordt LV, McMahon B, Hasselbalch SG, Frokjaer VG, Knudsen GM

Abstract
BACKGROUND: We have previously identified an inverse relationship between cerebral serotonin 4 receptor (5-HT 4R) 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-HT 4R binding and affective verbal memory recall.
METHODS: Twenty-four healthy volunteers were scanned with the 5-HT 4R radioligand [(11)C]SB207145 and positron emission tomography, and were tested with the Verbal Affective Memory Test-24. The association between 5-HT 4R binding and affective verbal memory was evaluated using a linear latent variable structural equation model.
RESULTS: We observed a significant inverse association across all regions between 5-HT 4R binding and affective verbal memory performances for positive (p = 5.5 × 10(-4)) and neutral (p = .004) word recall, and an inverse but nonsignificant association for negative (p = .07) word recall. Differences in the associations with 5-HT 4R binding between word categories (i.e., positive, negative, and neutral) did not reach statistical significance.
CONCLUSION: Our findings replicate our previous observation of a negative association between 5-HT 4R binding and memory performance in an independent cohort and provide novel evidence linking 5-HT 4R binding, as a biomarker for synaptic 5-HT levels, to the mnestic processing of positive and neutral word stimuli in healthy humans.

PMID: 28413715 [PubMed – in process]

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Pharmacologically Induced Sex Hormone Fluctuation Effects on Resting-State Functional Connectivity in a Risk Model for Depression: A Randomized Trial.

Neuropsychopharmacology. 2016 Oct 19;:

Authors: Fisher PM, Larsen CB, Beliveau V, Henningsson S, Pinborg A, Holst KK, Jensen PS, Svarer C, Siebner HR, Knudsen GM, Frokjaer VG

Abstract
Women are at relatively greater lifetime risk for depression than men. This elevated risk in women is partly due to heightened risk during time periods characterized by marked fluctuations in sex hormones, including postpartum and perimenopausal periods. How sex hormone fluctuations contribute to heightened risk is not fully understood but may involve intrinsic functional connectivity. We induced a biphasic ovarian sex hormone fluctuation using the gonadotropin-releasing hormone agonist (GnRHa) goserelin to determine, with a randomized placebo-controlled design, intervention effects on or GnRHa-provoked depressive symptoms associations with change in resting-state functional connectivity (rs-FC) in 58 healthy women for six seeds (amygdala, hippocampus, anterior cingulate cortex, dorsal raphe, median raphe, and posterior cingulate cortex). GnRHa intervention did not significantly affect rs-FC in any seeds. Considering the GnRHa group only, the emergence of depressive symptoms following intervention was positively associated with amygdala-right temporal cortex and negatively associated with hippocampus-cingulate rs-FC. A test for mediation suggested that rs-FC changes in these networks marginally mediated the association between decrease in estradiol and increase in depressive symptoms in the GnRHa group (p=0.07). Our findings provide novel evidence-linking changes in rs-FC networks, the emergence of depressive symptoms and sex hormone fluctuations. Notably, we observed evidence that changes in rs-FC may represent a key neurobiological intermediary between molecular changes induced by hormone fluctuations and the emergence of depressive symptoms. Taken together, our findings indicate that sex hormone fluctuations may contribute to heightened risk for developing depressive symptoms by affecting intrinsic functional connectivity of key limbic brain structures.Neuropsychopharmacology advance online publication, 19 October 2016; doi:10.1038/npp.2016.208.

PMID: 27649641 [PubMed – as supplied by publisher]

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Pharmacologically Induced Sex-Hormone Fluctuation Effects on Resting-State Functional Connectivity in a Risk Model for Depression: A Randomised Trial.

Neuropsychopharmacology. 2016 Sep 21;

Authors: Fisher PM, Larsen CC, Beliveau V, Henningsson S, Pinborg A, Holst KK, Jensen PS, Svarer C, Siebner HR, Knudsen GM, Frokjaer VG

Abstract
Women are at relatively greater lifetime risk for depression than men. This elevated risk in women is partly due to heightened risk during time periods characterized by dramatic fluctuations in sex hormones, including postpartum and perimenopausal periods. How sex hormone fluctuations contribute to heightened risk is not fully understood but may involve intrinsic functional connectivity. We induced a biphasic ovarian sex-hormone fluctuation using the gonadotropin releasing hormone agonist (GnRHa) goserelin to determine, with a randomized placebo-controlled design, intervention effects on or GnRHa-provoked depressive symptoms associations with change in resting-state functional connectivity (rs-FC) in 58 healthy women for six seeds (amygdala, hippocampus, anterior cingulate cortex, dorsal raphe, median raphe and posterior cingulate cortex). GnRHa intervention did not significantly affect rs-FC in any seeds. Considering the GnRHa group only, the emergence of depressive symptoms following intervention was positively associated with amygdala-right temporal cortex and negatively associated with hippocampus-cingulate rs-FC. A test for mediation suggested that rs-FC changes in these networks marginally mediated the association between decrease in estradiol and increase in depressive symptoms in the GnRHa group (p=0.07). Our findings provide novel evidence linking changes in rs-FC networks, the emergence of depressive symptoms and sex hormone fluctuations. Notably, we observed evidence that changes in rs-FC may represent a key neurobiological intermediary between molecular changes induced by hormone fluctuations and the emergence of depressive symptoms. Taken together, our findings indicate that sex hormone fluctuations may contribute to heightened risk for developing depressive symptoms by affecting intrinsic functional connectivity of key limbic brain structures.Neuropsychopharmacology accepted article preview online, 21 September 2016. doi:10.1038/npp.2016.208.

PMID: 27649641 [PubMed – as supplied by publisher]

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Low frontal serotonin 2A receptor binding is a state marker for schizophrenia?

Eur Neuropsychopharmacol. 2016 May 11;

Authors: Rasmussen H, Frokjaer VG, Hilker RW, Madsen J, Anhøj S, Oranje B, Pinborg LH, Glenthøj B, Knudsen GM

Abstract
Here we imaged serotonin 2A receptor (5-HT2AR) binding in a very rare population of monozygotic twins discordant for schizophrenia to provide insight into trait and state components in brain 5-HT2AR patterns. In four twin pairs not medicated with drugs that target 5-HT2AR, frontal 5-HT2AR binding was consistently lower (33%) in schizophrenic- relative to their healthy co-twins. Our results strongly imply low frontal 5-HT2AR availability as a state feature of schizophrenia. If replicated, ideally in a larger sample also including dizygotic twin pairs and drug-naïve patients, this finding critically advance our understanding of the complex pathophysiology of schizophrenia.

PMID: 27179966 [PubMed – as supplied by publisher]

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Brain serotonin 4 receptor binding is associated with the cortisol awakening response.

Psychoneuroendocrinology. 2016 Feb 11;67:124-132

Authors: Jakobsen GR, Fisher PM, Dyssegaard A, McMahon B, Holst KK, Lehel S, Svarer C, Jensen PS, Knudsen GM, Frokjaer VG

Abstract
Serotonin signalling is considered critical for an appropriate and dynamic adaptation to stress. Previously, we have shown that prefrontal serotonin transporter (SERT) binding is positively associated with the cortisol awakening response (CAR) (Frokjaer et al., 2013), which is an index of hypothalamic-pituitary-adrenal (HPA)-axis output dynamics. Here, we investigated in healthy individuals if cerebral serotonin 4 receptor (5-HT4r) binding, reported to be a proxy for serotonin levels, is associated with CAR. Thirty healthy volunteers (25 males, age range 20-56 years) underwent 5-HT4r PET imaging with [(11)C]-SB207145, genotyping of the SERT-linked polymorphic region (5-HTTLPR), and performed serial home sampling of saliva (5 time points from 0 to 60min from awakening) to assess CAR. The association between 5-HT4r binding in 4 regions of interest (prefrontal cortex, anterior cingulate cortex, pallidostriatum, and hippocampus) and CAR was tested using multiple linear regression with adjustment for age and 5-HTTLPR genotype. Finally, an exploratory voxel-based analysis of the association was performed. CAR was negatively associated with 5-HT4r binding in pallidostriatum (p=0.01), prefrontal cortex (p=0.03), and anterior cingulate cortex (p=0.002), respectively, but showed no association in hippocampus. The results remained significant when taking into account other potentially relevant covariates. In conclusion, our finding reinforces an association between HPA-axis function and serotonin signaling in vivo in humans. We suggest that higher synaptic serotonin concentration, here indexed by lower 5-HT4r binding, supports HPA-axis dynamics, which in healthy volunteers is reflected by a robust CAR.

PMID: 26894483 [PubMed – as supplied by publisher]

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

Brain. 2016 Mar 19;

Authors: Mc Mahon B, Andersen SB, Madsen MK, Hjordt LV, Hageman I, Dam H, Svarer C, da Cunha-Bang S, Baaré W, Madsen J, Hasholt L, Holst K, Frokjaer VG, Knudsen GM

Abstract
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.

PMID: 26994750 [PubMed – as supplied by publisher]

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