Helmholtz Research Institute

Utrecht, Netherlands

Helmholtz Research Institute

Utrecht, Netherlands

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Heitland I.,University Utrecht | Heitland I.,Helmholtz Research Institute | Kenemans J.L.,University Utrecht | Kenemans J.L.,Helmholtz Research Institute | And 3 more authors.
Behavioural Brain Research | Year: 2014

It has long been postulated that exogenous cannabinoids have a profound effect on human cognitive functioning. These cannabinoid effects are thought to depend, at least in parts, on alterations of phase-locking of local field potential neuronal firing. The latter can be measured as activity in the theta frequency band (4-7. Hz) by electroencephalogram. Theta oscillations are supposed to serve as a mechanism in neural representations of behaviorally relevant information. However, it remains unknown whether variability in endogenous cannabinoid activity is involved in theta rhythms and therefore, may serve as an individual differences index of human cognitive functioning. To clarify this issue, we recorded resting state EEG activity in 164 healthy human subjects and extracted EEG power across frequency bands (δ, θ, α, and β). To assess variability in the endocannabinoid system, two genetic polymorphisms (rs1049353, rs2180619) within the cannabinoid receptor 1 (CB1) were determined in all participants. As expected, we observed significant effects of rs1049353 on EEG power in the theta band at frontal, central and parietal electrode regions. Crucially, these effects were specific for the theta band, with no effects on activity in the other frequency bands. Rs2180619 showed no significant associations with theta power after Bonferroni correction. Taken together, we provide novel evidence in humans showing that genetic variability in the cannabinoid receptor 1 is associated with resting state EEG power in the theta frequency band. This extends prior findings of exogenous cannabinoid effects on theta power to the endogenous cannabinoid system. © 2014 Published by Elsevier B.V.


Heitland I.,University Utrecht | Heitland I.,Helmholtz Research Institute | Klumpers F.,University Utrecht | Klumpers F.,Helmholtz Research Institute | And 6 more authors.
Translational Psychiatry | Year: 2012

Failure to extinguish fear can lead to persevering anxiety and has been postulated as an important mechanism in the pathogenesis of human anxiety disorders. In animals, it is well documented that the endogenous cannabinoid system has a pivotal role in the successful extinction of fear, most importantly through the cannabinoid receptor 1. However, no human studies have reported a translation of this preclinical evidence yet. Healthy medication-free human subjects (N=150) underwent a fear conditioning and extinction procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex was measured to assess fear-conditioned responding, and subjective fear ratings were collected. Participants were genotyped for two polymorphisms located within the promoter region (rs2180619) and the coding region (rs1049353) of cannabinoid receptor 1. As predicted from the preclinical literature, acquisition and expression of conditioned fear did not differ between genotypes. Crucially, whereas both homozygote (G/G, N=23) and heterozygote (A/G, N=68) G-allele carriers of rs2180619 displayed robust extinction of fear, extinction of fear-potentiated startle was absent in A/A homozygotes (N=51). Additionally, this resistance to extinguish fear left A/A carriers of rs2180619 with significantly higher levels of fear-potentiated startle at the end of the extinction training. No effects of rs1049353 genotype were observed regarding fear acquisition and extinction. These results suggest for the first time involvement of the human endocannabinoid system in fear extinction. Implications are that genetic variability in this system may underlie individual differences in anxiety, rendering cannabinoid receptor 1 a potential target for novel pharmacological treatments of anxiety disorders. © 2012 Macmillan Publishers Limited All rights reserved.


Van Lutterveld R.,University Utrecht | Van Lutterveld R.,Rudolf Magnus Institute of Neuroscience | Koops S.,University Utrecht | Schutter D.J.L.G.,Helmholtz Research Institute | And 4 more authors.
Schizophrenia Research | Year: 2012

Objctive: Repetitive transcranial magnetic stimulation (rTMS) to the temporoparietal region has been proposed as a therapeutic option for auditory verbal hallucinations (AVH). However, most large randomized controlled trials failed to demonstrate a superior effect of rTMS treatment as compared to sham. Previous studies applied daily rTMS sessions for one or more weeks to summate its effects. However, the effect of a single rTMS treatment on AVH-severity has never been studied, making it unclear if there is an initial effect that could be increased by repeated treatment. Methods: In three separate sessions, twenty-four patients with a psychotic disorder received 1-Hz rTMS to the left temporoparietal cortex, its right-sided homologue or a centro-occipital control site. Severity of AVH was assessed before and after each rTMS session and resting-state EEGs were recorded to investigate the neuronal effects of rTMS. Results: Stimulation of the temporoparietal cortices was not more effective in reducing AVH-severity than control-site stimulation. In addition, EEG-related power and connectivity measures were not affected differently across stimulation sites and changes in neuronal activity did not correlate with changes in AVH-severity. Conclusions: These results may suggest a placebo effect of a single session of 1-Hz rTMS treatment on AVH-severity. © 2012 Elsevier B.V.


Heitland I.,University Utrecht | Heitland I.,Helmholtz Research Institute | Groenink L.,Utrecht Institute of Pharmaceutical science | van Gool J.M.,University Utrecht | And 4 more authors.
Genes, Brain and Behavior | Year: 2016

We recently showed that a genetic polymorphism (rs878886) in the human corticotropin-releasing hormone receptor 1 (CRHR1) is associated with reduced fear-conditioned responses to a threat cue. This is a potentially important finding considering that the failure to acquire fear contingencies can leave an individual in a maladaptive state of more generalized anxiety. Consistent with that idea, the CRHR1-dependent fear acquisition deficit translated into heightened contextual anxiety when taking genetic variability within the serotonin transporter long polymorphic region (5-HTTLPR) into account. To replicate our previous findings, we conducted a replication study in 224 healthy medication-free human subjects using the exact same cue and context virtual reality fear-conditioning procedure as in study by Heitland et al. (2013). In the replication study, consistent with the original findings, CRHR1 rs878886 G-allele carriers showed reduced acquisition of cue-specific fear-conditioned responses compared with C/C homozygotes. Also, in this larger sample the cue acquisition deficit of G-allele carriers translated into heightened contextual anxiety, even independent of 5-HTT gene variation. In contrast to our earlier findings, there was an additional interaction effect of CRHR1 rs878886 and the triallelic 5-HTTLPR/rs25531 variant on cued fear acquisition. In summary, this study replicated the initially reported association of the CRHR1 rs878886 G-allele with cued fear acquisition deficits, albeit with a different pattern of results regarding the interaction with 5-HTT variation. This further supports the notion that the human corticotropin-releasing hormone plays a role in the acquisition of fears. Potentiated-conditioned fear responses are dependent on genetic variability in CRHR1 (rs878886) across two large human samples. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.


Veldhuizen M.G.,The John B Pierce Laboratory | Veldhuizen M.G.,Yale University | Veldhuizen M.G.,Helmholtz Research Institute | Oosterhoff A.F.,The John B Pierce Laboratory | And 2 more authors.
Appetite | Year: 2010

The aim of this study was to explore the use of oral flavor stimuli in an implicit measure of attitudes; the affective priming paradigm. Unpleasant (cold instant coffee) and pleasant (strawberry lemonade) chemosensory flavor stimuli were used as primes in an affective cross-modal priming paradigm. Target stimuli were food words and non-food words, that were either affectively positive or negative, thus creating affectively congruent and incongruent prime-target pairs. We observed priming for congruent flavor-word pairs, i.e. if prime and target are both positive or both negative, this led to faster evaluation of the target words than for incongruent flavor-word pairs. Furthermore, the size of the priming effect was similar for food and non-food target words, suggesting that the affective priming effect is not augmented by the use of words that are semantically related. These results provide proof of concept of indirectly measuring attitudes to flavors with the affective priming paradigm, which may provide information on attitudes in addition to explicit pleasantness ratings. © 2009 Elsevier Ltd. All rights reserved.


Baas J.M.P.,University Utrecht | Baas J.M.P.,Helmholtz Research Institute | Heitland I.,University Utrecht | Heitland I.,Helmholtz Research Institute
International Journal of Psychophysiology | Year: 2015

In everyday life, aversive events are usually associated with certain predictive cues. Normally, the acquisition of these contingencies enables organisms to appropriately respond to threat. Presence of a threat cue clearly signals 'danger', whereas absence of such cues signals a period of 'safety'. Failure to identify threat cues may lead to chronic states of anxious apprehension in the context in which the threat has been imminent, which may be instrumental in the pathogenesis of anxiety disorders.In this study, existing data from 150 healthy volunteers in a cue and context virtual reality fear conditioning paradigm were reanalyzed. The aim was to further characterize the impact of cue acquisition and trait anxiety, and of a single nucleotide polymorphism in the serotonin 1A receptor gene (5-HTR1A, rs6295), on cued fear and contextual anxiety before and after fear contingencies were explicitly introduced. Fear conditioned responding was quantified with fear potentiation of the eyeblink startle reflex and subjective fear ratings.First, we replicated previous findings that the inability to identify danger cues during acquisition leads to heightened anxious apprehension in the threat context. Second, in subjects who did not identify the danger cue initially, contextual fear was associated with trait anxiety after the contingencies were explicitly instructed. Third, genetic variability within 5-HTR1A (rs6295) was associated with contextual fear independent of awareness or trait anxiety.These findings confirm that failure to acquire cue contingencies impacts contextual fear responding, in association with trait anxiety. The observed 5-HTR1A effect is in line with models of anxiety, but needs further replication. © 2014 Elsevier B.V.


Heitland I.,University Utrecht | Heitland I.,Helmholtz Research Institute | Groenink L.,University Utrecht | Bijlsma E.Y.,University Utrecht | And 3 more authors.
PLoS ONE | Year: 2013

The ability to identify predictors of aversive events allows organisms to appropriately respond to these events, and failure to acquire these fear contingencies can lead to maladaptive contextual anxiety. Recently, preclinical studies demonstrated that the corticotropin-releasing factor and serotonin systems are interactively involved in adaptive fear acquisition. Here, 150 healthy medication-free human subjects completed a cue and context fear conditioning procedure in a virtual reality environment. Fear potentiation of the eyeblink startle reflex (FPS) was measured to assess both uninstructed fear acquisition and instructed fear expression. All participants were genotyped for polymorphisms located within regulatory regions of the corticotropin releasing hormone receptor 1 (CRHR1 - rs878886) and the serotonin transporter (5HTTLPR). These polymorphisms have previously been linked to panic disorder and anxious symptomology and personality, respectively. G-allele carriers of CRHR1 (rs878886) showed no acquisition of fear conditioned responses (FPS) to the threat cue in the uninstructed phase, whereas fear acquisition was present in C/C homozygotes. Moreover, carrying the risk alleles of both rs878886 (G-allele) and 5HTTLPR (short allele) was associated with increased FPS to the threat context during this phase. After explicit instructions regarding the threat contingency were given, the cue FPS and context FPS normalized in all genotype groups. The present results indicate that genetic variability in the corticotropin-releasing hormone receptor 1, especially in interaction with the 5HTTLPR, is involved in the acquisition of fear in humans. This translates prior animal findings to the human realm. © 2013 Heitland et al.

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