A farmakológiai funkcionális mágneses rezonancia vizsgálat (phMRI) felhasználásának lehetőségei a hangulatzavarok kutatásában | Application of pharmaco functional magnetic resonance imaging (phMRI) in the research of affective disorders

Napjaink leggyakoribb pszichiátriai betegségei, a depresszió és a szorongásos zavarok, feltehetőleg a központi idegrendszer monoamin neurotranszmissziójának elégtelenségével kapcsolatosak. Ugyanakkor ezeknek a patofiziológiai folyamatoknak a vizsgálata az élő emberi agyban komoly kihívást jelent. A funkcionális mágneses rezonancia képalkotás (fMRI) olyan noninvazív módszer, ami lehetőséget nyújt az agyi aktivitás vizsgálatára. Legtöbb esetben az aktivitást előidéző stimulus kognitív pszichológiai feladat, azonban lehetőség nyílik arra, hogy farmakológiai funkcionális mágneses rezonancia (phMRI) vizsgálat során egy specifikus farmakon indukálta aktivitásváltozást vizsgáljunk. Jelen munkánk célja az ezzel a módszerrel végzett eredmények összefoglalása, melyet a PubMed adatai alapján készítettünk el. A challenge phMRI vizsgálatok során egy szelektív farmakon, például a szelektív szerotonin visszavétel gátló (SSRI) citalopram és escitalopram alkalmazásával a szerotonerg neurotranszmisszió és a gyógyszerhatásban résztvevő agyi területek aktivitásváltozása vizsgálható. Modulation phMRI segítségével megfigyelhetjük, milyen akut hatással van az adott farmakon alkalmazása az olyan kognitív pszichés funkciókra, mint az érzelemfeldolgozás, és hogyan változnak meg ezek a funkciók hosszabb távú gyógyszeralkalmazást követően. A phMRI különböző módszerei ezért komoly segítséget nyújthatnak abban, hogy az emberi agy szerotonerg transzmissziójának szerepét és az ezzel összefüggő pszichés betegségek patomechanizmusát jobban megérthessük | Many common psychiatric disorders such as depression and anxiety disorders are associated with dysfunction in the monoamine neurotransmission in the central nervous system. However, the investigation of these pathophysiological processes in the human living brain is difficult. In case of functional magnetic resonance imaging (fMRI), a non-invasive method for the examination of brain activity, the activity-inducing stimulus is generally a cognitive psychological test, while during pharmacological magnetic resonance imaging (phMRI) the activation is triggered by a specific pharmacon. In the present work we review the available scientific literature related to this method using literature search in PubMed. Through application of a selective pharmacon like the selective serotonine reuptake inhibitors (SSRIs) citalopram or escitalopram in a challenge phMRI study, the serotonergic neurotransmitter system can be examined specifically, the functioning brain areas involved in its effect become observable.. With modulation phMRI we can monitor the long-term effect of an antidepressant or we can examine the immediate effect of a single dose of the medication on congitive psychological functions like emotional processing. Thus, the application of phMRI methods may help deepen our understanding of serotonergic function in the living human brain as well as of diseases related to serotonergic neurotransmitter system dysfunction

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

One of the main effects of the endocannabinoid system in the brain is stress adaptation with presynaptic endocannabinoid receptor 1 (CB1 receptors) playing a major role. In the present study, we investigated whether the effect of the CB1 receptor coding CNR1 gene on migraine and its symptoms is conditional on life stress. In a cross-sectional European population (n = 2426), recruited from Manchester and Budapest, we used the ID-Migraine questionnaire for migraine screening, the Life Threatening Experiences questionnaire to measure recent negative life events (RLE), and covered the CNR1 gene with 11 SNPs. The main genetic effects and the CNR1 × RLE interaction with age and sex as covariates were tested. None of the SNPs showed main genetic effects on possible migraine or its symptoms, but 5 SNPs showed nominally significant interaction with RLE on headache with nausea using logistic regression models. The effect of rs806366 remained significant after correction for multiple testing and replicated in the subpopulations. This effect was independent from depression- and anxiety-related phenotypes. In addition, a Bayesian systems-based analysis demonstrated that in the development of headache with nausea all SNPs were more relevant with higher a posteriori probability in those who experienced recent life stress. In summary, the CNR1 gene in interaction with life stress increased the risk of headache with nausea suggesting a specific pathological mechanism to develop migraine, and indicating that a subgroup of migraine patients, who suffer from life stress triggered migraine with frequent nausea, may benefit from therapies that increase the endocannabinoid tone

Association between migraine frequency and neural response to emotional faces: An fMRI study

Previous studies have demonstrated that migraine is associated with enhanced perception and altered cerebralprocessing of sensory stimuli. More recently, it has been suggested that this sensory hypersensitivity mightreflect a more general enhanced response to aversive emotional stimuli. Using functional magnetic resonanceimaging and emotional face stimuli (fearful, happy and sad faces), we compared whole-brain activation between41 migraine patients without aura in interictal period and 49 healthy controls. Migraine patients showed in-creased neural activation to fearful faces compared to neutral faces in the right middle frontal gyrus and frontalpole relative to healthy controls. We also found that higher attack frequency in migraine patients was related toincreased activation mainly in the right primary somatosensory cortex (corresponding to the face area) to fearfulexpressions and in the right dorsal striatal regions to happy faces. In both analyses, activation differences re-mained significant after controlling for anxiety and depressive symptoms. Thesefindings indicate that enhancedresponse to emotional stimuli might explain the migraine trigger effect of psychosocial stressors that graduallyleads to increased somatosensory response to emotional clues and thus contributes to the progression orchronification of migrain

Variability in the Effect of 5-HTTLPR on Depression in a Large European Population: The Role of Age, Symptom Profile, Type and Intensity of Life Stressors.

BACKGROUND: Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity. METHODS: In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models. RESULTS: The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (</=30) individuals. LIMITATIONS: Our study is cross-sectional and applies self-report questionnaires. CONCLUSIONS: Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups

Increased activation of the pregenual anterior cingulate cortex to citalopram challenge in migraine: an fMRI study

Background: The anterior cingulate cortex (ACC) is a key structure of the pain processing network. Several structural and functional alterations of this brain area have been found in migraine. In addition, altered serotonergic neurotransmission has been repeatedly implicated in the pathophysiology of migraine, although the exact mechanism is not known. Thus, our aim was to investigate the relationship between acute increase of brain serotonin (5-HT) level and the activation changes of the ACC using pharmacological challenge MRI (phMRI) in migraine patients and healthy controls. Methods: Twenty-seven pain-free healthy controls and six migraine without aura patients participated in the study. All participant attended to two phMRI sessions during which intravenous citalopram, a selective serotonin reuptake inhibitor (SSRI), or placebo (normal saline) was administered. We used region of interest analysis of ACC to compere the citalopram evoked activation changes of this area between patients and healthy participants. Results: Significant difference in ACC activation was found between control and patient groups in the right pregenual ACC (pgACC) during and after citalopram infusion compared to placebo. The extracted time-series showed that pgACC activation increased in migraine patients compared to controls, especially in the first 8–10 min of citalopram infusion. Conclusions: Our results demonstrate that a small increase in 5-HT levels can lead to increased phMRI signal in the pregenual part of the ACC that is involved in processing emotional aspects of pain. This increased sensitivity of the pgACC to increased 5-HT in migraine may contribute to recurring headache attacks and increased stress-sensitivity in migraine

Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness

Neuropeptides are auxiliary messenger molecules that always co-exist in nerve cells with one or more small molecule (classic) neurotransmitters. Neuropeptides act both as transmitters and trophic factors, and play a role particularly when the nervous system is challenged, as by injury, pain or stress. Here neuropeptides and coexistence in mammals are reviewed, but with special focus on the 29/30 amino acid galanin and its three receptors GalR1, -R2 and -R3. In particular, galanin's role as a co-transmitter in both rodent and human noradrenergic locus coeruleus (LC) neurons is addressed. Extensive experimental animal data strongly suggest a role for the galanin system in depression-like behavior. The translational potential of these results was tested by studying the galanin system in postmortem human brains, first in normal brains, and then in a comparison of five regions of brains obtained from depressed people who committed suicide, and from matched controls. The distribution of galanin and the four galanin system transcripts in the normal human brain was determined, and selective and parallel changes in levels of transcripts and DNA methylation for galanin and its three receptors were assessed in depressed patients who committed suicide: upregulation of transcripts, e.g., for galanin and GalR3 in LC, paralleled by a decrease in DNA methylation, suggesting involvement of epigenetic mechanisms. It is hypothesized that, when exposed to severe stress, the noradrenergic LC neurons fire in bursts and release galanin from their soma/dendrites. Galanin then acts on somato-dendritic, inhibitory galanin autoreceptors, opening potassium channels and inhibiting firing. The purpose of these autoreceptors is to act as a 'brake' to prevent overexcitation, a brake that is also part of resilience to stress that protects against depression. Depression then arises when the inhibition is too strong and long lasting - a maladaption, allostatic load, leading to depletion of NA levels in the forebrain. It is suggested that disinhibition by a galanin antagonist may have antidepressant activity by restoring forebrain NA levels. A role of galanin in depression is also supported by a recent candidate gene study, showing that variants in genes for galanin and its three receptors confer increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events. In summary, galanin, a neuropeptide coexisting in LC neurons, may participate in the mechanism underlying resilience against a serious and common disorder, MDD. Existing and further results may lead to an increased understanding of how this illness develops, which in turn could provide a basis for its treatment