Olfactory genes affect major depression in highly educated, emotionally stable, lean women: a bridge between animal models and precision medicine.

Most current approaches to establish subgroups of depressed patients for precision medicine aim to rely on biomarkers that require highly specialized assessment. Our present aim was to stratify participants of the UK Biobank cohort based on three readily measurable common independent risk factors, and to investigate depression genomics in each group to discover common and separate biological etiology. Two-step cluster analysis was run separately in males (n = 149,879) and females (n = 174,572), with neuroticism (a tendency to experience negative emotions), body fat percentage, and years spent in education as input variables. Genome-wide association analyses were implemented within each of the resulting clusters, for the lifetime occurrence of either a depressive episode or recurrent depressive disorder as the outcome. Variant-based, gene-based, gene set-based, and tissue-specific gene expression test were applied. Phenotypically distinct clusters with high genetic intercorrelations in depression genomics were found. A two-cluster solution was the best model in each sex with some differences including the less important role of neuroticism in males. In females, in case of a protective pattern of low neuroticism, low body fat percentage, and high level of education, depression was associated with pathways related to olfactory function. While also in females but in a risk pattern of high neuroticism, high body fat percentage, and less years spent in education, depression showed association with complement system genes. Our results, on one hand, indicate that alteration of olfactory pathways, that can be paralleled to the well-known rodent depression models of olfactory bulbectomy, might be a novel target towards precision psychiatry in females with less other risk factors for depression. On the other hand, our results in multi-risk females may provide a special case of immunometabolic depression.

Embers of the Past: Early Childhood Traumas Interact with Variation in P2RX7 Gene Implicated in Neuroinflammation on Markers of Current Suicide Risk.

Both early childhood traumatic experiences and current stress increase the risk of suicidal behaviour, in which immune activation might play a role. Previous research suggests an association between mood disorders and P2RX7 gene encoding P2X7 receptors, which stimulate neuroinflammation. We investigated the effect of P2RX7 variation in interaction with early childhood adversities and traumas and recent stressors on lifetime suicide attempts and current suicide risk markers. Overall, 1644 participants completed questionnaires assessing childhood adversities, recent negative life events, and provided information about previous suicide attempts and current suicide risk-related markers, including thoughts of ending their life, death, and hopelessness. Subjects were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into logistic and linear regression models, followed by a clumping procedure to identify clumps of SNPs with a significant main and interaction effect. We identified two significant clumps with a main effect on current suicidal ideation with top SNPs rs641940 and rs1653613. In interaction with childhood trauma, we identified a clump with top SNP psy_rs11615992 and another clump on hopelessness containing rs78473339 as index SNP. Our results suggest that P2RX7 variation may mediate the effect of early childhood adversities and traumas on later emergence of suicide risk.

Microstructural differences in migraine: A diffusion-tensor imaging study.

BACKGROUND: Diffusion-tensor imaging can be applied to describe the microstructural integrity of the whole brain. As findings about microstructural alterations in migraine are inconsistent, we aimed to replicate the most frequent results and assess a relationship between migraine parameters and changes in microstructure. METHODS: Diffusion-weighted MRI data of 37 migraine patients and 40 controls were collected. Two indices of diffusion of water molecules, fractional anisotropy and mean diffusivity were used in a voxel-wise analysis. Group comparisons were carried out in SPM12 using age and sex as covariates. Statistically significant results survived family-wise error correction (pFWE < 0.05). Migraine intensity, frequency, and duration were self-reported and correlated with mean fractional anisotropy and mean diffusivity values across clusters. RESULTS: Migraine patients showed significantly lower fractional anisotropy in occipital regions, and significantly higher fractional anisotropy in thirteen clusters across the brain. Mean diffusivity of migraine patients was significantly decreased in the cerebellum and pons, but it was not increased in any area. Correlation between migraine duration and fractional anisotropy was significantly positive in the frontal cortex and significantly negative in the superior parietal lobule. CONCLUSION: We suggest that microstructural integrity of the migraine brain is impaired in visual areas and shows duration-related alterations in regions of the default mode network.

Towards precision medicine in migraine: Recent therapeutic advances and potential biomarkers to understand heterogeneity and treatment response.

After 35 years since the introduction of the International Classification of Headache Disorders (ICHD), we are living in the era of the second great revolution in migraine therapies. First, discoveries of triptans provided a breakthrough in acute migraine treatment utilizing bench-to-bedside research results on the role of serotonin in migraine. Next, the discovery of the role of neuropeptides, more specifically calcitonin gene-related peptide (CGRP) in migraine attack led to the development of anti-CGRP therapies that are effective both in acute and preventive treatment, and are also able to reduce migraine-related burden. Here, we reviewed the most recent clinical studies and real-world data on available migraine-specific medications, including triptans, ditants, gepants and anti-CGRP monoclonal antibodies. Novel drug targets, such as PACAP and amylins were also discussed. To address the main challenges of migraine therapy, the high heterogeneity of people with migraine, the prevalent presence of various comorbid disorders, and the insufficient medical care of migraine patients were covered. Promising novel approaches from the fields of omics, blood and saliva biomarker, imaging and provocation studies might bring solutions for these challenges with the potential to identify further drug targets, distinguish more homogeneous patient subgroups, contribute to more optimal drug selection strategies, and detect biomarkers in association with headache features or predicting treatment efficacy. In the future, the combined analysis of data of different biomarker modalities with machine learning algorithms may serve precision medicine in migraine treatment.

Variation along P2RX7 interacts with early traumas on severity of anxiety suggesting a role for neuroinflammation.

Emotional stress is a leading risk factor in the development of neuropsychiatric disorders possibly via immune activation. P2X7 receptors promote neuroinflammation, and research suggests a relationship between chromosome region 12q2431, in which the P2X7R gene is located, and development of mood disorders, however, few studies concentrate on its association with anxiety. Our aim was to investigate the effects of P2RX7 variation in interaction with early childhood traumas and recent stressors on anxiety. 1752 participants completed questionnaires assessing childhood adversities and recent negative life events, provided data on anxiety using the Brief Symptom Inventory, and were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into linear regression models followed by a linkage disequilibrium-based clumping procedure to identify clumps of SNPs with a significant main or interaction effect. We identified a significant clump with top SNP rs67881993 and containing a set of 29SNPs that are in high LD, which significantly interacted with early childhood traumas but not with recent stress conveying a protective effect against increased anxiety in those exposed to early adversities. Our study demonstrated that P2RX7 variants interact with distal and more etiological stressors in influencing the severity of anxiety symptoms, supporting previous scarce results and demonstrating its role in moderating the effects of stress.

Microcystin-LR, a Cyanobacterial Toxin, Induces Changes in the Organization of Membrane Compartments in Arabidopsis.

To evaluate the effects of the cyanobacterial toxin microcystin-LR (MCY-LR, a protein phosphatase inhibitor) and diquat (DQ, an oxidative stress inducer) on the organization of tonoplast, the effect of MCY-LR on plastid stromule formation and on mitochondria was investigated in wild-type Arabidopsis. Tonoplast was also studied in PP2A catalytic (c3c4) and regulatory subunit mutants (fass-5 and fass-15). These novel studies were performed by CLSM microscopy. MCY-LR is produced during cyanobacterial blooms. The organization of tonoplast of PP2A mutants of Arabidopsis is much more sensitive to MCY-LR and DQ treatments than that of wild type. In c3c4, fass-5 and fass-15, control and treated plants showed increased vacuole fragmentation that was the strongest when the fass-5 mutant was treated with MCY-LR. It is assumed that both PP2A/C and B" subunits play an important role in normal formation and function of the tonoplast. In wild-type plants, MCY-LR affects mitochondria. Under the influence of MCY-LR, small, round-shaped mitochondria appeared, while long/fused mitochondria were typical in control plants. Presumably, MCY-LR either inhibits the fusion of mitochondria or induces fission. Consequently, PP2A also plays an important role in the fusion of mitochondria. MCY-LR also increased the frequency of stromules appearing on chloroplasts after 1 h treatments. Along the stromules, signals can be transported between plastids and endoplasmic reticulum. It is probable that they promote a faster response to stress.

Genetic risk of depression is different in subgroups of dietary ratio of tryptophan to large neutral amino acids.

Manipulation of intake of serotonin precursor tryptophan has been exploited to rapidly induce and alleviate depression symptoms. While studies show that this latter effect is dependent on genetic vulnerability to depression, the effect of habitual tryptophan intake in the context of predisposing genetic factors has not been explored. Our aim was to investigate the effect of habitual tryptophan intake on mood symptoms and to determine the effect of risk variants on depression in those with high and low tryptophan intake in the whole genome and specifically in serotonin and kynurenine pathways. 63,277 individuals in the UK Biobank with data on depressive symptoms and tryptophan intake were included. We compared two subpopulations defined by their habitual diet of a low versus a high ratio of tryptophan to other large amino acids (TLR). A modest protective effect of high dietary TLR against depression was found. NPBWR1 among serotonin genes and POLI in kynurenine pathway genes were significantly associated with depression in the low but not in the high TLR group. Pathway-level analyses identified significant associations for both serotonin and kynurenine pathways only in the low TLR group. In addition, significant association was found in the low TLR group between depressive symptoms and biological process related to adult neurogenesis. Our findings demonstrate a markedly distinct genetic risk profile for depression in groups with low and high dietary TLR, with association with serotonin and kynurenine pathway variants only in case of habitual food intake leading to low TLR. Our results confirm the relevance of the serotonin hypothesis in understanding the neurobiological background of depression and highlight the importance of understanding its differential role in the context of environmental variables such as complexity of diet in influencing mental health, pointing towards emerging possibilities of personalised prevention and intervention in mood disorders in those who are genetically vulnerable.

B" and C subunits of PP2A regulate the levels of reactive oxygen species and superoxide dismutase activities in Arabidopsis.

The serine-threonine protein phosphatases PP2A regulate many cellular processes, however their role in oxidative stress responses and defence is less known. We show the involvement of its C (catalytic) and B" (a regulatory) subunits. The c3c4 (C subunit) and fass (B") subunit mutants and Col wt of Arabidopsis were used. Controls and treatments with the PP2A inhibitor microcystin-LR (MCY-LR) and reactive oxygen species (ROS) inducer diquat (DQ) were employed. ROS levels of primary roots were largely genotype dependent and both C and B" subunit mutants had increased sensitivity to MCY-LR and DQ indicating the involvement of these subunits in oxidative stress induction. Superoxide dismutases (SOD), mainly the Cu/Zn-SOD isoform, as key enzymes involved in ROS scavenging are also showing altered (mostly increased) activities in both c3c4 and fass mutants and have opposite relations to ROS induction. This indicates that the two types of subunits involved have partially different regulatory roles. In relation to this, control and MCY-LR/DQ treated B" subunit mutants were proven to have altered levels of phosphorylation of histone H2AX. γH2AX, the phosphorylated form indicates double stranded DNA damage during oxidative stress. Overall we point out the probable pivotal role of several PP2A subunits in the regulation of oxidative stress responses in plants and pave the way for future research to reveal the signaling pathways involved.

Inflammation and Blood-Brain Barrier in Depression: Interaction of CLDN5 and IL6 Gene Variants in Stress-Induced Depression.

BACKGROUND: Evidence from rodents indicated that after recent stress, reduced expression of tight junction protein claudin-5 may weaken the blood-brain barrier and allow interleukin-6 to induce depressive symptoms. Our aims were to prove this pathomechanism in humans. METHODS: We used a large population genetic database (UK Biobank, n = 277 501) to test whether variation in the CLDN5 gene could modulate effects of the IL6 gene variant in stress-induced depression. Three-way interaction of functional polymorphisms, rs885985 of CLDN5, and rs1800795 of IL6 with recent stressful life events were tested on current depressive symptoms. Analyses were performed in male and female populations as well. RESULTS: The 3-way interaction including recent stress yielded highly significant results on current depressive symptoms in the UK Biobank sample, which was more pronounced in men and could be replicated on trend level in an independent cohort (NewMood, n = 1638). None of any other associations or interactions, including, for example, childhood stressors and lifetime depression as an outcome, yielded significance. CONCLUSIONS: These findings provide genetic evidence in humans for the interaction among interleukin-6, claudin-5, and recent stress, suggesting that inflammation is involved in the development of depression and that stress-connected brain entry of inflammatory molecules is a key factor in this pathomechanism. These genetic polymorphisms may help to identify people at higher risk for recent stress-induced depression.

A sound mind in a sound body: a novel concept unravelling heterogeneity of depression.

Depression is a highly prevalent and debilitating condition, yet we still lack both in-depth knowledge concerning its etiopathology and sufficiently efficacious treatment options. With approximately one third of patients resistant to currently available antidepressants there is a pressing need for a better understanding of depression, identifying subgroups within the highly heterogeneous illness category and to understand the divergent underlying biology of such subtypes, to help develop and personalise treatments. The TRAJECTOME project aims to address such challenges by (1) identifying depression-related multimorbidity subgroups and shared molecular pathways based on temporal disease profiles from healthcare systems and biobank data using machine learning approaches, and by (2) characterising these subgroups from multiple aspects including genetic variants, metabolic processes, lifestyle and environmental factors. Following the identification of multimorbidity trajectories, a disease burden score related to depression and adjusted for multimorbidity was established summarising the current state of the patient to weigh the molecular mechanisms associated with depression. In addition, the role of genetic and environmental factors, and also their interactions were identified for all subgroups. The project also attempted to identify potential metabolomic markers for the early diagnostics of these multimorbidity conditions. Finally, we prioritized molecular drug candidates matching the multimorbidity pathways indicated for the individual subgroups which would potentially offer personalised treatment simultaneously for the observable multimorbid conditions yet minimising polypharmacy and related side effects. The present paper overviews the TRAJECTOME project including its aims, tasks, procedures and accomplishments. (Neuropsychopharmacol Hung 2023; 25(4): 183-193)

The neural correlates of context driven changes in the emotional response: An fMRI study.

Emotional flexibility reflects the ability to adjust the emotional response to the changing environmental context. To understand how context can trigger a change in emotional response, i.e., how it can upregulate the initial emotional response or trigger a shift in the valence of emotional response, we used a task consisting of picture pairs during functional magnetic resonance imaging sessions. In each pair, the first picture was a smaller detail (a decontextualized photograph depicting emotions using primarily facial and postural expressions) from the second (contextualized) picture, and the neural response to a decontextualized picture was compared with the same picture in a context. Thirty-one healthy participants (18 females; mean age: 24.44 ± 3.4) were involved in the study. In general, context (vs. pictures without context) increased activation in areas involved in facial emotional processing (e.g., middle temporal gyrus, fusiform gyrus, and temporal pole) and affective mentalizing (e.g., precuneus, temporoparietal junction). After excluding the general effect of context by using an exclusive mask with activation to context vs. no-context, the automatic shift from positive to negative valence induced by the context was associated with increased activation in the thalamus, caudate, medial frontal gyrus and lateral orbitofrontal cortex. When the meaning changed from negative to positive, it resulted in a less widespread activation pattern, mainly in the precuneus, middle temporal gyrus, and occipital lobe. Providing context cues to facial information recruited brain areas that induced changes in the emotional responses and interpretation of the emotional situations automatically to support emotional flexibility.

A cross-sectional study on the quality of life in migraine and medication overuse headache in a Hungarian sample: understanding the effect of headache characteristics.

Background and purpose: Previous studies using generic and disease specific instruments showed that both migraine and medication overuse headache are associated with lower health-related quality of life (HRQoL). The aim of our study was to assess HRQoL differences in migraineurs and in patients with MOH and to examine how headache characteristics such as years with headache, aura symptoms, triptan use, headache pain severity and headache frequency are related to HRQoL. Methods: In this cross-sectional study 334 participants were examined (248 were recruited from a tertiary headache centre and 86 via advertisements). The Comp-rehensive Headache-related Quality of life Questionnaire (CHQQ) was used to measure the participants' HRQoL. Data showed normal distribution, therefore beside Chi-squared test parametric tests (e.g. independent samples t-test) were used with a two-tailed p<0.05 threshold. Linear regression models were used to determine the independent effects of sex, age, recruitment method, headache type (migraine vs. MOH) and headache characteristics (presence of aura symptoms, years with headache, headache pain severity, headache frequency and triptan use) separately for each domain and for the total score of CHQQ. Significance threshold was adopted to p0.0125 (0.05/4) to correct for multiple testing and avoid Type I error. Results: Independent samples t-tests showed that patients with MOH had significantly lower scores on all CHQQ domains than migraineurs, except on the social subscale. Results of a series of regression analyses showed that triptan use was inversely related to all the domains of HRQoL after correction for multiple testing (p<0.0125). In addition, headache pain severity was associated with lower physical (p=0.001) and total scores (p=0.002) on CHQQ subscales. Conclusion: Based on the results, different headache characteristics (but not the headache type, namely migraine or MOH) were associated with lower levels of HRQoL in patients with headache. Determining which factors play significant role in the deterioration of HRQoL is important to adequately manage different patient populations and to guide public health policies regarding health service utilization and health-care costs.

Citalopram Neuroendocrine Challenge Shows Altered Tryptophan and Kynurenine Metabolism in Migraine.

Altered tryptophan (TRP) metabolism may have an important role in migraine susceptibility through its main metabolites, serotonin and kynurenine (KYN). Both affect pain processing and stress response by interfering with neural and brain hypersensitivity and by interacting with chemokines and cytokines that control vascular and inflammatory processes. The involvement of these pathways in migraine has been widely studied, but acute citalopram neuroendocrine challenge on TRP metabolism and cytokine profile has not been investigated yet. In our study, females with episodic migraine without aura and healthy controls were studied before and after acute citalopram or placebo in a double-blind setting. At baseline, increased TRP/large neutral amino acid (LNAA) ratio and decreased RANTES chemokine concentration were detected in migraine patients compared to controls. The challenge induced a significant increase in TRP, KYN, and TRP/LNAA in healthy controls, but not in migraine patients. Furthermore, migraine attack frequency negatively correlated with KYN/TRP ratio and positively correlated with the neuroendocrine-challenge-induced KYN concentration increase. Our results support a decreased breakdown of TRP via KYN pathway and a failure to modulate TRP-KYN pathway during citalopram-induced acute stress together with an increased vascular sensitivity in migraine. These mechanisms may provide useful drug targets for future drug development.

Towards personalised antidepressive medicine based on "big data": an up-to-date review on robust factors affecting treatment response.

Prescribing antidepressant medication is currently the most effective way of treating major depression, but only very few patients achieve permanent improvement. Therefore, it is important to identify objectively measurable markers for effective, personalized therapy. The aim of this review article is to collect all the markers that are robustly predictive of the outcome of therapy. We searched for systematic review articles that have simultaneously investigated the effects of as many different markers as possible on the response to antidepressant therapy in major depressive patients. From these we extracted markers that have been found to be significant by at least two independent review studies and that have proven replicable also within each of these reviews. A separate search was performed for meta-analyses of pharmacogenetic genome-wide association studies. Based on our results, onset time, symptom severity, presence of anhedonia, early treatment response, comorbid anxiety, alcohol consumption, frontal EEG theta activity, hippocampal volume, activity of anterior cingulate cortex, as well as a peripheral marker, serum BDNF levels have proven replicable predictors of antidepressant response. Pharmacogenomic studies to date have not yielded replicable results. Predictors identified as robust by our study may provide a starting point for future machine learning models within a 'big data' database of major depressive patients. (Neuropsychopharmacol Hung 2022; 24(1): 17-28).

Circadian Variation of Migraine Attack Onset Affects fMRI Brain Response to Fearful Faces.

Background: Previous studies suggested a circadian variation of migraine attack onset, although, with contradictory results - possibly because of the existence of migraine subgroups with different circadian attack onset peaks. Migraine is primarily a brain disorder, and if the diversity in daily distribution of migraine attack onset reflects an important aspect of migraine, it may also associate with interictal brain activity. Our goal was to assess brain activity differences in episodic migraine subgroups who were classified according to their typical circadian peak of attack onset. Methods: Two fMRI studies were conducted with migraine without aura patients (n = 31 in Study 1, n = 48 in Study 2). Among them, three subgroups emerged with typical Morning, Evening, and Varying start of attack onset. Whole brain activity was compared between the groups in an implicit emotional processing fMRI task, comparing fearful, sad, and happy facial stimuli to neutral ones. Results: In both studies, significantly increased neural activation was detected to fearful (but not sad or happy) faces. In Study 1, the Evening start group showed increased activation compared to the Morning start group in regions involved in emotional, self-referential (left posterior cingulate gyrus, right precuneus), pain (including left middle cingulate, left postcentral, left supramarginal gyri, right Rolandic operculum) and sensory (including bilateral superior temporal gyrus, right Heschl's gyrus) processing. While in Study 2, the Morning start group showed increased activation compared to the Varying start group at a nominally significant level in regions with pain (right precentral gyrus, right supplementary motor area) and sensory processing (bilateral paracentral lobule) functions. Conclusion: Our fMRI studies suggest that different circadian attack onset peaks are associated with interictal brain activity differences indicating heterogeneity within migraine patients and alterations in sensitivity to threatening fearful stimuli. Circadian variation of migraine attack onset may be an important characteristic to address in future studies and migraine prophylaxis.

Association of plasma tryptophan concentration with periaqueductal gray matter functional connectivity in migraine patients.

Altered periaqueductal gray matter (PAG) functional connectivity contributes to brain hyperexcitability in migraine. Although tryptophan modulates neurotransmission in PAG projections through its metabolic pathways, the effect of plasma tryptophan on PAG functional connectivity (PAG-FC) in migraine has not been investigated yet. In this study, using a matched case-control design PAG-FC was measured during a resting-state functional magnetic resonance imaging session in migraine without aura patients (n = 27) and healthy controls (n = 27), and its relationship with plasma tryptophan concentration (TRP) was assessed. In addition, correlations of PAG-FC with age at migraine onset, migraine frequency, trait-anxiety and depressive symptoms were tested and the effect of TRP on these correlations was explored. Our results demonstrated that migraineurs had higher TRP compared to controls. In addition, altered PAG-FC in regions responsible for fear-cascade and pain modulation correlated with TRP only in migraineurs. There was no significant correlation in controls. It suggests increased sensitivity to TRP in migraine patients compared to controls. Trait-anxiety and depressive symptoms correlated with PAG-FC in migraine patients, and these correlations were modulated by TRP in regions responsible for emotional aspects of pain processing, but TRP did not interfere with processes that contribute to migraine attack generation or attack frequency.

Genetic effects on educational attainment in Hungary.

INTRODUCTION: Educational attainment is a substantially heritable trait, and it has recently been linked to specific genetic variants by genome-wide association studies (GWASs). However, the effects of such genetic variants are expected to vary across environments, including countries and historical eras. METHODS: We used polygenic scores (PGSs) to assess molecular genetic effects on educational attainment in Hungary, a country in the Central Eastern European region where behavioral genetic studies are in general scarce and molecular genetic studies of educational attainment have not been previously published. RESULTS: We found that the PGS is significantly associated with the attainment of a college degree as well as the number of years in education in a sample of Hungarian study participants (N = 829). PGS effect sizes were not significantly different when compared to an English (N = 976) comparison sample with identical measurement protocols. In line with previous Estonian findings, we found higher PGS effect sizes in Hungarian, but not in English participants who attended higher education after the fall of Communism, although we lacked statistical power for this effect to reach significance. DISCUSSION: Our results provide evidence that polygenic scores for educational attainment have predictive value in culturally diverse European populations.

Biology of Perseverative Negative Thinking: The Role of Timing and Folate Intake.

Past-oriented rumination and future-oriented worry are two aspects of perseverative negative thinking related to the neuroticism endophenotype and associated with depression and anxiety. Our present aim was to investigate the genomic background of these two aspects of perseverative negative thinking within separate groups of individuals with suboptimal versus optimal folate intake. We conducted a genome-wide association study in the UK Biobank database (n = 72,621) on the "rumination" and "worry" items of the Eysenck Personality Inventory Neuroticism scale in these separate groups. Optimal folate intake was related to lower worry, but unrelated to rumination. In contrast, genetic associations for worry did not implicate specific biological processes, while past-oriented rumination had a more specific genetic background, emphasizing its endophenotypic nature. Furthermore, biological pathways leading to rumination appeared to differ according to folate intake: purinergic signaling and circadian regulator gene ARNTL emerged in the whole sample, blastocyst development, DNA replication, and C-C chemokines in the suboptimal folate group, and prostaglandin response and K+ channel subunit gene KCNH3 in the optimal folate group. Our results point to possible benefits of folate in anxiety disorders, and to the importance of simultaneously taking into account genetic and environmental factors to determine personalized intervention in polygenic and multifactorial disorders.

Inter-individual differences in pain anticipation and pain perception in migraine: Neural correlates of migraine frequency and cortisol-to-dehydroepiandrosterone sulfate (DHEA-S) ratio.

Previous studies targeting inter-individual differences in pain processing in migraine mainly focused on the perception of pain. Our main aim was to disentangle pain anticipation and perception using a classical fear conditioning task, and investigate how migraine frequency and pre-scan cortisol-to-dehydroepiandrosterone sulfate (DHEA-S) ratio as an index of neurobiological stress response would relate to neural activation in these two phases. Functional Magnetic Resonance Imaging (fMRI) data of 23 participants (18 females; mean age: 27.61± 5.36) with episodic migraine without aura were analysed. We found that migraine frequency was significantly associated with pain anticipation in brain regions comprising the midcingulate and caudate, whereas pre-scan cortisol-to DHEA-S ratio was related to pain perception in the pre-supplementary motor area (pre-SMA). Both results suggest exaggerated preparatory responses to pain or more general to stressors, which may contribute to the allostatic load caused by stressors and migraine attacks on the brain.

A replication study separates polymorphisms behind migraine with and without depression.

The largest migraine genome-wide association study identified 38 candidate loci. In this study we assessed whether these results replicate on a gene level in our European cohort and whether effects are altered by lifetime depression. We tested SNPs of the loci and their vicinity with or without interaction with depression in regression models. Advanced analysis methods such as Bayesian relevance analysis and a neural network based classifier were used to confirm findings. Main effects were found for rs2455107 of PRDM16 (OR = 1.304, p = 0.007) and five intergenic polymorphisms in 1p31.1 region: two of them showed risk effect (OR = 1.277, p = 0.003 for both rs11209657 and rs6686879), while the other three variants were protective factors (OR = 0.4956, p = 0.006 for both rs12090642 and rs72948266; OR = 0.4756, p = 0.005 for rs77864828). Additionally, 26 polymorphisms within ADGRL2, 2 in REST, 1 in HPSE2 and 33 mostly intergenic SNPs from 1p31.1 showed interaction effects. Among clumped results representing these significant regions, only rs11163394 of ADGRL2 showed a protective effect (OR = 0.607, p = 0.002), all other variants were risk factors (rs1043215 of REST with the strongest effect: OR = 6.596, p = 0.003). Bayesian relevance analysis confirmed the relevance of intergenic rs6660757 and rs12128399 (p31.1), rs1043215 (REST), rs1889974 (HPSE2) and rs11163394 (ADGRL2) from depression interaction results, and the moderate relevance of rs77864828 and rs2455107 of PRDM16 from main effect analysis. Both main and interaction effect SNPs could enhance predictive power with the neural network based classifier. In summary, we replicated p31.1, PRDM16, REST, HPSE2 and ADGRL2 genes with classic genetic and advanced analysis methods. While the p31.1 region and PRDM16 are worthy of further investigations in migraine in general, REST, HPSE2 and ADGRL2 may be prime candidates behind migraine pathophysiology in patients with comorbid depression.