The relationship between negative symptoms and depression in schizophrenia: a systematic review.

OBJECTIVE: To provide an update on the evidence base for the nature of the relationship between negative symptoms and depressive features in people with schizophrenia, and propose new models that reflect their complex relationship. METHOD: A systematic review following PRISMA guidelines. A total of 2210 articles were identified from EMBASE, PsychInfo and MEDLINE, and further two articles were hand-searched from references. Twenty-seven met inclusion criteria and were included in the review. RESULTS: In schizophrenia, primary evidence suggests symptoms of low mood, suicidal ideation and pessimism have more specificity for depression whereas alogia and blunted affect may have more specificity as negative symptoms. Anhedonia, anergia and avolition may be common to both. CONCLUSION: It may be possible to further distinguish depressive features from negative symptoms in schizophrenia when detailed phenomenology is considered. However, in a proposed dimensional model, these two domains continue to share certain phenomena, highlighting their close relationship.

A novel resting-state functional magnetic resonance imaging signature of resilience to recurrent depression.

BACKGROUND: A high proportion of patients with remitted major depressive disorder (MDD) will experience recurring episodes, whilst some develop resilience and remain in recovery. The neural basis of resilience to recurrence is elusive. Abnormal resting-state connectivity of the subgenual cingulate cortex (sgACC) was previously found in cross-sectional studies of MDD, suggesting its potential pathophysiological importance. The current study aimed to investigate whether resting-state connectivity to a left sgACC seed region distinguishes resilient patients from those developing recurring episodes. METHOD: A total of 47 medication-free remitted MDD patients and 38 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) at baseline. Over 14 months, 30 patients remained resilient whilst 17 experienced a recurring episode. RESULTS: Attenuated interhemispheric left-to-right sgACC connectivity distinguished the resilient from the recurring-episode and control groups and was not correlated with residual depressive symptoms. CONCLUSIONS: The current study revealed a neural signature of resilience to recurrence in MDD and thereby elucidates the role of compensatory adaptation in sgACC networks.

Social-economical decision making in current and remitted major depression.

BACKGROUND: Prosocial emotions related to self-blame are important in guiding human altruistic decisions. These emotions are elevated in major depressive disorder (MDD), such that MDD has been associated with guilt-driven pathological hyper-altruism. However, the impact of such emotional impairments in MDD on different types of social decision-making is unknown. METHOD: In order to address this issue, we investigated different kinds of altruistic behaviour (interpersonal cooperation and fund allocation, altruistic punishment and charitable donation) in 33 healthy subjects, 35 patients in full remission (unmedicated) and 24 currently depressed patients (11 on medication) using behavioural-economical paradigms. RESULTS: We show a significant main effect of clinical status on altruistic decisions (p = 0.04) and a significant interaction between clinical status and type of altruistic decisions (p = 0.03). More specifically, symptomatic patients defected significantly more in the Prisoner's Dilemma game (p < 0.05) and made significantly lower charitable donations, whether or not these incurred a personal cost (p < 0.05 and p < 0.01, respectively). Currently depressed patients also reported significantly higher guilt elicited by receiving unfair financial offers in the Ultimatum Game (p < 0.05). CONCLUSIONS: Currently depressed individuals were less altruistic in both a charitable donation and an interpersonal cooperation task. Taken together, our results challenge the guilt-driven pathological hyper-altruism hypothesis in depression. There were also differences in both current and remitted patients in the relationship between altruistic behaviour and pathological self-blaming, suggesting an important role for these emotions in moral and social decision-making abnormalities in depression.

Temporal discounting in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is associated with abnormalities in financial reward processing. Previous research suggests that patients with MDD show reduced sensitivity to frequency of financial rewards. However, there is a lack of conclusive evidence from studies investigating the evaluation of financial rewards over time, an important aspect of reward processing that influences the way people plan long-term investments. Beck's cognitive model posits that patients with MDD hold a negative view of the future that may influence the amount of resources patients are willing to invest into their future selves. METHOD: We administered a delay discounting task to 82 participants: 29 healthy controls, 29 unmedicated participants with fully remitted MDD (rMDD) and 24 participants with current MDD (11 on medication). RESULTS: Patients with current MDD, relative to remitted patients and healthy subjects, discounted large-sized future rewards at a significantly higher rate and were insensitive to changes in reward size from medium to large. There was a main effect of clinical group on discounting rates for large-sized rewards, and discounting rates for large-sized rewards correlated with severity of depressive symptoms, particularly hopelessness. CONCLUSIONS: Higher discounting of delayed rewards in MDD seems to be state dependent and may be a reflection of depressive symptoms, specifically hopelessness. Discounting distant rewards at a higher rate means that patients are more likely to choose immediate financial options. Such impairments related to long-term investment planning may be important for understanding value-based decision making in MDD, and contribute to ongoing functional impairment.

State-dependent changes in hippocampal grey matter in depression.

Reduced hippocampal volume has been reported in depression and may be involved in the aetiology of depressive symptoms and vulnerability to depressive relapse. Neuroplasticity following antidepressant drug treatment in the hippocampus has been demonstrated in animal models but adaptive changes after such treatment have not been shown in humans. In this study, we determined whether grey matter loss in the hippocampus in depression (1) is present in medication-free depressed (2) changes in response to antidepressant treatment and (3) is present as a stable trait in medication-free remitted patients. Sixty-four medication-free unipolar depressed patients: 39 currently depressed and 25 in remission, and 66 healthy controls (HC) underwent structural magnetic resonance imaging in a cross-sectional and longitudinal design. Thirty-two currently depressed participants were then treated with the antidepressant citalopram for 8 weeks. Adherence to treatment was evaluated by measuring plasma citalopram concentration. We measured regional variation in grey matter concentration by using voxel-based morphometry-Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra. Patients with current depression had bilaterally reduced grey matter in the hippocampus compared with HC and untreated patients in stable remission with the latter groups not differing. An increase in grey matter was observed in the hippocampus following treatment with citalopram in currently depressed patients. Grey matter reduction in the hippocampus appears specific to the depressed state and is a potential biomarker for a depressive episode.

Core dysfunction in schizophrenia: electrophysiology trait biomarkers.

OBJECTIVE: Core symptoms of schizophrenia, particularly in the cognitive domain are hypothesized to be due to an abnormality in neural connectivity. Biomarkers of connectivity may therefore be a promising tool in exploring the aetiology of schizophrenia. We used electrophysiological methods to demonstrate abnormal visual information processing during in patients performing a simple cognitive task. METHOD: Electrophysiological recordings were acquired from 20 chronically ill, medicated patients diagnosed with either schizophrenia or schizo-affective disorder and 20 healthy volunteers while they conducted a working memory (WM) task. RESULTS: The patient group had significantly lower accuracy on the WM task and a trend for slower responses. An early visual evoked response potential was reduced in patients. Analysis of the electroencephalographic oscillations showed a decreased phase-locking factor (in the theta, beta and gamma bands) and signal power (theta frequency band). The beta and gamma oscillatory abnormalities were confined to two sets of correlated fronto and occipital electrodes. CONCLUSION: The findings of event-related potential and oscillatory abnormalities in patients with schizophrenia confirm the sensitivity of early visual information processing measurements for identification of schizophrenia phenotype. The fronto-occipital distribution of the oscillatory abnormalities replicates our findings from a schizotypal sample and implicates a possible top-down dysfunction as a vulnerability trait.

Attenuated responses to emotional expressions in women with generalized anxiety disorder.

BACKGROUND: Generalized anxiety disorder (GAD) is under-researched despite its high prevalence and large impact on the healthcare system. There is a paucity of functional magnetic resonance imaging (fMRI) studies that explore the neural correlates of emotional processing in GAD. The present study investigated the blood oxygen level dependent (BOLD) response to processing positive and negative facial emotions in patients with GAD. METHOD: A total of 15 female GAD patients and 16 female controls undertook an implicit face emotion task during fMRI scanning. They also performed a face emotion recognition task outside the scanner. RESULTS: The only behavioural difference observed in GAD patients was less accurate detection of sad facial expressions compared with control participants. However, GAD patients showed an attenuated BOLD signal in the prefrontal cortex to fearful, sad, angry and happy facial expressions and an attenuated signal in the anterior cingulate cortex to happy and fearful facial expressions. No differences were found in amygdala response. CONCLUSIONS: In contrast with previous research, this study found BOLD signal attenuation in the ventrolateral and medial prefrontal cortex and the anterior cingulate cortex during face emotion processing, consistent with a hypothesis of hypo-responsivity to external emotional stimuli in GAD. These decreases were in areas that have been implicated in emotion and cognition and may reflect an altered balance between internally and externally directed attentional processes.

Interaction between a history of depression and rumination on neural response to emotional faces.

BACKGROUND: Both past depressive episodes and the personality trait of depressive rumination are strong risk factors for future depression. Depression is associated with abnormal emotional processing, which may be a neurobiological marker for vulnerability to depression. A consistent picture has yet to emerge as to how a history of depression and the tendency to ruminate influence emotional processing. The aim of this study was to investigate the relationship between rumination, past depression and neural responses when processing face emotions. METHOD: The Ruminative Responses Scale (RRS) was completed by 30 remitted depressives and 37 controls who underwent functional magnetic resonance imaging (fMRI) scanning while viewing happy, sad, fearful and neutral faces. RESULTS: The remitted depressives showed overall reductions in neural responses to negative emotions relative to the controls. However, in the remitted depressives, but not the controls, RRS scores were correlated with increased neural responses to negative emotions and decreased responses to happiness in limbic regions. CONCLUSIONS: Automatic emotion processing biases and rumination seem to be correlated to aspects of vulnerability to depression. However, remission from depression may be maintained by a general suppression of limbic responsiveness to negative emotion.

Hedonic and informational functions of the human orbitofrontal cortex.

Functional imaging studies have revealed roles for orbitofrontal cortex (OFC) in reward processing and decision making. In many situations, rewards signal that the current behavior should be maintained, whereas punishments cue a change in behavior. Thus, hedonic responses to reinforcers are conflated with their function as behavioral cues. In an attempt to disambiguate these functions, we performed a functional magnetic resonance imaging study of a 2-choice decision-making task. After each trial, subjects were rewarded or punished and independently provided with a cue to maintain or change behavior. We identified key regions of OFC involved in these processes. An anterior medial focus responded to reward, whereas bilateral lateral foci responded to punishment. The right-sided lateral region that responded to punishment also responded to cues for behavior change (shift), whereas a more ventral and anterior bilateral region responded to cues for behavioral maintenance (stay). The right-sided stay region responded specifically when stay cues were combined with punishment. These results support the view that OFC codes both hedonic responses to reinforcers and their behavioral consequences. Punishments and shift cues are associated with the same right lateral OFC focus, suggesting a fundamental connection between emotive response to negative reinforcement and use of negative information to cue behavioral change.

Quantitative analysis of the effect of lesions of the subthalamic nucleus on intertemporal choice: further evidence for enhancement of the incentive value of food reinforcers.

Recent evidence suggests that the subthalamic nucleus (STN) is involved in regulating the incentive value of food reinforcers. The objective of this study was to examine the effect of lesions of the STN on intertemporal choice (choice between reinforcers differing in size and delay). Rats with bilateral quinolinic acid-induced lesions of the STN (n = 15) or sham lesions (n = 14) were trained in a discrete-trials progressive delay schedule to press levers A and B for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after a delay d(B). d(B) increased across blocks of trials; d(A) was manipulated across phases of the experiment. Indifference delay, d(B(50)) (value of d(B) corresponding to 50% choice of B), was estimated for each rat in each phase, and linear indifference functions (d(B(50)) vs. d(A)) were derived. The STN-lesioned group showed a flatter slope of the indifference function (implying higher instantaneous reinforcer values) than the sham-lesioned group; the intercepts did not differ between the groups. The results agree with recent evidence for a role of the STN in incentive value. Unlike some earlier studies, these results do not indicate a role of the STN in delay discounting.

Glycopyrrolate in comparison to hyoscine hydrobromide and placebo in the treatment of hypersalivation induced by clozapine (GOTHIC1): a feasibility study.

BACKGROUND: Clozapine-induced hypersalivation (CIH) is a common side effect of clozapine treatment and is disliked by clozapine patients, potentially threatening adherence to clozapine treatment. We proposed a trial of alternative medications, hyoscine and glycopyrrolate, for the treatment of CIH and the primary objective of the feasibility study was to assess the recruitment and retention of community clozapine patients as well as assess the metrics of the primary hypersalivation measure. METHODS: This 11-month trial took place in two NHS trusts in northwest UK. Participants were community-dwelling clozapine patients aged 18-65 years who were suffering from CIH, and were recruited from community mental health clinics. They were randomised using a telephone randomisation service to receive either hyoscine (1 week at 0.6 mg daily, 3 weeks at 0.9 mg daily), glycopyrrolate (1 week at 2 mg daily, 3 weeks at 3 mg daily) or placebo. Participants and investigators were blinded to which study arm the participants had been randomised to. We collected data on salivation levels and side effects on a weekly basis and also assessed cognition at the beginning and end of the trial. We also interviewed a sample of participants after the trial to gather information on their experience of having taken part. RESULTS: One hundred and thirty-eight potential participants agreed to being contacted by researchers about participation in the trial and of these, 29 participants were randomised. Of these, four participants exited the trial before taking any trial medication, and two participants left the study owing to concerns of side effects. Data from four participants was missing, and complete data was available for 19 participants who completed the trial. The mean recruitment rate overall was 1.3 participants per site per month, and the overall retention rate was 76%. Interview data suggested that participants' experiences of trial participation were overwhelmingly positive. CONCLUSIONS: The feasibility study demonstrated that a trial of alternative medications in the treatment of CIH is feasible; patients were willing to be randomised to the trial and retention rate was high. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02613494, registered 24 November 2015.

Medial orbitofrontal cortex codes relative rather than absolute value of financial rewards in humans.

Functional imaging studies in recent years have confirmed the involvement of orbitofrontal cortex (OFC) in human reward processing and have suggested that OFC responses are context-dependent. A seminal electrophysiological experiment in primates taught animals to associate abstract visual stimuli with differently valuable food rewards. Subsequently, pairs of these learned abstract stimuli were presented and firing of OFC neurons to the medium-value stimulus was measured. OFC firing was shown to depend on the relative value context. In this study, we developed a human analogue of this paradigm and scanned subjects using functional magnetic resonance imaging. The analysis compared neuronal responses to two superficially identical events, which differed only in terms of the preceding context. Medial OFC response to the same perceptual stimulus was greater when the stimulus predicted the more valuable of two rewards than when it predicted the less valuable. Additional responses were observed in other components of reward circuitry, the amygdala and ventral striatum. The central finding is consistent with the primate results and suggests that OFC neurons code relative rather than absolute reward value. Amygdala and striatal involvement in coding reward value is also consistent with recent functional imaging data. By using a simpler and less confounded paradigm than many functional imaging studies, we are able to demonstrate that relative financial reward value per se is coded in distinct subregions of an extended reward and decision-making network.

Assessing human 5-HT function in vivo with pharmacoMRI.

A number of novel ways of using magnetic resonance imaging (MRI) to visualise the action of drugs on animal and human brain (pharmacoMRI or phMRI) are becoming established tools in translational psychopharmacology. Using drugs with known pharmacology it is possible to investigate how neurotransmitter systems are involved in neural systems engaged by other processes, such as cognitive challenge (modulation phMRI) or to examine the acute effects of the drug itself in the brain (challenge phMRI). In this article we discuss the principles behind phMRI and review studies investigating the effect of serotonin (5-HT) manipulations. 5-HT modulation phMRI studies show the involvement of 5-HT in a broad range of neural processes ranging from motor function through 'cold' cognition, such as memory and response inhibition, to emotional processing. We highlight findings in brain areas that show some consistency or complementarity across studies, such as the ventrolateral orbitofrontal cortex where modulation by 5-HT is task-specific, and the amygdala in emotional processing where 5-HT is predominantly inhibitory. 5-HT challenge phMRI is promising but as yet few studies have been carried out. New ways of analysing phMRI data include connectivity analysis which holds the promise of going beyond identifying isolated areas of activation/modulation to understanding functional circuits and their neurochemistry. 5-HT phMRI now needs to be taken into patient populations and methods of investigating treatment effects need to be developed. If this is successful then phMRI will provide a genuinely exciting opportunity for the rapid development of better treatments for psychiatric conditions.

Effect of quinolinic acid-induced lesions of the nucleus accumbens core on performance on a progressive ratio schedule of reinforcement: implications for inter-temporal choice.

RATIONALE: The nucleus accumbens core (AcbC) is believed to contribute to the control of operant behaviour by reinforcers. Recent evidence suggests that it is not crucial for determining the incentive value of immediately available reinforcers, but is important for maintaining the values of delayed reinforcers. OBJECTIVE: This study aims to examine the effect of AcbC lesions on performance on a progressive-ratio schedule using a quantitative model that dissociates effects of interventions on motor and motivational processes (Killeen 1994 Mathematical principles of reinforcement. Behav Brain Sci 17:105-172). MATERIALS AND METHODS: Rats with bilateral quinolinic acid-induced lesions of the AcbC (n = 15) or sham lesions (n = 14) were trained to lever-press for food-pellet reinforcers under a progressive-ratio schedule. In Phase 1 (90 sessions) the reinforcer was one pellet; in Phase 2 (30 sessions), it was two pellets; in Phase 3, (30 sessions) it was one pellet. RESULTS: The performance of both groups conformed to the model of progressive-ratio performance (group mean data: r2 > 0.92). The motor parameter, delta, was significantly higher in the AcbC-lesioned than the sham-lesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was sensitive to changes in reinforcer size, but did not differ significantly between the two groups. The AcbC-lesioned group showed longer post-reinforcement pauses and lower running response rates than the sham-lesioned group. CONCLUSIONS: The results suggest that destruction of the AcbC impairs response capacity but does not alter the efficacy of food reinforcers. The results are consistent with recent findings that AcbC lesions do not alter sensitivity to reinforcer size in inter-temporal choice schedules.

Effect of disconnecting the orbital prefrontal cortex from the nucleus accumbens core on inter-temporal choice behaviour: a quantitative analysis.

Previous experiments showed that destruction of the orbital prefrontal cortex (OPFC) or the nucleus accumbens core (AcbC) in rats altered choice between two delayed food reinforcers. Application of a quantitative model of inter-temporal choice suggested that lesions of either structure increased the delay-dependent degradation of reinforcer value (delay discounting); destruction of the OPFC (but not the AcbC) also increased the relative value of the larger reinforcer. This experiment examined the effect of disconnecting the OPFC from the AcbC on inter-temporal choice. Rats received excitotoxin-induced contralateral lesions of the OPFC and AcbC (disconnection), severing of the anterior corpus callosum (callosotomy), a combined lesion (disconnection+callosotomy) or sham lesions. They were trained in a discrete-trials progressive delay schedule to press levers A and B for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after a delay d(B). d(B) increased across blocks of trials; d(A) was manipulated across phases of the experiment. Indifference delay, d(B50) (value of d(B) corresponding to 50% choice of B), was estimated for each rat in each phase, and linear indifference functions (d(B50)vs. d(A)) were derived. The disconnection+callosotomy group showed a lower intercept of the indifference function (implying a higher rate of delay discounting) than the sham-lesioned group; the disconnection group showed a similar but less robust effect, whereas the callosotomy group did not differ significantly from the sham-lesioned group. The results suggest that OPFC-AcbC connections are involved in delay discounting of food reinforcers, but provide no evidence for an involvement of OPFC-AcbC connections in regulating sensitivity to reinforcer size.

Electrophysiological evidence that drug cues have greater salience than other affective stimuli in opiate addiction.

Previous research has demonstrated that drug cues are able to capture attentional resources in addicted populations. However, few studies have controlled for the possibility that drug users find all motivationally significant (i.e., affective) stimuli particularly salient. We examined this issue in opiate addiction, by exploring the impact of drug-related and affective stimuli on central attentional processes. Sixteen male heroin addicts (seven on opiate pharmacotherapy and nine recently detoxified subjects) and 12 matched controls were studied. Subjects were fitted with a 32-channel electrode cap and were instructed to passively view a series of neutral, affective and opiate-related images. The P300 elicited by drug-related stimuli was significantly larger than that elicited by affective and neutral stimuli in opiate users but not controls. Baseline ratings of craving were also found to predict the degree of P300 facilitation to the drug-related stimuli in the addicted group. Further, the opiate group demonstrated an absence of the typical enhancement of ERP responses to non-drug affective stimuli. These results suggest that opiate addicts demonstrate greater cortical processing of drug cues than other types of affective stimuli. Further research is required to assess whether addiction is specifically associated with reduced sensitivity to natural rewards, aversive stimuli or affective cues in general.

Construction and Validation of the Touch Experiences and Attitudes Questionnaire (TEAQ): A Self-report Measure to Determine Attitudes Toward and Experiences of Positive Touch.

Despite growing interest in the beneficial effects of positive touch experiences throughout our lives, and individual differences in how these experiences are perceived, there is not yet available a contemporary self-report measure of touch experiences and attitudes, for which the factor structure has been validated. This article describes four studies carried out during the construction and validation of the Touch Experiences and Attitudes Questionnaire (TEAQ). The original TEAQ, containing 117 items relating to positive touch experiences was systematically constructed. Principal component analysis reduced this measure to 57 items and identified six components relating to touch experiences during childhood and adult experiences relating to current intimate touch and touch with friends and family. Three attitudinal components were identified relating to attitude to intimate touch, touch with unfamiliar people, and self-care. The structure of this questionnaire was confirmed through confirmatory factor analysis carried out on data obtained from a second sample. Good concurrent and predictive validity of the TEAQ compared to other physical touch measures currently available was identified. Known-group validity in terms of gender, marital status and age was determined, with expected group differences identified. This study demonstrates the TEAQ to have good face validity, internal consistency, construct validity in terms of discriminant validity, known-group validity and convergent validity, and criterion-related validity in terms of predictive validity and concurrent validity. We anticipate this questionnaire will be a valuable tool for the field of physical touch research.

Effects of quinolinic acid-induced lesions of the nucleus accumbens core on inter-temporal choice: a quantitative analysis.

RATIONALE: There is evidence that lesions of the nucleus accumbens core (AcbC) promote preference for smaller earlier reinforcers over larger delayed reinforcers in inter-temporal choice paradigms. It is not known whether this reflects an effect of the lesion on the rate of delay discounting, on sensitivity to reinforcer magnitude, or both. AIM: We examined the effect of AcbC lesions on inter-temporal choice using a quantitative method that allows effects on delay discounting to be distinguished from effects on sensitivity to reinforcer size. MATERIALS AND METHODS: Sixteen rats received bilateral quinolinic acid-induced lesions of the AcbC; 14 received sham lesions. They were trained under a discrete-trials progressive delay schedule to press two levers (A and B) for a sucrose solution. Responses on A delivered 50 microl of the solution after a delay d(A); responses on B delivered 100 microl after d(B). d(B) increased across blocks of trials, while d(A) was manipulated across phases of the experiment. Indifference delay d(B(50)) (value of d(B) corresponding to 50% choice of B) was estimated in each phase, and linear indifference functions (d(B(50)) vs d(A)) derived. RESULTS: d(B(50)) increased linearly with d(A) (r(2) > 0.95 in each group). The intercept of the indifference function was lower in the lesioned than the sham-lesioned group; slope did not differ between groups. The lesioned rats had extensive neuronal loss in the AcbC. CONCLUSIONS: The results confirm that lesions of the AcbC promote preference for smaller, earlier reinforcers and suggest that this reflects an effect of the lesion on the rate of delay discounting.

Adult neurogenesis and schizophrenia: a window on abnormal early brain development?

Adult neurogenesis is one of the most rapidly growing areas in neuroscience research and there is great interest in its potential role in the pathophysiology of psychiatric illness. In parallel with early development, adult neurogenesis occurs through the proliferation of precursor cells which migrate to specific regions and differentiate into neurons with characteristics indistinguishable from existing mature neurons. These findings have led to the re-definition of the concept of network plasticity in the adult brain, to include the formation of new neurons as well as new connections. This review examines the idea that adult neurogenesis may be disturbed in schizophrenia. We discuss evidence for abnormal mechanisms of neurogenesis and expression of developmental genes in schizophrenia, the influence of antipsychotic drugs on neurogenesis and the role of candidate schizophrenia susceptibility genes in adult neurogenesis. The recent discovery of molecular markers transiently expressed in newborn neurons within adult neurogenic brain regions could be used to probe whether neurogenesis is disturbed in schizophrenia. Adult neurogenesis could also be used as a unique tool for investigating genes involved in early brain development using post-mortem brains. This is particularly relevant for brain disorders with developmental origins such as schizophrenia.

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.