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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.

Objectives Cognitive dysfunction (CD) and depression are interlinked comorbidities of SLE. They may be the result of altered brain mechanisms. This study aimed to examine SLE effects on functional connectivity (FC) within the default mode network (DMN) using resting state fMRI, and how depression may impact this. Methods Demographic, clinical and psychiatric data were collected from 19 SLE-active, 23 SLE-stable and 30 healthy controls (HC) participants. A T2*-weighted rsfMR scan was acquired and analysed using independent component analysis. Group z-scores for nodes associated with the DMN were tested. Significant nodes were entered into a factor analysis. The combined factor was used in correlations with factors of interest. Significant variables were used in a mediation analysis. Results 14 DMN nodes were defined using independent component analysis. In five nodes, the SLE groups had significantly reduced FC compared with the HC group (P Conclusions Altered FC was evident in DMN nodes for SLE groups irrespective of disease activity. Depression accounts for some of this effect but SLE directly accounted for more. Further studies are needed to assess if these changes may be a precursor to CD in SLE. If so, rs-fMRI could be an early marker for CD in SLE and help in future CD in SLE treatment trials.

Objectives Factors common across many chronic diseases, such as fatigue and depression affect cognitive dysfunction (CD) but the effect of SLE disease activity on CD remains unclear. We aimed to explore the effects of disease activity in SLE on cognitive function whilst taking into consideration other potential mediators. Methods Two groups of SLE patients were recruited; stable/low disease activity (SLE-S, n = 36) and active disease (SLE-F, n = 26). The SLE-F group were studied during a flare; with a second visit when disease activity had reduced. In addition to demographic, clinical and psychiatric data, CD was measured using a computerised battery of tests (CANTAB®). Functional MRI (fMRI) was used to examine neuronal responses to working memory and emotional processing tasks. Results No differences between the groups/visits were found using the CANTAB® battery. The fMRI results showed that the SLE-F group had a less attenuated response in the medial prefrontal cortex (a default mode network—DMN region) compared with the SLE-S group during the working memory task (P =0.012). Exploratory correlations within the SLE-F group showed associations between neuronal responses and depression, cognitive fatigue, disease activity measures and IL-6. Conclusion Functional brain processes but not cognitive behavioural measures were affected by disease activity. Flaring SLE patients were less able to suppress DMN regions during a working memory task. This could reflect emotional interference during cognitive tasks and may cause cognitive fatigue. A number of factors are associated with brain function in flaring patients, which has potential implications for holistic treatments.

Mindfulness-Based-Cognitive-Therapy (MBCT) reduces vulnerability for relapse into depression by helping individuals to counter tendencies to engage in maladaptive repetitive patterns of thinking and respond more compassionately to negative self-judgment. However, little is known about the neural correlates underlying these effects. To elucidate these correlates, we investigated fMRI brain activation during a task eliciting feelings of blaming oneself or others. Sixteen participants in remission from major depressive disorder (MDD) completed fMRI assessments before and after MBCT, alongside self-reported levels of self-compassion, mindfulness, and depression symptoms. Analyses of self-blame versus other-blame contrasts showed a reduction in activation in the bilateral dorsal anterior cingulate/medial superior frontal gyrus after MBCT compared to baseline. Further, exploratory analyses showed that increases in self-kindness after MBCT correlated with reduced activation in the posterior cingulate cortex (PCC)/precuneus in self-blame versus rest contrasts. These findings suggest that MBCT is associated with a reduction in activations in cortical midline regions to self-blame which may be mediated by increasing self-kindness. However, this is a small, uncontrolled study with 16 participants and therefore our results will need confirmation in a controlled study.

The skin and brain have a close bi-directional anatomical and functional connection. Historically, the skin-brain axis and the brain-skin axis have been well described. However, brain function in this context has only recently been demystified with the introduction of functional neuroimaging in dermatology. Functional neuroimaging, especially functional magnetic resonance imaging (fMRI), allows indirect visualisation of brain function. This review looks back to the beginnings of functional neuroimaging in dermatology, summarises the currently available dermatology-related fMRI studies and discusses the potential future role of fMRI as a stratifying tool in clinical dermatology and in the development of novel therapies. According to the main body of research made in this field, the focus is placed on experimental itch studies, which described the brain structures involved in itch processing, the regulation of the scratch response, contagious itch and itch suppression.

BackgroundCurrent training tasks to improve the cognitive deficits thought to be involved in sustained heavy drinking need further investigation to optimize their effectiveness.PurposeThe present study investigated whether combining implementation intention provision with a cognitive training task had a measurable effect on alcohol consumption in heavy drinkers and explored the neural mechanisms underpinning any reductions in subsequent alcohol consumption.MethodsThirty-two heavy-drinking participants completed approach-avoidance and visual probe training tasks preintervention and postintervention during functional Magnetic Resonance Imaging. Participants in the intervention group were randomized to form implementation intentions and participants in the control condition read a goal intention. Alcohol consumption was recorded preintervention and at 1 month follow-up.ResultsCompared to the control group, implementation intention provision significantly improved performance on alcohol-avoidance tasks postintervention, t(30) = −2.315, p = .028, d = .85, and reduced alcohol consumption by 6.9 units/week (1 unit = 10 mL or 8 g ethanol), F(1,30) = 4.263, p = .048 (d = .74), at follow-up. However, the analysis of functional Magnetic Resonance Imaging data revealed no significant differences between groups.ConclusionsThese findings show for the first time that implementation intentions targeting cognitive processes can significantly reduce alcohol consumption among heavy drinkers. However, there was no evidence that the effects were mediated by changes in neural activity. Further work is required to explore the neural mechanisms underpinning the operation of implementation intentions.Trial RegistrationThis trial was registered (ISRCTN:35503634) and is available at https://www.isrctn.com/ISRCTN35503634.

Background The initial effects of selective serotonin reuptake inhibitors (SSRIs) in the human living brain are poorly understood. We carried out a 3T resting state fMRI study with pharmacological challenge to determine the brain activation changes over time following different dosages of citalopram. Methods During the study, 7.5 mg i.v. citalopram was administered to 32 healthy subjects. In addition, 11.25 mg citalopram was administered to a subset of 9 subjects to investigate the dose-response. Associations with neuroticism (assessed by the NEO PI-R) of the emerging brain activation to citalopram was also investigated. Results Citalopram challenge evoked significant activation in brain regions that are part of the default mode network, the visual network and the sensorimotor network, extending to the thalamus, and midbrain. Most effects appeared to be dose-dependent and this was statistically significant in the middle cingulate gyrus. Individual citalopram-induced brain responses were positively correlated with neuroticism scores and its subscales in specific brain areas; anxiety subscale scores in thalamus and midbrain and self-consciousness scores in middle cingulate gyrus. There were no sex differences. Limitations We investigated only healthy subjects and we used a relatively low sample size in the 11.25 mg citalopram analysis. Discussion Our results suggest that SSRIs acutely induce an increased arousal-like state of distributed cortical and subcortical systems that is mediated by enhanced serotonin neurotransmission according to levels of neuroticism and underpins trait sensitivity to environmental stimuli and stressors. Studies in depression are needed to determine how therapeutic effects eventually emerge. This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

Objectives Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Experimental design Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250 ml) of: 1 M glucose + predosing with dexloxiglumide (CCK1 receptor antagonist), 1 M glucose + placebo, or 0.9% saline (control) + placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Principal observations Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose + dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. Conclusions Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway., Highlights • We have identified two distinct CNS responses to glucose in man. • A CCK1 receptor (CCK1R)-dependent BOLD signal increase in the motor cortex. • A CCK1R-independent BOLD signal decrease in the brainstem and hypothalamus. • The BOLD signal decrease was mediated by changes in blood glucose and insulin

C-tactile afferents (CTs) are slowly conducting nerve fibres, present only in hairy skin. They are optimally activated by slow, gentle stroking touch, such as those experienced during a caress. CT-stimulation activates affective processing brain regions, alluding to their role in affective touch perception. We tested a theory that CT-activating touch engages the pro-social functions of serotonin, by determining whether reducing serotonin, through acute tryptophan depletion, diminishes subjective pleasantness and affective brain responses to gentle touch. A tryptophan depleting amino acid drink was administered to 16 healthy females, with a further 14 receiving a control drink. After 4 hours, participants underwent an fMRI scan, during which time CT-innervated forearm skin and CT non-innervated finger skin was stroked with 3 brushes of differing texture, at CT-optimal force and velocity. Pleasantness ratings were obtained post-scanning. The control group showed a greater response in ipsilateral orbitofrontal cortex to CT-activating forearm touch compared to touch to the finger where CTs are absent. This differential response was not present in the tryptophan depleted group. This interaction effect was significant. Additionally, control participants showed a differential primary somatosensory cortex response to brush texture applied to the finger, a purely discriminatory touch response, which was not observed in the tryptophan depleted group. This interaction effect was also significant. Pleasantness ratings were comparable across treatment groups. These results implicate serotonin in the differentiation between CT-activating and purely discriminatory touch responses. Such effects could contribute to some of the social abnormalities seen in psychiatric disorders associated with abnormal serotonin function. This article is protected by copyright. All rights reserved.

Calibration experiments precede multicenter trials to identify potential sources of variance and bias. In support of future imaging studies of mental health disorders and their treatment, the Neuro/PsyGRID consortium commissioned a calibration experiment to acquire functional and structural MRI from twelve healthy volunteers attending five centers on two occasions. Measures were derived of task activation from a working memory paradigm, fractal scaling (Hurst exponent) from resting fMRI, and grey matter distributions from T(1)‐weighted sequences. At each intracerebral voxel a fixed‐effects analysis of variance estimated components of variance corresponding to factors of center, subject, occasion, and within‐occasion order, and interactions of center‐by‐occasion, subject‐by‐occasion, and center‐by‐subject, the latter (since there is no intervention) a surrogate of the expected variance of the treatment effect standard error across centers. A rank order test of between‐center differences was indicative of crossover or noncrossover subject‐by‐center interactions. In general, factors of center, subject and error variance constituted >90% of the total variance, whereas occasion, order, and all interactions were generally

Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, induces antidepressant effects with a similar time course to ketamine. We investigated whether a single dose lanicemine infusion would reproduce the previously reported decrease in subgenual anterior cingulate cortex (sgACC) activity evoked by ketamine, a potential mechanism of antidepressant efficacy. Sixty un-medicated adults meeting the criteria for major depressive disorder were randomly assigned to receive constant intravenous infusions of ketamine, lanicemine or saline during a 60min pharmacological magnetic resonance imaging (phMRI) scan. Both ketamine and lanicemine gradually increased the blood oxygen level dependent signal in sgACC and rostral ACC as the primary outcome measure. No decreases in signal were seen in any region. Interviewer-rated psychotic and dissociative symptoms were minimal following administration of lanicemine. There was no significant antidepressant effect of either infusion compared to saline. The previously reported deactivation of sgACC after ketamine probably reflects the rapid and pronounced subjective effects evoked by the bolus-infusion method used in the previous study. Activation of the ACC was observed following two different NMDA compounds in both Manchester and Oxford using different 3T MRI scanners, and this effect predicted improvement in mood 1 and 7 days post-infusion. These findings suggest that the initial site of antidepressant action for NMDA antagonists may be the ACC (NCT01046630. A Phase I, Multi-centre, Double-blind, Placebo-controlled Parallel Group Study to Assess the pharmacoMRI Effects of AZD6765 in Male and Female Subjects Fulfilling the Criteria for Major Depressive Disorder; http://clinicaltrials.gov/show/NCT01046630).

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.

Functional magnetic resonance imaging (fMRI) has proved to be useful for analyzing the effects of illness and pharmacological agents on brain activation. Many fMRI studies now incorporate effective connectivity analyses on data to assess the networks recruited during task performance. The assessment of the sample size that is necessary for carrying out such calculations would be useful if these techniques are to be confidently applied. Here, we present a method of estimating the sample size that is required for a study to have sufficient power. Our approach uses Bayesian Model Selection to find a best fitting model and then uses a bootstrapping technique to provide an estimate of the parameter variance. As illustrative examples, we apply this technique to two different tasks and show that for our data, ~20 volunteers per group is sufficient. Due to variability between task, volunteers, scanner, and acquisition parameters, this would need to be evaluated on individual datasets. This approach will be a useful guide for Dynamic Causal Modeling studies.

Background Patellar taping is a common treatment modality for physical therapists managing patellofemoral pain. However, the mechanisms of action remain unclear, with much debate as to whether its efficacy is due to a change in patellar alignment or an alteration in sensory input. Objective The purpose of this study was to investigate the sensory input hypothesis using functional magnetic resonance imaging when taping was applied to the knee joint during a proprioception task. Design This was an observational study with patellar taping intervention. Methods Eight male volunteers who were healthy and right-leg dominant participated in a motor block design study. Each participant performed 2 right knee extension repetitive movement tasks: one simple and one proprioceptive. These tasks were performed with and without patellar taping and were auditorally paced for 400 seconds at 72 beats/min (1.2 Hz). Results The proprioception task without patellar taping caused a positive blood oxygenation level–dependant (BOLD) response bilaterally in the medial supplementary motor area, the cingulate motor area, the basal ganglion, and the thalamus and medial primary sensory motor cortex. For the proprioception task with patellar taping, there was a decreased BOLD response in these regions. In the lateral primary sensory cortex, there was a negative BOLD response with less activity for the proprioception task with taping. Limitations This study may have been limited by the small sample size, a possible learning effect due to a nonrandom order of tasks, and use of a single-joint knee extension task. Conclusions This study demonstrated that patellar taping modulates brain activity in several areas of the brain during a proprioception knee movement task.

The neuroplastic pathway, which includes cyclic adenosine monophosphate response element-binding protein 1 (CREB1), brain-derived neurotrophic factor (BDNF), and its receptor (neurotrophic tyrosine kinase receptor, type 2 [NTRK2]), plays a crucial role in the adaptation of brain to stress, and thus variations of these genes are plausible risk factors for depression.A population-based sample was recruited, subsets of which were interviewed and underwent functional magnetic resonance imaging. We investigated the association of nine polymorphisms throughout the CREB1-BDNF-NTRK2 pathway with lifetime depression, rumination, current depression severity, negative life events, and sad face emotion processing in a three-level design.In the population study, BDNF-rs6265 and CREB1-rs2253206 major alleles were significantly associated with rumination and through rumination with current depression severity. However, childhood adversity increased the risk of lifetime depression in the minor allele carriers of BDNF-rs6265 and CREB1-rs2253206 and in alleles of six other single nucleotide polymorphisms (SNPs). We validated our findings in the interviewed subjects using structural equation modeling. Finally, using functional magnetic resonance imaging, we found that viewing sad faces evoked greater activity in depression-related areas in healthy control subjects possessing the minor alleles of BDNF-rs6265 and CREB1-rs2253206.Genetic variation associated with reduced function in the CREB1-BDNF-NTRK2 pathway has multiple, sometimes opposing, influences on risk mechanisms of depression, but almost all the SNPs studied amplified the effect of childhood adversity. The use of cognitive and neural intermediate phenotypes together with a molecular pathway approach may be critical to understanding how genes influence risk of depression.

BackgroundGeneralized 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.MethodA 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.ResultsThe 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.ConclusionsIn 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.

BACKGROUND & AIMS: In human beings, as in most vertebrates, the release of the intestinal peptide cholecystokinin (CCK) by ingested food plays a major role both in digestion and the regulation of further food intake, but the changes in brain function and their underlying activation mechanisms remain unknown. Our aim was to explore, using a novel physiologic magnetic resonance imaging approach, the temporospatial brain activation matrix, in response to ingestion of a lipid meal and, by use of a CCK-1 receptor antagonist, to define the role of CCK in this activation. METHODS: We studied, in 19 healthy subjects, the brain activation responses to ingested lipid (dodecanoic acid) or saline (control) with magnetic resonance imaging. Gallbladder volume, plasma CCK levels, and subjective hunger and fullness scores were also recorded. The experiment was then repeated, with and without prior administration of the CCK-1 receptor antagonist dexloxiglumide (600 mg orally) with a controlled, randomized order, latin-square design. RESULTS: Ingested lipid activated bilaterally a matrix of brain areas, particularly the brain stem, pons, hypothalamus, and also cerebellum and motor cortical areas. These activations were abolished by dexloxiglumide, indicating a CCK-mediated pathway, independent of any nutrient-associated awareness cues. CONCLUSION: The identification of these activations now defines the lipid-activated brain matrix and provides a means by which the gut-derived homeostatic mechanisms of food regulation can be distinguished from secondary sensory and hedonic cues, thereby providing a new approach to exploring aberrant human gastrointestinal responses and eating behavior.

Effective connectivity is becoming an increasingly popular technique for obtaining additional information from functional magnetic resonance imaging (fMRI) cognitive activation studies. It is potentially important for investigating psychiatric illnesses, which are thought to depend on disrupted connections and in observing the action of psychoactive drugs used to treat these disorders. If researchers are to apply these techniques confidently then it is important to establish the level of power that is available in an experiment. This study compares the level of power available when applying effective connectivity to test for differences between groups using parametric tests and permutation testing. Permutation testing has previously been shown to have superior sensitivity to parametric tests in fMRI studies. As an illustrative example, both the parametric t-test and equivalent permutation test were applied to a comparison between healthy controls and remitted depressed volunteers performing an emotional face processing task. Permutation testing was found to provide superior power compared with the nonparametric equivalent.

Individuals with antisocial personality disorder (ASPD) are impulsive and show impairment in reinforcement processing. There is increasing evidence for a neurobiological basis of psychopathy, which shares some of the characteristics of ASPD, but research on the neuronal correlates of neuropsychological processes in ASPD remains limited. Furthermore, no research has examined the effects of serotonergic manipulation on brain activations in antisocial groups. In this study, 25 male participants with ASPD (mean age 42.1) and 32 male control participants (mean age 30.5; 25 participants providing usable scans) were randomly allocated to receive the 5-HT(2C)-agonist mCPP or placebo. Participants were scanned using functional magnetic resonance imaging (fMRI) during a behavioural inhibition (Go/NoGo) and a reward task. In comparison to healthy controls the ASPD group showed reduced task related activations in the dorsolateral prefrontal cortex (DLPFC) but increased signal in the pre/subgenual anterior cingulate cortex (ACC) in the Go/No-Go task and increased activation in OFC in the reward task. mCPP modulated brain responses in both tasks in the whole group. Interactions between group and drug occured in bilateral OFC, caudate and ventral pallidum during the reward task but no significant interactions were found in the Go/No-Go task. This suggests that ASPD involves altered serotonin modulation of reward, but not motor inhibition pathways. These findings suggest that ASPD involves altered DLPFC, ACC and OFC function. Altered serotonergic modulation of reward pathways seen in the ASPD group raises the possibility that targeting serotonin systems may be therapeutic.

Psoriasis produces significant psychosocial disability; however, little is understood about the neurocognitive mechanisms that mediate the adverse consequences of the social stigma associated with visible skin lesions, such as disgusted facial expressions of others. Both the feeling of disgust and the observation of disgust in others are known to activate the insula cortex. We investigated whether the social impact of psoriasis is associated with altered cognitive processing of disgust using (i) a covert recognition of faces task conducted using functional magnetic resonance imaging (fMRI) and (ii) the facial expression recognition task (FERT), a decision-making task, conducted outside the scanner to assess the ability to recognize overtly different intensities of disgust. Thirteen right-handed male patients with psoriasis and 13 age-matched male controls were included. In the fMRI study, psoriasis patients had significantly (P

The syndromic heterogeneity of major depressive disorder (MDD) hinders understanding of the etiology of predisposing vulnerability traits and underscores the importance of identifying neurobiologically valid phenotypes. Distinctive fMRI biomarkers of vulnerability to MDD subtypes are currently lacking. This study investigated whether remitted melancholic MDD patients, who are at an elevated lifetime risk for depressive episodes, demonstrate distinctive patterns of resting-state connectivity with the subgenual cingulate cortex (SCC), known to be of core pathophysiological importance for severe and familial forms of MDD. We hypothesized that patterns of disrupted SCC connectivity would be a distinguishing feature of melancholia. A total of 63 medication-free remitted MDD (rMDD) patients (33 melancholic and 30 nonmelancholic) and 39 never-depressed healthy controls (HC) underwent resting-state fMRI scanning. SCC connectivity was investigated with closely connected bilateral a priori regions of interest (ROIs) relevant to MDD (anterior temporal, ventromedial prefrontal, dorsomedial prefrontal cortices, amygdala, hippocampus, septal region, and hypothalamus). Decreased (less positive) SCC connectivity with the right parahippocampal gyrus and left amygdala distinguished melancholic rMDD patients from the nonmelancholic rMDD and HC groups (cluster-based familywise error-corrected p⩽0.007 over individual a priori ROIs corresponding to approximate Bonferroni-corrected p⩽0.05 across all seven a priori ROIs). No areas demonstrating increased (more positive) connectivity were observed. Abnormally decreased connectivity of the SCC with the amygdala and parahippocampal gyrus distinguished melancholic from nonmelancholic rMDD. These results provide the first resting-state neural signature distinctive of melancholic rMDD and may reflect a subtype-specific primary vulnerability factor given a lack of association with the number of previous episodes.

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.

Decision making is guided by the likely consequences of behavioural choices. Neuronal correlates of financial reward have been described in a number of functional imaging studies in humans. Areas implicated in reward include ventral striatum, dopaminergic midbrain, amygdala and orbitofrontal cortex. Response to loss has not been as extensively studied but may involve prefrontal and medial temporal cortices. It has been proposed that increased sensitivity to reward and reduced sensitivity to punishment underlie some of the psychopathology in impulsive personality disordered individuals. However, few imaging studies using reinforcement tasks have been conducted in this group. In this fMRI study, we investigate the effects of positive (monetary reward) and negative (monetary loss) outcomes on BOLD responses in two target selection tasks. The experimental group comprised eight people with Cluster B (antisocial and borderline) personality disorder, whilst the control group contained fourteen healthy participants. A key finding was the absence of prefrontal responses and reduced BOLD signal in the subcortical reward system in the PD group during positive reinforcement. Impulsivity scores correlated negatively with prefrontal responses in the PD but not the control group during both, reward and loss. Our results suggest dysfunctional responses to rewarding and aversive stimuli in Cluster B personality disordered individuals but do not support the notion of hypersensitivity to reward and hyposensitivity to loss.

Theory of Mind (ToM), the ability to attribute mental states to others, and empathy, the ability to infer emotional experiences, are important processes in social cognition. Brain imaging studies in healthy subjects have described a brain system involving medial prefrontal cortex, superior temporal sulcus and temporal pole in ToM processing. Studies investigating networks associated with empathic responding also suggest involvement of temporal and frontal lobe regions. In this fMRI study, we used a cartoon task derived from Sarfati et al. (1997) [Sarfati, Y., Hardy-Bayle, M.C., Besche, C., Widlocher, D. 1997. Attribution of intentions to others in people with schizophrenia: a non-verbal exploration with comic strips. Schizophrenia Research 25, 199-209.]with both ToM and empathy stimuli in order to allow comparison of brain activations in these two processes. Results of 13 right-handed, healthy, male volunteers were included. Functional images were acquired using a 1.5 T Phillips Gyroscan. Our results confirmed that ToM and empathy stimuli are associated with overlapping but distinct neuronal networks. Common areas of activation included the medial prefrontal cortex, temporoparietal junction and temporal poles. Compared to the empathy condition, ToM stimuli revealed increased activations in lateral orbitofrontal cortex, middle frontal gyrus, cuneus and superior temporal gyrus. Empathy, on the other hand, was associated with enhanced activations of paracingulate, anterior and posterior cingulate and amygdala. We therefore suggest that ToM and empathy both rely on networks associated with making inferences about mental states of others. However, empathic responding requires the additional recruitment of networks involved in emotional processing. These results have implications for our understanding of disorders characterized by impairments of social cognition, such as autism and psychopathy.

Serotonin (5-hydroxytryptamine, 5-HT) is implicated in the aetiology and treatment of a variety of psychiatric disorders. A limitation of research has been the necessity to use indirect measures of 5-HT function. We describe a method of analysing pharmacoMRI data using SPM and apply it to the direct i.v. infusion of selective 5-HT reuptake inhibitor, citalopram, in 12 healthy volunteers. Scanning took place on a 1.5-T Philips MRI scanner. Areas implicated in depression and its treatment were observed to have increasing signal with respect to time. These areas included the caudate, the amygdala, the hippocampus, the striatum and the thalamus. Direct pMRI using i.v. citalopram opens new ways of investigating 5-HT mechanism in depression and its treatment.

Cognitive dysfunction is a common aspect of systemic lupus erythematosus (SLE) and is increasingly reported as a problem by patients. In many cases the exact cause is unclear. Limited correlations between specific autoantibodies or structural brain abnormalities and cognitive dysfunction in SLE have been reported. It may be that the most appropriate biomarkers have yet to be found. Functional magnetic resonance imaging (fMRI) is a technique used in many other conditions and provides sensitive measures of brain functionality during cognitive tasks. It is now beginning to be employed in SLE studies. These studies have shown that patients with SLE often perform similarly to healthy controls in terms of behavioural measures on cognitive tasks. However, SLE patients appear to employ compensatory brain mechanisms, such as increased response in fronto-parietal regions, to maintain adequate cognitive performance. As there have been only a few studies using fMRI in SLE to investigate cognitive dysfunction, many questions remain unanswered. Further research could, however, help to identify biomarkers for cognitive dysfunction in SLE.

Resting state functional magnetic resonance imaging (fMRI) examines the spontaneous low frequency neural activity of the brain to reveal networks of correlated neural activity. A number of different methodologies, each with its own advantages and disadvantages, have been used to examine networks of neural activity that may be related to clinical presentation. Major depressive disorder (MDD) research has largely focused on the default mode network (DMN), which is most active at rest and may relate to negative rumination. However, other networks can be discerned in the resting state such as salience and affective and cognitive control networks, all of which may be relevant to MDD psychopathology. This article reviews the rapidly increasing literature on resting state networks. A number of state- and trait-dependent abnormalities have been reported in MDD in a wide variety of regions including the cerebellum, lingual gyrus, anterior cingulate cortex (ACC), middle frontal gyrus (MFG), dorsolateral prefrontal cortex (dlPFC), amygdala and insula. Current and chronic medication is often a potential confound. Few trials have examined the immediate or delayed effects of antidepressants on resting state networks. This article presents a novel approach to the analysis of drug effects, the identification of signatures of efficacy, and thus for drug development.

OBJECTIVE: Increased amygdala response to negative emotions seen in functional MRI (fMRI) has been proposed as a biomarker for negative emotion processing bias underlying depressive symptoms and vulnerability to depressive relapse that are normalized by antidepressant drug treatment. The purpose of this study was to determine whether abnormal amygdala responses to face emotions in depression are related to specific emotions or change in response to antidepressant treatment and whether they are present as a stable trait in medication-free patients in remission. METHOD: Sixty-two medication-free unipolar depressed patients (38 were currently depressed, and 24 were in remission) and 54 healthy comparison subjects underwent an indirect face-emotion processing task during fMRI. Thirty-two currently depressed patients were treated with the antidepressant citalopram for 8 weeks. Adherence to treatment was evaluated by measuring citalopram plasma concentrations. RESULTS: Patients with current depression had increased bilateral amygdala responses specific to sad faces relative to healthy comparison subjects and nonmedicated patients in stable remission. Treatment with citalopram abolished the abnormal amygdala responses to sad faces in currently depressed patients but did not alter responses to fearful faces. CONCLUSIONS: Aberrant amygdala activation in response to sad facial emotions is specific to the depressed state and is a potential biomarker for a negative affective bias during a depressive episode.

Objective Gut-derived humoural factors activate central nervous system (CNS) mechanisms controlling energy intake and expenditure, and autonomic outflow. Ghrelin is secreted from the stomach and stimulates food intake and gastric emptying, but the relevant mechanisms are poorly understood. Nutrient-activated CNS systems can be studied in humans by physiological/pharmacological MRI (phMRI). This method has been used to examine the CNS responses to exogenous ghrelin. Design phMRI was used to study the CNS responses in healthy people to a ghrelin bolus (0.3 nmol/kg, intravenous) in the post-prandial state, and an intravenous infusion of ghrelin (1.25 pmol/kg/min) alone and after intragastric lipid (dodecanoate, C12) in people who have fasted. Results A ghrelin bolus decreased the blood oxygenation level dependent (BOLD) signal detected by phMRI in feeding-activated areas of the CNS in the post-prandial state. Infusion of ghrelin reversed the effect of C12 in delaying gastric emptying but had no effect on hunger. Intragastric C12 caused strong bilateral activation of a matrix of CNS areas, including the brain stem, hypothalamus and limbic areas which was attenuated by exogenous ghrelin. Ghrelin infusion alone had a small but significant stimulatory effect on CNS BOLD signals. Conclusion Ghrelin inhibits activation of the hypothalamus and brain stem induced by ingested nutrients, suggesting a role in suppression of gut-derived satiety signals in humans.

BACKGROUND: Pruritus, or itch, is the most prevalent symptom of allergic and inflammatory skin disease. Although it is known that itch induces activation of a neural network in the brain, the temporal dynamics of the network as well as the pathophysiology and neurobiology are not well understood. OBJECTIVES: The study aimed to elucidate (i) the temporal dynamics of the itch response identified in earlier studies and (ii) the relationship between central and subjective responses to itch. METHODS: Using a novel time-series analysis, we performed a double-blind, placebo-controlled, randomized, within-subject functional magnetic resonance imaging (fMRI) study of the cerebral processing of histamine-induced itch in healthy volunteers (n = 16) by tracking the 8-min period following a single skin prick. RESULTS: Histamine-induced itch compared with saline resulted in significant area under the curve blood oxygen level dependent (BOLD) signal changes in the middle/superior temporal gyrus and right inferior frontal gyrus/insula. We observed negative itch-induced BOLD signal changes compared with saline in (i) the pregenual anterior cingulate cortex (ACC)/medial frontal gyrus, (ii) subgenual ACC/ventral striatum, (iii) bilateral temporal pole/parahippocampal gyrus and (iv) several regions within the cerebellum. We noted a trend significance in the left precentral gyrus part of the motor cortex. The BOLD signal change in several of these regions correlated with perception of itch intensity. CONCLUSIONS: In contrast to other fMRI studies we observed a multifocal negative signal. An improved understanding of both activated and deactivated brain regions during the itch response may in the long term facilitate development of more effective management strategies.

Impaired hippocampal function is believed to be important in the pathogenesis of depression. The hippocampus contains a high concentration of both mineralocorticoid (MR) and glucocorticoid receptors (GR), and the experimental administration of corticosteroids has been reported to mimic memory impairments seen in depression. Using pharmacological functional magnetic resonance imaging (phMRI) we investigated whether hippocampal function is altered after acute administration of hydrocortisone. Changes in BOLD signal following infusion of 100mg hydrocortisone given as a rapid intravenous bolus were measured in 14 healthy volunteers in a within-subject placebo-controlled crossover design. Subsequently, subjects completed an n-back task during an fMRI scan. Hydrocortisone infusion caused a significant, time-dependent increase in fMRI BOLD signal in hippocampus reaching a maximal effect at 11-19min. The n-back task increased BOLD signal in prefrontal and parietal cortical areas and decreased it in the hippocampus. After hydrocortisone the left hippocampal decrease in BOLD signal was attenuated with the magnitude of attenuation correlating with the increase seen after hydrocortisone infusion. No difference in behavioural task performance was observed. The results suggest acute hydrocortisone has rapid direct and modulatory influences on hippocampal function, probably acting through non-genomic GR or MR signalling. Hydrocortisone infusion phMRI may be a useful tool to investigate hippocampal corticosteroid receptor function in depression.

Background Brain morphometry is extensively used in cross-sectional studies. However, the difference in the estimated values of the morphometric measures between patients and healthy subjects may be small and hence overshadowed by the scanner-related variability, especially with multicentre and longitudinal studies. It is important therefore to investigate the variability and reliability of morphometric measurements between different scanners and different sessions of the same scanner. Methods We assessed the variability and reliability for the grey matter, white matter, cerebrospinal fluid and cerebral hemisphere volumes as well as the global sulcal index, sulcal surface and mean geodesic depth using Brainvisa. We used datasets obtained across multiple MR scanners at 1.5 T and 3 T from the same groups of 13 and 11 healthy volunteers, respectively. For each morphometric measure, we conducted ANOVA analysis and verified whether the estimated values were significantly different across different scanners or different sessions of the same scanner. The between-centre and between-visit reliabilities were estimated from their contribution to the total variance, using a random-effects ANOVA model. To estimate the main processes responsible for low reliability, the results of brain segmentation were compared to those obtained using FAST within FSL. Results In a considerable number of cases, the main effects of both centre and visit factors were found to be significant. Moreover, both between-centre and between-visit reliabilities ranged from poor to excellent for most morphometric measures. A comparison between segmentation using Brainvisa and FAST revealed that FAST improved the reliabilities for most cases, suggesting that morphometry could benefit from improving the bias correction. However, the results were still significantly different across different scanners or different visits. Conclusions Our results confirm that for morphometry analysis with the current version of Brainvisa using data from multicentre or longitudinal studies, the scanner-related variability must be taken into account and where possible should be corrected for. We also suggest providing some flexibility to Brainvisa for a step-by-step analysis of the robustness of this package in terms of reproducibility of the results by allowing the bias corrected images to be imported from other packages and bias correction step be skipped, for example.

BackgroundBoth 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.MethodThe 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.ResultsThe 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.ConclusionsAutomatic 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.

Aberrant signalling through central 5-HT(2C) receptor pathways has been implicated in various psychiatric disorders but this has not been amenable to experimental investigation in the absence of a valid in-vivo biomarker of functional 5-HT(2C) neurotransmission. One approach is drug-challenge pharmaco-magnetic resonance imaging (phMRI). We have previously shown that intravenous administration of the 5-HT(2C) agonist m-chlorophenylpiperazine (mCPP) elicits increases in blood oxygenation dependent signal (BOLD) in regions consistent with the distribution of 5-HT(2C) receptors. In the current study we determined whether BOLD signal responses to mCPP could be blocked by pre-treatment with a 5-HT(2C) antagonist. Healthy male volunteers received oral mirtazapine, 5-HT(2)/5-HT(3) receptor antagonist, or placebo 90min prior to intravenous mCPP challenge phMRI. BOLD signal increases following mCPP infusion occurred in areas known to be rich in 5-HT(2C) receptors such as the substantia nigra, hypothalamus, pallidum and amygdala. These responses were attenuated by mirtazapine pre-treatment. The results suggest that mCPP-challenge phMRI produces reliable patterns of response that are mediated by 5-HT(2C) receptors; these responses may therefore be useful in-vivo measures of 5-HT(2C) function in psychiatric disorders.

Chronic exposure to adverse interpersonal environment in schizophrenia is associated with vulnerability to relapse. The construct of expressed emotion (EE) measures the quality of interpersonal environment, of which criticism is a main component. To use functional magnetic resonance imaging and to investigate the neural basis of vulnerability of schizophrenic patients to EE, the effects of critical comments on brain mechanisms in 11 patients with schizophrenia were examined, comparing evoked responses to familiar (key relative) and unfamiliar (matched stranger) critical and neutral commentary. High EE stimuli evoked enhanced activation of brain regions concerned with the processing of aversive social information. Activations in the right BA44, rostral anterior cingulate, middle superior frontal gyrus, bilateral middle frontal gyrus, left temporal pole, left inferior frontal gyrus, and left insula were significantly modulated to familiar criticism. Such a pattern of neural response may represent a putative neural network responsible for mediating High EE in schizophrenia.

Both reduced serotonergic (5-HT) function and negative emotional biases have been associated with vulnerability to depression. In order to investigate whether these might be related we examined 5-HT modulation of affective processing in 14 remitted depressed subjects compared with 12 never depressed controls matched for age and sex. Participants underwent function magnetic resonance imaging (fMRI) during a covert face emotion task with and without intravenous citalopram (7.5mg) pretreatment. Compared with viewing neutral faces, and irrespective of group, citalopram enhanced left anterior cingulate blood oxygen level dependent (BOLD) response to happy faces, right posterior insula and right lateral orbitofrontal responses to sad faces, and reduced amygdala responses bilaterally to fearful faces. In controls, relative to remitted depressed subjects, citalopram increased bilateral hippocampal responses to happy faces and increased right anterior insula response to sad faces. These findings were not accounted for by changes in BOLD responses to viewing neutral faces. These results are consistent with previous findings showing 5-HT modulation of affective processing; differences found in previously depressed participants compared with controls may contribute to emotional processing biases underlying vulnerability to depressive relapse.

Magnetic resonance imaging (MRI) is widely used in brain imaging research (neuroimaging) to explore structural and functional changes across dispersed neural networks visible only via multisubject experiments. Multicenter investigations are an effective way to increase recruitment rates. This article describes image‐based power calculations for a two‐group, cross‐sectional design specified by the mean effect size and its standard error, sample size, false discovery rate (FDR), and size of the network (i.e., proportion of image locations) that truly demonstrates an effect. Minimum sample size (for fixed effect size) and the minimum effect size (for fixed sample size) are calculated by specifying the acceptable power threshold. Within‐center variance was estimated in five participating centers by repeat MRI scanning of 12 healthy participants from whom distributions of gray matter were estimated. The effect on outcome measures when varying FDR and the proportion of true positives is presented. Their spatial patterns reflect within‐center variance, which is consistent across centers. Sample sizes 3–6 times larger are needed when detecting effects in subcortical regions compared to the neocortex. Hypothesized multicenter studies of patients with first episode psychosis and control participants were simulated with varying proportions of the cohort recruited at each center. There is little penalty to sample size for recruitment at five centers compared to the center with the lowest variance alone. At 80% power 80 participants per group are required to observe differences in gray matter in high variance regions. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

Endocannabinoids have a variety of effects by acting through cannabinoid 1 (CB1) receptors located throughout the brain. However, since CB1 receptors are located presynaptically, and because the strength of downstream coupling varies with brain region, expression studies alone do not provide a firm basis for interpreting sites of action. Likewise, to date most functional studies have used high doses of drugs, which can bias results toward non-relevant adverse effects, and which mask more behaviourally-relevant actions. Here we use a low, orexigenic dose of the full CB1 agonist, CP55940, to map responsive brain regions using the complementary techniques of pharmacological-challenge functional magnetic resonance imaging (phMRI) and immediate-early gene activity. Areas of interest demonstrate a drug interaction when the CB1 receptor inverse agonist, rimonabant, is co-administered. This analysis highlights the corticostriatal-hypothalamic pathway, which is central to the motivational drive to eat.

BackgroundThere is relatively little existing information regarding the neural correlates of deception in individuals with psychopathic traits.AimsTo investigate the relationship between neural responses during deception and psychopathic personality traits in a sample of male participants drawn from the normal population.MethodTwenty-four male participants carried out a simple deception paradigm while undergoing functional magnetic resonance imaging. Psychopathic traits were assessed in the sample using the Psychopathic Personality Inventory (PPI).ResultsMean response times were greater for the lie than truth condition. Lie responses resulted in enhanced activation of the ventrolateral prefrontal cortex. The PPI sub-scales, coldheartedness, fearlessness, Machiavellian egocentricity, social potency and stress immunity were found to be correlated with activation patterns in the brain circuitry implicated in both deception and related processes such as behavioural restraint and social cognition.ConclusionsThis is a novel technology that may prove useful in our understanding of some of the key components of the psychopathy construct in both clinical and non-clinical contexts.

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.

CONTEXT: Ketamine evokes psychosislike symptoms, and its primary action is to impair N-methyl-D-aspartate glutamate receptor neurotransmission, but it also induces secondary increases in glutamate release. OBJECTIVES: To identify the sites of action of ketamine in inducing symptoms and to determine the role of increased glutamate release using the glutamate release inhibitor lamotrigine. DESIGN: Two experiments with different participants were performed using a double-blind, placebo-controlled, randomized, crossover, counterbalanced-order design. In the first experiment, the effect of intravenous ketamine hydrochloride on regional blood oxygenation level-dependent (BOLD) signal and correlated symptoms was compared with intravenous saline placebo. In the second experiment, pretreatment with lamotrigine was compared with placebo to identify which effects of ketamine are mediated by increased glutamate release. SETTING: Wellcome Trust Clinical Research Facility, Manchester, England. PARTICIPANTS: Thirty-three healthy, right-handed men were recruited by advertisements. INTERVENTIONS: In experiment 1, participants were given intravenous ketamine (1-minute bolus of 0.26 mg/kg, followed by a maintenance infusion of 0.25 mg/kg/h for the remainder of the session) or placebo (0.9% saline solution). In experiment 2, participants were pretreated with 300 mg of lamotrigine or placebo and then were given the same doses of ketamine as in experiment 1. MAIN OUTCOME MEASURES: Regional BOLD signal changes during ketamine or placebo infusion and Brief Psychiatric Rating Scale and Clinician-Administered Dissociative States Scale scores. RESULTS: Ketamine induced a rapid, focal, and unexpected decrease in ventromedial frontal cortex, including orbitofrontal cortex and subgenual cingulate, which strongly predicted its dissociative effects and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions (r = 0.90). Activations correlated with Brief Psychiatric Rating Scale psychosis scores. Lamotrigine pretreatment prevented many of the BOLD signal changes and the symptoms. CONCLUSIONS: These 2 changes may underpin 2 fundamental processes of psychosis: abnormal perceptual experiences and impaired cognitive-emotional evaluation of their significance. The results are compatible with the theory that the neural and subjective effects of ketamine involve increased glutamate release.

In this study, pharmacological-challenge magnetic resonance imaging was used to further characterize the central action of serotonin on feeding. In both feeding and pharmacological-challenge magnetic resonance imaging experiments, we combined 5-HT(1B/2C) agonist m-chlorophenylpiperazine (mCPP) challenge with pre-treatment with the selective 5-HT(1B) and 5-HT(2C) receptor antagonists, SB 224289 (2.5 mg/kg) and SB 242084 (2 mg/kg), respectively. Subcutaneous injection of mCPP (3 mg/kg) completely blocked fast-induced refeeding in freely behaving, non-anaesthetized male rats, an effect that was not modified by the 5-HT(1B) receptor antagonist but was partially reversed by the 5-HT(2C) receptor antagonist. mCPP alone induced both positive and negative blood oxygen level-dependent (BOLD) responses in the brains of anaesthetized rats, including in the limbic system and basal ganglia. Overall, the 5-HT(2C) antagonist SB 242084 reversed the effects elicited by mCPP, whereas the 5-HT(1B) antagonist SB 224289 had virtually no impact. SB 242084 eliminated BOLD signal in nuclei associated with the limbic system and diminished activation in basal ganglia. In addition, BOLD signal was returned to baseline levels in the cortical regions and cerebellum. These results suggest that mCPP may reduce food intake by acting specifically on brain circuits that are modulated by 5-HT(2C) receptors in the rat.

BackgroundThe nosological status of auditory hallucinations in non-clinical samples is unclearAimsTo investigate the functional neural basis of non-clinical hallucinationsMethodAfter selection from 1206 people, 68 participants of high, medium and low hallucination proneness completed a task designed to elicit verbal hallucinatory phenomena under conditions of stimulus degradation. Eight subjects who reported hearing a voice when none was present repeated the task during functional imagingResultsDuring the signal detection task, the high hallucination-prone participants reported a voice to be present when it was not (false alarms) significantly more often than the average or low participants (PPConclusionsAuditory hallucinatory experiences reported in non-clinical samples appear to be mediated by similar patterns of cerebral activation as found during hallucinations in schizophrenia

This study investigated the serotonergic modulation of face emotion processing using blood oxygen level-dependent (BOLD) functional MRI. In a placebo-controlled, balanced order design, intravenous citalopram (7.5 mg) was given to 12 male volunteers 60 min before a covert face emotion recognition task. Angry, disgusted and fearful faces produced BOLD signal responses, which were broadly consistent with previous findings. Citalopram enhanced the BOLD signal response in the left posterior insula (together with nonprespecified pulvinar and visual cortex) but attenuated activation in the left amygdala to disgusted faces and right amygdala activation to fearful faces. No citalopram modulation of BOLD responses to angry faces were found. These results suggest that serotonin modulates low-level amygdala activation to aversive stimuli.

Serotonin (5-HT) has been implicated in the aetiology of a number of psychiatric conditions, including depression, anxiety and antisocial personality disorder. The development of these disorders may arise from alterations in underlying motivational and cognitive processes such as emotional recognition, reinforcement processing and central inhibitory control. This study aimed to localize where in the brain 5-HT modulates neuropsychological processes relevant to putative 5-HT disorders, using functional magnetic resonance imaging. We examined the effect of the antidepressant mirtazapine on brain activations associated with behavioural inhibition and reinforcement processing in healthy subjects. Forty-five men were randomly allocated to receiving mirtazapine or placebo in a double-blind fashion. A Go/No-Go, Reward/No-Reward and Loss/No-loss task were performed during functional magnetic resonance imaging using a 1.5 Tesla Philips Gyroscan scanner. Blood oxygenation level dependent (BOLD) responses were analysed using SPM2. Task activations were largely consistent with previous findings. Mirtazapine modulated brain activations in the Go/No-Go and Reward/No-Reward task. During behavioural inhibition, enhanced activations were observed in the right orbitofrontal cortex (BA47). Increased activations in bilateral parietal cortex were found during the Reward task while no significant interaction was observed in the Loss task. Our results support the suggestion of an important role of serotonin in modulating basic processes involved in psychiatric disorders. Combining drug challenge with fMRI (pharmacoMRI; pMRI) is a promising tool for investigating these processes in healthy as well as patient groups.

Changes in serotonin neurotransmission have also been implicated in the etiology and treatment of impulse control disorders, depression, and anxiety. We have investigated the effect of enhancing serotonin function on fundamental brain processes that we have proposed are abnormal in these disorders. In all, 12 male volunteers received citalopram (7.5?mg intravenously) and placebo pretreatment in a single-blind crossover design before undertaking Go/No-go, Loss/No-loss, and covert (aversive) face emotion recognition tasks during functional magnetic resonance imaging (fMRI). Blood oxygenation level dependent responses were analyzed using Statistical Parametric Mapping (SPM2). The tasks activated prefrontal and subcortical regions generally consistent with literature with lateral orbitofrontal cortex (BA47) common to the three tasks. Citalopram pretreatment enhanced the right BA47 responses to the No-go condition, but attenuated this response to aversive faces. Attenuations were seen following citalopram in the medial orbitofrontal (BA11) responses to the No-go and No-loss (ie relative reward compared with Loss) conditions. The right amygdala response to aversive faces was attenuated by citalopram. These results support the involvement of serotonin in modulating basic processes involved in psychiatric disorders but argue for a process-specific, rather than general effect. The technique of combining drug challenge with fMRI (pharmacoMRI) has promise for investigating human psychiatric disorders.

BACKGROUND: Vulnerability to relapse persists after remission of an acute episode of major depressive disorder. This has been attributed to abnormal biases in the processing of emotional stimuli in limbic circuits. However, neuroimaging studies have not so far revealed consistent evidence of abnormal responses to emotional stimuli in limbic structures, such as the amygdala, in remitted depression. This suggests the problem might lie in the integrated functioning of emotion processing circuits. METHODS: We recruited 22 unmedicated patients in remission from major depressive disorder (rMDD) and 21 age-matched healthy control subjects. Functional magnetic resonance imaging was performed during a face emotion processing task. Dynamic causal modeling was used with Bayesian model selection to determine the most likely brain networks and valence-specific modulation of connectivity in healthy control subjects and rMDD. RESULTS: In healthy volunteers, sad faces modulated bi-directional connections between amygdala and orbitofrontal cortex and between fusiform gyrus and orbitofrontal cortex. Happy faces modulated unidirectional connections from fusiform gyrus to orbitofrontal cortex. In rMDD, the opposite pattern was observed, with evidence of happy faces modulating bidirectional frontotemporal connections and sad faces modulating unidirectional fusiform-orbitofrontal connections. CONCLUSIONS: Participants with rMDD have abnormal modulation of frontotemporal effective connectivity in response to happy and sad face emotions, despite normal activations within each region. Specifically, processing of mood incongruent happy information was associated with a more richly modulated frontotemporal brain network, whereas mood congruent sad information was associated with less network modulation. This supports a hypothesis of dysfunction within cortico-limbic connections in individuals vulnerable to depression.