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Non-nutritive sweeteners have potential effects on brain function. We investigated neural correlates of responses to beverages differing in sweetness and calories. Healthy participants completed 4 randomised sessions: water vs. water with stevia, glucose, or maltodextrin. Blood-oxygenation level-dependent (BOLD) contrast was monitored for 30 min post-ingestion by functional Magnetic Resonance Imaging. A food visual probe task at baseline was repeated at 30 min. A significant interaction of taste-by-calories-by-time was demonstrated mainly in motor, frontal, and insula cortices. Consumption of the stevia-sweetened beverage resulted in greater BOLD decrease, especially in the 20–30 min period, compared to other beverages. There was a significant interaction of taste-by-time in BOLD response in gustatory and reward areas; sweet beverages induced greater reduction in BOLD compared to non-sweet. The interaction calories-by-time showed significantly greater incremental area under the curve in thalamic, visual, frontal, and parietal areas for glucose and maltodextrin 10–20 min post-consumption only, compared to water. In the visual cue task, the water demonstrated an increased response in the visual cortex to food images post-consumption; however, no difference was observed for the three sweet/caloric beverages. In conclusion, both sweet taste and calories exert modulatory effects, but stevia showed a more robust and prolonged effect.

Background: Stevia is a zero-calorie alternative to caloric sugars. Substituting caloric sweeteners with noncaloric sweeteners reduces available energy, but their effects on appetite, subsequent food intake, and neurocognitive responses are still unclear. Objective: The aim was to examine whether sweetness with or without calories influences food intake, appetite, blood glucose concentrations, and attentional bias (AB) to food cues. Methods: This was a randomized, controlled, double-blind crossover study. Healthy participants [n = 20; aged 27 ± 5 y, 55% female; BMI (kg/m2): 21.8 ± 1.5] completed 5 visits, consuming 5 study beverages: 330 mL water (control, no sweet taste, no calories) and either 330 mL water containing 40 g glucose or sucrose (sweet taste; calories, both 160 kcal), maltodextrin (no sweet taste; calories, 160 kcal), or 240 ppm stevia (sweet taste, no calories). Glucose and stevia beverages were matched for sweetness. Subjective appetite ratings and blood glucose were measured at baseline and at 15, 30, and 60 min postprandially. At 15 min participants performed a visual-dot probe task to assess AB to food cues; at 30 min, participants were offered an ad libitum lunch; food intake was measured. Results: Subjective appetite ratings showed that preload sweetness and calorie content both affected appetite. The total AUC for glycemia was significantly higher after the caloric beverages (mean ± SD: maltodextrin, 441 ± 57.6; glucose, 462 ± 68.1; sucrose, 425 ± 53.6 mmol × min × L-1 ) compared with both stevia (320 ± 34.2 mmol × min × L-1) and water (304 ± 32.0 mmol × min × L-1) (all P < 0.001). Total energy intake (beverage and meal) was significantly lower after the stevia beverage (727 ± 239 kcal) compared with water (832 ± 198 kcal, P = 0.013), with no significant difference between the water and caloric beverages (P = 1.00 for water vs. maltodextrin, glucose, and sucrose). However, food-related AB did not differ across conditions (P = 0.140). Conclusions: This study found a beneficial and specific effect of a stevia beverage consumed prior to a meal on appetite and energy intake in healthy adults. This trial is registered at clinicaltrials.gov as NCT03711084.

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 Cognitive dysfunction (CD) affects up to 90% of systemic lupus erythematosus (SLE) patients and significantly impacts patient quality of life. The cause is multifaceted with many factors common across chronic diseases. It is thus difficult to ascertain the direct impact active disease in SLE has upon immediate cognitive function. Objectives The aim of this study was to investigate the effects of active disease in SLE on CD. We compared cognitive measures in SLE patients with stable disease activity (SLE-S) to those with active disease (SLE-F). Methods 34 SLE-S and 24 SLE-F were recruited, all meeting 1997 ACR criteria. Active disease was defined as BILAG A or B with a change in treatment. Stable disease was defined as SLEDAI-2K ≤4. Overall 14/24 SLE-F patients were assessed again at 2nd visit (v1 vs v2) when their disease activity had reduced. CD was measured using tests from a computerized battery of tests (CANTAB®). fMRI was used to examine neuronal responses to a working memory and attention task (n-back) and a facial emotional processing task (FERT). Analysis compared the SLE-S and SLE-F groups as well as a within group comparison for v1 vs v2. fMRI data were analysed using SPM12. All other data were analysed using SPSS 22. Results There were no differences between the SLE-S and SLE-F groups or between v1 and v2 on demographic and clinical measures except disease activity. The SLE-F group scored higher than the SLE-S group on the MADRS depression scale (p=0.003) but no other significant differences in psychiatric symptoms were observed. There were no significant differences on the CANTAB® for either comparison (table 1). The fMRI showed a SLE-S vs SLE-F difference in n-back related response in the medial prefrontal cortex (p=0.012; figure 1). No v1 vs v2 differences were found, nor for either comparison for the FERT. Conclusion In a cohort well matched on confounding factors these results suggest that active disease does not impair cognitive function. However, the differences in the medial frontal cluster during the working memory task may indicate the use of compensatory mechanisms to maintain cognitive function as has been found elsewhere. Alternatively, as this is a default mode network region, often implicated in self-reflective processes it may be that CD is more directly associated with differences in mood. As such when treating SLE patients with self-reported CD it is important to consider factors other than disease activity. Acknowledgement This study was partially funded by an unrestricted grant from Sanofi Genzyme and supported by the NIHR Manchester Biomedical Research Centre. Disclosure of Interests Michelle Barraclough Grant/research support from: This study was partially funded by an unrestricted grant from Sanofi Genzyme., Rebecca Elliott: None declared, Shane McKie: None declared, Ben Parker Grant/research support from: GSK, Consultant for: AZ, UCB, GSK, Ian N. Bruce Grant/research support from: Genzyme Sanofi, GlaxoSmithKline, Consultant for: AstraZeneca, Eli Lilly, GlaxoSmithKline, ILTOO Pharma, MedImmune, Merck Serono, Speakers bureau: GlaxoSmithKline, UCB Pharma

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’.

Eating behaviour requires that internal metabolic changes are recognized by the central nervous system which regulates brain responses to food cues. This function may be altered in obesity. The aim of this study was to examine potential differences in neurocognitive responses to visual food cues as a function of metabolic state and weight status. A crossover study with two participant groups was conducted, one group with normal-weight (n = 20) and one group with overweight/obesity (n = 22), who completed a novel battery of neurocognitive tests assessing food-cue elicited behavior in both fasted and fed states. The test battery included a visual-dot probe task (VPT), a stimulus-response compatibility task (SRCT) and an implicit association task (IAT). Results from the VPT showed a significant main effect of metabolic state on attentional bias (F(1,40) = 9.90, p = .003, η2p = .198), with participants in the fasted state showing a significantly greater attentional bias for food stimuli than in the fed state. No significant main effect of metabolic state on approach food bias, assessed via the SRCT, or implicit attitudes to food cues, assessed via the IAT, was found and overall, no difference in neurocognitive processing of food cues was demonstrated between participant groups. In the fed state, attentional bias to food cues decreases in both normal-weight controls and participants with overweight/obesity, indicating that changes in current metabolic state can be reflected in attentional processing of visual food cues independently of weight status. Neurocognitive tasks which can effectively and sensitively identify differences in food cue perception according to changes in metabolic status will be useful tools in exploring more complicated interactions between homeostatic and hedonic drives of food intake.

Background:Obsessive-compulsive disorder (OCD) is more prevalent in systemic autoimmune diseases when compared to healthy controls. This is in part due to inflammatory mechanisms, common across both conditions. Neuroinflammation and specifically problems within the basal ganglia are associated with OCD.Objectives:The primary objective of this analysis was to investigate the effects of disease activity in systemic lupus erythematosus (SLE) on OCD. Other variables investigated included psychiatric aspects, inflammatory biomarkers and structural brain abnormalities.Methods:SLE patients who met ACR or SLICC criteria were recruited. Demographic and clinical data were collected and data measuring disease activity (BILAG and SLEDAI-2K), disease damage (SLICC-DI), depression (MADRS, BDI-II, HADS), anxiety (HADS, STAI), fatigue (FSMC), quality of life (LupusQoL and EQ5D), inflammatory and endothelial activation (EA) biomarkers (IL-6, ESR, TNF-α, MCP-1, hsCRP, BLyS, VCAM-1, VEGF, EMVs) and OCD (OCI-R). MRI FLAIR structural scans were also used to examine signal hyperintensities in the brain. Participants with active disease (SLE-F) also had a 2ndvisit approx. 4 months later. Non-parametric correlations with the OCI-R were undertaken for all SLE participants and for the change over time scores for the SLE-F participants (n=11).Results:39 participants were included in the analysis and were typical for a SLE population. 6 (23%) patients had scores above the threshold for OCD. OCI-R significantly correlated with disease activity, quality of life, fatigue, depression and anxiety measures for all the SLE participants. Change in monocyte chemoattractant protein-1 (MCP-1) correlated with the OCI-R for the within SLE-F group analysis (Table 1). No significant correlations were found with the full SLE group for inflammatory or EA biomarkers or with either group for the structural brain analysis.Table 1.Significant correlations with the OCI-R for: a) all SLE participants; b) the SLE-F group only (visit 1 minus visit 2).Variablersp-valuea)All SLE participants, n=39Disease activity: BILAG global score0.4080.01Quality of life: LupusQoL – Physical-0.4950.001 – Pain-0.535 – Planning-0.586 – Intimate-0.3420.03 – Burden-0.5040.001 – Emotion-0.3970.01 – Fatigue-0.4710.002 EQ5D: VAS-0.4180.01 total-0.3590.03Fatigue measures (FSMC): Cognitive0.5210.001 Motor0.4480.004Depression measures: MADRS0.4670.003 HADS – D0.545Anxiety measure: HADS-A0.3750.02b)SLE-F group (v1-v2), n=11Inflammatory marker: MCP-10.7710.006BILAG The British Isles Lupus Assessment Group index, LupusQoL Lupus quality of life, EQ5D European quality of life, VAS visual analogue scale, FSMC Fatigue scale for motor and cognitive function, MADRS Montgomery Asberg depression rating scale, HADS Hospital anxiety and depression scale, D-depression, A-anxiety score, MCP-1 monocyte chemoattractant protein-1Conclusion:OCD in lupus is strongly related to other psychological co-morbidities, fatigue and quality of life. Our results also support a role for inflammatory pathways in mediating some of these changes and so obsessive-compulsive features should be assessed in SLE patients who flare. A larger study is underway to better understand the mechanisms underlying these associations.Acknowledgments:This study was partially funded by an unrestricted grant from Sanofi Genzyme and supported by the NIHR Manchester Biomedical Research Centre.Disclosure of Interests: :Michelle Barraclough Grant/research support from: This study was partially funded by an unrestricted grant from Sanofi Genzyme., Ben Parker Grant/research support from: GSK and Sanofi Genzyme, Consultant of: GSK, AstraZenaca, UCV, Abbvie, Pfizer, BMS, Celltrion, Shane McKie: None declared, Philip Pemberton: None declared, Alan Jackson: None declared, Rebecca Elliott: None declared, Ian N. Bruce Grant/research support from: Genzyme Sanofi, GSK, and UCB, Consultant of: Eli Lilly, AstraZeneca, UCB, Iltoo, and Merck Serono, Speakers bureau: UCB

The need for rapid acting antidepressants is widely recognised. There has been much interest in glutamate mechanisms in major depressive disorder (MDD) as a promising target for the development of new antidepressants. A single intravenous infusion of ketamine, a N-methyl-d-aspartate (NMDA) receptor antagonist anaesthetic agent, can alleviate depressive symptoms in patients within hours of administration. The mechanism of action appears to be in part through glutamate release onto non-NMDA receptors including α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and metabotropic receptors. However these are also reported effects on 5-HT, dopamine and intracellular effects on the mammalian target of rapamycin (mTOR) pathway. The effects of SSRI (Selective Serotonin Reuptake Inhibitor) antidepressants may also involve alterations in NMDA function. The article reviews the effect of current antidepressants on NMDA and examines the efficacy and mechanism of ketamine. Response to ketamine is also discussed and comparison with other glutamate drugs including lamotrigine, amantadine, riluzole, memantine, traxoprodil, GLYX-13, MK-0657, RO4917523, AZD2066 and Coluracetam. Future studies need to link the rapid antidepressant effects seen with ketamine to inflammatory theories in MDD.

OBJECTIVES: Non-nutritive sweeteners (NNS) are zero- or low-calorie alternatives to caloric sugars and substituting caloric sweeteners with NNS is expected to reduce energy intake. The aim of this study was to examine appetite and food intake following the consumption of a beverage preload containing a natural zero calorie sweetener or caloric sweeteners (sugars). METHODS: This was a randomised controlled double-blind crossover study. Healthy participants (n = 20, 9 males, mean body mass index 21.8 kg/m(2)) completed five separate visits, corresponding to five study beverages: 330 mL of water (control-no calories and no taste) and either 330 mL of water containing 40 g glucose or sucrose (sweet taste and calories), maltodextrin (calories and no sweet taste), or 240 ppm all natural sweetener, stevia (Truvia RA-95-sweet taste and no calories). Subjective appetite ratings and blood glucose was measured at baseline and then study beverages were administered, with appetite ratings and blood glucose again measured at 15, 30 and 60 minutes. At 30 minutes participants were offered an ad libitum lunch and food intake was measured. RESULTS: Stevia and glucose preloads were rated to have equal sweetness levels, while water and maltodextrin the lowest levels of sweetness. Only glucose, sucrose and maltodextrin elevated blood glucose. Both calories and sweet taste affected appetite as there was a significant effect on suppressed subjective appetite ratings following the stevia and caloric preloads compared to water at 15 and 30 minutes postprandially. Compared to water preload, food intake was significantly lower after the consumption of each of the sweet or caloric preloads. Analysis of cumulative energy intake (preload and lunch) showed that total energy intake was lower after the stevia preload compared to the water preload with no differences between the water and caloric preloads (Figure 1). CONCLUSIONS: This study, found a beneficial effect of a stevia beverage consumed prior to a meal on appetite and subsequent energy intake compared to water. This study was registered in clinicaltrial.gov as NCT03711084. FUNDING SOURCES: This research was supported by a BBSRC Case Studentship. SUPPORTING TABLES, IMAGES AND/OR GRAPHS

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

Functional mapping of human brain activation has made it possible to understand how different nutrients in the gut impact on homeostatic and appetitive brain responses. Current data are limited, but nutrient-specific effects are observed, with differential responses to lipid and sugars. Responses are not a simple function of calorie intake. Gut hormones such as CCK, PYY, GLP-1 and ghrelin are implicated in these responses, but may not exert effects directly on the brain. Research is now addressing how these homeostatic signalling states (fasting/fed) interact with hedonic responses, such as those evoked by images of appealing food. Differences are also beginning to emerge in obese versus lean subjects. These platforms will enable a new understanding of normal and disordered eating behaviours in humans.

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).

Rationale:\ud \ud Working memory impairments in schizophrenia have been attributed to dysfunction of the dorsolateral prefrontal cortex (DLPFC) which in turn may be due to low DLPFC dopamine innervation. Conventional antipsychotic drugs block DLPFC D2 receptors, and this may lead to further dysfunction and working memory impairments. Aripiprazole is a D2 receptor partial agonist hypothesised to enhance PFC dopamine functioning, possibly improving working memory.\ud \ud Objectives:\ud \ud We probed the implications of the partial D2 receptor agonist actions of aripiprazole within the DLPFC during working memory. Investigations were carried out in healthy volunteers to eliminate confounds of illness or medication status. Aripiprazole’s prefrontal actions were compared with the D2/5-HT2A blocker risperidone to separate aripiprazole’s unique prefrontal D2 agonist actions from its serotinergic and striatal D2 actions that it shares with risperidone.\ud \ud Method:\ud \ud A double-blind, placebo-controlled, parallel design was implemented. Participants received a single dose of either 5 mg aripiprazole, 1 mg risperidone or placebo before performing the n-back task whilst undergoing fMRI scanning.\ud \ud Results:\ud \ud Compared with placebo, the aripiprazole group demonstrated enhanced DLPFC activation associated with a trend for improved discriminability (d’) and speeded reaction times. In contrast to aripiprazole’s neural effects, the risperidone group demonstrated a trend for reduced DLPFC recruitment. Unexpectedly, the risperidone group demonstrated similar effects to aripiprazole on d’ and additionally had reduced errors of commission compared with placebo.\ud \ud Conclusion:\ud \ud Aripiprazole has unique DLPFC actions attributed to its prefrontal D2 agonist action. Risperidone’s serotinergic action that results in prefrontal dopamine release may have protected against any impairing effects of its prefrontal D2 blockade.

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.

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.

Although a relationship between emotional state and feeding behavior is known to exist, the interactions between signaling initiated by stimuli in the gut and exteroceptively generated emotions remain incompletely understood. Here, we investigated the interaction between nutrient-induced gut-brain signaling and sad emotion induced by musical and visual cues at the behavioral and neural level in healthy nonobese subjects undergoing functional magnetic resonance imaging. Subjects received an intragastric infusion of fatty acid solution or saline during neutral or sad emotion induction and rated sensations of hunger, fullness, and mood. We found an interaction between fatty acid infusion and emotion induction both in the behavioral readouts (hunger, mood) and at the level of neural activity in multiple pre-hypothesized regions of interest. Specifically, the behavioral and neural responses to sad emotion induction were attenuated by fatty acid infusion. These findings increase our understanding of the interplay among emotions, hunger, food intake, and meal-induced sensations in health, which may have important implications for a wide range of disorders, including obesity, eating disorders, and depression. ispartof: Journal of Clinical Investigation vol:121 issue:8 pages:3094-3099 ispartof: location:United States status: published

Impulsivity has been associated with several psychiatric disorders including drug addiction and gambling. Impulsive subjects typically have a preference for short-term over long-term rewards and make risky choices. This study used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of self-rated impulsivity and venturesomeness during tasks involving delayed and risky choice. A broader sampling approach was taken by recruiting participants with behaviors that have been linked to impulsivity (gambling N=15, and recreational drug use N=10) and those without these behaviors (N=9). Selection between delayed or probabilistic rewards was associated with activation in fronto-parietal regions in line with previous research. When selecting between delayed rewards, activity within the pregenual anterior cingulate cortex and ventrolateral prefrontal cortex correlated positively with impulsivity scores while activity within the orbitofrontal cortex, subgenual anterior cingulate cortex and caudate correlated positively with venturesomeness scores. Selection between probabilistic rewards revealed no correlation between scores and regional activations. The results from this study provide targets for future research investigating the neural substrates of impulsivity. They also provide targets for the further investigation into the pathophysiology of addiction and impulse-control disorders.

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.

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

This study assessed the effects of a session of eye movement desensitization and reprocessing (EMDR) with auditory alternating bilateral stimulation (ABS) using functional magnetic resonance imaging (fMRI) of brain activations. A case study was conducted with a female participant who was suffering from posttraumatic stress disorder following a severe assault. The fMRI scan began with safe-place imagery, for purposes of comparison, and then attention to the trauma memory without ABS. After this, ABS was provided as she began using EMDR procedures to process the traumatic memory. At postsession, the traumatic memory showed robust and significant changes on self-report measures. The initiation of the EMDR protocol with provision of ABS was associated with a marked change in brain activation within the prefrontal cortex demonstrating a ventromedial shift. The authors argue that the structure of the EMDR protocol encourages such a ventromedial activation, which is then intensified by ABS to overcome the block to information processing that has been preventing natural healing from occurring spontaneously.

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.

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.