Effects of ulotaront on brain circuits of reward, working memory, and emotion processing in healthy volunteers with high or low schizotypy.

Ulotaront, a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptor agonist without antagonist activity at dopamine D2 or the serotonin 5-HT2A receptors, has demonstrated efficacy in the treatment of schizophrenia. Here we report the phase 1 translational studies that profiled the effect of ulotaront on brain responses to reward, working memory, and resting state connectivity (RSC) in individuals with low or high schizotypy (LS or HS). Participants were randomized to placebo (n = 32), ulotaront (50 mg; n = 30), or the D2 receptor antagonist amisulpride (400 mg; n = 34) 2 h prior to functional magnetic resonance imaging (fMRI) of blood oxygen level-dependent (BOLD) responses to task performance. Ulotaront increased subjective drowsiness, but reaction times were impaired by less than 10% and did not correlate with BOLD responses. In the Monetary Incentive Delay task (reward processing), ulotaront significantly modulated striatal responses to incentive cues, induced medial orbitofrontal responses, and prevented insula activation seen in HS subjects. In the N-Back working memory task, ulotaront modulated BOLD signals in brain regions associated with cognitive impairment in schizophrenia. Ulotaront did not show antidepressant-like biases in an emotion processing task. HS had significantly reduced connectivity in default, salience, and executive networks compared to LS participants and both drugs reduced this difference. Although performance impairment may have weakened or contributed to the fMRI findings, the profile of ulotaront on BOLD activations elicited by reward, memory, and resting state is compatible with an indirect modulation of dopaminergic function as indicated by preclinical studies. This phase 1 study supported the subsequent clinical proof of concept trial in people with schizophrenia.Clinical trial registration: Registry# and URL: ClinicalTrials.gov NCT01972711, https://clinicaltrials.gov/ct2/show/NCT01972711.

Mapping the Homeostatic and Hedonic Brain Responses to Stevia Compared to Caloric Sweeteners and Water: A Double-Blind Randomised Controlled Crossover Trial in Healthy Adults.

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.

The effects of disease activity, inflammation, depression and cognitive fatigue on resting state fMRI in systemic lupus erythematosus.

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 < 0.01). Factor analysis generated one factor that only depression score correlated with for both the HC group (rs = -0.510) and SLE groups combined (rs = -0.390). Mediation analysis revealed depression score accounted for 22% of the altered FC in the DMN. Disease state accounted for the remaining 78%. 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.

The effects of disease activity on neuronal and behavioural cognitive processes in systemic lupus erythematosus.

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.

Changes in the neural correlates of self-blame following mindfulness-based cognitive therapy in remitted depressed participants.

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.

Stevia Beverage Consumption prior to Lunch Reduces Appetite and Total Energy Intake without Affecting Glycemia or Attentional Bias to Food Cues: A Double-Blind Randomized Controlled Trial in Healthy Adults.

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.

A Unique Brain Connectome Fingerprint Predates and Predicts Response to Antidepressants.

More than six decades have passed since the discovery of monoaminergic antidepressants. Yet, it remains a mystery why these drugs take weeks to months to achieve therapeutic effects, although their monoaminergic actions are present rapidly after treatment. In an attempt to solve this mystery, rather than studying the acute neurochemical effects of antidepressants, here we propose focusing on the early changes in the brain functional connectome using traditional statistics and machine learning approaches. Capitalizing on three independent datasets (n = 1,261) and recent developments in data and network science, we identified a specific connectome fingerprint that predates and predicts response to monoaminergic antidepressants. The discovered fingerprint appears to generalize to antidepressants with differing mechanism of action. We also established a consensus whole-brain hierarchical connectivity architecture and provided a set of model-based features engineering approaches suitable for identifying connectomic signatures of brain function in health and disease.

Spatiotemporal brain activation pattern following acute citalopram challenge is dose dependent and associated with neuroticism: A human phMRI study.

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'.

Evidence That Implementation Intentions Enhance Cognitive Training and Reduce Alcohol Consumption in Heavy Drinkers: A Randomized Trial.

BACKGROUND: Current training tasks to improve the cognitive deficits thought to be involved in sustained heavy drinking need further investigation to optimize their effectiveness. PURPOSE: The 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. METHODS: Thirty-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. RESULTS: Compared 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. CONCLUSIONS: These 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 REGISTRATION: This trial was registered (ISRCTN:35503634) and is available at https://www.isrctn.com/ISRCTN35503634.

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

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

Attentional bias to food varies as a function of metabolic state independent of weight status.

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.

Altered cognitive function in systemic lupus erythematosus and associations with inflammation and functional and structural brain changes.

OBJECTIVES: Cognitive dysfunction (CD) is common in systemic lupus erythematosus (SLE) but the cause remains unclear and treatment options are limited. We aimed to compare cognitive function in SLE and healthy controls (HCs) using both behavioural and neuroimaging techniques. METHODS: Patients with SLE with stable disease and HCs were recruited. Clinical and psychological data were collected along with a blood sample for relevant biomarkers. Neurocognitive function was assessed using tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and functional magnetic resonance imaging (fMRI) was used to examine brain responses to working memory (WM) and emotional processing (facial emotional recognition task, FERT) tasks. RESULTS: Compared with HCs (n=30), patients with SLE (n=36) scored higher on measures of depression, fatigue and had higher hsCRP (p=0.013), IL-6 (p=0.003) and B lymphocyte stimulator (p<0.001). Patients with SLE had poorer performance on a task of sustained attention (p=0.002) and had altered brain responses, particularly in default mode network (DMN) regions and the caudate, during the WM task. Higher organ damage and higher VCAM-1 were associated with less attenuation of the DMN (p=0.005 and p=0.01, respectively) and lower BOLD signal in the caudate areas (p=0.005 and p=0.001, respectively). Increased IL-6 was also associated with lower BOLD signal in caudate areas (p=0.032). CONCLUSIONS: Sustained attention was impaired in patients with SLE. Poor attenuation of the DMN may contribute to cognitive impairments in SLE and our data suggest that in addition to mood and fatigue inflammatory mechanisms and organ damage impact cognitive functioning in SLE. The multifaceted nature of CD in SLE means any therapeutic interventions should be individually tailored.

Regional default mode network connectivity in major depressive disorder: modulation by acute intravenous citalopram.

The relationship between altered default mode network (DMN) connectivity and abnormal serotonin function in major depressive disorder (MDD) has not been investigated. Using intravenous citalopram and resting-state fMRI, we investigated DMN intra-network connectivity and serotonin function in 77 healthy controls and patients with MDD. There were no significant main effects of MDD or citalopram on DMN intra-network connectivity; however, significant interactions indicated that group differences under saline were modified by citalopram. In MDD patients during saline infusion, in contrast with controls, the DMN (i) did not include the precuneus that was instead part of an anti-correlated network but (ii) did include amygdala that was part of the anti-correlated network in controls. Citalopram infusion in MDD patients restored the pattern seen in controls under saline. In healthy controls, citalopram infusion disengaged the precuneus from the DMN and engaged the amygdala, partially reproducing the abnormalities seen under saline in MDD. In exploratory analyses within the MDD group, greater rumination self-ratings were associated with greater intra-network connectivity of the anterior cingulate cortex with the DMN. We hypothesise that, in MDD, disengagement of the precuneus from the DMN relates to overgeneral memory bias in rumination. The opposite effect, with greater engagement of the amygdala in the DMN, reflects the negative valence of rumination. Reversal of these abnormalities by citalopram suggests that they may be related to impaired serotonin function. That citalopram engaged the amygdala in the DMN in controls may relate to the paradoxical effects on aversive processing seen with acute SSRIs in healthy subjects.

Ketamine, but Not the NMDAR Antagonist Lanicemine, Increases Prefrontal Global Connectivity in Depressed Patients.

BACKGROUND: Identifying the neural correlates of ketamine treatment may facilitate and expedite the development of novel, robust, and safe rapid-acting antidepressants. Prefrontal cortex (PFC) global brain connectivity with global signal regression (GBCr) was recently identified as a putative biomarker of major depressive disorder (MDD). Accumulating evidence have repeatedly shown reduced PFC GBCr in MDD, an abnormality which appears to normalize following ketamine treatment. METHODS: Fifty-six unmedicated participants with MDD were randomized to intravenous placebo (normal saline; n = 18), ketamine (0.5mg/kg; n = 19) or lanicemine (100mg; n = 19). PFC GBCr was computed using time series from functional magnetic resonance imaging (fMRI) scans that were completed at baseline, during infusion, and 24h post-treatment. RESULTS: Compared to placebo, ketamine significantly increased average PFC GBCr during infusion (p = 0.01) and 24h post-treatment (p = 0.02). Lanicemine had no significant effects on GBCr during infusion (p = 0.45) and 24h post-treatment (p = 0.23), compared to placebo. Average delta PFC GBCr (during minus baseline) showed a pattern of positively predicting depression improvement in participants receiving ketamine (r = 0.44; p = 0.06; d = 1.0) or lanicemine (r = 0.55; p = 0.01; d = 1.3), but not those receiving placebo (r = -0.1; p = 0.69; d = 0.02). Follow-up vertex-wise analyses showed ketamine-induced GBCr increases in the dorsolateral, dorsomedial, and frontomedial PFC during infusion, and in the dorsolateral and dorsomedial PFC 24h post-treatment (corrected p < 0.05). Exploratory vertex-wise analyses examining the relationship with depression improvement showed positive correlation with GBCr in the dorsal PFC during infusion and 24h post-treatment, but negative correlation with GBCr in the ventral PFC during infusion (uncorrected p < 0.01). CONCLUSIONS: In a randomized placebo-controlled approach, the results provide the first evidence in MDD of ketamine-induced increases in PFC GBCr during infusion, and suggests that ketamine's rapid-acting antidepressant properties are related to its acute effects on prefrontal connectivity. Overall, the study findings underscore the similarity and differences between ketamine and another N-methyl-D-aspartate receptor (NMDAR) antagonist, while proposing a pharmacoimaging paradigm for optimization of novel rapid-acting antidepressants prior to testing in costly clinical trials.

Time-dependent neuronal changes associated with craving in opioid dependence: an fMRI study.

Relapse after initially successful treatment is a significant problem facing the treatment of opioid dependence. Evidence suggests craving elicited by re-exposure to drug cues may precipitate relapse. Attempts to identify neural biomarkers of cue-elicited craving have yielded inconsistent findings. We aimed to apply a novel continuous functional magnetic resonance imaging technique to follow the minute-to-minute evolution of brain responses, which correlate with the waxing and waning of craving. Newly detoxified male opioid-dependent patients and healthy control participants attended two separate, counterbalanced, functional magnetic resonance imaging scanning sessions during which they viewed a 10-minute video (drug cue or neutral cue) followed by 5 minutes of fixation. Participants rated the intensity of their craving throughout each session. We hypothesized that subcortical/ventral prefrontal cortex (PFC) regions and dorsal PFC regions would show different associations with craving reflecting their putative roles in appetitive processing versus cognitive control. Compared with controls, drug cue (minus neutral cue) video recruited the left amygdala and was temporally correlated with craving. In contrast, dorsal anterior cingulate blood-oxygen-level-dependent signal time course was higher than controls only during a period after cue exposure when craving levels were declining. Against expectations, neither the ventral striatum nor ventral PFC was significantly recruited by drug cue exposure. Findings suggest that the amygdala has a central role in craving, whereas the dorsal anterior cingulate may control craving in treatment-seeking patients. Time course analysis yielded new insights into the neural substrates of craving that could objectively validate development of psychological and pharmacological approaches to sustained abstinence.

Functional magnetic resonance imaging in dermatology: The skin, the brain and the invisible.

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.

Human brain responses to gastrointestinal nutrients and gut hormones.

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.

Effects of acute tryptophan depletion on central processing of CT-targeted and discriminatory touch in humans.

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 h, participants underwent an fMRI scan, during which time CT-innervated forearm skin and CT non-innervated finger skin was stroked with three 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. In addition, 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 similar 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.

Comparing the actions of lanicemine and ketamine in depression: key role of the anterior cingulate.

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).