Variability in the analysis of a single neuroimaging dataset by many teams.

Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses1. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset2-5. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.

Symptom flares in women with chronic pelvic pain: Questionnaire study within a cohort study (translational research in pelvic pain (TRiPP)).

OBJECTIVE: To quantify the variation, triggers and impact on quality of life of symptom flares in women with chronic pelvic pain (CPP). DESIGN: Cross-sectional questionnaire within the Translational Research in Pelvic Pain clinical cohort study. SETTING: Women with CPP, with subgroups of women with endometriosis (EAP), interstitial cystitis/bladder pain syndrome (BPS), comorbid endometriosis and interstitial cystitis/bladder pain syndrome (EABP), and those with pelvic pain without endometriosis or interstitial cystitis/bladder pain syndrome (PP). POPULATION OR SAMPLE: A total of 100 participants. METHODS: Descriptive and comparative analysis from flares questionnaire. MAIN OUTCOME MEASURES: The prevalence, characteristics and triggers of short, medium and long symptom flares in CPP. RESULTS: We received 100 responses of 104 questionnaires sent. Seventy-six per cent of women with CPP have ever experienced symptom flares of at least one length (short, medium and/or long). Flares are associated with painful and non-painful symptoms. There is large variation for the frequency, duration, symptoms and triggers for flares. Over 60% of participants reported flares as stopping them from doing things they would usually do, >80% reported thinking about symptoms of flares and >80% reported flares being bothersome. CONCLUSIONS: Flares are prevalent and clinically very important in CPP. More research is needed to elucidate the mechanisms and characteristics underlying flares. Clinical practice should include an enquiry into flares with the aim of finding strategies to lessen their burden.

A comprehensive evaluation of increasing temporal resolution with multiband-accelerated protocols and effects on statistical outcome measures in fMRI.

Accelerated functional Magnetic Resonance Imaging (fMRI) with 'multiband' protocols is now relatively widespread. These protocols can be used to dramatically reduce the repetition time (TR) and produce a time-series sampled at a higher temporal resolution, which may produce benefits in the statistical methods typically used to analyse fMRI data. We tested the effects of higher temporal resolutions for fMRI on statistical outcome measures in a comprehensive manner on two different MRI scanner platforms. Spatial resolution was maintained at a constant of 3 mm isotropic voxels, and an in-plane acceleration factor of 2 was used for all experiments. Experiment 1 tested a range of acceleration factors (1-6) against a standard EPI protocol on a single composite task that mapped a number of basic sensory, motor, and cognitive networks. Experiment 2 compared the standard protocol with acceleration factors of 2 and 3 on both resting-state and two task paradigms (an N-back task, and faces/places task), with a number of different analysis approaches. Results from experiment 1 showed modest but relatively inconsistent effects of the higher sampling rate on statistical outcome measures. Experiment 2 showed strong benefits of the multiband protocols on results derived from resting-state data, but more varied effects on results from the task paradigms. Notably, the multiband protocols were superior when Multi-Voxel Pattern Analysis was used to interrogate the faces/places data, but showed less benefit in conventional General Linear Model analyses of the same data. In general, ROI-derived measures of statistical effects benefitted only modestly from higher sampling resolution, with greater effects seen when using a measure of the top range of statistical values. Across both experiments, results from the two scanner platforms were broadly comparable. The statistical benefits of high temporal resolution fMRI with multiband protocols may therefore depend on a number of factors, including the nature of the investigation (resting-state vs. task-based), the experimental design, the particular statistical outcome measure, and the type of analysis used.

Current developments in endometriosis-associated pain.

Endometriosis-associated pain is burdensome to both the individual and wider society. However, current treatment leaves many with persisting pain. Here, we highlight how recent work considering endometriosis in the context of chronic pain has altered our understanding and how this has the potential to improve clinical care.

Clinical profiling of specific diagnostic subgroups of women with chronic pelvic pain.

Introduction: Chronic pelvic pain (CPP) is a common condition affecting up to 26.6% of women, with many suffering for several years before diagnosis and/or treatment. Its clinical presentation is varied and there are frequently comorbid conditions both within and outside the pelvis. We aim to explore whether specific subgroups of women with CPP report different clinical symptoms and differing impact of pain on their quality of life (QoL). Methods: The study is part of the Translational Research in Pelvic Pain (TRiPP) project which is a cross-sectional observational cohort study. The study includes 769 female participants of reproductive age who completed an extensive set of questions derived from standardised WERF EPHect questionnaires. Within this population we defined a control group (reporting no pelvic pain, no bladder pain syndrome, and no endometriosis diagnosis, N = 230) and four pain groups: endometriosis-associated pain (EAP, N = 237), interstitial cystitis/bladder pain syndrome (BPS, N = 72), comorbid endometriosis-associated pain and BPS (EABP, N = 120), and pelvic pain only (PP, N = 127). Results: Clinical profiles of women with CPP (13-50 years old) show variability of clinical symptoms. The EAP and EABP groups scored higher than the PP group (p < 0.001) on the pain intensity scales for non-cyclical pelvic pain and higher than both the BPS and PP groups (p < 0.001) on the dysmenorrhoea scale. The EABP group also had significantly higher scores for dyspareunia (p < 0.001), even though more than 50% of sexually active participants in each pain group reported interrupting and/or avoiding sexual intercourse due to pain in the last 12 months. Scores for the QoL questionnaire (SF-36) reveal that CPP patients had significantly lower QoL across all SF-36 subscales (p < 0.001). Significant effects were also observed between the pain groups for pain interference with their work (p < 0.001) and daily lives (p < 0.001), with the EABP suffering more compared to the EAP and PP groups (p < 0.001). Discussion: Our results demonstrate the negative impact that chronic pain has on CPP patients' QoL and reveal an increased negative impact of pain on the comorbid EABP group. Furthermore, it demonstrates the importance of dyspareunia in women with CPP. Overall, our results demonstrate the need for further exploration of interventions targeting QoL more broadly and suggest that novel approaches to classifying women with CPP are needed.

Comprehensive quantitative sensory testing shows altered sensory function in women with chronic pelvic pain: results from the Translational Research in Pelvic Pain (TRiPP) Study.

ABSTRACT: Chronic pelvic pain (CPP), despite its high prevalence, is still relatively poorly understood mechanistically. This study, as part of the Translational Research in Pelvic Pain (TRiPP) project, has used a full quantitative sensory testing (QST) paradigm to profile n = 85 women with and without CPP (endometriosis or bladder pain specifically). We used the foot as a control site and abdomen as the test site. Across 5 diagnostically determined subgroups, we found features which are common across different aetiologies, eg, gain of function in pressure pain threshold (PPT) when assessing responses from the lower abdomen or pelvis (referred pain site). However, disease-specific phenotypes were also identified, eg, greater mechanical allodynia in endometriosis, despite there being large heterogeneities within diagnostic groups. The most common QST sensory phenotype was mechanical hyperalgesia (>50% across all the groups). A "healthy' sensory phenotype was seen in <7% of CPP participants. Specific QST measures correlated with sensory symptoms assessed by the painDETECT questionnaire (pressure-evoked pain [painDETECT] and PPT [QST] [ r = 0.47, P < 0.001]; mechanical hyperalgesia (painDETECT) and mechanical pain sensitivity [MPS from QST] [ r = 0.38, P = 0.009]). The data suggest that participants with CPP are sensitive to both deep tissue and cutaneous inputs, suggesting that central mechanisms may be important in this cohort. We also see phenotypes such as thermal hyperalgesia, which may be the result of peripheral mechanisms, such as irritable nociceptors. This highlights the importance of stratifying patients into clinically meaningful phenotypes, which may have implications for the development of better therapeutic strategies for CPP.

Individual and combined effects of cannabidiol and Δ9-tetrahydrocannabinol on striato-cortical connectivity in the human brain.

BACKGROUND: Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. AIMS: To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor). METHOD: Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach. RESULTS: Study 1 (N = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 (N = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks. OUTCOMES: THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.

Weight Loss by Low-Calorie Diet Versus Gastric Bypass Surgery in People With Diabetes Results in Divergent Brain Activation Patterns: A Functional MRI Study.

OBJECTIVE: Weight loss achieved with very-low-calorie diets (VLCDs) can produce remission of type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesized that in patients living with obesity and prediabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference. RESEARCH DESIGN AND METHODS: Sixteen participants underwent gastric bypass surgery, and 19 matched participants undertook a VLCD (meal replacement) for 4 weeks. Brain responses to food cues and resting-state functional connectivity were assessed with functional MRI pre- and postintervention and compared across groups. RESULTS: We show that Roux-en-Y gastric bypass surgery (RYGB) results in three divergent brain responses compared with VLCD-induced weight loss: 1) VLCD resulted in increased brain reward center food cue responsiveness, whereas in RYGB, this was reduced; 2) VLCD resulted in higher neural activation of cognitive control regions in response to food cues associated with exercising increased cognitive restraint over eating, whereas RYGB did not; and 3) a homeostatic appetitive system (centered on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD. CONCLUSIONS: Taken together, these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast to enduring weight loss after RYGB.

Kisspeptin modulates gamma-aminobutyric acid levels in the human brain.

Gamma-aminobutyric acid (GABA) is a key inhibitory neurotransmitter that has been implicated in the aetiology of common mood and behavioural disorders. By employing proton magnetic resonance spectroscopy in man, we demonstrate that administration of the reproductive neuropeptide, kisspeptin, robustly decreases GABA levels in the limbic system of the human brain; specifically the anterior cingulate cortex (ACC). This finding defines a novel kisspeptin-activated GABA pathway in man, and provides important mechanistic insights into the mood and behaviour-altering effects of kisspeptin seen in rodents and humans. In addition, this work has therapeutic implications as it identifies GABA-signalling as a potential target for the escalating development of kisspeptin-based therapies for common reproductive disorders of body and mind.

The Global Impact of COVID-19 on the Care of People With Endometriosis.

Endometriosis is a chronic condition affecting ~10% of women globally. Little is known about the impact of the coronavirus disease 2019 (COVID-19) pandemic on their care. This brief report is aimed to explore the impact of COVID-19 on the care of people with endometriosis around the world, their priorities in relation to their clinical care during and coming out of the pandemic, and whether they believed that endometriosis makes them more vulnerable to COVID-19. An internet-based survey collected data in five languages between May 11, 2020, and June 8, 2020. Only participants with a surgical or radiological diagnosis of endometriosis aged 18 years or over were included. A total of 6,729 eligible respondents completed the survey with 80.7% [95% CI (79.7, 81.6)] reporting a negative impact on their care. This included difficulties obtaining medication (20.3%), cancelled/postponed gynaecology appointments (50.0%), and cancelled/postponed procedures (37.2%). More than half worried that their endometrioses make them more vulnerable to COVID-19 [54.2%; 95% CI (53.0, 55.4)]. The top three priorities were remarkably consistent around the world: contact with gynaecologists, knowing when procedures would be performed, and support with mental health (20.3% prioritising this aspect during the pandemic and 13.0% as restrictions begin to ease). This study shows the substantial impact the COVID-19 pandemic has had on people with endometriosis and describes how they would like care prioritised moving forwards. The findings regarding significant support needs for mental health add further weight to the growing recognition of attending to such issues as part of good patient-centred care.

The Effects of Kisspeptin on Brain Response to Food Images and Psychometric Parameters of Appetite in Healthy Men.

CONTEXT: The hormone kisspeptin has crucial and well-characterized roles in reproduction. Emerging data from animal models also suggest that kisspeptin has important metabolic effects including modulation of food intake. However, to date there have been no studies exploring the effects of kisspeptin on brain responses to food stimuli in humans. OBJECTIVE: This work aims to investigate the effects of kisspeptin administration on brain responses to visual food stimuli and psychometric parameters of appetite, in healthy men. DESIGN: A double-blinded, randomized, placebo-controlled, crossover study was conducted. PARTICIPANTS: Participants included 27 healthy, right-handed, eugonadal men (mean ± SEM: age 26.5 ± 1.1 years; body mass index 23.9 ± 0.4 kg/m2). INTERVENTION: Participants received an intravenous infusion of 1 nmol/kg/h of kisspeptin or rate-matched vehicle over 75 minutes. MAIN OUTCOME MEASURES: Measurements included change in brain activity on functional magnetic resonance imaging in response to visual food stimuli and change in psychometric parameters of appetite, during kisspeptin administration compared to vehicle. RESULTS: Kisspeptin administration at a bioactive dose did not affect brain responses to visual food stimuli or psychometric parameters of appetite compared to vehicle. CONCLUSIONS: This is the first study in humans investigating the effects of kisspeptin on brain regions regulating appetite and demonstrates that peripheral administration of kisspeptin does not alter brain responses to visual food stimuli or psychometric parameters of appetite in healthy men. These data provide key translational insights to further our understanding of the interaction between reproduction and metabolism.

Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression.

BACKGROUND: Psilocybin has shown promise as a treatment for depression but its therapeutic mechanisms are not properly understood. In contrast to the presumed actions of antidepressants, we recently found increased amygdala responsiveness to fearful faces one day after open-label treatment with psilocybin (25 mg) in 19 patients with treatment-resistant depression, which correlated with treatment efficacy. AIMS: Aiming to further unravel the therapeutic mechanisms of psilocybin, the present study extends this basic activation analysis. We hypothesised changed amygdala functional connectivity, more precisely decreased amygdala-ventromedial prefrontal cortex functional connectivity, during face processing after treatment with psilocybin. METHODS: Psychophysiological interaction analyses were conducted on functional magnetic resonance imaging data from a classic face/emotion perception task, with the bilateral amygdala and ventromedial prefrontal cortex time-series as physiological regressors. Average parameter estimates (beta weights) of significant clusters were correlated with clinical outcomes at one week. RESULTS: Results showed decreased ventromedial prefrontal cortex-right amygdala functional connectivity during face processing post- (versus pre-) treatment; this decrease was associated with levels of rumination at one week. This effect was driven by connectivity changes in response to fearful and neutral (but not happy) faces. Independent whole-brain analyses also revealed a post-treatment increase in functional connectivity between the amygdala and ventromedial prefrontal cortex to occipital-parietal cortices during face processing. CONCLUSION: These results are consistent with the idea that psilocybin therapy revives emotional responsiveness on a neural and psychological level, which may be a key treatment mechanism for psychedelic therapy. Future larger placebo-controlled studies are needed to examine the replicability of the current findings.

Kisspeptin enhances brain responses to olfactory and visual cues of attraction in men.

Successful reproduction is a fundamental physiological process that relies on the integration of sensory cues of attraction with appropriate emotions and behaviors and the reproductive axis. However, the factors responsible for this integration remain largely unexplored. Using functional neuroimaging, hormonal, and psychometric analyses, we demonstrate that the reproductive hormone kisspeptin enhances brain activity in response to olfactory and visual cues of attraction in men. Furthermore, the brain regions enhanced by kisspeptin correspond to areas within the olfactory and limbic systems that govern sexual behavior and perception of beauty as well as overlap with its endogenous expression pattern. Of key functional and behavioral significance, we observed that kisspeptin was most effective in men with lower sexual quality-of-life scores. As such, our results reveal a previously undescribed attraction pathway in humans activated by kisspeptin and identify kisspeptin signaling as a new therapeutic target for related reproductive and psychosexual disorders.

Dissociable effects of cannabis with and without cannabidiol on the human brain's resting-state functional connectivity.

BACKGROUND: Two major constituents of cannabis are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the main psychoactive component; CBD may buffer the user against the harmful effects of THC. AIMS: We examined the effects of two strains of cannabis and placebo on the human brain's resting-state networks using fMRI. METHODS: Seventeen healthy volunteers (experienced with cannabis, but not regular users) underwent three drug treatments and scanning sessions. Treatments were cannabis containing THC (Cann-CBD; 8 mg THC), cannabis containing THC with CBD (Cann+CBD; 8 mg THC + 10 mg CBD), and matched placebo cannabis. Seed-based resting-state functional connectivity analyses were performed on three brain networks: the default mode (DMN; defined by positive connectivity with the posterior cingulate cortex: PCC+), executive control (ECN; defined by negative connectivity with the posterior cingulate cortex: PCC-) and salience (SAL; defined by positive connectivity with the anterior insula: AI+) network. RESULTS: Reductions in functional connectivity (relative to placebo) were seen in the DMN (PCC+) and SAL (AI+) networks for both strains of cannabis, with spatially dissociable effects. Across the entire salience network (AI+), Cann-CBD reduced connectivity relative to Cann+CBD. The PCC in the DMN was specifically disrupted by Cann-CBD, and this effect correlated with subjective drug effects, including feeling 'stoned' and 'high'. CONCLUSIONS: THC disrupts the DMN, and the PCC is a key brain region involved in the subjective experience of THC intoxication. CBD restores disruption of the salience network by THC, which may explain its potential to treat disorders of salience such as psychosis and addiction.

A short, robust brain activation control task optimised for pharmacological fMRI studies.

BACKGROUND: Functional magnetic resonance imaging (fMRI) is a popular method for examining pharmacological effects on the brain; however, the BOLD response is dependent on intact neurovascular coupling, and potentially modulated by a number of physiological factors. Pharmacological fMRI is therefore vulnerable to confounding effects of pharmacological probes on general physiology or neurovascular coupling. Controlling for such non-specific effects in pharmacological fMRI studies is therefore an important consideration, and there is an additional need for well-validated fMRI task paradigms that could be used to control for such effects, or for general testing purposes. METHODS: We have developed two variants of a standardized control task that are short (5 minutes duration) simple (for both the subject and experimenter), widely applicable, and yield a number of readouts in a spatially diverse set of brain networks. The tasks consist of four functionally discrete three-second trial types (plus additional null trials) and contain visual, auditory, motor and cognitive (eye-movements, and working memory tasks in the two task variants) stimuli. Performance of the tasks was assessed in a group of 15 subjects scanned on two separate occasions, with test-retest reliability explicitly assessed using intra-class correlation coefficients. RESULTS: Both tasks produced robust patterns of brain activation in the expected brain regions, and region of interest-derived reliability coefficients for the tasks were generally high, with four out of eight task conditions rated as 'excellent' or 'good', and only one out of eight rated as 'poor'. Median values in the voxel-wise reliability measures were also >0.7 for all task conditions, and therefore classed as 'excellent' or 'good'. The spatial concordance between the most highly activated voxels and those with the highest reliability coefficients was greater for the sensory (auditory, visual) conditions than the other (motor, cognitive) conditions. DISCUSSION: Either of the two task variants would be suitable for use as a control task in future pharmacological fMRI studies or for any other investigation where a short, reliable, basic task paradigm is required. Stimulus code is available online for re-use by the scientific community.

Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression.

Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments' therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions. TRIAL REGISTRATION: ISRCTN, number ISRCTN14426797. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Modulations of human resting brain connectivity by kisspeptin enhance sexual and emotional functions.

BACKGROUND: Resting brain connectivity is a crucial component of human behavior demonstrated by disruptions in psychosexual and emotional disorders. Kisspeptin, a recently identified critical reproductive hormone, can alter activity in certain brain structures but its effects on resting brain connectivity and networks in humans remain elusive. METHODS: We determined the effects of kisspeptin on resting brain connectivity (using functional neuroimaging) and behavior (using psychometric analyses) in healthy men, in a randomized double-blinded 2-way placebo-controlled study. RESULTS: Kisspeptin's modulation of the default mode network (DMN) correlated with increased limbic activity in response to sexual stimuli (globus pallidus r = 0.500, P = 0.005; cingulate r = 0.475, P = 0.009). Furthermore, kisspeptin's DMN modulation was greater in men with less reward drive (r = -0.489, P = 0.008) and predicted reduced sexual aversion (r = -0.499, P = 0.006), providing key functional significance. Kisspeptin also enhanced key mood connections including between the amygdala-cingulate, hippocampus-cingulate, and hippocampus-globus pallidus (all P < 0.05). Consistent with this, kisspeptin's enhancement of hippocampus-globus pallidus connectivity predicted increased responses to negative stimuli in limbic structures (including the thalamus and cingulate [all P < 0.01]). CONCLUSION: Taken together, our data demonstrate a previously unknown role for kisspeptin in the modulation of functional brain connectivity and networks, integrating these with reproductive hormones and behaviors. Our findings that kisspeptin modulates resting brain connectivity to enhance sexual and emotional processing and decrease sexual aversion, provide foundation for kisspeptin-based therapies for associated disorders of body and mind. FUNDING: NIHR, MRC, and Wellcome Trust.

Investigating the neural correlates of smoking: Feasibility and results of combining electronic cigarettes with fMRI.

Cigarette addiction is driven partly by the physiological effects of nicotine, but also by the distinctive sensory and behavioural aspects of smoking, and understanding the neural effects of such processes is vital. There are many practical difficulties associated with subjects smoking in the modern neuroscientific laboratory environment, however electronic cigarettes obviate many of these issues, and provide a close simulation of smoking tobacco cigarettes. We have examined the neural effects of 'smoking' electronic cigarettes with concurrent functional Magnetic Resonance Imaging (fMRI). The results demonstrate the feasibility of using these devices in the MRI environment, and show brain activation in a network of cortical (motor cortex, insula, cingulate, amygdala) and sub-cortical (putamen, thalamus, globus pallidus, cerebellum) regions. Concomitant relative deactivations were seen in the ventral striatum and orbitofrontal cortex. These results reveal the brain processes involved in (simulated) smoking for the first time, and validate a novel approach to the study of smoking, and addiction more generally.

Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms.

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other 'psychedelics' yet were related to clinical outcomes. A 'reset' therapeutic mechanism is proposed.