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Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [±SD] age: 24.1 [±4.8] years, 15 F) showed significantly elevated rCBF compared to HC (mean [±SD] age: 26.5 [±5.1] years, 11 F) in the hippocampus ( F (1,41) = 24.7, p FDR  < 0.001) and across its subfields (all p FDR  < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all p FDR  < 0.001) was significantly reduced ( t (69) = −5.1, p FDR  < 0.001) and normalized to HC levels ( F (1,41) = 0.4, p FDR  = 0.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis.

For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4–16 years and had abnormal TCD flow velocities (≥200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140–146) in children who received standard transfusions and 138 cm/s (135–142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10–8·98). Non-inferiority (p=8·82 × 10−16) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. National Heart, Lung, and Blood Institute, National Institutes of Health.

BackgroundPerforming mechanical thrombectomy (MT) in patients with basilar artery occlusion (BAO) is currently not evidence-based.ObjectiveTo compare patients’ outcome, relative merits of achieving recanalization, and predictors of futile recanalization (FR) between BAO and anterior circulation large vessel occlusion (ACLVO) MT.MethodsIn the multicenter BEYOND-SWIFT registry (NCT03496064), univariate and multivariate (displayed as adjusted Odds Ratios, aOR and 95% confidence intervals, 95%-CI) outcome comparisons between BAO (N=165) and ACLVO (N=1574) were performed. The primary outcome was favorable outcome at 90 days (modified Rankin Scale, mRS 0-2). Secondary outcome included mortality, symptomatic intracranial hemorrhage (sICH) and FR. The relative merits of achieving successful recanalization between ACLVO and BAO were evaluated with interaction terms.ResultsMT in BAO was more often technically effective and equally safe in regards to mortality and sICH when compared to ACLVO. When adjusting for baseline differences, there was no significant difference between BAO vs ACLVO regarding rates of favorable outcome (aOR 0.986, 95%-CI 0.553 – 1.758). However, BAO were associated with increased rates of FR (aOR 2.146, 95%-CI 1.267 – 3.633). Predictors for FR were age, stroke severity, maneuver count and intracranial stenting. No significant heterogeneity on the relative merits of achieving successful recanalization on several outcome parameters were observed when comparing BAO and ACLVO.ConclusionsIn selected patients, similar outcomes can be achieved in BAO and ACLVO patients treated with MT. Randomized controlled trials comparing patient selection and interventional strategies seem warranted to avoid FR.Trial registration number NCT03496064

Could nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We address this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders. Intranasal oxytocin can affect brain function either by direct entry to the brain or by increasing oxytocin levels in blood plasma. Here, the authors show that increases in plasmatic oxytocin account for some but not all of the changes observed following intranasal oxytocin administration.

Major depressive disorder (MDD) is one of the most prevalent and disabling illnesses worldwide. Treatment of MDD typically relies on trial-and-error to find an effective approach. Identifying early response-related biomarkers that predict response to antidepressants would help clinicians to decide, as early as possible, whether a particular treatment might be suitable for a given patient. Data were from the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial. A whole-brain, voxel-wise, mixed-effects model was applied to identify early-treatment cerebral blood flow (CBF) changes as biomarkers of treatment response. We examined changes in CBF measured with arterial spin labeling 1-week after initiating double-masked sertraline/placebo. We tested whether these early 1-week scans could be used to predict response observed after 8-weeks of treatment. Response to 8-week placebo treatment was associated with increased cerebral perfusion in temporal cortex and reduced cerebral perfusion in postcentral region captured at 1-week of treatment. Additionally, CBF response in these brain regions was significantly correlated with improvement in Hamilton Depression Rating Scale score in the placebo group. No significant associations were found for selective serotonin reuptake inhibitor treatment. We conclude that early CBF responses to placebo administration in multiple brain regions represent candidate neural biomarkers of longer-term antidepressant effects.

Purpose Short-term intake of the egg-protein hydrolysate Newtricious (NWT)-03 improved executive function, but underlying mechanisms and long-term effects, including other cognitive domains, are unknown. Methods A 36-week randomized controlled trial involving 44 overweight/obese individuals experiencing elevated Subjective Cognitive Failures (SCF; aged 60–75 years) assessed the impact of daily consumption of 5.7 g of NWT-03 or placebo powders on cognitive performance (psychomotor speed, executive function, memory) and Cerebral Blood Flow (CBF), a marker of brain vascular function. Cognitive performance was evaluated using a neurophysiological test battery (CANTAB) and CBF was measured using magnetic resonance imaging perfusion method Arterial Spin Labeling (ASL). Serum samples were collected to determine brain-derived neurotrophic factor (BDNF) concentrations. Results Anthropometrics, and energy and nutrient intakes remained stable throughout the trial. NWT-03 was well tolerated, and compliance was excellent (median: 99%; range: 87–103%). No overall intervention effects were observed on cognitive performance or CBF, but post-hoc analyses revealed significant improvements on executive function in women, but not men. Specifically, a reduction of 74 ms in reaction latency on the multitasking task (95% CI: −134 to −15; p  = 0.02), a reduction of 9 between errors (95%CI: −14 to −3; p  < 0.001), and a reduction of 9 total errors (95%CI: −15 to −3; p  < 0.001) on the spatial working memory task were found in women. No intervention effects were observed on serum BDNF concentrations ( p  = 0.31). Conclusion Long-term consumption of NWT-03 improved multitasking abilities and working memory in women with elevated SCF. Brain vascular function remained unaffected. Sex differences in executive function require additional clarification.

Posttraumatic stress disorder (PTSD)-a chronic, debilitating condition, broadly characterized by emotion dysregulation-is prevalent among US military personnel who have returned from Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF). Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for PTSD, but treatment mechanisms are unknown and patient response varies. SSRIs may exert their effects by remediating emotion regulatory brain activity and individual differences in patient response might be explained, in part, by pre-treatment differences in neural systems supporting the downregulation of negative affect. Thirty-four OEF/OIF veterans, 17 with PTSD and 17 without PTSD underwent 2 functional magnetic resonance imaging scans 12 weeks apart. At each scan, they performed an emotion regulation task; in the interim, veterans with PTSD were treated with the SSRI, paroxetine. SSRI treatment increased activation in both the left dorsolateral prefrontal cortex (PFC) and supplementary motor area (SMA) during emotion regulation, although only change in the SMA over time occurred in veterans with PTSD and not those without PTSD. Less activation of the right ventrolateral PFC/inferior frontal gyrus during pre-treatment emotion regulation was associated with greater reduction in PTSD symptoms with SSRI treatment, irrespective of pre-treatment severity. Patients with the least recruitment of prefrontal emotion regulatory brain regions may benefit most from treatment with SSRIs, which appear to augment activity in these regions.

Recent research has examined the effects of oxytocin (OT) and vasopressin (AVP) on human social behavior and brain function. However, most participants have been male, while previous research in our lab demonstrated sexually differentiated effects of OT and AVP on the neural response to reciprocated cooperation. Here we extend our previous work by significantly increasing the number of participants to enable the use of more stringent statistical thresholds that permit more precise localization of OT and AVP effects in the brain. In a double-blind, placebo-controlled study, 153 men and 151 women were randomized to receive 24 IU intranasal OT, 20 IU intranasal AVP or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner’s Dilemma Game with same-sex partners. Sex differences were observed for effects of OT on the neural response to reciprocated cooperation, such that OT increased the caduate/putamen response among males, whereas it decreased this response among females. Thus, 24 IU OT may increase the reward or salience of positive social interactions among men, while decreasing their reward or salience among women. Similar sex differences were also observed for AVP effects within bilateral insula and right supramarginal gyrus when a more liberal statistical threshold was employed. While our findings support previous suggestions that exogenous nonapeptides may be effective treatments for disorders such as depression and autism spectrum disorder, they caution against uniformly extending such treatments to men and women alike.

Recent research indicates that the hypothalamic neuropeptide hormone oxytocin is a key central nervous system factor in the regulation of food intake and weight. However, the mechanisms underlying the anorexigenic effects of oxytocin in humans are unknown and critical to study to consider oxytocin as a neurohormonal weight loss treatment. We performed a randomized, double-blind, placebo-controlled crossover study with single-dose intranasal oxytocin (24 IU) in ten overweight or obese, otherwise healthy men. Following oxytocin/placebo administration, participants completed an established functional magnetic resonance imaging food motivation paradigm. We hypothesized that oxytocin would reduce the blood oxygenation level-dependent (BOLD) signal to high-calorie food vs non-food visual stimuli in the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic reward system. Following oxytocin administration, compared to placebo, participants showed bilateral VTA hypoactivation to high-calorie food stimuli. A secondary exploratory whole-brain analysis revealed hypoactivation in additional hedonic (orbitofrontal cortex, insula, globus pallidus, putamen, hippocampus, and amygdala) and homeostatic (hypothalamus) food motivation and hyperactivation in cognitive control (anterior cingulate and frontopolar cortex) brain regions following oxytocin administration vs placebo. Oxytocin administration reduces the BOLD signal in reward-related food motivation brain regions, providing a potential neurobiological mechanism for the anorexigenic oxytocin effects in humans. Furthermore, our data indicate that oxytocin administration reduces activation in homeostatic and increases activation in cognitive control brain regions critically involved in regulating food intake and resolving affective conflict, respectively. Future studies are required to link these changes in brain activation to oxytocin effects on food intake and weight.

Animal models point towards a key role of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in mediating exercise-induced structural and functional changes in the hippocampus. Recently, also platelet derived growth factor-C (PDGF-C) has been shown to promote blood vessel growth and neuronal survival. Moreover, reductions of these neurotrophic and angiogenic factors in old age have been related to hippocampal atrophy, decreased vascularization and cognitive decline. In a 3-month aerobic exercise study, forty healthy older humans (60 to 77years) were pseudo-randomly assigned to either an aerobic exercise group (indoor treadmill, n=21) or to a control group (indoor progressive-muscle relaxation/stretching, n=19). As reported recently, we found evidence for fitness-related perfusion changes of the aged human hippocampus that were closely linked to changes in episodic memory function. Here, we test whether peripheral levels of BDNF, IGF-I, VEGF or PDGF-C are related to changes in hippocampal blood flow, volume and memory performance. Growth factor levels were not significantly affected by exercise, and their changes were not related to changes in fitness or perfusion. However, changes in IGF-I levels were positively correlated with hippocampal volume changes (derived by manual volumetry and voxel-based morphometry) and late verbal recall performance, a relationship that seemed to be independent of fitness, perfusion or their changes over time. These preliminary findings link IGF-I levels to hippocampal volume changes and putatively hippocampus-dependent memory changes that seem to occur over time independently of exercise. We discuss methodological shortcomings of our study and potential differences in the temporal dynamics of how IGF-1, VEGF and BDNF may be affected by exercise and to what extent these differences may have led to the negative findings reported here. •Exercise-related changes in BDNF, IGF, VEGF and PDGF were measured in older adults•Changes in hippocampal perfusion, volume (via 7T MRI) and memory were assessed•Fitness-related vascular hippocampal plasticity was not linked to growth factors•Changes in IGF-I, hippocampal volume and memory were linked independent of exercise•Potential reasons for negative findings and methodological shortcomings are discussed