Double-blind Placebo-controlled Crossover Research Articles

Effects of GSH on Alcohol Metabolism and Hangover Improvement in Humans: A Randomized Double-Blind Placebo-Controlled Crossover Clinical Trial.

The definition of alcohol hangovers refers to a combination of mental and physical side effects that occur after drinking. One of the ways that hangovers can be ameliorated is by promoting the rapid and effective elimination of acetaldehyde to alleviate the discomfort it causes. This study aimed to investigate the effects of GSH (yeast extract containing 50 mg of glutathione) on the hangover-relieving effect. A randomized double-blind placebo-controlled crossover clinical trial was conducted with 40 participants who reported experiencing hangover symptoms. Participants consumed alcohol at a rate of 0.78 g per kg body weight with 40% whiskey, adjusted according to their weight. Alcohol and acetaldehyde concentrations in serum were analyzed at 0, 0.25, 1, 2, 4, 6, and 15 h after alcohol consumption. In the GSH group, the serum alcohol concentration decreased, although this change was not statistically significant. The serum acetaldehyde concentration was significantly lower in the GSH group in comparison to the placebo group (at 0.25, 1, 4, and 6 h (p < 0.01) and at 0.5, 2, and 15 h (p < 0.001) after alcohol consumption). However, there was no significant difference between the two groups on questionnaires such as the Acute Hangover Scale and the Alcohol Hangover Severity Scale. Overall, we consider the discovery that GSH lowered acetaldehyde concentration, a crucial factor in alcohol metabolism, to be more considerable. Therefore, GSH administration effectively reduces acetaldehyde levels in serum. This result suggests that this effect may contribute to the relief of hangover symptoms.

Cholinergic modulation of motor sequence learning.

The cholinergic system plays a key role in motor function, but whether pharmacological modulation of cholinergic activity affects motor sequence learning is unknown. The acetylcholine receptor antagonist biperiden, an established treatment in movement disorders, reduces attentional modulation, but whether it influences motor sequence learning is not clear. Using a randomized, double-blind placebo-controlled crossover design, we tested 30 healthy young participants and showed that biperiden impairs the ability to learn sequential finger movements, accompanied by widespread oscillatory broadband power changes (4-25 Hz) in the motor sequence learning network after receiving biperiden, with greater power in the theta, alpha and beta bands over ipsilateral motor and bilateral parietal-occipital areas. The reduced early theta power during a repeated compared with random sequence, likely reflecting disengagement of top-down attention to sensory processes, was disrupted by biperiden. Alpha synchronization during repeated sequences reflects sensory gating and lower visuospatial attention requirements compared with visuomotor responses to random sequences. After biperiden, alpha synchronization was greater, potentially reflecting excessive visuospatial attention reduction, affecting visuomotor responding required to enable sequence learning. Beta oscillations facilitate sequence learning by integrating visual and somatosensory inputs, stabilizing repeated sequences and promoting prediction of the next stimulus. The beta synchronization after biperiden fits with a disruption of the selective visuospatial attention enhancement associated with initial sequence learning. These findings highlight the role of cholinergic processes in motor sequence learning.

Targeting histamine receptor 4 in cholinergic urticaria with izuforant (LEO 152020): results from a phase IIa randomized double-blind placebo-controlled multicentre crossover trial.

Cholinergic urticaria (CholU) is a common subtype of chronic inducible urticaria, where signs and symptoms (e.g. pruritic wheals and angioedema) are triggered by sweating due to physical exercise, passive warming and by other sweat-inducing situations. While guidelines recommend treatment with second-generation H1 antihistamines, approximately 90% of patients report uncontrolled disease. Targeting the histamine 4 receptor (H4R) has shown promise in preclinical/clinical studies of allergic/inflammatory diseases. Izuforant (LEO 152020) is a selective oral H4R antagonist with expected dual antipruritic and anti-inflammatory effects. To assess the effects of izuforant in adults with CholU, a common type of chronic urticaria driven by histamine and characterized by high skin levels of H4R expression. This was a phase IIa randomized double-blind placebo-controlled multicentre crossover trial where patients with CholU with an inadequate response to ≥ 1 standard dose of H1 antihistamine received izuforant 100 mg twice daily or placebo (EUCTR2020-004961-38-DE; NCT04853992). The primary endpoint was change from baseline in Urticaria Activity Score. Exploratory endpoints included CholU activity score over 7 days, urticaria control test, Physician Global Assessment, patient global assessment of severity (PGA-S), provocation tests, Dermatology Life Quality Index and CholU quality of life (CholU-QoL). Pharmacokinetic and pharmacodynamic parameters, and serum biomarkers were assessed, as well as safety and tolerability. Nineteen patients were randomized and included in the full analysis set; 18 completed treatment [mean (SD) age 29.5 (9.8) years; mean (SD) CholU duration 8.0 (6.3) years]. The primary and most of prespecified exploratory endpoints were not met; there were significant improvements in PGA-S for izuforant vs. placebo (P = 0.02), and nonsignificant improvements for other endpoints in quality of life and histamine skin prick test. All adverse events (AEs) experienced with izuforant were considered mild. The most frequently reported (> 1 patient) were nausea (three patients) and upper abdominal pain (two patients), occurring more frequently with izuforant vs. placebo (one patient each). There were no treatment-related serious AEs and no patient receiving izuforant discontinued the study. Treatment with izuforant did not cause downregulation of H4R. This is the first study to explore the role of H4R as a therapeutic target in urticaria. Targeting H4R with izuforant was well tolerated but did not demonstrate significant improvements vs. placebo in the primary endpoint and all but one prespecified exploratory endpoint in CholU.

Effect of twice daily inhaled albuterol on cardiopulmonary exercise outcomes, dynamic hyperinflation, and symptoms in secondhand tobacco-exposed persons with preserved spirometry and air trapping: a randomized controlled trial

BackgroundIn tobacco-exposed persons with preserved spirometry (active smoking or secondhand smoke [SHS] exposure), air trapping can identify a subset with worse symptoms and exercise capacity. The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear. The aim of this study was to examine the underlying pathophysiology of air trapping in the context of preserved spirometry and to determine the utility of bronchodilators in SHS tobacco-exposed persons with preserved spirometry and air trapping.MethodsWe performed a double-blinded placebo-controlled crossover randomized clinical trial in nonsmoking individuals at risk for COPD due to exposure to occupational SHS who had preserved spirometry and air trapping defined as either a residual volume-to-total lung capacity ratio (RV/TLC) > 0.35 or presence of expiratory flow limitation (EFL, overlap of tidal breathing on maximum expiratory flow-volume loop) on spirometry at rest or during cardiopulmonary exercise testing (CPET). Those with asthma or obesity were excluded. Participants underwent CPET at baseline and after 4-week trials of twice daily inhalation of 180 mcg of albuterol or placebo separated by a 2-week washout period. The primary outcome was peak oxygen consumption (VO2) on CPET. Data was analyzed by both intention-to-treat and per-protocol based on adherence to treatment prescribed.ResultsOverall, 42 participants completed the entire study (66 ± 8 years old, 91% female; forced expiratory volume in 1 s [FEV1] = 103 ± 16% predicted; FEV1 to forced vital capacity [FVC] ratio = 0.75 ± 0.05; RV/TLC = 0.39 ± 0.07; 85.7% with EFL). Adherence was high with 87% and 93% of prescribed doses taken in the treatment and placebo arms of the study, respectively (P = 0.349 for comparison between the two arms). There was no significant improvement in the primary or secondary outcomes by intention-to-treat or per-protocol analysis. In per-protocol subgroup analysis of those with RV/TLC > 0.35 and ≥ 90% adherence (n = 27), albuterol caused an improvement in peak VO2 (parameter estimate [95% confidence interval] = 0.108 [0.014, 0.202]; P = 0.037), tidal volume, minute ventilation, dynamic hyperinflation, and oxygen-pulse (all P < 0.05), but no change in symptoms or physical activity.ConclusionsAlbuterol may improve exercise capacity in the subgroup of SHS tobacco-exposed persons with preserved spirometry and substantial air trapping. These findings suggest that air trapping in pre-COPD may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction.

N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study

BackgroundNiemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code “IB1001-301”) for the chronic treatment of symptoms in adult and pediatric patients with NPC.MethodsThis multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.DiscussionPre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.Trial registrationsThe trial (IB1001-301) has been registered at www.clinicaltrials.gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021–005356-10). Registered on 20 December 2021.

Acetyl-L-Leucine for Niemann-Pick type C: A Multinational Double-blind Randomized Placebo-controlled Crossover Study (P14-11.001)

<h3>Objective:</h3> To assess the clinical efficacy (symptomatic and long-term) of N-acetyl-L-Leucine on symptoms of ataxia, functioning, and quality of life for patients with NPC. To evaluate the safety and tolerability of N-acetyl-L-leucine at 4 g/day in patients with NPC aged ≥4 years and older. Extension Phase Only: Characterize the pharmacokinetics of N-acetyl-L-leucine in NPC patients. <h3>Background:</h3> Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded Phase IIb clinical trial. <h3>Design/Methods:</h3> This multinational double-blind randomized placebo-controlled crossover Phase III study enrolls patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites (NCT05163288). Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments. The Parent Study is followed by the 1-year Extension Phase. <h3>Results:</h3> The clinical trial has been initiated in July 2022. Twenty-one patients have been screened, 15 patients have been recruited. Approximately 53 patients will be enrolled, 46 patients will be analyzed according to the Intention to Treat (ITT). <h3>Conclusions:</h3> Given the lack of global symptomatic or disease-modifying therapies for NPC and other lysosomal diseases there is an urgent need for effective and well-tolerated drug treatments. This clinical trial was designed through a collaboration between National Regulatory Agencies, leading Clinical Experts, Patient Organizations, and the industry Sponsor. <b>Disclosure:</b> Dr. Bremova-Ertl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Intrabio. The institution of Dr. Bremova-Ertl has received research support from InnoSuisse. Dr. Bremova-Ertl has received research support from Baasch-Medicus. Ms. Fields has received personal compensation for serving as an employee of IntraBio. Ms. Fields has stock in IntraBio. Ms. Fields has received intellectual property interests from a discovery or technology relating to health care. Dr. Martakis has nothing to disclose. Dr. Strupp has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for IntraBio. Dr. Strupp has received personal compensation in the range of $0-$499 for serving as a Consultant for AurisMedical. Dr. Strupp has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. Dr. Strupp has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers. Dr. Strupp has stock in IntraBio.

Sirolimus suppresses circulating fibrocytes in idiopathic pulmonary fibrosis in a randomized controlled crossover trial.

Fibrocytes are bone marrow-derived circulating cells that traffic to the injured lungs and contribute to fibrogenesis. The mTOR inhibitor, sirolimus, inhibits fibrocyte CXCR4 expression, reducing fibrocyte traffic and attenuating lung fibrosis in animal models. We sought to test the hypothesis that short-term treatment with sirolimus reduces the concentration of CXCR4+ circulating fibrocytes in patients with idiopathic pulmonary fibrosis (IPF). We conducted a short-term randomised double-blind placebo-controlled crossoverpilot trial to assess the safety and tolerability of sirolimus in IPF. Subjects were randomly assigned to sirolimus or placebo for approximately 6 weeks, and after a 4 week washout, assigned to the alternate treatment. Toxicity, lung function, and the concentration of circulating fibrocytes were measured before and after each treatment. In the 28 study subjects, sirolimus resulted in a statistically significant 35% decline in the concentration of total fibrocytes, 34% decline in CXCR4+ fibrocytes, and 42% decline in fibrocytes expressing ɑ-smooth muscle actin, but no significant change in these populations occurred on placebo. Respiratory adverse events occurred more frequently during treatment with placebo than sirolimus; the incidence of adverse events and drug tolerability did not otherwise differ during therapy with drug and placebo. Lung function was unaffected by either treatment with the exception of a small decline in gas transfer during treatment with placebo. As compared with placebo, short-term treatment with sirolimus resulted inreduction of circulating fibrocyte concentrations in subjects with IPF with an acceptable safety profile. gov identifier number NCT01462006FUNDING. NIH R01HL098329 and American Heart Association 18TPA34170486.

The effects of first-dose methylphenidate on the neural signatures of visual selective attention in children with attention-deficit/hyperactivity disorder

Although methylphenidate (MPH) has been shown to significantly improve selective attention in children with attention-deficit/hyperactivity disorder (ADHD), the neural mechanism of this effect remains unclear. We investigated the effects of first-dose MPH on the neural signatures of visual selective attention in children with ADHD. We measured the impact of first-dose MPH on electrophysiological indexes from eighteen children with ADHD (8.9–15.2 years; 15 boys) while they performed a visual search task. MPH was administered in a double-blind placebo-controlled crossover design. MPH led to decreases in behavioral error rates and reaction times. For the electrophysiological indexes, MPH significantly increased the target-elicited N2pc amplitude and posterior P3 amplitude during the selective attention process. The trial-based correlation analysis revealed that the enhanced N2pc (more negative) and P3 (more positive) promoted the behavioral response speed for children with ADHD. The lower individual P3 amplitude was associated with higher severity of inattention symptoms. The severer inattention symptoms were related to weaker MPH effect on N2pc amplitude. These findings suggest that N2pc and P3 are closely related to the mechanism of MPH in the ADHD treatment.

The neurophysiological effect of NMDA-R antagonism of frontotemporal lobar degeneration is conditional on individual GABA concentration

There is a pressing need to accelerate therapeutic strategies against the syndromes caused by frontotemporal lobar degeneration, including symptomatic treatments. One approach is for experimental medicine, coupling neurophysiological studies of the mechanisms of disease with pharmacological interventions aimed at restoring neurochemical deficits. Here we consider the role of glutamatergic deficits and their potential as targets for treatment. We performed a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study in 20 people with symptomatic frontotemporal lobar degeneration (10 behavioural variant frontotemporal dementia, 10 progressive supranuclear palsy) and 19 healthy age- and gender-matched controls. Both magnetoencephalography sessions recorded a roving auditory oddball paradigm: on placebo or following 10 mg memantine, an uncompetitive NMDA-receptor antagonist. Ultra-high-field magnetic resonance spectroscopy confirmed lower concentrations of GABA in the right inferior frontal gyrus of people with frontotemporal lobar degeneration. While memantine showed a subtle effect on early-auditory processing in patients, there was no significant main effect of memantine on the magnitude of the mismatch negativity (MMN) response in the right frontotemporal cortex in patients or controls. However, the change in the right auditory cortex MMN response to memantine (vs. placebo) in patients correlated with individuals’ prefrontal GABA concentration. There was no moderating effect of glutamate concentration or cortical atrophy. This proof-of-concept study demonstrates the potential for baseline dependency in the pharmacological restoration of neurotransmitter deficits to influence cognitive neurophysiology in neurodegenerative disease. With changes to multiple neurotransmitters in frontotemporal lobar degeneration, we suggest that individuals’ balance of excitation and inhibition may determine drug efficacy, with implications for drug selection and patient stratification in future clinical trials.

Methylphenidate remediates aberrant brain network dynamics in children with attention‐deficit/hyperactivity disorder: A randomized controlled trial

Methylphenidate is a widely used first-line treatment for attention deficit/hyperactivity disorder (ADHD), but the underlying circuit mechanisms are poorly understood. Here we investigate whether a single dose of osmotic release oral system methylphenidate can remediate attention deficits and aberrancies in functional circuit dynamics in cognitive control networks, which have been implicated in ADHD. In a randomized placebo-controlled double-blind crossover design, 27 children with ADHD were scanned twice with resting-state functional MRI and sustained attention was examined using a continuous performance task under methylphenidate and placebo conditions; 49 matched typically-developing (TD) children were scanned once for comparison. Dynamic time-varying cross-network interactions between the salience (SN), frontoparietal (FPN), and default mode (DMN) networks were examined in children with ADHD under both administration conditions and compared with TD children. Methylphenidate improved sustained attention on a continuous performance task in children with ADHD, when compared to the placebo condition. Children with ADHD under placebo showed aberrancies in dynamic time-varying cross-network interactions between the SN, FPN and DMN, which were remediated by methylphenidate. Multivariate classification analysis confirmed that methylphenidate remediates aberrant dynamic brain network interactions. Furthermore, dynamic time-varying network interactions under placebo conditions predicted individual differences in methylphenidate-induced improvements in sustained attention in children with ADHD. These findings suggest that a single dose of methylphenidate can remediate deficits in sustained attention and aberrant brain circuit dynamics in cognitive control circuits in children with ADHD. Findings identify a novel brain circuit mechanism underlying a first-line pharmacological treatment for ADHD, and may inform clinically useful biomarkers for evaluating treatment outcomes.

Modulation of the N13 component of the somatosensory evoked potentials in an experimental model of central sensitization in humans

The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of dorsal horn neurons. In this neurophysiological study, we aimed to verify whether N13 SEP might reflect excitability changes of dorsal horn neurons during central sensitization. In 22 healthy participants, we investigated how central sensitization induced by application of topical capsaicin to the ulnar nerve territory of the hand dorsum modulated N13 SEP elicited by ulnar nerve stimulation. Using a double-blind placebo-controlled crossover design, we also tested whether pregabalin, an analgesic drug with proven efficacy on the dorsal horn, influenced capsaicin-induced N13 SEP modulation. Topical application of capsaicin produced an area of secondary mechanical hyperalgesia, a sign of central sensitization, and increased the N13 SEP amplitude but not the peripheral N9 nor the cortical N20-P25 amplitude. This increase in N13 SEP amplitude paralleled the mechanical hyperalgesia and persisted for 120 min. Pregabalin prevented the N13 SEP modulation associated with capsaicin-induced central sensitization, whereas capsaicin application still increased N13 SEP amplitude in the placebo treatment session. Our neurophysiological study showed that capsaicin application specifically modulates N13 SEP and that this modulation is prevented by pregabalin, thus suggesting that N13 SEP may reflect changes in dorsal horn excitability and represent a useful biomarker of central sensitization in human studies.

Hypogonadism in the Prader-Willi syndrome from birth to adulthood: a 28-year experience in a single centre.

BackgroundHypogonadism is a key feature of Prader–Willi syndrome (PWS) but clear strategies for hormone replacement are lacking.ObjectiveTo evaluate the gonadal status and outcome in patients attending a Scottish PWS clinic from 1991 to 2019.MethodsIn 93 (35F:56M) patients, median follow-up 11.2 years, gonadal and pubertal status were assessed clinically. Pelvic ultrasound findings and basal/stimulated gonadotrophins were compared with age-matched controls.ResultsFemales:of 22 patients aged > 11, 9 had reached B4–5, while 5 were still at B2–3, and 6 remained prepubertal. Eight patients experienced menarche aged 9.8–21.4 years, none with a normal cycle. Uterine length and ovarian volumes were normal but uterine configuration remained immature, with low follicular counts. Gonadotrophins were unremarkable, serum oestradiol 129 (70–520) pmol/L. Only 5 patients received oestrogen replacement. Males:fifty-four (96%) patients were cryptorchid (9 unilateral). Weekly hCG injections resulted in unilateral/bilateral descent in 2/1 of 25 patients. Of 37 boys aged > 11, 14 (9 with failed/untreated bilateral cryptorchidism) failed to progress beyond G1, 15 arrested at G2–3 (testes 3–10 mL), and 8 reached G4–5. Gonadotrophins were unremarkable except in boys at G2–5 in whom FSH was elevated: 12.3/27.3 vs 3.25/6.26 U/L in controls (P < 0.001). In males aged > 13, testosterone was 3.1 (0.5–8.4) nmol/L. Androgen therapy, given from 13.5 to 29.2 years, was stopped in 4/24 patients owing to behavioural problems.ConclusionDespite invariable hypogonadism, few females and only half the males with PWS in this study received hormone replacement. Double-blind placebo-controlled crossover trials of sex steroids are required to address unproven behavioural concerns.

Short‐term ketone monoester supplementation improves cerebral blood flow and cognitive function in adults with obesity: A randomized‐crossover trial

Background/Objectives Adults with obesity are at increased risk of neurocognitive impairments, due in part to reductions in cerebral blood flow (CBF) and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) are a purported therapeutic strategy for improving brain health in at-risk populations. We tested the hypothesis that short-term β-OHB supplementation will elevate CBF and BDNF, and in turn improve cognitive function in individuals with obesity. Subjects/Methods In a placebo-controlled double-blind crossover design 14 adults with obesity (10F; age=56±12 yrs; BMI=33.8±6.9 kg/m2) consumed 30 mL of either placebo or ketone supplement (12 g β-OHB) thrice-daily for 14 days. Participants were provided with all meals and snacks, which were matched between each 14-day period. CBF, cerebrovascular conductance (CVC), and shear rate were measured in the common carotid (CCA), internal carotid (ICA), and vertebral (VA) arteries by duplex ultrasound. Plasma and serum BDNF were measured by ELISA. Cognitive function was assessed by the digit-symbol substitution task (DSST), Stroop test, and task-switching test. All measures were taken in the fasting, non-supplemented state. Results CCA blood flow (25 mL×min-1 [12, 38], P=0.001), ICA shear rate (42 s-1 [15, 69], P=0.004), VA blood flow (18 mL×min-1 [10, 26], P<0.001), VACVC (0.08 mL×min-1×mmHg-1 [0.01, 0.15], P=0.027), and VA shear rate (34 s-1 [10, 59], P=0.008) significantly increased following 14-days of ketone supplementation. DSST performance (correct responses; CR) increased following ketone supplementation (+2.7 CR [1.3, 4.1], P<0.001) and this was positively associated with CCA blood flow (0.001 mL×min-1×CR-1 [0.001, 0.02], P=0.033) and CCACVC (1.24 ml×min-1×mmHg-1 CR-1 [0.24, 2.24], P=0.024), VA blood flow (0.034 mL×min-1×CR-1 [0.002, 0.066], P=0.039) and VACVC (3.32 1.24 ml×min-1×mmHg-1 CR-1 [0.20, 6.43], P=0.04). There were no differences in serum (301.8 pg/mL [-1033.4, 1637.2], P=0.65) and plasma BDNF (-380.4 pg/mL [-1023.9, 263.2], P=0.24) following ketone supplementation. Conclusions Short-duration ketone supplementation improved aspects of cognitive function, which may have been facilitated by enhanced CBF in adults with obesity. Ketone supplementation was well-tolerated and appears safe for cerebrovascular health, suggesting potential therapeutic benefits of β-OHB for brain health in adults with obesity.

D-cycloserine normalizes long-term motor plasticity after transcranial magnetic intermittent theta-burst stimulation in major depressive disorder

ObjectivesMajor Depressive Disorder (MDD) is associated with glutamatergic alterations, including the N-methyl-D-aspartate receptor (NMDA-R). The NMDA-R plays an important role in synaptic plasticity, and individuals with MDD have been shown to have impairments in repetitive Transcranial Magnetic Stimulation (rTMS) motor plasticity. Here, we test whether D-cycloserine, a NMDA-R partial agonist, can rescue TMS motor plasticity in MDD. MethodsWe conducted randomized double-blind placebo-controlled crossover studies in healthy (n = 12) and MDD (n = 12) participants. We stimulated motor cortex using TMS intermittent theta burst stimulation (iTBS) with placebo or D-cycloserine (100 mg). Motor evoked potentials (MEPs) were sampled before and after iTBS. Stimulus response curves (SRC) were characterized at baseline, +90 minutes, and the following day. ResultsAcute iTBS MEP facilitation is reduced in MDD and is not rescued by D-cycloserine. After iTBS, SRCs shift to indicate sustained decrease in excitability in healthy participants, yet increased in excitability in MDD participants. D-cycloserine normalized SRC changes from baseline to the following day in MDD participants. In both healthy and MDD participants, D-cycloserine stabilized changes in SRC. ConclusionMDD is associated with alterations in motor plasticity that are rescued and stabilized by NMDA-R agonism. SignificanceAgonism of NMDA receptors rescues iTBS motor plasticity in MDD.

Effects of 6-(Methylsulfinyl)hexyl Isothiocyanate Ingestion on Muscle Damage after Eccentric Exercise in Healthy Males: A Pilot Placebo-Controlled Double-Blind Crossover Study

An animal study demonstrated that 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC), a major bioactive compound in Japanese pungent spice wasabi, has an action of inhibiting the activation of calpain-1 (a protease). Increases in calpain activity can cause continual strength loss after eccentric exercise. It remains to be determined in humans whether 6-MSITC intake would modulate calpain and/or muscle damage responses after eccentric exercise. We performed a randomized, double-blind, crossover design study wherein eight healthy young males were randomly assigned to ingest 9 mg/day of 6-MSITC or placebo from 1 day before exercise to 4 days after exercise (30 maximal isokinetic eccentric contractions of the elbow flexors using an isokinetic dynamometer). Calpain-1 concentration, inflammatory and muscle damage markers (creatine kinase activity, urinary titin concentration, muscle strength, range of motion, muscle soreness and transverse relaxation time) were assessed. Plasma calpain-1 concentration after eccentric exercise was similar between the placebo- and 6-MSITC-treated conditions. All muscle damage and inflammatory markers were not affected by 6-MSITC relative to those in the placebo-treated condition. Our results suggest that 6-MSITC has no effect on plasma calpain-1 concentration and muscle damage and inflammatory markers measured after eccentric exercise.

Intranasal oxytocin enhances the perception of ambiguous averted gaze in women but not in men.

Perceiving accurately that others are looking away from us (averted gaze) is as important, for social interactions, as perceiving that others are looking at us (direct gaze). However, previous studies have revealed that when the deflection angle of averted gaze is small, individuals tend to falsely perceive it as direct gaze. Oxytocin (OXT) has been shown to increase orientation to the eye region. Therefore, a critical question is whether and how OXT would facilitate the perception of ambiguous averted gaze. The present study aimed to measure the effects of OXT on the performance of males and females in distinguishing ambiguous averted gaze from direct gaze of different emotional faces. In a double-blind placebo-controlled crossover experiment, 48 participants were presented successively two emotional faces with direct gaze (defined as 0, indicating the center of the eye) or averted gaze (defined as ±4, indicating the corner of the eye; +4 means that the iris moves 4 steps to the right; and -4 means that the iris moves 4 steps to the left) following intranasal oxytocin or placebo treatment and asked to make judgments on whether or not the two faces were the same in terms of identity. The interference effect of gaze direction was calculated by subtracting the mean accuracy and reaction time in the congruent gaze condition from those in the incongruent gaze condition. The logic of the measurement was if intranasal OXT would facilitate the detection of ambiguous averted gaze, we would observe a larger interference effect in the gaze incongruent condition compared with the gaze congruent condition, leading to longer RT or/and lower accuracy for identification judgment in the gaze incongruent condition. While there were no OXT effects in accuracy, we found a significant interaction between treatment, sex, and gaze congruency in reaction times. That is, following OXT as compared to placebo, women displayed stronger interference of gaze direction, whereas in men no significant difference was observed. Besides, this interaction did not vary across different emotional expressions. Our findings provide the first evidence for sex-dependent effects of OXT on the perception of ambiguous averted gaze. Given potential therapeutic applications of OXT to patients with developmental and psychiatric disorders, who are characterized as atypical in encoding gaze features, the findings suggest that rather different treatment outcomes could be anticipated in males and females.

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.

Does paracetamol improve quality of life, discomfort, pain and neuropsychiatric symptoms in persons with advanced dementia living in long-term care facilities? A randomised double-blind placebo-controlled crossover (Q-PID) trial

BackgroundThe objectives of this study are to determine the effects of regularly scheduled administration of paracetamol (acetaminophen) on quality of life (QoL), discomfort, pain and neuropsychiatric symptoms of persons with dementia living in long-term care facilities (LTCFs).MethodsA multicentre randomised double-blind placebo-controlled crossover trial for 13 weeks (January 2018 to June 2019) in 17 LTCFs across the west of the Netherlands. Inclusion criteria were age ≥ 65 years, (advanced) dementia and a moderate to low QoL, independent of the presence of pain (QUALIDEM ≤ 70). Exclusion criteria were the use of regular pain treatment, allergies to the study medication, severe liver disease, use of > 4 units of alcohol/day, weight < 50 kg and/or concomitant use of flucloxacillin. Participants received study medication (paracetamol/placebo) in two periods of 6 weeks each (1 week in between as a wash-out period). Randomisation decided in which order participants received paracetamol and placebo. Primary outcomes included QoL (QUALIDEM) and discomfort (DS-DAT), secondary outcomes included pain (MOBID-2) and neuropsychiatric symptoms (NPI-NH).ResultsNinety-five LTCF residents (mean age 83.9 years [SD 7.6], 57.9% females) were included. Repeated linear mixed models showed no difference in mean differences of QUALIDEM (paracetamol +1.3 [95% CI -1.0–3.5], placebo +1.5 [95% CI -0.7–3.8]), DS-DAT (paracetamol -0.1 [95% CI -1.4–1.2], placebo 0.6 [95 CI -0.7–1.8]), MOBID-2 (paracetamol 0.0 [95% CI -0.5–0.5], placebo -0.2 [95% CI -0.7–0.3]) and NPI-NH (paracetamol +1.5 [95% CI -2.3–5.4], placebo -2.1 [95% CI -6.0–1.7]) in favour of either paracetamol or placebo.ConclusionsCompared to placebo, paracetamol showed no positive effect on QoL, discomfort, pain and neuropsychiatric symptoms in persons with advanced dementia with low QoL. It is important to find out more specifically which individual persons with advanced dementia could benefit from pain treatment with paracetamol, and for clinicians to acknowledge that a good assessment, monitoring and multidomain approach is vital for improving QoL in this vulnerable group.Trial registrationNetherlands Trial Register NTR6766. Trial registration date: 20 October 2017

A Low Glutamate Diet Improves Cognitive Functioning in Veterans with Gulf War Illness

Abstract Objectives The objective of this research was to investigate a novel low glutamate dietary intervention for Gulf War Illness (GWI), a chronic multi-symptom disorder that includes cognitive dysfunction. Methods Forty GW veterans with GWI were recruited from across the US. As part of a larger clinical trial, participants completed computerized cognitive testing and the Adult ADHD Self-Report Scale (ASRS) using CNS Vital Signs® (CNSVS) software. Before diet initiation, subjects received intensive dietary counseling. Post-diet assessments were completed after 1 month on the diet, and then participants were randomized to a 2-week double-blind placebo-controlled crossover challenge with glutamate (MSG)/placebo administered over 3 days of each week. The CNSVS battery was administered again on the 3rd day of each challenge week. The challenge data have not yet been un-blinded, and therefore will not be included in this abstract. Pre-post testing (t-test or Wilcoxon Signed Rank test) was conducted for each domain in the CNSVS battery, including an overall marker of neurocognitive function (NCI) and the ASRS. Results Several cognitive domains were significantly improved after 1-month on the low glutamate diet, including NCI (P &amp;lt; 0.01), executive functioning (P = 0.01), cognitive flexibility (P &amp;lt; 0.05), motor speed (P &amp;lt; 0.01), processing speed (P &amp;lt; 0.05), and psychomotor speed (P = 0.001). However, reaction time was slower at post-diet testing (P = 0.01). ADHD symptoms were also significantly improved at post-diet (P &amp;lt; 0.0001). Conclusions Veterans with GWI showed major improvements in cognitive function after 1-month on a low glutamate diet, including improvement in overall neurocognitive status. Upcoming analysis of the double-blind placebo-controlled crossover challenge data will provide additional information on which cognitive domains are directly affected by challenge with glutamate relative to placebo. Funding Sources The US Army Medical Research Acquisition Activity, 820 Chandler St, Fort Detrick MD 21,702–5014 is the awarding and administering acquisition office. This work is supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Gulf War Illness Research Program. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

The Low Glutamate Diet Significantly Improves Pain and Other Symptoms in Veterans with Gulf War Illness

Abstract Objectives The objective was to examine if a low glutamate diet can reduce symptoms in Gulf War Illness (GWI), a multi-symptom chronic pain condition. Methods Forty GW veterans were recruited from across the US. Baseline measures included assessment of symptoms, myalgic score, tender point count, and dolorimetry. Subjects were randomized to the low glutamate diet, or to a wait-listed control group, starting the diet one month later. Measures were evaluated post-diet, and then subjects were randomized to a double-blind placebo-controlled crossover challenge with monosodium glutamate (MSG)/placebo to assess whether symptoms return/worsen in each condition. Challenge data have not yet been un-blinded, and thus are not included in this abstract. Symptom scores were compared between those randomized to immediate dietary intervention versus wait-listed controls (independent t-tests). After everyone completed the 1-month diet, change scores were analyzed for the whole group (Wilcoxon Signed Rank tests). Improvement was defined as ‘much’ or ‘very much’ improved on the patient global impression of change (PGIC) score, and the effect size was calculated (Cohen's d). Results After 1-month, overall symptom number (mean (SD)) significantly differed between the diet group (11(6)) and the wait-listed controls (18(6)), P = 0.0007. The diet had a very large effect size, d = 1.17, with no adverse effects reported. When comparing pre-post scores after all subjects followed the 1-month diet, the number of symptoms went from a mean(SD) of 21(5) at baseline to 12(6) post-diet, P &amp;lt; 0.0001. The severity of remaining symptoms was also significantly reduced (all P &amp;lt; 0.0001). Seventy-two % of subjects met the PGIC criteria for improvement. Highly significant improvements in pain measures were also observed for myalgic score (P &amp;lt; 0.0001), number of tender points (P &amp;lt; 0.0001), and average dolorimetry (P &amp;lt; 0.001). Conclusions These striking results suggest that the low glutamate diet may be an effective treatment for chronic pain and symptoms associated with Gulf War Illness. Funding Sources Department of Defense (DoD), US Army Medical Research Acquisition Activity, Office of the Assistant Secretary of Defense for Health Affairs through the GWI Research Program. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the DoD.