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Objectives: The present study constitutes the first randomized controlled trial to investigate the relation of lutein (L) and zeaxanthin (Z) to brain function using functional magnetic resonance imaging (fMRI). It was hypothesized that L and Z supplementation in older adults would enhance neural efficiency (i.e., reduce activation) and cognitive performance on a verbal learning task relative to placebo. Methods: A total of 44 community-dwelling older adults (mean age=72 years) were randomly assigned to receive either placebo or L+Z supplementation (12 mg/daily) for 1 year. Neurocognitive performance was assessed at baseline and post-intervention on an fMRI-adapted task involving learning and recalling word pairs. Imaging contrasts of blood-oxygen-level-dependent (BOLD) signal were created by subtracting active control trials from learning and recall trials. A flexible factorial model was employed to investigate the expected group (placebo vs. supplement) by time (baseline vs. post-intervention) interaction in pre-specified regions-of-interest. Results: L and Z appeared to buffer cognitive decline on the verbal learning task (Cohen’s d=.84). Significant interactions during learning were observed in left dorsolateral prefrontal cortex and anterior cingulate cortex (p < .05, family-wise-error corrected). However, these effects were in the direction of increased rather than decreased BOLD signal. Although the omnibus interaction was not significant during recall, within-group contrasts revealed significant increases in left prefrontal activation in the supplement group only. Conclusions: L and Z supplementation appears to benefit neurocognitive function by enhancing cerebral perfusion, even if consumed for a discrete period of time in late life. (JINS, 2018, 24, 77–90)

Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met the criteria for cognitive impairment (ie, scoring below the 25th percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and that clinical data implicate as being associated with prefrontal D1 availability: (1) the Paced Auditory Serial Addition Test (PASAT); and (2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days, with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen's d=1.14). Performance on the N-back ratio was also significantly improved; however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well tolerated, with no serious medical or psychiatric adverse events; common side effects were mild to moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive measures, eg, co-administered normal saline. Although preliminary, these findings lend further clinical support to the potential of D1 receptor agonists to treat schizophrenia-spectrum working memory impairments. These data suggest a need for further studies with larger group sizes, serum DAR-0100A levels, and a more comprehensive neuropsychological battery.

RationaleRecent reports have shown increased cannabis use among women, leading to growing concerns about cannabis use disorder (CUD). While there is preclinical evidence suggesting biological sex influences cannabinoid effects, human research remains scant. We investigated sex differences in the acute response to oral tetrahydrocannabinol (THC) in humans.Methods56 healthy men and women with prior exposure to cannabis but no history of CUD participated in a randomized, placebo-controlled, human laboratory study where they received a single 10 mg dose of oral THC (dronabinol). Subjective psychoactive effects were assessed by the visual analog scale of “high”, psychotomimetic effects by the Clinician-Administered Dissociative Symptoms Scale and Psychotomimetic States Inventory, verbal learning and memory by Rey Auditory Verbal Learning Test (RAVLT), and physiological effects by heart rate. Outcomes were regularly measured on the test day, except for the RAVLT, which was assessed once. Peak differences from baseline were analyzed using a nonparametric method for repeated measures.ResultsOral THC (10 mg) demonstrated significant dose-related effects in psychotomimetic and physiological domains, but not in RAVLT outcomes. A notable interaction between THC dose and sex emerged concerning the subjective “high” scores, with women reporting heightened sensations (p = 0.05). No other significant effects of sex and THC dose interaction were observed.ConclusionOral THC (10 mg) yields similar acute psychotomimetic and physiological effects across sexes, but women may experience a pronounced subjective psychoactive effect. Further research is needed to identify individual vulnerabilities and facilitate tailored interventions addressing CUD.Clinicaltrials.gov registration:https://clinicaltrials.gov/study/NCT02781519?term=Ranganathan&intr=THC&rank=3.

Recent advances in the understanding of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis. In a 3-day, double-blind, randomized, and counterbalanced study, the behavioral, cognitive, and endocrine effects of 0, 2.5, and 5 mg intravenous delta-9-tetrahydrocannabinol (Delta-9-THC) were characterized in 22 healthy individuals, who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder. Prospective safety data at 1, 3, and 6 months poststudy was also collected. Delta-9-THC (1) produced schizophrenia-like positive and negative symptoms; (2) altered perception; (3) increased anxiety; (4) produced euphoria; (5) disrupted immediate and delayed word recall, sparing recognition recall; (6) impaired performance on tests of distractibility, verbal fluency, and working memory (7) did not impair orientation; (8) increased plasma cortisol. These data indicate that Delta-9-THC produces a broad range of transient symptoms, behaviors, and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses. These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders.

There is a need to develop treatments for cognitive impairment associated with schizophrenia (CIAS). The significant role played by N -methyl- d -aspartate receptors (NMDARs) in both the pathophysiology of schizophrenia and in neuronal plasticity suggests that facilitation of NMDAR function might ameliorate CIAS. One strategy to correct NMDAR hypofunction is to stimulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) as AMPAR and NMDAR functioning are coupled and interdependent. In rats and nonhuman primates (NHP), AMPAR potentiators reduce spatial working memory deficits caused by the nonselective NMDAR antagonist ketamine. The current study assessed whether the AMPAR potentiator PF-04958242 would attenuate ketamine-induced deficits in verbal learning and memory in humans. Healthy male subjects ( n =29) participated in two randomized treatment periods of daily placebo or PF-04958242 for 5 days separated by a washout period. On day 5 of each treatment period, subjects underwent a ketamine infusion for 75 min during which the effects of PF-04958242/placebo were assessed on ketamine-induced: (1) impairments in verbal learning and recall measured by the Hopkins Verbal Learning Test; (2) impairments in working memory on a CogState battery; and (3) psychotomimetic effects measured by the Positive and Negative Syndrome Scale and Clinician-Administered Dissociative Symptoms Scale. PF-04958242 significantly reduced ketamine-induced impairments in immediate recall and the 2-Back and spatial working memory tasks (CogState Battery), without significantly attenuating ketamine-induced psychotomimetic effects. There were no pharmacokinetic interactions between PF-04958242 and ketamine. Furthermore, PF-04958242 was well tolerated. ‘High-impact’ AMPAR potentiators like PF-04958242 may have a role in the treatment of the cognitive symptoms, but not the positive or negative symptoms, associated with schizophrenia. The excellent concordance between the preclinical (rat, NHP) and human studies with PF-04958242, and in silico modeling of AMPAR–NMDAR interactions in the hippocampus, highlights the translational value of this study.

Rationale After stimulation with nitric oxide, soluble guanylate cyclase (sGC) produces cyclic guanosine monophosphate (cGMP), which stimulates an important signalling pathway for long-term potentiation (LTP). By upregulating cGMP, LTP could be stimulated and thereby enhancing memory processes. The present study investigated the effects of the sGC stimulator riociguat on cognition in healthy volunteers. Participants were pre-treated with and without biperiden, which impairs memory performance, to investigate the memory-enhancing effects of riociguat. Methods Twenty volunteers participated in a double-blind placebo-controlled six-way crossover design with a cognitive test battery including the verbal learning task (VLT), n -back task, spatial memory test, the attention network test, and a reaction time task. Treatments were placebo and riociguat 0.5 mg, placebo and riociguat 1.0 mg, biperiden 2.0 mg and placebo, biperiden 2.0 mg and riociguat 0.5 mg and biperiden 2.0 mg and riociguat 1.0 mg. Results Blood pressure was found to be decreased and heart rate to be increased after administration of riociguat. Cognitive performance was not enhanced after administration of riociguat. Biperiden decreased episodic memory on the VLT, yet this deficit was not reversed by riociguat. Conclusion This supports the notion that biperiden might be a valuable pharmacological model to induce episodic memory impairments as observed in AD/MCI.

High cortisol levels are found in severe mood disorders, particularly bipolar disorder. Hypercortisolaemia may cause or exacerbate both neurocognitive impairment and depressive symptoms. We hypothesized that antiglucocorticoid treatments, particularly corticosteroid receptor antagonists, would improve neurocognitive functioning and attenuate depressive symptoms in this disorder. To test this hypothesis, 20 bipolar patients were treated with 600 mg/day of the corticosteroid receptor antagonist mifepristone (RU-486) or placebo for 1 week in a double-blind crossover design. Over the total 6 weeks of the study, neurocognitive and neuroendocrine function were evaluated at baseline, days 21 and 42. Mood symptoms were evaluated weekly. Nineteen subjects completed the protocol; there were no drop-outs due to adverse events. Following treatment with mifepristone, selective improvement in neurocognitive functioning was observed. Spatial working memory performance was significantly improved compared to placebo (19.8% improvement over placebo). Measures of verbal fluency and spatial recognition memory were also improved after mifepristone. Beneficial effects on mood were found; Hamilton Depression Rating Scale scores were significantly reduced compared to baseline (mean reduction of 5.1 points) as were Montgomery-Asberg Depression Rating Scale scores (mean reduction of 6.05 points). No significant change occurred after placebo. These data require replication but provide preliminary evidence that glucocorticoid receptor antagonists may have useful cognitive-enhancing and possibly antidepressant properties in bipolar disorder.

Tamoxifen (TMX) is a selective estrogen receptor modulator that is used as an estrogen receptor antagonist for the treatment and prevention of breast cancer. Whether TMX has antagonist activities in the human brain is less clear and its effects on cognitive function have not been experimentally explored. This study examined how TMX affected cognitive performance in older women using a model of anticholinergic drug-induced cognitive dysfunction. Twenty-one postmenopausal women were administered 20 mg of oral TMX or placebo for 3 months. Participants then took part in five drug challenges using the anticholinergic antinicotinic agent mecamylamine (MECA) and antimuscarinic agent scopolamine (SCOP) and were tested on a comprehensive battery including tasks of attention and psychomotor function, verbal episodic memory, and spatial navigation. After a 3-month placebo washout, participants were then crossed over to the alternate treatment and repeated the drug challenges after 3 months. Compared with placebo treatment, TMX significantly attenuated the impairment from cholinergic blockade on tasks of verbal episodic memory and spatial navigation, but effects on attentional/psychomotor tasks were more variable. Analysis by APOE genotype showed that APO ɛ4+ women showed a greater beneficial effect of TMX on reversing the cholinergic impairment than APO ɛ4- women on most tasks. This study provides evidence that TMX may act as an estrogen-like agonist to enhance cholinergic system activity and hippocampally mediated learning.

Background Research on the neurobiological foundations of memory has shown that multiple neurotransmitters play an important role in memory processing. To study the interaction between neurotransmitters such as acetylcholine and serotonin, pharmacological models can be used. In this study, we tested the effects of the muscarinic M1 antagonist biperiden, acute tryptophan depletion (ATD), and the interaction between the two on episodic memory using the verbal learning task. Methods The study was conducted according to a double-blind, placebo-controlled, four-way crossover design. Seventeen participants received biperiden (2.0 mg), ATD (SolugelP), a combination of both, or a placebo in counterbalanced order with a wash out of at least 7 days. A verbal learning task was performed while recording electroencephalography. The task consisted of an immediate and delayed recall as well as a recognition part. Results Results revealed decreased scores on the delayed recall after biperiden and ATD separately but no significant interaction between the two. However, the event-related potential components P3b, N400, and P600 did show an interaction during encoding. Conclusion These results indicate that both BIP and ATD impair episodic memory. However, an interaction between the serotonergic and cholinergic system on memory performance is not supported.

Rationale Nicotinic agonists may improve attention and memory in humans and may ameliorate some cognitive deficits associated with neuropsychiatric disorders such as schizophrenia. Materials and methods We investigated the effects of a single dose of nicotine on episodic memory performance in 10 adults with schizophrenia and 12 healthy controls. Participants were nonsmokers in order to avoid confounding effects of nicotine withdrawal and reinstatement on memory. At each of two study visits, participants performed a test of episodic memory before and 4 h after application of a 14-mg transdermal nicotine (or identical placebo) patch in counterbalanced order. Results Compared with placebo, nicotine treatment was associated with more rapid and accurate recognition of novel items. There was a trend for a treatment by diagnosis interaction, such that the effect of nicotine to reduce false alarms was stronger in the schizophrenia than the control group. There was no effect of nicotine on accuracy or reaction time for identification of previously viewed items. Conclusions These data suggest that nicotine improves novelty detection in non-smokers, an effect that may be more pronounced in non-smokers with schizophrenia. Because memory deficits are associated with functional impairment in schizophrenia and because impaired novelty detection has been linked to the positive symptoms of schizophrenia, study of the effects of chronic nicotinic agonist treatment on novelty detection may be warranted.