Improvement In Spatial Working Memory Research Articles

No Effect of Calorie Restriction or Dietary Patterns on Spatial Working Memory During a 2-Year Intervention: A Secondary Analysis of the CALERIE Trial

BackgroundThe effect of calorie restriction (CR) on cognitive function is not well understood, and the impact of the dietary patterns consumed during CR has not been investigated. ObjectivesWe analyzed the combined association of CR and dietary quality with spatial working memory (SWM) in healthy adults without obesity. MethodsThe Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial was a 2-y, multisite clinical trial. This trial was registered at clinicaltrials.gov as NCT00427193. Participants were randomized to a 25% reduction in EI (n = 143) or an ad libitum Control (n = 76). The Dietary Inflammatory Index (DII) and the Healthy Eating Index (HEI) captured dietary quality, with a lower DII and higher HEI score indicating a healthier diet. The Cambridge Neuropsychological Test Automated Battery battery was used to assess SWM. Longitudinal associations between each dietary pattern index and SWM for CR and Control were assessed by multivariable negative binomial models that included baseline, 12-mo, and 24-mo visits. ResultsParticipants were aged 38.1 ± 7.2 y with a BMI of 25.1 ± 1.7 kg/m2. A total of 70% of the participants were female. Baseline mean DII and HEI scores were −0.15 (range: −3.77, 4.21) and 59.1 (24.1, 91.0) and did not differ between groups. Improvements in DII and HEI were significantly different between CR and Control over 2 y (both P-interaction = 0.001). In longitudinal analyses, there was no association of either index with SWM. Furthermore, though within-group improvements in SWM were observed at 12 mo, there was no statistically significant difference between CR (SWM errors: 9.0; 95% CI: 1.9, 41.6) and Control (11.7; 95% CI: 2.6, 53.5; P > 0.99), holding DII constant. Comparable results were observed at 24 mo and for the HEI. ConclusionsDietary quality during CR was not associated with measures of SWM over 2 y in healthy adults without obesity. These results suggest that, in healthy populations, dietary patterns and CR may have a limited impact on working memory. Further research is required to understand the concurrent effect of these nutritional strategies.

No Effect of Calorie Restriction or Dietary Patterns on Spatial Working Memory During a Two-Year Intervention: A Secondary Analysis of the CALERIE Trial

ObjectivesThe effect of calorie restriction (CR) on cognitive function is controversial, and the effects of consuming a healthy dietary pattern during CR have not been investigated. Furthermore, there is no consensus on what dietary pattern may be the most beneficial for cognition. We analyzed the combined effects of CR and self-selected diet on measures of spatial working memory (SWM) in healthy adults without obesity.MethodsPublicly available data from the CALERIE trial were analyzed. Participants were randomized to a 2-year CR intervention (n = 143) or an ad libitum Control (n = 76). Food records were collected at baseline, 12, and 24 months. The Dietary Inflammatory Index (DII) and the Healthy Eating Index (HEI-2015) were calculated to quantify different measures of dietary healthfulness, where a lower DII and a higher HEI-2015 indicate a healthier score. Cognitive function was assessed by the CANTAB battery, with fewer errors indicating better SWM. Changes in each index during the intervention were assessed by linear mixed models. Longitudinal associations between the indices and SWM were assessed by multivariable negative binomial models.ResultsOn average, participants were 38.1 ± 7.2 years old with a BMI of 25.1 ± 1.7 kg/m2. The average DII and HEI-2015 scores at baseline were −0.47 (range: −4.02, 3.19) and 59.1 (24.1, 91.0) and did not significantly differ between groups. Improvements in DII and HEI-2015 were significantly different between CR and Control over time (P interaction < 0.0001), with greater improvements in CR. In longitudinal analyses, there was no significant effect of improving the healthfulness of the DII or HEI-2015 on SWM. In addition, though there were significant within-group improvements in SWM at 12 months, there was no significant difference between the changes observed in CR (adjusted mean difference: 10.0; 95% CI: 2.2, 45.7) and Control (13.1; 95% CI: 2.9, 59.3; P = 0.93). Comparable results were observed at 24 months.ConclusionsNeither CR nor the healthfulness of the diet were associated with SWM, suggesting that that the potential for CR and dietary patterns to have beneficial effects on working memory may be limited in healthy populations. Further research is required to understand the role of diet in cognitive function in at-risk populations.Funding SourcesJean Mayer USDA HNRCA Doctoral Scholarship; USDA agreement #8050-51,000-105-01S.

Anterior thalamic nuclei neurons sustain memory.

A hippocampal-diencephalic-cortical network supports memory function. The anterior thalamic nuclei (ATN) form a key anatomical hub within this system. Consistent with this, injury to the mammillary body-ATN axis is associated with examples of clinical amnesia. However, there is only limited and indirect support that the output of ATN neurons actively enhances memory. Here, in rats, we first showed that mammillothalamic tract (MTT) lesions caused a persistent impairment in spatial working memory. MTT lesions also reduced rhythmic electrical activity across the memory system. Next, we introduced 8.5 Hz optogenetic theta-burst stimulation of the ATN glutamatergic neurons. The exogenously-triggered, regular pattern of stimulation produced an acute and substantial improvement of spatial working memory in rats with MTT lesions and enhanced rhythmic electrical activity. Neither behaviour nor rhythmic activity was affected by endogenous stimulation derived from the dorsal hippocampus. Analysis of immediate early gene activity, after the rats foraged for food in an open field, showed that exogenously-triggered ATN stimulation also increased Zif268 expression across memory-related structures. These findings provide clear evidence that increased ATN neuronal activity supports memory. They suggest that ATN-focused gene therapy may be feasible to counter clinical amnesia associated with dysfunction in the mammillary body-ATN axis.

Lower cognitive baseline scores predict cognitive training success after 6 months in healthy older adults: Results of an online RCT.

Identifying predictors for general cognitive training (GCT) success in healthy older adults has many potential uses, including aiding intervention and improving individual dementia risk prediction, which are of high importance in health care. However, the factors that predict training improvements and the temporal course of predictors (eg, do the same prognostic factors predict training success after a short training period, such as 6 weeks, as well as after a longer training period, such as 6 months?) are largely unknown. Data (N = 4,184 healthy older individuals) from two arms (GCT vs. control) of a three-arm randomized controlled trial were reanalyzed to investigate predictors of GCT success in five cognitive tasks (grammatical reasoning, spatial working memory, digit vigilance, paired association learning, and verbal learning) at three time points (after 6 weeks, 3 months, and 6 months of training). Possible investigated predictors were sociodemographic variables, depressive symptoms, number of training sessions, cognitive baseline values, and all interaction terms (group*predictor). Being female was predictive for improvement in grammatical reasoning at 6 weeks in the GCT group, and lower cognitive baseline scores were predictive for improvement in spatial working memory and verbal learning at 6 months. Our data indicate that predictors seem to change over time; remarkably, lower baseline performance at study entry is only a significant predictor at 6 months training. Possible reasons for these results are discussed in relation to the compensation hypothesis. J Am Geriatr Soc 68:-, 2020.

Neuroprotective effects of resveratrol in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, which is commonly seen in older individuals. This is characterized by cognitive dysfunction, which leads to dementia. Pharmacological treatments for AD are mainly targeted on its symptoms like memory loss and cognitive impairment. The pathophysiology involved in AD is intra-neuronal accumulation of hyper-phosphorylated tau protein as neurofibrillary tangle and extra cellular beta amyloid plaque deposition, which is due to oxidative stress. Here we review the neuro-protective effects of Resveratrol (RSV) and its treatment efficacy in AD. RSV is a naturally available polyphenolic compound, which has antioxidant, anti-cancerous, anti-inflammatory and anti-aging properties. RSV crosses blood brain barrier and exerts its antioxidant effect by enhancing the anti-oxidant enzymes. RSV is involved in Sirtuin (SIRT1) mediated lifespan extension activity. RSV has reduced glial activation and helped in increasing the hippocampal neurogenesis. RSV was able to decrease the expression of amyloid precursor protein, along with improvement of spatial working memory. Since RSV acts as an antioxidant, it can be safely used as oral drug.

A Temporal Study on Learning and Memory at High Altitude in Two Ethnic Groups.

Introduction: Cognitive function has been compromised during high-altitude (HA) exposure due to slowing of mental processing. Materials and Methods: A total of 20 Indian and 20 Kyrgyz soldiers were studied at 4111 m to assess cognitive function in two different ethnic groups. Paired associate learning, pattern recognition memory, spatial span (SSP), spatial working memory (SWM), choice reaction time (CRT), and simple reaction time (SRT) were evaluated at sea level and on days 3, 7, 14, and 21 of HA stay and on day 3 of deinduction. Results: All the parameters were significantly affected at HA. Indian soldiers were acclimatized by 7 days but Kyrgyz soldiers required 21 days for acclimatization. A slow impairment in SWM, CRT, and SRT was observed in Kyrgyz soldiers than in Indian soldiers and it continues throughout 21 days of HA stay, but for Indian soldiers the deterioration was maximum on day 7 and improvement in SWM, CRT, and SRT was observed on day 14 and close to baseline value on day 21. After deinduction, although Indian soldiers attained the normal value, Kyrgyz soldiers had higher value than baseline in SSP, SWM, CRT, and SRT. Conclusion: Difference in the cognitive performances of Indian and Kyrgyz soldiers may be due to the ethnogenetic diversity of these two groups.

Developmental changes of neuropsychological functioning in individuals with and without childhood ADHD from early adolescence to young adulthood: a 7-year follow-up study.

Our knowledge about the developmental change of neuropsychological functioning in attention-deficit/hyperactivity disorder (ADHD) is limited. This prospective longitudinal study examined the changes in neuropsychological functions and their associations with the changes of ADHD symptoms across the developmental stages from early adolescence to young adulthood. We followed up 53 individuals diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) ADHD during childhood (mean age 12.77 years at time 1, 19.81 years at time 2) and 50 non-ADHD controls (mean age 12.80 years at time 1, 19.36 years at time 2) with repeated psychiatric interviews at two time points to confirm ADHD and other psychiatric diagnoses. Neuropsychological functions with high- and low-executive demands, measured by the Cambridge Neuropsychological Testing Automated Battery (CANTAB) at two time points, were compared. Both groups showed improvements in all neuropsychological tasks except reaction time in the ADHD group. Despite having a greater improvement in spatial working memory (SWM) than controls, individuals with ADHD still performed worse in various neuropsychological tasks than controls at follow-up. Better baseline intra-dimension/extra-dimension shift and parental occupation predicted fewer ADHD symptoms at follow-up independent of baseline ADHD symptoms. The degree of ADHD symptom reduction was not significantly linearly correlated to the magnitude of neuropsychological function improvement. Individuals with ADHD and controls had parallel developments in neuropsychological functioning, except a catch-up in SWM in ADHD. Almost all neuropsychological functions herein were still impaired in ADHD at late adolescence/young adulthood. There may be a threshold (i.e. non-linear) relationship between neuropsychological functioning and ADHD symptoms.

F70. COMPUTERIZED SOCIAL COGNITIVE TRAINING (SCT) IMPROVES COGNITION AND RESTORES FUNCTIONAL CONNECTIVITY IN RECENT ONSET PSYCHOSIS: AN INTERIM REPORT

BackgroundNeurocognitive impairments are a core and enduring feature of psychosis that continue to persist despite pharmacological interventions. Neurocognitive interventions have emerged as a supplementary treatment option to improve cognition in early psychosis patients. Recently, focus has shifted to using social cognitive training (SCT) as evidence suggests that targeting social cognition may lead to improvements not only in cognition but also in real-world functioning (Horan et al., 2011). This improvement is thought to be mediated by restoration of functional brain activity in patients undergoing neurocognitive interventions, especially associated with medial prefrontal cortex (Hooker et al., 2014). In this study, we report our interim findings of the effects of a 10-hour SCT on cognition and resting-state functional connectivity (rsFC). Our hypothesis was that training would improve cognition and normalize functional connectivity.MethodsIn this randomized-controlled study, one recent onset psychosis (ROP) patient arm (n=18) underwent a 6-week (10-hour) computerized SCT (Brain HQ, Posit Science, https://www.brainhq.com/), while another naturalistic arm (n=18) received treatment as usual (TAU). Both treatment arms were assessed on a battery of neurocognitive tests and underwent a multimodal imaging protocol, including a 10 min resting-state fMRI, at two timepoints (baseline, T0; follow-up, FU). Seed-based voxel-wise rsFC was performed and individual-level rsFC correlation maps were calculated between the bilateral medial prefrontal cortex (mPFC) and the whole brain.ResultsThe SCT group showed significant improvements in the domain of spatial working memory (p<0.05), processing speed (p<0.05) and resilience to both immediate and delayed memory decline over 6 weeks (p<0.05), as compared to TAU. Comparison of FC between the two measurement time points, suggested increased FC between mPFC and left inferior temporal gyrus (ITG), as well as increased FC between mPFC and left somatosensory area in ROP patients that underwent SCT relative to TAU.DiscussionWe have shown improvements in processing speed, verbal memory, and spatial working memory that agree with previous studies using computerized cognitive interventions. Moreover, the improvement in the spatial working memory domain was significant in the most demanding test condition with 10 elements - indicative of benefits from the fine-tuning of higher-level executive functions. The neuroimaging results also suggested that the improvements may have been mediated by the improvement of FC in regions typically associated with social cognition and facial recognition (Adolphs et al., 2009). These results are in line with recent studies investigating not only the feasibility of SCT as an intervention, but also the effects on cognition and underlying neural alterations resulting from intensive computerized neurocognitive interventions (Hooker et al., 2012; Nahum et al., 2014; Subramaniam et al., 2014). Future studies using machine learning methods will be necessary to determine functional biomarkers in order to personalize SCT at the individual-level.

58. Focusing on the Significance of, and the Mechanisms Underlying, Cannabis-Induced Psychosis

Overall Abstract: Dr Marta Di Forti Cannabis use across Europe and its interaction with the polygenic risk score for schizophrenia. Dr Di Forti examined the pattern of cannabis use across 16 European sites as part of the EU-GEI study. She will show striking differences in incidence of psychosis (high in North and low in South), and how differences in pattern of cannabis use result in differences in the proportion of new cases of psychosis attributable to cannabis use across Europe (highest in London and Amsterdam). Dr Di Forti will examine the effects of cannabis use on incidence of psychosis, and show how cannabis use interacts with the Schizophrenia Polygenic Risk Score (in 1200 cases and similar number of controls). Dr David Lewis Adolescent Cannabis Use, Cortical Circuitry and Schizophrenia Dr Lewis studied both adolescent monkeys and boys. In adolescent monkeys, repeated exposure to Δ9-tetrahydrocannabinol (THC) blunted the trajectory of accuracy improvements in spatial working memory. These effects were more marked and more persistent in male than in female monkeys. In a longitudinal human study, 1006 boys were followed regularly through their adolescence. For each year that they engaged in regular marijuana use, their expected odds of experiencing subsequent subclinical paranoia or hallucinations rose by 133% and 92%, respectively. Dr Steve Laviolette The Molecular and Neuronal Effects of Adolescent THC Exposure in Mesocorticolimbic Circuitry. Dr Laviolette has discovered that neurodevelopmental exposure to THC dramatically dysregulates dopamine transmission in the mesocorticolimbic circuit, inducing a hyper-DAergic phenotype into adulthood; schizophrenia-like abnormalities are found in affective and cognitive processes and schizophrenia-like molecular adaptations in the prefrontal cortex (PFC) and nucleus accumbens involving the GSK-3 pathway. Developmental THC exposure leads to deficits in GABAergic inhibitory substrates within the PFC and a loss of control over subcortical DAergic activity states. Dr Anissa Abi Dargham Chronic cannabis use is associated with abnormal dopaminergic function. Dr Abi Dargham measured amphetamine induced dopamine release with PET and D2 radiotracers in striatal subdivisions in multiple cohorts of patients with schizophrenia, patients with schizophrenia and comorbid substance use disorders, in patients with cannabis use, and in controls matched to each cohort. Her studies show that substance use disorders, and cannabis use, result in blunting of dopamine release. In addition, patients with schizophrenia exposed to chronic substance use show excess responsivity of the D2 system associated with psychosis, despite low presynaptic storage capacity. These findings will be discussed and compared to address the contribution of cannabis use to the dopaminergic dysfunction in schizophrenia.

P192 Investigating the role of the parietal and prefrontal cortices in spatial working memory using transcranial direct current stimulation

Question Working memory involves the temporary storage, processing, and manipulation of information. Previous studies have suggested that the posterior parietal cortex (PPC), and dorsolateral prefrontal cortex (DLPFC) are involved in spatial working memory, and spatial and object working memory, respectively. The aim of the present pilot study was to investigate whether modulation of the activity of the left PPC and the left DLPFC changes spatial, and object working memory performance. Transcranial direct current stimulation (tDCS) was used for this purpose. Based on past literature we expected to see improvement of both spatial and object working memory after tDCS of the left DLPFC as well as improvement of spatial working memory after tDCS of the left PPC. Methods Participants ( n = 12) attended three experimental sessions with different stimulation conditions. Fifteen minutes of 1.5 mA anodal tDCS was applied over either the left PPC, left DLPFC or occipital lobe as control condition, beginning five minutes before the task. Participants were required to perform a 2-back spatial and object working memory task; i.e., they were required to pay attention to both objects and their location. Abstract objects were presented on either of an eight locations placed on a virtual circle around the centre of the screen. In addition to a 2-back object working memory task, occasionally participants were asked to indicate the location of the object they saw two screens previously. Performance in three different conditions was measured for analysis: (1) 2-back working memory task for the cases in which both cue and target objects were presented in the same location (OWM-same), (2) in different location (OWM-different) and (3) spatial working memory (SWM). Results Preliminary results showed that performance in the OWM-different condition was lower than OWM-same. There, however, was no significant different between different stimulation conditions. Conclusions These results suggest that anodal tDCS to the left PPC and left DLPFC might not be able to modulate spatial, and object working memory performance. Further studies are needed to investigate the differential role(s) of the DLPFC and PPC in spatial and working memory.

The effect of sodium nitroprusside on psychotic symptoms and spatial working memory in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial.

Sodium nitroprusside (SNP) has been reported to rapidly reduce psychotic symptoms in patients with schizophrenia. This has the potential to revolutionize treatment for schizophrenia. In this study, we tested the hypothesis that SNP leads to a reduction in psychotic symptoms and an improvement in spatial working memory (SWM) performance in patients with schizophrenia. This was a single-centre, randomized, double-blind, placebo-controlled trial performed from 27 August 2014 to 10 February 2016 (clinicaltrials.gov identifier: NCT02176044). Twenty patients with schizophrenia aged 18-60 years with a diagnosis of schizophrenia or schizoaffective disorder were recruited from psychiatric outpatient clinics in the South London and Maudsley NHS Trust, London, UK. Baseline symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18), and SWM was assessed using the CANTAB computerized test. Participants received either an infusion of SNP (0.5 μg/kg per min for 4 h) or placebo and were re-assessed for symptoms and SWM performance immediately after the infusion, and 4 weeks later. SNP did not lead to any reduction in psychotic symptoms or improvement in SWM performance compared to placebo. Although this study was negative, it is possible that the beneficial effects of SNP may occur in patients with a shorter history of illness, or with more acute exacerbation of symptoms.

Activation of matrix metalloproteinase in dorsal hippocampus drives improvement in spatial working memory after intra-VTA nicotine infusion in rats.

The hippocampus receives dopaminergic projections from the ventral tegmental area (VTA) and substantia nigra. These inputs appear to provide a modulatory signal that influences hippocampus-dependent behaviors. Enhancements in working memory performance have been previously reported following acute smoking/nicotine exposure. However, the underlying mechanism remains unclear. This study investigated the effects of nicotine on spatial working memory (SWM) and the mechanisms involved. Delayed alternation T-maze task was used to assess SWM. In situ and gel gelatin zymography were used to detect matrix metalloproteinase-9 (MMP-9) in SWM. Systemic or local (intra-VTA) administration of nicotine significantly improves SWM, which was accompanied by increased MMP-9 activity in dorsal hippocampus (dHPC). Intra-dHPC administration of MMP inhibitor FN-439 abolished the memory enhancement induced by intra-VTA nicotine infusion. FN-439 had no effect on locomotor behavior. Our data suggest that intra-VTA nicotine infusion activates MMP-9 in dHPC to improve SWM in rats.

The Effects of Long-Chain Omega-3 Fish Oils and Multivitamins on Cognitive and Cardiovascular Function: A Randomized, Controlled Clinical Trial

Objective: Fish oils and multivitamins are two of the most commonly used dietary supplements. Fish oil use may reduce vascular risk factors associated with cognitive decline, thus providing benefits to both heart and brain health. Multivitamins may also have direct effects on brain function. The present study investigated the effects of fish oil, with and without the addition of a multivitamin, on cognitive and cardiovascular function.Methods: In a randomized, placebo-controlled, double-blind fashion, 160 healthy adults aged 50–70 years were randomized to receive either 3 g of fish oil (240 mg eicosapentaenoic acid [EPA] + 240 mg docosahexaenoic acid [DHA]) with a multivitamin, 6 g of fish oil (480 mg EPA + 480 mg DHA) with a multivitamin, or 6 g of fish oil without a multivitamin or a placebo. Cognitive performance, brachial blood pressure, and aortic (central) blood pressure were measured at baseline, 6 weeks, and 16 weeks.Results: Treatment allocation had no effect on the primary cognitive outcomes at endpoint. Absolute increases in the red blood cell omega-3/6 ratio were associated with improvements in spatial working memory. The group receiving 6 g fish oil without the multivitamin displayed a significant decrease in aortic pulse pressure and aortic augmentation pressure, two measures of aortic blood pressure and aortic stiffness.Conclusions: Fish oil decreased aortic pulse pressure and augmentation pressure. Reductions in aortic blood pressure were not accompanied by consistent improvements in cognition.

&amp;lt;i&amp;gt;Vitamin&amp;lt;/i&amp;gt; D&amp;lt;sub&amp;gt;3&amp;lt;/sub&amp;gt; Receptor Activation Rescued Corticostriatal Neural Activity and Improved Motor-Cognitive Function in -D&amp;lt;sub&amp;gt;2&amp;lt;/sub&amp;gt;R Parkinsonian Mice Model

Background: fourth generation antipsychotics have been implicated in the blockade of calcium signalling through inhibition of dopamine receptive sites on dopaminergic D2 Receptor (D3R). As a result of the abnormal calcium signalling associated with D2R inhibition, changes occur in the motor and memory neural axis leading to the observed behavioural deficits after prolonged haloperidol. Thus, Vitamin D3 receptor (VD3R), a calcium controlling receptor in the striatum can be targeted to relief the neurological symptoms associated with haloperidol (-D2R) induced PD. Aim: This study sets to investigate the role of VD3R activation in vitro and in vivo after haloperidol-induced Dopaminergic (D2R) blockade. In addition, we examined the associated neural activity and behavioural changes in parkinsonian and VDRA intervention mice. Methods: Dopaminergic D2R inhibition was investigated in vitro using Melanocytes isolated from the scale of a Tilapia. In four separate set ups, the cells were cultured in calcium free Ringer’s solution as follows; 300 μM haloperidol, 100 μM VD3, 100 mM calcium chloride and a combination of 300 μM haloperidol and 100 μM VD3. Subsequently, dopaminergic vesicle accumulation and calcium signalling were observed in bright field microscopy using blue and green fluorescence probes. In the second phase, PD was induced in adult BALB/c mice (-D2; n = 8) after 14 days of intraperitoneal haloperidol treatment (10 mg/Kg). A set of n = 4 mice were untreated (-D2) while the other group (n = 4) received 100 mg/Kg of VD3 for 7 days (-D2/+VDR). The control groups (n = 4 each) were treated with normal saline (NS) and VD3 (+VDR) for 14 days. At the end of the treatment phase, the animals were assessed in Rotarod, parallel bar-, cylinder-, Y-Maze-, one trial place recognition- and novel object recognition-(NOR) tests. Neural activity was measured using chronic electrode implants placed in the M1 (motor cortex), CPu (striatum), CA1 (hippocampus) and PFC (prefrontal cortex). Neural activity was compared with the outcomes of behavioural tests for memory and motor functions and data was expressed as mean ± SEM (analysed using ANOVA with Tukey post-hoc test, significant level was set at 0.05). Results/Discussion: in vitro outcomes show that VDR increase calcium signalling and reverses the effect of haloperidol; specifically by reducing dopaminergic vesicle accumulation in the cell body. Similarly, in vivo neural recordings suggest an increase in calcium hyperpolarization currents in the CPu and PFC of intervention mice (-D2/+VDR) when compared with the parkinsonian mice (-D2). These animals (-D2/+VDR) also recorded an improvement in spatial working memory and motor function versus the Parkinsonian mice (-D2). These outcomes suggest the role of CPu-PFC corticostriatal outputs in the motor-cognitive decline seen in parkinsonian mice. Similarly, VDRA reduced the neural deficits through restoration of calcium currents (burst activities) in the intervention mice (-D2/+VDR). Conclusion: VDRA treatment reduced the motor-cognitive defects observed in haloperidol induced PD. Our findings suggest the role of VDRA in restoration of calcium currents associated with PFC and CPu corticostriatal outputs seen as burst frequencies in in vivo neural recording.

Phenolic Acid Intake, DeliveredViaModerate Champagne Wine Consumption, Improves Spatial Working MemoryViathe Modulation of Hippocampal and Cortical Protein Expression/Activation

While much data exist for the effects of flavonoid-rich foods on spatial memory in rodents, there are no such data for foods/beverages predominantly containing hydroxycinnamates and phenolic acids. To address this, we investigated the effects of moderate Champagne wine intake, which is rich in these components, on spatial memory and related mechanisms relative to the alcohol- and energy-matched controls. In contrast to the isocaloric and alcohol-matched controls, supplementation with Champagne wine (1.78 ml/kg BW, alcohol 12.5% vol.) for 6 weeks led to an improvement in spatial working memory in aged rodents. Targeted protein arrays indicated that these behavioral effects were paralleled by the differential expression of a number of hippocampal and cortical proteins (relative to the isocaloric control group), including those involved in signal transduction, neuroplasticity, apoptosis, and cell cycle regulation. Western immunoblotting confirmed the differential modulation of brain-derived neurotrophic factor, cAMP response-element-binding protein (CREB), p38, dystrophin, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, mammalian target of rapamycin (mTOR), and Bcl-xL in response to Champagne supplementation compared to the control drink, and the modulation of mTOR, Bcl-xL, and CREB in response to alcohol supplementation. Our data suggest that smaller phenolics such as gallic acid, protocatechuic acid, tyrosol, caftaric acid, and caffeic acid, in addition to flavonoids, are capable of exerting improvements in spatial memory via the modulation in hippocampal signaling and protein expression. Changes in spatial working memory induced by the Champagne supplementation are linked to the effects of absorbed phenolics on cytoskeletal proteins, neurotrophin expression, and the effects of alcohol on the regulation of apoptotic events in the hippocampus and cortex.

A head-to-head randomized clinical trial of methylphenidate and atomoxetine treatment for executive function in adults with attention-deficit hyperactivity disorder

Results regarding the effects of methylphenidate and atomoxetine on executive functions were inconsistent and no study has directly compared the efficacy of these two medications in improving executive functions in adults with attention-deficit hyperactivity disorder (ADHD). We conducted an 8-10 wk, open-label, head-to-head, randomized clinical trial involving adults with a clinical diagnosis of ADHD confirmed by psychiatric interview. The two treatment arms were immediate-release methylphenidate (IR-methylphenidate) (n = 31) and atomoxetine once daily (n = 32). Executive functions were assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB), including spatial working memory, spatial span, intra-extra dimensional set shifts, rapid visual information processing and Stockings of Cambridge (SOC). In addition to the symptom assessments at baseline (week 0), visit 2 (week 4-5) and visit 3 (week 8–10), they received CANTAB assessments at baseline and visit 3 (60.4 ± 6.3 d). Compared to baseline, adults treated with atomoxetine showed significant improvement in spatial working memory, spatial short-term memory, sustained attention and spatial planning at visit 3; adults treated with IR-methylphenidate showed significant improvement in spatial working memory at visit 3. Comparing the magnitude of improvement in executive functions between these two medications, the effect was generally similar for the two groups, although atomoxetine might have significantly greater efficacy than IR-methylphenidate in terms of improving spatial planning (SOC). Our results provide evidence to support that both IR-methylphenidate and atomoxetine improved various executive functions in adults with ADHD with greater improvement in atomoxetine than IR-methylphenidate in spatial planning.

Dietary Levels of Pure Flavonoids Improve Spatial Memory Performance and Increase Hippocampal Brain-Derived Neurotrophic Factor

Evidence suggests that flavonoid-rich foods are capable of inducing improvements in memory and cognition in animals and humans. However, there is a lack of clarity concerning whether flavonoids are the causal agents in inducing such behavioral responses. Here we show that supplementation with pure anthocyanins or pure flavanols for 6 weeks, at levels similar to that found in blueberry (2% w/w), results in an enhancement of spatial memory in 18 month old rats. Pure flavanols and pure anthocyanins were observed to induce significant improvements in spatial working memory (p = 0.002 and p = 0.006 respectively), to a similar extent to that following blueberry supplementation (p = 0.002). These behavioral changes were paralleled by increases in hippocampal brain-derived neurotrophic factor (R = 0.46, p<0.01), suggesting a common mechanism for the enhancement of memory. However, unlike protein levels of BDNF, the regional enhancement of BDNF mRNA expression in the hippocampus appeared to be predominantly enhanced by anthocyanins. Our data support the claim that flavonoids are likely causal agents in mediating the cognitive effects of flavonoid-rich foods.

Behavioral Effects of Physical Exercise and Exogenous Testosterone in Male Rats

The aim of our study was to analyze the interrelation between the effects of exogenous testosterone and physical exercise on behavior in adult male rats. During two weeks, male Wistar rats underwent a gradual daily-increasing forced swimming exercise (trained, groups, tr) or not (non-trained groups, ntr) and were injected with testosterone (TSt groups) or solvent olive oil, control, Ctrl groups). The average swimming times until reaching the platform in the Morris water maze were significantly shorter in the TSt tr group as compared to other groups during the first day. Intergroup differences between the results from other behavioral tests did not reach the significance levels. Our results indicate that the combination of testosterone administration and physical exercise leads to improvement of spatial working memory. Further studies are needed to uncover the mechanism of this effect.

A Randomized Trial to Examine the Effect of Mifepristone on Neuropsychological Performance and Mood in Patients with Bipolar Depression

Deficits in neuropsychological performance are found in patients with bipolar disorder and represent a potential treatment target for novel therapeutic strategies. We have previously demonstrated a beneficial effect on spatial working memory (SWM) of treatment for 1 week with the progesterone and glucocorticoid receptor antagonist mifepristone, evident 2 weeks after the cessation of treatment. We examined the longer-term efficacy of 600 mg/day of mifepristone as an adjunctive treatment, for 1 week, in a placebo-controlled, randomized, double-blind trial in 60 patients with bipolar depression, with SWM as the primary outcome measure. A comparator group of healthy control subjects was also recruited. At baseline, neuropsychological performance of patients was impaired, but hypothalamic-pituitary-adrenal axis function did not differ from that of control subjects. Mifepristone treatment was associated with a time-limited increase in cortisol awakening response and with a sustained improvement in SWM performance, which was evident 7 weeks after the cessation of treatment. The magnitude of this neuropsychological response was predicted by the magnitude of the cortisol response to mifepristone. The response occurred in the absence of a significant improvement in depressed mood. These data accord with the findings of animal studies and demonstrate that brief treatment with mifepristone is associated with a sustained improvement in SWM, an effect that might be mediated by a persistent enhancement in hippocampal mineralocorticoid receptor function.

Carotenoids but not flavonoids are associated with improvements in spatial working memory in younger adults in a flavonoid-rich v. -poor fruit and vegetable intervention study

Findings from animal studies suggest that components of fruit and vegetables (F&V) may protect against, and even reverse, age-related decline(1,2) in aspects of cognitive functioning such as spatial working memory (SWM). Human subjects in vivo and in vitro studies indicate that anti-inflammatory, anti-oxidant and cell-signalling properties of flavonoids and carotenoids, non-nutrient components of F&V, may underpin this protective effect(3–5). The Flavonoid University of Reading Study (FLAVURS), designed to explore the dose-response relationship between dietary F&V flavonoids and CVD, enabled the investigation of such an association with SWM. FLAVURS is an 18-week parallel three-arm randomised controlled dietary intervention trial with four time points, measured at 6-weekly intervals from baseline. Low F&V consumers at risk of CVD aged 26–70 years were randomly assigned to high flavonoid (HF), low flavonoid (LF) or control group. F&V intake increased by two daily 80 g portions every 6 weeks, with either HF or LF F&V, in addition to each participant's habitual diet, while controls maintained their habitual diet. At each visit, participants completed a cognitive test battery with SWM as the primary outcome. The HF group showed significantly higher levels of urinary flavonoids than LF or controls at 12 weeks (P<0.001) as expected, but surprisingly only higher levels than LF at 18 weeks (P<0.01). The LF group showed higher levels of plasma carotenoids than the other groups at 18 weeks (P<0.001). No group differences were found for SWM overall, however, age-group sub-analyses (26–50 and 51–70 years of age) showed differences from 0 to 18 weeks for younger adults, with LF improving significantly more than the other two groups on SWM (P<0.05). As nutritional absorption is known to decrease with age, separate stepwise regressions were performed on the two age groups irrespective of dietary group, with urinary flavonoids and plasma carotenoids as predictors. For younger adults, improved SWM performance from 0 to 18 weeks was associated with higher carotenoid levels, β=0.28, t(55)=2.10, P<0.05, accounting for 7.5% of the variance, R2=0.075, F(1,54)=4.41, P=0.040. For older adults, no between-group SWM differences were found. Findings suggest that F&V-based flavonoids and carotenoids may provide benefits for cognitive function, and that carotenoids in particular may improve cognitive performance in SWM. Given that these benefits were restricted to younger adults, future work is needed to test the reliability of this finding, as well as determine the mechanisms by which age-dependent differences in F&V responsiveness occur.