Improvement In Working Memory Research Articles

Effects of treadmill exercise on PI3K/AKT/GSK-3β pathway and tau protein in high-fat diet-fed rats.

[Purpose]This study aimed to clearly evaluate the effects of obesity on cerebral health. Thus, we induced obesity in rats using a long-term high-fat diet (HFD), then investigated its effects on insulin signaling and tau hyperphosphorylation. Additionally, we examined the effects of 8 weeks of treadmill exercise (TE) on insulin signaling and tau hyperphosphorylation.[Methods]Rats were separated into Normal Diet-Control, HFD-Control, and HFD-TE groups. TE loads were gradually increased. A passive avoidance test was used to evaluate cognitive function. Western blots were used to examine the abundance of the insulin receptor,phosphoinositide 3-kinase, protein kinase B, glycogen synthase kinase-3β, and tau proteins in the cerebral cortex; immunohistochemical analyses were used to examine the abundance of hyperphosphorylated tau in the cerebral cortex.[Results]TE in HFD-fed rats resulted in a significant lowering of bodyweight, abdominal visceral fat (AVF), the area under the glucose response curve, and the homeostatic model assessment-insulin resistance index, while it improved working memory. In addition, TE in HFD-fed rats decreased tau hyperphosphorylation and aggregation, while increasing insulin signaling-related protein activity.[Conclusion]After a 20-week HFD, the experimental animals exhibited increased weight, as well as impaired insulin resistance and blood glucose metabolism. HFD rats demonstrated abnormal insulin signaling and tau hyperphosphorylation in the cerebral cortex, as well as memory impairments that suggested reduced cerebral function. However, TE reduced AVF, improved insulin resistance in the peripheral tissues by increasing insulin sensitivity, and alleviated memory impairments by restoring insulin signaling and reducing tau hyperphosphorylation in the cerebral cortex.

Working-memory training following neonatal critical illness

__Objective__ To test the immediate and long-term effectiveness of Cogmed Working-Memory Training (CWMT) following ECMO and/or CDH. __Design__ A nationwide randomized controlled trial assessing neuropsychological outcome immediately and one year post-CWMT, conducted between October 2014-June 2017. Researchers involved in the follow-up assessments were blinded to group allocation. __Setting__ Erasmus MC-Sophia Children’s Hospital, Rotterdam and Radboud University Medical Center, Nijmegen, the Netherlands. __Patients__ Eligible participants were neonatal ECMO and/or CDH survivors (8-12 years) with an IQ ≥ 80 and a z-score ≤ -1.5 on at least one (working)memory test at first assessment. __Interventions__ CWMT, comprising 25 sessions of 45 minutes for five consecutive weeks at home. __Measurements and Main Results__ Participants were randomized to CWMT (n = 19) or no intervention (n = 24) (two dropped out after T0). Verbal working-memory (estimated coefficient = 0.87; p = .002) and visuospatial working-memory (estimated coefficient = 0.96, p = .003) had significantly improved in the CWMT group at T1, but was similar between groups at T2 (verbal, p = .902; visuospatial, p = .416). Improvements were found at T2 on long-term visuospatial memory following CWMT (estimated coefficient = 0.95, p = .003). Greater improvements in this domain at T2 following CWMT were associated with better self-rated school functioning (r = .541, p = .031) and parent-rated attention (r = .672, p = .006). __Conclusions__ Working-memory improvements after CWMT disappeared one year post-training in neonatal ECMO and/or CDH survivors. Gains in visuospatial memory persisted one year post-intervention. CWMT may be beneficial for survivors with visuospatial memory deficits.

Performance test for prototype game for children with adhd

The gaming industry has become one of the fastest growing industries in the world. In recent years there have been several studies that have used games, especially computer-based ones to improve the executive function of children with Attention Deficit Hyperactivity Disorder (ADHD) especially in working memory improvements. There are still several obstacles in using computer-based games that have been circulating today in Indonesia. The aim of this research is to develop and create a prototype game that can be used to improve working memory of children with ADHD using Bahasa Indonesia. The prototype game application is a race game with matching colors and memory work tasks; developed using Construct2. Players will play as a driver, delivering certain fruits to specific homes with different colors. The game also included visuospatial tasks such as remembering the objects. For performance test, CPU utilization, average FPS and image memory usage has been tested in several browsers. In conclusion, the performance tests results show that the first type of the prototype game is good enough to be played in desktop or laptop.

Prenatal dexamethasone treatment in the context of at risk CAH pregnancies: Long-term behavioral and cognitive outcome

Dexamethasone (DEX) is used to prevent prenatal virilization in female fetuses with congenital adrenal hyperplasia (CAH). Since treatment has to be started before the genotype of the fetus is known, 7 out of 8 fetuses will be exposed to DEX without benefit. Previously, we have observed negative effects on cognition and behavior in DEX treated children. Here we evaluated neuropsychological functions, psychopathology and autistic traits in non-CAH DEX-treated adults exposed during the first trimester of fetal life (duration 6.2 ± 2.2 weeks). Cognitive functions, psychopathology and autistic traits were compared between DEX-treated subjects (n = 23) and non-exposed controls (n = 58). Cognitive outcome was also evaluated longitudinally for DEX-treated participants. We used neuropsychological tests (Wechsler Scales and the Stroop Interference Test) and questionnaires assessing executive functions (the Barkley Deficit in Executive Functioning Scale), psychopathology (the Montgomery Åsberg Depression Ratings Scale, the Hospital Anxiety and Depression Scale, the Liebowitz Social Anxiety Scale) and autistic traits (Autism Quota).We did not observe any significant differences in cognition, psychopathology or autistic traits between DEX-treated individuals and population controls. A significant improvement in verbal working memory (p = 0.038) and in impulse inhibition (p = 0.011) was seen when subjects were evaluated longitudinally.In summary, first-trimester DEX-exposed adult individuals do not show any significant neuropsychological deficits nor an increase in anxiety, depression or autistic traits, compared with a control group from the general population. The results also suggest that the observed deficits in executive functioning during childhood may improve with time.

Uncovering the Signaling Pathway behind Extracellular Guanine-Induced Activation of NO System: New Perspectives in Memory-Related Disorders.

Mounting evidence suggests that the guanine-based purines stand out as key player in cell metabolism and in several models of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases. Guanosine (GUO) and guanine (GUA) are extracellular signaling molecules derived from the breakdown of the correspondent nucleotide, GTP, and their intracellular and extracellular levels are regulated by the fine-tuned activity of two major enzymes, purine nucleoside phosphorylase (PNP) and guanine deaminase (GDA). Noteworthy, GUO and GUA, seem to play opposite roles in the modulation of cognitive functions, such as learning and memory. Indeed GUO, despite exerting neuroprotective, anti-apoptotic and neurotrophic effects, causes a decay of cognitive activities, whereas GUA administration in rats results in working memory improvement (prevented by L-NAME pre-treatment). This study was designed to investigate, in a model of SH-SY5Y neuroblastoma cell line, the signal transduction pathway activated by extracellular GUA. Altogether, our results showed that: (i) in addition to an enhanced phosphorylation of ASK1, p38 and JNK, likely linked to a non-massive and transient ROS production, the PKB/NO/sGC/cGMP/PKG/ERK cascade seems to be the main signaling pathway elicited by extracellular GUA; (ii) the activation of this pathway occurs in a pertussis-toxin sensitive manner, thus suggesting the involvement of a putative G protein coupled receptor; (iii) the GUA-induced NO production, strongly reduced by cell pre-treatment with L-NAME, is negatively modulated by the EPAC-cAMP-CaMKII pathway, which causes the over-expression of GDA that, in turn, reduces the levels of GUA. These molecular mechanisms activated by GUA may be useful to support our previous observation showing that GUA improves learning and memory functions through the stimulation of NO signaling pathway, and underscore the therapeutic potential of oral administration of guanine for treating memory-related disorders.

The worrying mind in control: An investigation of adaptive working memory training and cognitive bias modification in worry-prone individuals

Worry refers to the experience of uncontrollable negative thoughts. Cognitive models suggest that the combination of negative information processing biases along with diminished attentional control contribute to worry. In the current study we investigate whether promoting a) adaptive interpretation bias and b) efficient deployment of attentional control would influence the tendency to worry. Worry-prone individuals (n = 60) received either active cognitive bias modification for interpretation bias (CBM-I) combined with sham working memory training (WMT), adaptive WMT combined with sham CBM-I, or sham WMT combined with sham CBM-I. Neither of the active training conditions reduced worry during a breathing focus task relative to the control condition. However, when considering inter-individual differences in training-related improvements, we observed a relation between increases in positive interpretation bias and a decrease in negative intrusions. Moreover, increases in working memory performance were related to a reduction in reactivity of negative intrusions to a worry period. Our findings show that facilitating a more benign interpretation bias and improving working memory capacity can have beneficial effects in terms of worry, but also highlight that transfer related gains from existing training procedures can be dependent upon improvement levels on the training task.

Abstract TP89: Angiotensin Receptor (AT2R) Agonist C21 Accelerates Cognitive Functional Recovery After Permanent Stroke in Aged Animals

Background and objectives: Post stroke cognitive impairment (PSCI) is an understudied, long-term complication of stroke, impacting nearly 30-40% of all stroke survivors. No cure is available once the cognitive deterioration manifests. Compound 21 (C21), a novel selective non-peptide angiotensin receptor (AT2R) agonist, has also shown therapeutic efficacy in a variety of experimental stroke models, but C21 effect on PSCI model is lacking. To our knowledge, this is the first study to investigate the long-term effects of C21 treatment on the development of PSCI in aged animals. Methods: Distal docal cerebral ischemia was induced in 14-month-old male Wistar rats by direct electro-coagulation of middle cerebral artery for permanent occlusion (pMCAO). Animals were randomly assigned to receive either C21 or vehicle which was initiated the following day, and continued for a total of 30 days (0.12 mg/kg/d, orally). Outcome measures for sensorimotor and cognitive function were performed using a sequence of tests, all blindly conducted and assessed at baseline as well as at different time points post-pMCAO. Repeated measures ANOVA mixed models were used to examine differences in behavioral outcomes. Results: C21 reduced weight loss and enhanced recovery (Table). Treatment with C21 showed significant improvement in non-spatial and short-term working memory compared to vehicle. Moreover, C21 preserved reference memory and facilitated associative learning compared to vehicle treated rats after pMCAO. Further, C21 prevented Aβ 1-42 . C21 did not show any effect on motor deficits score compared to vehicle. Conclusion: Our findings demonstrate that the angiotensin receptor (AT2R) agonist C21 effectively preserves cognitive function and prevents the development of PSCI in aged animals.

The impact of happy and angry faces on working memory in depressed adolescents

Recent cognitive models suggest that the ability to control emotional information in working memory (WM) may be implicated in the etiology and maintenance of depression. However, few studies have examined the effects of processing relevant and irrelevant emotional stimuli on WM performance in depressed adolescents. In the current study, depressed adolescents (n = 27) and healthy adolescents (n = 49) completed two versions of an emotional n-back task: a low WM load (0-back) task and a high WM load (2-back) task. In the emotion-relevant condition participants were asked to attend to the emotional expression of an angry, happy, or neutral face, whereas in the emotion-irrelevant condition participants were asked to attend to the gender of the face. The results showed a WM improvement for happy faces in the emotion-relevant condition and a WM impairment for happy faces in the emotion-irrelevant condition for healthy adolescents but not for depressed adolescents. No biases toward angry faces were found. These results demonstrate that depressed adolescents do not show a preferential processing of angry faces but rather fail to show a positivity bias as seen in healthy adolescents. This supports the theoretical notion that a depressive disorder is characterized by a blunted reactivity toward positive information and may provide new insights into the underlying mechanisms of youth depression.

ERP and Behavioral Effects of Physical and Cognitive Training on Working Memory in Aging: A Randomized Controlled Study.

Working memory (WM) performance decreases with age. A promising method to improve WM is physical or cognitive training. The present randomized controlled study is aimed at evaluating the effects of different training methods on WM. A sample of 141 healthy older adults (mean age 70 years) was assigned to one of four groups: physical training, cognitive training, a social control group, and a no-contact control group. The participants trained for four months. Before and after the training, n-back task during an EEG recording was applied. The results show that cognitive training enhanced the target detection rate in the 2-back task. This was corroborated by an increased number of repeated digits in the backward digit-span test but not in other memory tests. The improvement of WM was supported by an increased P3a prior to a correct target and an increased P3b both in nontarget and target trials. No ERP effects in the physical and no-contact control groups were found, while a reduction of P3a and P3b was found in the social control group. Thus, cognitive training enhances frontal and parietal processing related to the maintenance of a stored stimulus for subsequent matching with an upcoming stimulus and increases allocation of cognitive resources. These results indicate that multidomain cognitive training may increase WM capacity and neuronal activity in older age.

Effects of Visual and Spatial Working Memory Improvement training Program on Elderly Driving Behavior

The aim of this study is to investigate the changes of multifaceted driving behavior features of the elderly through visual and spatial memory ability improvement training. A training program to improve visual and spatial memory ability of the elderly was conducted five times. Three groups-trained elderly group, non-trained elderly group, and adult group (i.e. comparison group)-were selected to comparethe effect of the training. To measure multifaceted driving behaviors, three indicators were used: driving performance indicator, eye movement indicator, and physiological response indicator. Using the driving simulator, the parameters of the driving performance indicator were collected: approach velocity, transit time, the speed variation at the intersection, and the handling variation. The parameters of the eye movement indicator were collected using the eye maker: the ratio of visual scanning time: forward, left, and right visual fields. The parameters of physiological response indicator-the heart rate of electrocardiogram and the skin conductance level of skin electrical activity at the intersection-were collected and examined. As for the driving performance indicator, the result showed that the general adult drivers, the comparison group, pass through the intersection more rapidly than the elderly, who enter the intersections quickly and smoothly, and the changes by the training programs were not significant. As for the eye movement indicator, the elderly drivers participating in the training program showed a similar pattern to that of the general adult drivers, who were in the comparison group, in terms of the ratio of visual scanning time: forward, left, and right visual fields. As for the physiological response indicator, the overall arousal level of the elderly participating in the training program was significantly lower than that before the training program, and relatively lower than the elderly who did not participate in the training program. The implication of this study is to clarify the positive changes of the multifaceted driving behaviors by providing training for the elderly to improve their visual and spatial working memory ability.

Task demands, tDCS intensity, and the COMT val158met polymorphism impact tDCS-linked working memory training gains

Working memory (WM) training paired with transcranial direct current stimulation (tDCS) can improve executive function in older adults. The unclear mechanism of tDCS likely depends on tDCS intensity, and task relevant genetic factors (e.g., for WM: COMT val158met, DAT, BDNF val66met). Higher tDCS intensity does not always lead to greater cognitive gains, and genetic polymorphisms may modulate tDCS-linked WM improvements. To evaluate these factors, 137 healthy older adults provided DNA samples and received Visual and Spatial WM training paired with tDCS (sham, 1, 1.5, 2 mA). After one session of tDCS, significant group differences in WM performance were predicted by COMT val158met status. One month after training, there was a significant interaction of tDCS intensity, COMT genotype, and WM task. Specifically, val/val homozygotes benefited most from 1.5 mA tDCS on Visual WM and from 1 mA tDCS on Spatial WM. For met/met homozygotes, 2 mA resulted in significantly poorer performance compared to 1.5 mA on Spatial WM. While this pattern was observed with relatively small sample sizes, these data indicate that variations in COMT val158met may predict the nature of WM improvement after initial and longitudinal tDCS. This contributes to our understanding of the underlying mechanism by which tDCS affects behaviour.

Avocado Consumption Increases Macular Pigment Density in Older Adults: A Randomized, Controlled Trial.

Lutein is selectively incorporated into the macula and brain. Lutein levels in the macula (macular pigment; MP) and the brain are related to better cognition. MP density (MPD) is a biomarker of brain lutein. Avocados are a bioavailable source of lutein. This study tests the effects of the intake of avocado on cognition. This was a six-month, randomized, controlled trial. Healthy subjects consumed one avocado (n = 20, 0.5 mg/day lutein, AV) vs. one potato or one cup of chickpeas (n = 20, 0 mg/day lutein, C). Serum lutein, MPD, and cognition were assessed at zero, three, and six months. Primary analyses were conducted according to intent-to-treat principles, with repeated-measures analysis. At six months, AV increased serum lutein levels by 25% from baseline (p = 0.001). C increased by 15% (p = 0.030). At six months, there was an increase in MPD from baseline in AV (p = 0.001) and no increase in C. For both groups, there was an improvement in memory and spatial working memory (p = 0.001; p = 0.032, respectively). For AV only there was improved sustained attention (p = 0.033), and the MPD increase was related to improved working memory and efficiency in approaching a problem (p = 0.036). Dietary recommendations including avocados may be an effective strategy for cognitive health.

Consequences of Adolescent Exposure to the Cannabinoid Receptor Agonist WIN55,212-2 on Working Memory in Female Rats.

Marijuana is a prevalent illicit substance used by adolescents, and several studies have indicated that adolescent use can lead to long-term cognitive deficits including problems with attention and memory. However, preclinical animal studies that observe cognitive deficits after cannabinoid exposure during adolescence utilize experimenter administration of doses of cannabinoids that may exceed what an organism would choose to take, suggesting that contingency and dose are critical factors that need to be addressed in translational models of consequences of cannabinoid exposure. Indeed, we recently developed an adolescent cannabinoid self-administration paradigm in male rats, and found that prior adolescent self-administration of the cannabinoid receptor agonist WIN55,212-2 (WIN) resulted in improved working memory performance in adulthood. In addition, the doses self-administered were not as high as those that are found to produce memory deficits. However, given known sex differences in both drug self-administration and learning and memory processes, it is possible that cannabinoid self-administration could have different cognitive consequences in females. Therefore, we aimed to explore the effects of self-administered vs. experimenter-administered WIN in adolescent female rats on adult cognitive function. Female rats were trained to self-administer WIN daily throughout adolescence (postnatal day 34–59). A control group self-administered vehicle solution. The acute effects of adolescent WIN self-administration on memory were determined using a short-term spatial memory test 24 h after final SA session; and the long-term effects on cognitive performance were assessed during protracted abstinence in adulthood using a delayed-match-to-sample working memory task. In a separate experiment, females were given daily intraperitoneal (IP) injections of a low or high dose of WIN, corresponding to self-administered and typical experimenter-administered doses, respectively, or its vehicle during adolescence and working memory was assessed under drug-free conditions in adulthood. While self-administration of WIN in adolescence had no significant effects on short-term spatial memory or adult working memory, experimenter administration of WIN resulted in improved adult working memory performance that was more pronounced in the low dose group. Thus, low-dose adolescent WIN exposure, whether self-administered or experimenter-administered, results in either improvements or no change in adult working memory performance in female rats, similar to previous results found in males.

Contribution of underlying processes to improved visuospatial working memory associated with physical activity.

BackgroundWorking memory is critical for various cognitive processes and can be separated into two stages: short-term memory storage and manipulation processing. Although previous studies have demonstrated that increased physical activity (PA) improves working memory and that males outperform females on visuospatial working memory tasks, few studies have determined the contribution of the two underlying stages to the visuospatial working memory improvement associated with PA. Thus, the aims of the present study were to verify the relationship between physical activity and visuospatial working memory, determine whether one or both stages were affected by PA, and investigate any sex differences.MethodsA total of 56 undergraduate students were recruited for this study. Their scores on the International Physical Activity Questionnaire (IPAQ) were used to separate them into either a lower PA (n = 26; IPAQ score ≤3,000 metabolic equivalent [MET]-min/week) or higher PA (n = 30; IPAQ score >3,000 MET-min/week) group. Participants were required to complete three tasks: a visuospatial working memory task, a task that examines the short-term memory storage stage, and a mental rotation task that examines the active manipulation stage.ResultsParticipants in the higher PA group maintained similar accuracy but displayed significantly faster reaction times (RT) than those in the lower PA group on the visuospatial working memory and manipulation tasks. By contrast, no difference was observed between groups on the short-term memory storage task. In addition, no effects of sex were detected.DiscussionOur results confirm that PA was positively to visuospatial working memory and that this positive relationship was associated with more rapid cognitive processing during the manipulation stage, with little or no relationship between PA and the memory storage stage of visuospatial working memory.

Working Memory after Traumatic Brain Injury: The Neural Basis of Improved Performance with Methylphenidate.

Traumatic brain injury (TBI) often results in cognitive impairments for patients. The aim of this proof of concept study was to establish the nature of abnormalities, in terms of activity and connectivity, in the working memory network of TBI patients and how these relate to compromised behavioral outcomes. Further, this study examined the neural correlates of working memory improvement following the administration of methylphenidate. We report behavioral, functional and structural MRI data from a group of 15 Healthy Controls (HC) and a group of 15 TBI patients, acquired during the execution of the N-back task. The patients were studied on two occasions after the administration of either placebo or 30 mg of methylphenidate. Between group tests revealed a significant difference in performance when HCs were compared to TBI patients on placebo [F(1, 28) = 4.426, p < 0.05, ηp2 = 0.136]. This difference disappeared when the patients took methylphenidate [F(1, 28) = 3.665, p = 0.66]. Patients in the middle range of baseline performance demonstrated the most benefit from methylphenidate. Changes in the TBI patient activation levels in the Left Cerebellum significantly and positively correlated with changes in performance (r = 0.509, df = 13, p = 0.05). Whole-brain connectivity analysis using the Left Cerebellum as a seed revealed widespread negative interactions between the Left Cerebellum and parietal and frontal cortices as well as subcortical areas. Neither the TBI group on methylphenidate nor the HC group demonstrated any significant negative interactions. Our findings indicate that (a) TBI significantly reduces the levels of activation and connectivity strength between key areas of the working memory network and (b) Methylphenidate improves the cognitive outcomes on a working memory task. Therefore, we conclude that methylphenidate may render the working memory network in a TBI group more consistent with that of an intact working memory network.

Improvements in Reading Comprehension Performance After a Training Program Focusing on Executive Processes of Working Memory

Reading comprehension is a complex cognitive task crucial to success in formal education and everyday life activities. Working memory (WM) and associated executive processes have been shown to be implicated in reading comprehension abilities. The aim of the present study was to assess the efficacy of a program for improving reading comprehension skills based on reading activities that require WM and associated executive processes. The study involved 48 third-graders (8–9 years old), who were assigned to three groups: a trained group that received training on reading comprehension and on the mechanisms related to this ability; an active control group that attended extra in-school activities designed to improve children’s reading comprehension; and a passive control group that only attended normal lessons. The training program consisted of ten sessions conducted in the classroom, focusing on WM and associated executive functions embedded in reading comprehension activities. The efficacy of the training was examined in terms of both specific improvements in reading comprehension and WM, and transfer effects to more ecological reading comprehension and nonverbal reasoning tasks. Long-term gains were also examined after 2 months. The results showed that the training was effective in directly improving the children’s reading comprehension and WM, with some maintenance effects too, while it elicited limited gains in the more ecological reading comprehension task, and no transfer effects on nonverbal reasoning. Overall, the present findings suggest that training involving the use of WM and its executive processes during reading comprehension activities is a promising approach to sustaining reading comprehension.

A randomized controlled trial of cognitive remediation and work therapy in the early phase of substance use disorder recovery for older veterans: Neurocognitive and substance use outcomes.

Cognitive remediation therapy (CRT) is reported to improve neurocognitive and substance use disorder (SUD) outcomes in residential treatments. This National Institute of Drug Abuse funded pilot study reports on CRT as an augmentation to outpatient treatment for SUD. Recovering outpatient veterans were randomized into CRT + Work Therapy (n = 24) or work therapy (n = 24) with treatment-as-usual. Blind assessments of neurocognition and substance use were performed at baseline, 3 months (end of treatment), and 6-month follow-up. Baseline assessments revealed high rates of cognitive impairment with 87.5% showing significant decline from premorbid IQ on at least 1 measure (median = 3/14 measures). Adherence to treatment was excellent. Follow-up rates were 95.7% at 3 months and 87.5% at 6 months. Mixed effects models of cognitive change over time revealed significant differences favoring CRT + Work Therapy on working memory (WM) and executive function indices. Global index of cognition showed a nonsignificant trend (effect size [ES] = .37) favoring CRT + Work Therapy. SUD outcomes were excellent for both conditions. CRT + Work Therapy had a mean of 97% days of abstinence at 3 months, 94% in the 30 days prior to 6-month follow-up, and 24/26 weeks of total abstinence; differences between conditions were not significant. CRT was well accepted by outpatient veterans with SUDs and led to significant improvements in WM and executive functions beyond that of normal cognitive recovery. No difference between conditions was found for SUD outcomes, perhaps because work therapy obscured the benefits of CRT. (PsycINFO Database Record

SU16. Predictors of Treatment Response of Adjunct Minocycline to Clozapine in Refractory Schizophrenia

Background: Accumulating evidence suggests minocycline (MINO) is effective as an adjunct treatment in schizophrenia. We previously reported significant improvement in avolition, anxiety/depression and working memory and a trend for positive symptoms and total Brief Psychiatric Rating Scale (BPRS) scores with MINO in a double-blind, placebo-controlled trial. We also found a >30% reduction in total BPRS scores in 25% of the MINO group compared to 4% in placebo (P = .04). Here we examine variables associated with symptom improvements. Methods: Participants with persistent positive symptoms of schizophrenia and schizoaffective disorder, despite adequate clozapine dosing, were randomized to receive adjunct MINO (100-mg BID) (N = 29) or placebo (N = 23). Both the BPRS and the Schedule for the Assessment of Negative Symptoms (SANS) were assessed biweekly in this 10-week trial. We examined demographic variables, duration of illness, baseline symptoms, serum cytokine levels, and CLZ blood levels to BPRS and SANS changes using Spearman’s correlation coefficients. Results: Symptom improvements were not related to demographic variables except that a shorter duration of illness related to SANS improvement in the MINO group (P = .04). Baseline total BPRS was associated with greater BPRS reduction (r = −0.51, P < .001), stronger in the MINO group than in placebo (difference in line slopes (F(1,45) = 5.13, P = .03). A greater increase in IFN-gamma with MINO was associated with a greater decrease in BPRS positive symptoms (r = −0.45, P = .02). SANS total score improvement was associated with an increase in TNF-alpha (r = −0.4, P = .045) and a trend for increased IFN-gamma (r = −0.38, P = .053). Lastly, CLZ levels were not related to BPRS; however, a greater decrease in CLZ levels related to a improvement in the SANS total score in the MINO group (r = 0.48, P = .01). In the placebo group, higher total CLZ was associated with greater SANS (difference in line slopes F(1, 42) = 4.43, P = .04). Conclusion: Variables associated with improvement on BPRS and positive symptoms include a higher baseline BPRS score and an increase in IFN-gamma levels. Variables associated with negative symptom improvement include shorter duration of illness, a decrease in CLZ levels, an increase in TNF-alpha, and trend for increase in IFN-gamma levels. These data suggest that despite MINO increasing CLZ levels (data not shown here) this does not contribute to MINO’s treatment effect. More research is needed to help define predictors of treatment response to MINO in larger samples.

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.

Memory skills mediating superior memory in a world-class memorist

ABSTRACTLaboratory studies have investigated how individuals with normal memory spans attained digit spans over 80 digits after hundreds of hours of practice. Experimental analyses of their memory skills suggested that their attained memory spans were constrained by the encoding time, for the time needed will increase if the length of digit sequences to be memorised becomes longer. These constraints seemed to be violated by a world-class memorist, Feng Wang (FW), who won the World Memory Championship by recalling 300 digits presented at 1 digit/s. In several studies we examined FW’s memory skills underlying his exceptional performance. First FW reproduced his superior memory span of 200 digits under laboratory condition, and we obtained his retrospective reports describing his encoding/retrieval processes (Experiment 1). Further experiments used self-paced memorisation to identify temporal characteristics of encoding of digits in 4-digit clusters (Experiment 2), and explored memory encoding at presentation speeds much faster than 1 digit/s (Experiment 3). FW’s superiority over previous digit span experts is explained by his acquisition of well-known mnemonic techniques and his training that focused on rapid memorisation. His memory performance supports the feasibility of acquiring memory skills for improved working memory based on storage in long-term memory.