Can pharmacological enhancement of the placebo effect be a novel therapy for working memory impairments?

AbstractWorking memory is considered as a core aspect of cognitive function and its impairment in a wide range of mental disorders has resulted in it being considered as an important transdiagnostic feature. To date pharmacological and behavioural strategies for augmenting working memory have achieved only moderate success. Here we have taken a different approach by combining expectancy effects with intranasal oxytocin as an adjunct given previous evidence that it may enhance placebo effects. In a randomised controlled clinical trial we demonstrate that while working memory performance is not influenced by expectancy per se when it is given in conjunction with oxytocin performance in terms of accuracy can be significantly enhanced following positive expectancy induction (placebo effect) and impaired following negative expectancy induction (nocebo effect). Thus combining expectancy effects with intranasal oxytocin may represent a radical new approach for improving working memory function in mental disorders.

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Ecstasy use and higher-level cognitive functions: weak effects of ecstasy after control for potential confounds

Psychological Medicine ◽

10.1017/s0033291708002730 ◽

2008 ◽

Vol 38 (9) ◽

pp. 1319-1330 ◽

Cited By ~ 36

Author(s):

G. Bedi ◽

J. Redman

Keyword(s):

Working Memory ◽

Cognitive Functions ◽

Verbal Memory ◽

Drug Users ◽

Memory Performance ◽

Memory Function ◽

Inverse Association ◽

Cross Sectional ◽

Cohort Design ◽

Larger Sample

BackgroundAlthough there have been several reports linking ecstasy use with lowered cognitive function, much previous research suffers from substantial methodological limitations. The present study aimed to examine associations between ecstasy use and higher-level cognitive functions, using a larger sample size than most previous research and better controlling for a range of potential confounds.MethodA cross-sectional cohort design assessed 45 currently abstinent ecstasy polydrug users (EP), 48 cannabis polydrug users (CP) and 40 legal drug users (LD). Standardized neuropsychological tests were used to measure attention, verbal, visual and working memory and executive function. Prospective memory function was also assessed.ResultsIt was not possible to discriminate between groups on the basis of the cognitive functions assessed. Regression analyses showed an inverse association between lifetime dose of ecstasy and verbal memory performance. A combination of drug-use variables, including measures of ecstasy use, contributed to prediction of attention/working memory. However, individual associations were small, explaining 1–6% of variance in cognitive scores.ConclusionsAlthough the results suggest that heavy use of ecstasy is associated with some lowering of higher-level cognitive functions, they do not indicate a clinical picture of substantial cognitive dysfunction.

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Chemogenetic actuator drugs impair prefrontal cortex-dependent working memory in rhesus monkeys

10.1101/864140 ◽

2019 ◽

Author(s):

Nicholas A. Upright ◽

Mark G. Baxter

Keyword(s):

Working Memory ◽

Prefrontal Cortex ◽

Rhesus Monkeys ◽

Memory Performance ◽

Memory Function ◽

Muscarinic Acetylcholine Receptor ◽

Designer Drugs ◽

Delayed Response ◽

Response Task ◽

Delayed Response Task

AbstractThe most common chemogenetic neuromodulatory system, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), uses a non-endogenous actuator ligand to activate a modified muscarinic acetylcholine receptor that is no longer sensitive to acetylcholine. It is crucial in studies using these systems to test the potential effects of DREADD actuators prior to any DREADD transduction, so that effects of DREADDs can be attributed to the chemogenetic system rather than the actuator drug. We investigated working memory performance after injections of three DREADD agonists, clozapine, olanzapine, and deschloroclozapine, in male rhesus monkeys tested in a spatial delayed response task. Performance at 0.1 mg/kg clozapine and 0.1 mg/kg deschloroclozapine did not differ from mean performance after vehicle in any of the four subjects. Administration of 0.2 mg/kg clozapine impaired working memory function in three of the four monkeys. Two monkeys were impaired after administration of 0.1 mg/kg olanzapine and two monkeys were impaired after the 0.3 mg/kg dose of deschloroclozapine. We speculate that the unique neuropharmacology of prefrontal cortex function makes the primate prefrontal cortex especially vulnerable to off-target effects of DREADD actuator drugs with affinity for endogenous monoaminergic receptor systems. These findings underscore the importance of within-subject controls for DREADD actuator drugs to confirm that effects following DREADD receptor transduction are not due to the actuator drug itself, as well as validating the behavioral pharmacology of DREADD actuator drugs in the specific tasks under study.Significance StatementChemogenetic technologies, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), allow for precise and remote manipulation of neuronal circuits. In the present study, we tested monkeys in a spatial delayed response task after injections of three actuator drugs – clozapine, olanzapine, and deschloroclozapine. We found that monkeys showed significant working memory impairments after 0.2 mg/kg clozapine, 0.1 mg/kg olanzapine, and 0.3 mg/kg deschloroclozapine compared to vehicle performance. In monkeys that showed impairments, these deficits were particularly apparent at longer delay periods. It is imperative to validate the drugs and dosages in the particular behavioral test to ensure any behavior after DREADD transduction can be attributed to activation of the receptors and not administration of the actuator drug itself.

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Naturalistic coding of working memory in primate prefrontal cortex

10.1101/2020.06.19.162446 ◽

2020 ◽

Author(s):

Megan Roussy ◽

Rogelio Luna ◽

Lyndon Duong ◽

Benjamin Corrigan ◽

Roberto A. Gulli ◽

...

Keyword(s):

Working Memory ◽

Prefrontal Cortex ◽

Memory Performance ◽

Memory Function ◽

Nmda Receptor Antagonist ◽

Inhibitory Neurons ◽

Natural Behavior ◽

Neuronal Populations ◽

Memory Representations ◽

Decoding Accuracy

SummaryThe primate lateral prefrontal cortex (LPFC) is considered fundamental for temporarily maintaining and manipulating mental representations that serve behavior, a cognitive function known as working memory1. Studies in non-human primates have shown that LPFC lesions impair working memory2 and that LPFC neuronal activity encodes working memory representations3. However, such studies have used simple displays and constrained gaze while subjects held information in working memory3, which put into question their ethological validity4,5. Currently, it remains unclear whether LPFC microcircuits can support working memory function during natural behavior. We tested macaque monkeys in a working memory navigation task in a life-like virtual environment while their gaze was unconstrained. We show that LPFC neuronal populations robustly encode working memory representations in these conditions. Furthermore, low doses of the NMDA receptor antagonist, ketamine, impaired working memory performance while sparing perceptual and motor skills. Ketamine decreased the firing of narrow spiking inhibitory interneurons and increased the firing of broad spiking cells reducing population decoding accuracy for remembered locations. Our results show that primate LPFC generates robust neural codes for working memory in naturalistic settings and that such codes rely upon a fine balance between the activation of excitatory and inhibitory neurons.

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Fractionation of Verbal Memory Impairment in Schizophrenia and Schizophreniform Psychosis

Australian & New Zealand Journal of Psychiatry ◽

10.1080/00048670701517926 ◽

2007 ◽

Vol 41 (9) ◽

pp. 732-739 ◽

Cited By ~ 10

Author(s):

Stephen J. Wood ◽

Aleks U. Tarnawski ◽

Tina M. Proffitt ◽

Warrick J. Brewer ◽

Greg R. Savage ◽

...

Keyword(s):

Working Memory ◽

Associative Learning ◽

Verbal Memory ◽

Memory Performance ◽

Memory Function ◽

Verbal Working Memory ◽

First Episode ◽

Story Recall ◽

Associate Learning ◽

The Impact

Objectives: The characterization, aetiology, and course of verbal memory deficits in schizophrenia remain ill defined. The impact of antipsychotic medications is also unclear. The purpose of the present paper was to investigate verbal memory performance in established schizophrenia (SZ) and first-episode schizophreniform psychosis (FE). Method: Performances of 32 SZ and 33 FE patients were compared to those of 47 healthy volunteers on measures of verbal working memory, verbal associative learning and story recall. Results: Story recall deficits, but not deficits in working memory or paired associate learning, were demonstrated by both patient groups. Patients treated with typical neuroleptics had more impairment in associative learning with arbitrary word pairings than those treated with atypicals, regardless of patient group. Conclusions: The results are consistent with the notion that some neuropsychological impairment is present at the time of psychosis onset and that this impairment is non-progressive. However, deficits may be specific to subclasses of memory function.

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Verbal Memory Function in Intellectually Well-Functioning Adults With ADHD: Relations to Working Memory and Response Inhibition

Journal of Attention Disorders ◽

10.1177/1087054715580842 ◽

2015 ◽

Vol 23 (10) ◽

pp. 1188-1198 ◽

Cited By ~ 6

Author(s):

Astri J. Lundervold ◽

Helene Barone Halleland ◽

Erlend Joramo Brevik ◽

Jan Haavik ◽

Lin Sørensen

Keyword(s):

Working Memory ◽

Executive Function ◽

Response Inhibition ◽

Verbal Memory ◽

Memory Performance ◽

Memory Function ◽

Verbal Learning ◽

Substantial Part ◽

Adhd Group ◽

Immediate Memory

Objective: To investigate verbal memory function with relation to working memory (WM) and response inhibition (RI) in adults with ADHD. Method: Verbal memory function was assessed by the California Verbal Learning Test–Second Edition (CVLT-II), WM by the Paced Serial Addition Test, and RI by the Color-Word Interference Test from Delis–Kaplan Executive Function System in a sample of adults with normal to high intellectual function (IQ). Results: The ADHD group ( n = 74) obtained lower scores than controls on measures of learning, recall, and immediate memory (CVLT-II). WM and RI explained a substantial part of verbal memory performance in both groups. A group to executive function (EF) interaction effect was identified for the total number of intrusions and false positive responses on the CVLT-II recognition trial. Conclusion: Verbal memory performance only partially overlaps with EF in intellectually well-functioning adults with ADHD. Both EF and verbal memory function should be assessed as part of a neuropsychological evaluation of adults with ADHD. (J. of Att. Dis. XXXX; XX(X) XX-XX)

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Behavioral and neural signatures of working memory in childhood

10.1101/659409 ◽

2019 ◽

Cited By ~ 1

Author(s):

Monica D. Rosenberg ◽

Steven A. Martinez ◽

Kristina M. Rapuano ◽

May I. Conley ◽

Alexandra O. Cohen ◽

...

Keyword(s):

Working Memory ◽

Individual Differences ◽

Fluid Intelligence ◽

Short Term Memory ◽

Memory Performance ◽

Memory Function ◽

The United States ◽

Reward Processing ◽

Stop Signal Task ◽

Back Task

AbstractWorking memory function changes across development and varies across individuals. The patterns of behavior and brain function that track individual differences in working memory during development, however, are not well understood. Here we establish associations between working memory, cognitive abilities, and functional MRI activation in data from over 4,000 9–10-year-olds enrolled in the Adolescent Brain Cognitive Development study, an ongoing longitudinal study in the United States. Behavioral analyses reveal robust relationships between working memory, short-term memory, language skills, and fluid intelligence. Analyses relating out-of-scanner working memory performance to memory-related fMRI activation in an emotional n-back task demonstrate that frontoparietal activity in response to an explicit memory challenge indexes working memory ability. Furthermore, this relationship is domain-specific, such that fMRI activation related to emotion processing during the emotional n-back task, inhibitory control during a stop-signal task, and reward processing during a monetary incentive delay task does not track memory abilities. Together these results inform our understanding of the emergence of individual differences in working memory and lay the groundwork for characterizing the ways in which they change across adolescence.

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Network Structure During Encoding Predicts Working Memory Performance

10.1101/409615 ◽

2018 ◽

Cited By ~ 1

Author(s):

Anirudh Wodeyar ◽

Ramesh Srinivasan

Keyword(s):

Working Memory ◽

Graphical Model ◽

Structural Characteristics ◽

Brain Activity ◽

Memory Performance ◽

Memory Function ◽

Brain Networks ◽

Memory Task ◽

Functional Clustering ◽

Network Properties

ABSTRACTWorking memory operates through networks that integrate distributed modular brain activity. We characterize the structure of networks in different electroencephalographic frequency bands while individuals perform a working memory task. The objective was to identify network properties that support working memory function during the encoding, maintenance, and retrieval of memory. In each EEG frequency band, we estimated a complex-valued Gaussian graphical model to characterize the structure of brain networks using measures from graph theory. Critically, the structural characteristics of brain networks that facilitate performance are all established during encoding, suggesting that they reflect the effect of attention on the quality of the representation in working memory. Segregation of networks in the alpha and beta bands during encoding increased with accuracy. In the theta band, greater integration of functional clusters involving the temporal lobe with other cortical areas predicted faster response time, starting in the encoding interval and persisting throughout the task, indicating that functional clustering facilitates rapid memory manipulation.

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Effects of Smartphone-based Memory Training for Older Adults with Subjective Memory Complaints

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.2075 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S176-S176 ◽

Cited By ~ 1

Author(s):

M.S. Shin ◽

S.J. Oh ◽

S. Seo ◽

J.H. Lee ◽

M.J. Song

Keyword(s):

Older Adults ◽

Working Memory ◽

Healthy Aging ◽

Memory Performance ◽

Memory Function ◽

Self Report ◽

Memory Training ◽

Subjective Memory Complaints ◽

Subjective Memory ◽

Memory Complaints

IntroductionBrain health has garnered increasing attention as a requisite condition for healthy aging. The rapid growth in mobile health and increasing smartphone ownership among older adults has paved the way for smartphones to be utilized as effective tools for improving mental fitness.ObjectivesThere are few studies that have explored the efficacy of smartphone-based cognitive training. The present study examined the memory-enhancing effects of smartphone-based memory training for older adults.AimsWe explored whether newly developed application “Smartphone-based brain Anti-aging and memory Reinforcement Training (SMART)” improved memory performance in older adults with subjective memory complaints.MethodsA total of 53 adults (mean age: 59.3 years) were randomised into either one of two smartphone-based intervention groups (SMART vs. Fit Brains®) or a wait-list group. Participants in the intervention groups underwent 15–20 minutes of training per day, five days per week for 8 weeks. We used objective cognitive measures to evaluate changes with respect to four domains: attention, memory, working memory (WM), and executive function (inhibition, fluency, etc.). In addition, we included self-report questionnaires to assess levels of subjective memory complaints.ResultsThe performance on WM test increased significantly in the SMART group (t[17] = 6.27, P < 0.0001) but not in the control groups. Self-reports of memory contentment, however, increased in the Fit Brains® group only (t[18] = 2.12, P = 0.048).ConclusionsUse of an 8-week smartphone-based memory training program may improve working memory function in older adults. However, objective improvement in performance does not necessarily lead to decreased subjective memory complaints.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Distinct cellular mediators drive the Janus Faces of Toll-like Receptor 4 regulation of network excitability which impacts working memory performance after brain Injury

10.1101/750869 ◽

2019 ◽

Author(s):

Akshata A. Korgaonkar ◽

Ying Li ◽

Susan Nguyen ◽

Jenieve Guevarra ◽

Kevin C H Pang ◽

...

Keyword(s):

Working Memory ◽

Brain Injury ◽

Memory Performance ◽

Memory Function ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Tlr4 Signaling ◽

Injured Brain ◽

Cellular Mediators

AbstractThe mechanisms by which the neurophysiological and inflammatory responses to brain injury contribute to memory impairments are not fully understood. Recently, we reported that the innate immune receptor, toll-like receptor 4 (TLR4) enhances AMPA receptor (AMPAR) currents and excitability in the dentate gyrus after fluid percussion brain injury (FPI) while limiting excitability in controls. Here we examine the cellular mediators underlying TLR4 regulation of dentate excitability and its impact on memory performance. In ex vivo slices, astrocytic and microglial metabolic inhibitors selectively abolished TLR4 antagonist modulation of excitability in controls, without impacting FPI rats, demonstrating that glial signaling contributes to TLR4 regulation of excitability in controls. In glia-depleted neuronal cultures from naïve mice, TLR4 ligands bidirectionally modulated AMPAR charge transfer demonstrating the ability of neuronal TLR4 to regulate excitability, as observed after brain injury. In vivo TLR4 antagonism reduced early post-injury increases in mediators of MyD88-dependent and independent TLR4 signaling without altering expression in controls. Blocking TNFα, a downstream effector of TLT4, mimicked effects of TLR4 antagonist and occluded TLR4 agonist modulation of excitability in slices from both control and FPI rats. Functionally, transiently blocking TLR4 in vivo improved impairments in working memory observed one week and one month after FPI, while the same treatment impaired memory function in uninjured controls. Together these data identify that distinct cellular signaling mechanisms converge on TNFα to mediate TLR4 modulation of network excitability in the uninjured and injured brain and demonstrate a role for TLR4 in regulation of working memory function.HighlightsTLR4 suppresses dentate excitability in controls through signaling involving gliaNeuronal TLR4 signaling underlies enhanced dentate excitability after brain injuryTNFα contributes to TLR4 regulation of excitability in the injured brainAltering TLR4 signaling impacts working memory performanceTLR4 signaling is a potential target to improve working memory after brain trauma

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History of Alcohol Consumption and HIV Status Related to Functional Connectivity Differences in the Brain During Working Memory Performance

Current HIV Research ◽

10.2174/1570162x18666200217100123 ◽

2020 ◽

Vol 18 (3) ◽

pp. 181-193 ◽

Cited By ~ 1

Author(s):

Vaughn E. Bryant ◽

Joseph M. Gullett ◽

Eric C. Porges ◽

Robert L. Cook ◽

Kendall J. Bryant ◽

...

Keyword(s):

Working Memory ◽

Functional Connectivity ◽

Alcohol Consumption ◽

Memory Performance ◽

Memory Function ◽

Brain Networks ◽

Memory Task ◽

Hiv Positive ◽

Hiv Status ◽

Using Data

Background: Poorer working memory function has previously been associated with alcohol misuse, Human Immunodeficiency Virus (HIV) positive status, and risky behavior. Poorer working memory performance relates to alterations in specific brain networks. Objective: The current study examined if there was a relationship between brain networks involved in working memory and reported level of alcohol consumption during an individual’s period of heaviest use. Furthermore, we examined whether HIV status and the interaction between HIV and alcohol consumption was associated with differences in these brain networks. Methods: Fifty adults, 26 of whom were HIV positive, engaged in an n-back working memory task (0-back and 2-back trials) administered in a magnetic resonance imaging (MRI) scanner. The Kreek- McHugh-Schluger-Kellogg (KMSK) scale of alcohol consumption was used to characterize an individual’s period of heaviest use and correlates well with their risk for alcohol dependence. Connectivity analyses were conducted using data collected during n-back task. Results: Functional connectivity differences associated with greater alcohol consumption included negative connectivity, primarily from parietal attention networks to frontal networks. Greater alcohol consumption was also associated with positive connectivity from working memory nodes to the precuneus and paracingulate. HIV positive status was associated with more nodes of negative functional connectivity relative to alcohol consumption history alone, particularly in the frontoparietal networks. The HIV positive individuals with heavier drinking history related to negative fronto-parietal connectivity, along with positive connectivity from working memory nodes to mesolimbic regions. Conclusion: Findings allow for a better understanding of brain networks affected by HIV and alcohol and may provide avenues for interventions.

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