The Efficacy of "Foundations," a Digital Mental Health App to Improve Mental Well-being During COVID-19: Proof-of-Principle Randomized Controlled Trial.

BACKGROUND: Against a long-term trend of increasing demand, the COVID-19 pandemic has led to a global rise in common mental disorders. Now more than ever, there is an urgent need for scalable, evidence-based interventions to support mental well-being. OBJECTIVE: The aim of this proof-of-principle study was to evaluate the efficacy of a mobile-based app in adults with self-reported symptoms of anxiety and stress in a randomized control trial that took place during the first wave of the COVID-19 pandemic in the United Kingdom. METHODS: Adults with mild to severe anxiety and moderate to high levels of perceived stress were randomized to either the intervention or control arm. Participants in the intervention arm were given access to the Foundations app for the duration of the 4-week study. All participants were required to self-report a range of validated measures of mental well-being (10-item Connor-Davidson Resilience scale [CD-RISC-10], 7-item Generalized Anxiety Disorder scale [GAD-7], Office of National Statistics Four Subjective Well-being Questions [ONS-4], World Health Organization-5 Well-Being Index [WHO-5]) and sleep (Minimal Insomnia Scale [MISS]) at baseline and at weeks 2 and 4. The self-reported measures of perceived stress (10-item Perceived Stress Score [PSS-10]) were obtained weekly. RESULTS: A total of 136 participants completed the study and were included in the final analysis. The intervention group (n=62) showed significant improvements compared to the control group (n=74) on measures of anxiety, with a mean GAD-7 score change from baseline of -1.35 (SD 4.43) and -0.23 (SD 3.24), respectively (t134=1.71, P=.04); resilience, with a mean change in CD-RISC score of 1.79 (SD 4.08) and -0.31 (SD 3.16), respectively (t134=-3.37, P<.001); sleep, with a mean MISS score change of -1.16 (SD 2.67) and -0.26 (SD 2.29), respectively (t134=2.13, P=.01); and mental well-being, with a mean WHO-5 score change of 1.53 (SD 5.30) and -0.23 (SD 4.20), respectively (t134=-2.16, P=.02), within 2 weeks of using Foundations, with further improvements emerging at week 4. Perceived stress was also reduced within the intervention group, although the difference did not reach statistical significance relative to the control group, with a PSS score change from baseline to week 2 of -2.94 (SD 6.84) and -2.05 (SD 5.34), respectively (t134= 0.84, P=.20). CONCLUSIONS: This study provides a proof of principle that the digital mental health app Foundations can improve measures of mental well-being, anxiety, resilience, and sleep within 2 weeks of use, with greater effects after 4 weeks. Foundations therefore offers potential as a scalable, cost-effective, and accessible solution to enhance mental well-being, even during times of crisis such as the COVID-19 pandemic. TRIAL REGISTRATION: OSF Registries osf.io/f6djb; https://osf.io/vm3xq.

Ongoing Electroencephalographic Rhythms Related to Exploratory Movements in Transgenic TASTPM Mice.

BACKGROUND: The European PharmaCog study (http://www.pharmacog.org) has reported a reduction in delta (1-6 Hz) electroencephalographic (EEG) power (density) during cage exploration (active condition) compared with quiet wakefulness (passive condition) in PDAPP mice (hAPP Indiana V717F mutation) modeling Alzheimer's disease (AD) amyloidosis and cognitive deficits. OBJECTIVE: Here, we tested the reproducibility of that evidence in TASTPM mice (double mutation in APP KM670/671NL and PSEN1 M146V), which develop brain amyloidosis and cognitive deficits over aging. The reliability of that evidence was examined in four research centers of the PharmaCog study. METHODS: Ongoing EEG rhythms were recorded from a frontoparietal bipolar channel in 29 TASTPM and 58 matched "wild type" C57 mice (range of age: 12-24 months). Normalized EEG power was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during the passive and active conditions. RESULTS: Compared with the "wild type" group, the TASTPM group showed a significantly lower reduction in IDF power during the active over the passive condition (p < 0.05). This effect was observed in 3 out of 4 EEG recording units. CONCLUSION: TASTPM mice were characterized by "poor reactivity" of delta EEG rhythms during the cage exploration in line with previous evidence in PDAPP mice. The reliability of that result across the centers was moderate, thus unveiling pros and cons of multicenter preclinical EEG trials in TASTPM mice useful for planning future studies.

How much is spent on mental health research: developing a system for categorising grant funding in the UK.

Knowing how much money is invested in funding mental health research, and in which areas, is essential to inform strategy and track trends to achieve the best allocation of limited resources. However, no comprehensive categorisation system for mental health research is available and, therefore, national and international data on mental health research funding are minimal and not comparable. In this Health Policy paper, we consider the complexities involved in generating such data and propose an approach to classify mental health research grants. We then describe a method using search terms and algorithms for automatic identification and categorisation of mental health research grants listed in a major international database (Dimensions, Digital Science). The automated approach was validated using manually categorised grants data from funders based in the UK, which showed that the accuracy of this approach is satisfactory and comparable to manual classification. Finally, we consider areas of research that are difficult to classify, and how the automated approach can be refined using machine-learning. We argue that agreed definitions and automated approaches could facilitate collaborative reporting of mental health research funders nationally and internationally and improve the strategic dialogue in this area of research.

Ongoing Electroencephalographic Activity Associated with Cortical Arousal in Transgenic PDAPP Mice (hAPP V717F).

BACKGROUND: It has been shown that theta (6-10 Hz) and delta (1-6 Hz) ongoing electroencephalographic (EEG) rhythms revealed variations in the cortical arousal in C57 Wild Type (WT) mice during cage exploration (active condition) compared to awake quiet behavior (passive condition; IMI PharmaCog project, www.pharmacog.eu). OBJECTIVE: The objective was to test if these EEG rhythms might be abnormal in old PDAPP mice modeling Alzheimer's disease (AD) with a hAPP Indiana V717F mutation (They show abnormal neural transmission, cognitive deficits, and brain accumulation of Aß1-42). METHODS: Ongoing EEG rhythms were recorded by a frontoparietal bipolar channel in 15 PDAPP and 23 WT C57 male mice (mean age of 22.8 months ±0.4 and 0.3 standard error, respectively). EEG absolute power (density) was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during passive and active states in the wakefulness. RESULTS: Compared with the WT group, the PDAPP group showed higher frequency of the IDF during the passive condition and lower frequency of the ITF during the active state. Furthermore, the WT but not PDAPP group showed significant changes in the frontoparietal EEG power (IDF, ITF) during active over passive state. CONCLUSION: PDAPP mice were characterized by less changes in the brain arousal during an active state as revealed by frontoparietal EEG rhythms. Future studies will have to cross-validate the present results on large animal groups, clarify the neurophysiological underpinning of the effect, and test if the disease modifying drugs against AD amyloidosis normalize those candiate EEG biomarkers in PDAPP mice.

On-going electroencephalographic rhythms related to cortical arousal in wild-type mice: the effect of aging.

Resting state electroencephalographic (EEG) rhythms reflect the fluctuation of cortical arousal and vigilance in a typical clinical setting, namely the EEG recording for few minutes with eyes closed (i.e., passive condition) and eyes open (i.e., active condition). Can this procedure be back-translated to C57 (wild type) mice for aging studies? On-going EEG rhythms were recorded from a frontoparietal bipolar channel in 85 (19 females) C57 mice. Male mice were subdivided into 3 groups: 25 young (4.5-6 months), 18 middle-aged (12-15 months), and 23 old (20-24 months) mice to test the effect of aging. EEG power density was compared between short periods (about 5 minutes) of awake quiet behavior (passive) and dynamic exploration of the cage (active). Compared with the passive condition, the active condition induced decreased EEG power at 1-2 Hz and increased EEG power at 6-10 Hz in the group of 85 mice. Concerning the aging effects, the passive condition showed higher EEG power at 1-2 Hz in the old group than that in the others. Furthermore, the active condition exhibited a maximum EEG power at 6-8 Hz in the former group and 8-10 Hz in the latter. In the present conditions, delta and theta EEG rhythms reflected changes in cortical arousal and vigilance in freely behaving C57 mice across aging. These changes resemble the so-called slowing of resting state EEG rhythms observed in humans across physiological and pathological aging. The present EEG procedures may be used to enhance preclinical phases of drug discovery in mice for understanding the neurophysiological effects of new compounds against brain aging.

Striatum and entorhinal cortex atrophy in AD mouse models: MRI comprehensive analysis.

Alzheimer's disease is experimentally modeled in transgenic (Tg) mice overexpressing mutated forms of the human amyloid precursor protein either alone or combined with mutated presenilins and tau. In the present study, we developed a systematic approach to compare double (TASTPM) and triple (APP/PS2/Tau) Tg mice by serial magnetic resonance imaging and spectroscopy analysis from 4 to 26 months of age to define homologous biomarkers between mice and humans. Hippocampal atrophy was found in Tg mice compared with WT. In APP/PS2/Tau the effect was age-dependent, whereas in TASTPM it was detectable from the first investigated time point. Importantly, both mice displayed an age-related entorhinal cortex thinning and robust striatal atrophy, the latter associated with a significant loss of synaptophysin. Hippocampal magnetic resonance spectroscopy revealed lower glutamate levels in both Tg mice and a selective myo-inositol increase in TASTPM. This noninvasive magnetic resonance imaging analysis, revealed common biomarkers between humans and mice, and could, thus, be promoted as a fully translational tool to be adopted in the preclinical investigation of therapeutic approaches.

A review of the effects of hypoxia, sleep deprivation and transcranial magnetic stimulation on EEG activity in humans: challenges for drug discovery for Alzheimer's disease.

Different kinds of challenge can alter cognitive process and electroencephalographic (EEG) rhythms in humans. This can provide an alternative paradigms to evaluate treatment effects in drug discovery. Here, we report recent findings on the effects of challenges represented by sleep deprivation (SD), transient hypoxia, and transcranial magnetic stimulation (TMS) in healthy volunteers on cognitive processes and EEG rhythms to build a knowledge platform for novel research for drug discovery in AD Alzheimer's disease (AD). Sleep pressure enhanced frontal delta rhythms (< 4 Hz) during the night, while SD increased slow rhythms in the theta range (4-7 Hz), and reduced resting state alpha rhythms (8-12 Hz) after the following day. Furthermore, SD transiently affected cognitive performance. In contrast, transient experimental hypoxia induced abnormal posterior resting state delta and alpha rhythms in healthy volunteers that resemble the abnormal EEG rhythms typically recorded in AD patients. However, the relationship between the cognitive and EEG effects of such challenges is poorly understood. TMS reversibly interfered with higher brain functions during EEG recordings, but few studies have investigated the relationship between the cognitive and EEG effects of TMS. In conclusion, SD is the most mature challenge model for testing new drugs for AD. Future investigation is needed to better understand the opportunities offered by TMS and hypoxia challenges.

Deficits of psychomotor and mnesic functions across aging in mouse lemur primates.

Owing to a similar cerebral neuro-anatomy, non-human primates are viewed as the most valid models for understanding cognitive deficits. This study evaluated psychomotor and mnesic functions of 41 young to old mouse lemurs (Microcebus murinus). Psychomotor capacities and anxiety-related behaviors decreased abruptly from middle to late adulthood. However, mnesic functions were not affected in the same way with increasing age. While results of the spontaneous alternation task point to a progressive and widespread age-related decline of spatial working memory, both spatial reference and novel object recognition (NOR) memory tasks did not reveal any tendency due to large inter-individual variability in the middle-aged and old animals. Indeed, some of the aged animals performed as well as younger ones, whereas some others had bad performances in the Barnes maze and in the object recognition test. Hierarchical cluster analysis revealed that declarative-like memory was strongly impaired only in 7 out of 25 middle-aged/old animals. These results suggest that this analysis allows to distinguish elder populations of good and bad performers in this non-human primate model and to closely compare this to human aging.

An automated maze task for assessing hippocampus-sensitive memory in mice.

Memory deficits associated with hippocampal dysfunction are a key feature of a number of neurodegenerative and psychiatric disorders. The discrete-trial rewarded alternation T-maze task is highly sensitive to hippocampal dysfunction. Normal mice have spontaneously high levels of alternation, whereas hippocampal-lesioned mice are dramatically impaired. However, this is a hand-run task and handling has been shown to impact crucially on behavioural responses, as well as being labour-intensive and therefore unsuitable for high-throughput studies. To overcome this, a fully automated maze was designed. The maze was attached to the mouse's home cage and the subject earned all of its food by running through the maze. In this study the hippocampal dependence of rewarded alternation in the automated maze was assessed. Bilateral hippocampal-lesioned mice were assessed in the standard, hand-run, discrete-trial rewarded alternation paradigm and in the automated paradigm, according to a cross-over design. A similarly robust lesion effect on alternation performance was found in both mazes, confirming the sensitivity of the automated maze to hippocampal lesions. Moreover, the performance of the animals in the automated maze was not affected by their handling history whereas performance in the hand-run maze was affected by prior testing history. By having more stable performance and by decreasing human contact the automated maze may offer opportunities to reduce extraneous experimental variation and therefore increase the reproducibility within and/or between laboratories. Furthermore, automation potentially allows for greater experimental throughput and hence suitability for use in assessment of cognitive function in drug discovery.

Cell clocks and neuronal networks: neuron ticking and synchronization in aging and aging-related neurodegenerative disease.

Body function rhythmicity has a key function for the regulation of internal timing and adaptation to the environment. A wealth of recent data has implicated endogenous biological rhythm generation and regulation in susceptibility to disease, longevity, cognitive performance. Concerning brain diseases, it has been established that many molecular pathways implicated in neurodegeneration are under circadian regulation. At the molecular level, this regulation relies on clock genes forming interconnected, self-sustained transcriptional/translational feedback loops. Cells of the master circadian pacemaker, the hypothalamic suprachiasmatic nucleus, are endowed with this molecular clockwork. Brain cells in many other regions, including those which play a key role in learning and memory, as well as peripheral cells show a circadian oscillatory behavior regulated by the same molecular clockwork. We here address the question as to whether intracellular clockwork signaling and/or the intercellular dialogue between "brain clocks" are disrupted in aging-dependent neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. The potential implications of clock genes in cognitive functions in normal conditions, clinical disturbances of circadian rhythms, and especially the sleep-wake cycle, in aging-dependent neurodegenerative diseases and data in animal models are reviewed. The currently limited knowledge in this field is discussed in the context of the more extensive body of data available on cell clocks and molecular clockwork during normal aging. Hypotheses on implications of the synchronization between brain oscillators in information processing in neural networks lay ground for future studies on brain health and disease.

Effects of pharmacological agents, sleep deprivation, hypoxia and transcranial magnetic stimulation on electroencephalographic rhythms in rodents: towards translational challenge models for drug discovery in Alzheimer's disease.

Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms in animal models, thus providing paradigms to evaluate treatment effects in drug discovery. The effects of challenges represented by pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation (TMS) on EEG rhythms are here reviewed to build a knowledge platform for innovative translational models for drug discovery in Alzheimer's disease (AD). It has been reported that antagonists of cholinergic neurotransmission cause synchronisation of spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs may restore a normal pattern of EEG desynchronisation. Sleep deprivation and hypoxia challenges have also been reported to elicit abnormal synchronisation of spontaneous ongoing EEG rhythms in rodents. The feasibility and reproducibility of TMS have been demonstrated in rodents but information on a consistent modulation of EEG after TMS manipulation is very limited. Transgenic mice over-expressing human amyloid precursor protein complementary DNAs (cDNAs) harbouring the 'Swedish' mutation and PS-1 cDNAs harbouring the A264E mutation, which recapitulate some of the pathological features of AD, exhibit alterations of spontaneous ongoing EEG rhythms at several low and high frequencies. This does not appear, however, to be a consequence of beta-amyloid deposition in the brain. The present review provides a critical evaluation of changes of spontaneous ongoing EEG rhythms due to the experimental manipulations described above, in order to stimulate the promote more adherent models fitting dynamics in humans.

Effects of acetylcholinesterase inhibitors and memantine on resting-state electroencephalographic rhythms in Alzheimer's disease patients.

Acetylcholinesterase inhibitors (AChEIs) are the most widely used symptomatic treatment for mild to severe Alzheimer's disease (AD) patients, while N-methyl-d-aspartic acid (NMDA) receptor antagonist memantine is licensed for use in moderate to severe AD patients. In this article, the effect of these compounds on resting state eyes-closed electroencephalographic (EEG) rhythms in AD patients is reviewed to form a knowledge platform for the European Innovative Medicine Initiative project "PharmaCog" (IMI Grant Agreement No. 115009) aimed at developing innovative translational models for drug testing in AD. Indeed, quite similar EEG experiments and the same kind of spectral data analysis can be performed in animal models of AD and in elderly individuals with prodromal or manifest AD. Several studies have shown that AChEIs affect both resting state EEG rhythms and cognitive functions in AD patients. After few weeks of successful treatment, delta (0-3 Hz) or theta (4-7 Hz) rhythms decrease, dominant alpha rhythms (8-10 Hz) increase, and cognitive functions slightly improve. Beneficial effects of these rhythms and cognitive functions were also found in AD responders to the long-term successful treatment (i.e. 6-12 months). In contrast, only one study has explored the long-term effects of memantine on EEG rhythms in AD patients, showing reduced theta rhythms. The present review enlightens the expected effects of AChEIs on resting state EEG rhythms in AD patients as promising EEG markers for the development of translational protocols both within the PharmaCog project and for wider use.

NMDA receptors, cognition and schizophrenia--testing the validity of the NMDA receptor hypofunction hypothesis.

Cognitive dysfunction is core to schizophrenia, and remains poorly treated by existing therapies. A prominent hypothesis suggests that many symptoms arise from N-methyl-d-aspartate receptor (NMDAR) hypofunction. Subsequently, there has emerged a widespread use of many preclinical and clinical NMDAR antagonist models in the search for novel treatments. Clinically, ketamine is broadly purported to induce cognitive symptoms similar to those of schizophrenia. Preclinically, acute, subchronic and neonatal NMDAR antagonist administration models are all utilised in this context, as well as NMDAR transgenic animals. In this review, key strengths and weaknesses of each of these approaches are described with regard to their ability to recapitulate the deficits seen in patients. Given the breadth of literature and vogue for research in this topic, instances of NMDAR antagonist effects in the desired domains can readily be found preclinically. However, it is surprisingly difficult to identify any single aspect of cognitive function that possesses complete translational integrity. That is, there does not seem to be an NMDAR antagonist regimen proven to engage NMDARs equivalently in humans and animals that reliably produces the same cognitive effects in each species. This is likely due to the diverse range of techniques and models used by preclinical researchers, a paucity of research describing pharmacokinetic-pharmacodynamic relationships of NMDAR antagonist regimens, little capability to measure target engagement, and the lack of harmonized procedures between preclinical and clinical studies. Realizing the potential of the NMDAR hypofunction hypothesis to model cognitive impairment in schizophrenia will require some of these issues to be addressed.

A comparison of the effects of ketamine and phencyclidine with other antagonists of the NMDA receptor in rodent assays of attention and working memory.

RATIONALE: N-methyl-D: -Aspartate receptor (NMDAR) antagonists such as ketamine induce cognitive symptoms in man similar to those of schizophrenia and therefore might be useful as models of the disease in animals. However, it is unclear which NMDAR antagonist(s) offer the best means to produce cognitive deficits in attention and working memory and to what extent those deficits can be measured selectively in rats. OBJECTIVES: The present study systematically compared the effects of eight different NMDAR antagonists-MK-801, phencyclidine, (S)-(+)-ketamine, memantine, SDZ-220,581, Ro 25-6981, CP 101-606 and NVP-AAM077-in rats using standard tests of visual attention, the five-choice serial reaction time task (5CSRT), and working memory, the delayed matching to position task (DMTP). RESULTS: Drug-induced responses varied qualitatively and quantitatively in both a compound- and a task-dependent manner. Effects were generally confounded by concomitant motor and motivational disruption, although individual doses of phencyclidine for example appeared to impair selectively cognitive functions. Interestingly, GluN2B selective antagonists were unique in their effects; inducing potential performance benefit in the 5CSRT. CONCLUSIONS: Overall, the opportunity to induce a selective cognitive deficit in attention (5CSRT) or working memory (DMTP) in the rat is limited by both the NMDAR antagonist and the dose range used. The importance of a preclinical focus on ketamine, which is used more frequently in clinical settings, is limited by the extent to which cognitive effects can be both detected and quantified using this exposure regimen within these two operant assays.

A within-subject cognitive battery in the rat: differential effects of NMDA receptor antagonists.

RATIONALE: The range of cognitive and psychotomimetic effects produced by antagonists of the N-methyl-D-aspartate (NMDA) receptor has lead to widespread usage of these molecules as pharmacological models of cognitive impairment for drug discovery. Historically, NMDA receptor antagonists have been used interchangeably on the assumption that they produce analogous effects. OBJECTIVES: To profile a subset of these antagonists across a novel within-subject cognitive battery in the rat. METHODS: Naïve male Lister Hooded rats were subjected to a series of tests in which they were required to learn a simple visuo-auditory conditional discrimination. They then underwent testing in a delayed discrimination test followed by rule reversal and rule extinction tests. RESULTS: All NMDA receptor antagonists tested impaired acquisition performance and, with the exception of ketamine and the GluN2A preferring antagonist, NVP-AAM077, impaired consolidation of extinction. GluN2B antagonism produced a singular profile with potentially enhanced delayed discrimination performance and reduced hit rates in the reversal phase. Only PCP (phencyclidine) and ketamine disrupted performance in the delay phase but did so in a delay-independent manner. MK-801, PCP and memantine all increased the hit rate in the reversal phase; whilst only MK-801 and PCP impaired extinction per se. CONCLUSIONS: NMDA receptor-dependent mechanisms are requisite in the acquisition of a simple conditional discrimination and consolidation of extinction. Their role in working memory and reversal tasks appear to be less critical and potentially specific to the paradigm and NMDA receptor antagonist used. It is clearly misleading to generalise across NMDA antagonists with respect to their preclinical cognitive profile.

Diverse and often opposite behavioural effects of NMDA receptor antagonists in rats: implications for "NMDA antagonist modelling" of schizophrenia.

RATIONALE: Little attention has been paid to the relative equivalence of behavioural effects of NMDA receptor antagonists in rodents, with different compounds often used interchangeably to "model" aspects of schizophrenia in preclinical studies. OBJECTIVES: To further resolve such conjecture, the present study systematically compared eight different NMDA receptor antagonists: MK-801, PCP, ketamine, memantine, SDZ 220,581, Ro 25-6981, CP 101-606 and NVP-AAM077, in a series of variable interval (VI) schedules of reinforcement. Aspects of motivation as indexed in these tasks may well be impaired in schizophrenia and undoubtedly impact on the capacity to perform more complex, explicit tasks of cognition. METHODS AND RESULTS: An initial locomotor activity assessment demonstrated that all antagonists tested, except the NR2A-subunit preferring antagonist NVP-AAM077, induced hyperactivity, albeit of greatly differing magnitudes, qualities and temporal profiles. Three distinct patterns of antagonist effect were evident from the VI assays used: a uniform decrease in responding produced by (S)-(+)-ketamine, memantine and NVP-AAM077, a uniform increase in responding caused by the NR2B-subunit preferring antagonists Ro 25-6981 and CP 101-606, and variable bidirectional effects of PCP, SDZ 220,581 and MK-801. CONCLUSION: Despite nominally common mechanisms of action and often presumed biological equivalence, the NMDA antagonists tested produced very diverse effects on the expression of instrumental action. Other aspects of responding were left intact, including switching and matching behaviours, and the ability to respond to conditional stimuli. The implications of such findings with regard to animal modelling of schizophrenic psychotic symptoms are manifold.

AMPA receptor potentiators as cognitive enhancers.

With an aging population, cognitive decline as a result of aging, Alzheimer's disease and other neurological conditions has become a major problem. Many of the current medications (eg, acetylcholinesterase inhibitors) for cognitive disorders show limited efficacy and are effective only in certain populations. Several other pharmacological pathways are therefore being explored in an attempt to develop superior medications. Glutamate and glutamate receptors are well recognized to play a key role in long-term potentiation (LTP), a process that is believed to underlie memory formation. Glutamate antagonists have been demonstrated to block LTP and to disrupt memory in both rodents and humans. Based on these data, it is not surprising that boosting glutamatergic transmission has been explored as a means of enhancing cognition. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors have been demonstrated to control fast synaptic transmission. Several classes of AMPA receptor potentiators have been described in the last decade. These molecules bind to allosteric sites on AMPA receptors, slow desensitization and thereby enhance signaling through the receptors. Some AMPA receptor potentiator agents have been explored in rodent models and are now entering clinical trials. Research complexity for these agents arises from the multiple AMPA receptor subtypes on which the molecules can act differentially, as well as from the distribution of AMPA receptors and the difficulty in studying cognition in naïve rodents. Nevertheless, boosting Ca(2+) flux through the AMPA receptor, and enhancing LTP and downstream pathways may provide a novel approach to the treatment of cognitive deficits.

Using the BOLD MR signal to differentiate the stereoisomers of ketamine in the rat.

RATIONALE: Ketamine is a chiral molecule that is reported to model aspects of schizophrenia. OBJECTIVES: To investigate the stereospecificity of the isomers of ketamine using pharmacological magnetic resonance imaging (phMRI) in order to further understand ketamine's pharmacodynamic actions. METHOD: Responses to 25 mg kg-1S(+) isomer, R(-) isomer and racemic ketamine in independent groups of Sprague-Dawley rats were investigated using a prepulse inhibition paradigm, locomotor observations, MRI and 2-deoxyglucose techniques. RESULTS: Racemic ketamine and the S(+) isomer were both capable of disrupting sensorimotor gating as measured using prepulse inhibition and produced a longer period of hyperlocomotion comparative to the R(-) isomer. In contrast, large alterations in the BOLD MR signal were observed with R(-) isomer, whereas S(+) isomer and racemate precipitated more localized BOLD signal changes predominantly in cortical, hippocampal and hindbrain regions. Glucose utilization rates in conscious animals are in agreement with previously published data and verify the BOLD responses in the racemic group. However, no significant changes in glucose utilization were observed in the anesthetized cohort. CONCLUSIONS: Ketamine and its isomers have stereospecific effects on sensorimotor gating and locomotion that correlate with the enantiomer's affinity for the NMDA receptor. It would appear that anesthesia, as required for preclinical MRI procedures, may interact with and potentially attenuate the drug's response. Although analysis of the main effect of isomers in comparison to each other or the racemate offers an alternative analysis method that should be less susceptible to anesthetic interactions, only the R(-) isomer comparative to the racemate offers significant differences of interest.

Sparing of the familiarity component of recognition memory in a patient with hippocampal pathology.

Subject KN has a persistent anterograde amnesia as a result of brain injury following meningitis in 1993. MRI scans reveal a bilateral decrease in the volume of his hippocampal region (dentate gyrus, CA1-4, subicular cortices) of approximately 45% in both the right and left hemispheres, although the volume of his perirhinal cortex appears normal. Aside from some changes to his occipital lobe and bilateral shrinkage of the amygdala, the rest of his brain appears normal on recent quantitative MRI scans. A striking feature of his memory loss is his ability to perform at normal levels on some tests of recognition, despite his consistent deficit on tests of recall. Two tests designed specifically to distinguish performance of two putative divisions of recognition memory (the Remember/Know procedure and the use of receiver operating characteristics to distinguish familiarity and recollection), provide evidence for a selective sparing of the familiarity component of recognition. The dissociation within recognition memory supports dual-process models of recognition, and also supports proposals that anatomically linked regions within the medial temporal lobe make qualitatively different contributions to recognition.