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Rationale and Objectives: Adolescence is a sensitive period of brain development, during which there may be a heightened vulnerability to the effects of drug use. Despite this, the long-term effects of cannabis use during this developmental period on cognition are poorly understood., Methods: We exposed adolescent rats to escalating doses of Δ9-tetrahydrocannabinol (THC)-the primary psychoactive component of cannabis-or vehicle solution during postnatal days (PND) 35-45, a period of development that is analogous to human adolescence (THC doses: PND 35-37, 2.5 mg/kg; PND 38-41, 5 mg/kg; PND 42-45, 10 mg/kg). After a period of abstinence, in adulthood, rats were tested on an automated touchscreen version of a paired-associates learning (PAL) task to assess their ability to learn and recall object-location associations. Prepulse inhibition (PPI) of the startle response was also measured at three time points (5 days, 4 months, and 6 months after exposure) to assess sensorimotor gating, the ability to filter out insignificant sensory information from the environment., Results: Compared to rats exposed to vehicle alone, rats exposed to THC during adolescence took longer to learn the PAL task when tested in adulthood, even when trials contained visually identical stimuli that differed only in location. Despite this, no differences were observed later in testing, when trials contained visually distinct stimuli in different locations. Rats exposed to THC also displayed impairments in sensorimotor gating, as measured by prepulse inhibition of the startle response, though this deficit did appear to decrease over time., Conclusion: Taken together, THC exposure during adolescence produces long-term deficits in associative learning and sensorimotor gating, though the impact of these deficits seems to diminish with time. Thus, adolescence may represent a period of neurocognitive development that is vulnerable to the harms of cannabis use, though the stability of such harms is uncertain.

Agonists at the nicotinic acetylcholine alpha 7 receptor (nAChR α7) subtype have the potential to treat cognitive deficits in patients with Alzheimer's disease (AD) or schizophrenia. Visuo-spatial paired associates learning (vsPAL) is a task that has been shown to reliably predict conversion from mild cognitive impairment to AD in humans and can also be performed by nonhuman primates. Reversal of scopolamine-induced impairment of vsPAL performance may represent a translational approach for the development of nAChR α7 agonists. The present study investigated the effect of treatment with the acetylcholinesterase inhibitor, donepezil, or three nAChR α7 agonists, BMS-933043, EVP-6124 and RG3487, on vsPAL performance in scopolamine-treated cynomolgus monkeys. Scopolamine administration impaired vsPAL performance accuracy in a dose- and difficulty- dependent manner. The impairment of eventual accuracy, a measure of visuo-spatial learning during the task, was significantly ameliorated by treatment with donepezil (0.3 mg/kg, i.m.), EVP-6124 (0.01 mg/kg, i.m.) or BMS-933043 (0.03, 0.1 and 0.3 mg/kg, i.m.). Both nAChR α7 agonists showed inverted-U shaped dose-effect relationships with EVP-6124 effective at a single dose only whereas BMS-933043 was effective across at least a 10 fold dose/exposure range. RG3487 was not efficacious in this paradigm at the dose range examined (0.03-1 mg/kg, i.m.). These results are the first demonstration that the nAChR α7 agonists, EVP-6124 and BMS-933043, can ameliorate scopolamine-induced cognitive deficits in nonhuman primates performing the vsPAL task.

Here we tested in rats effects of the procognitive drugs modafinil and methylphenidate on post-acquisition performance in an object-location paired-associates learning (PAL) task. Modafinil (32; 64 mg/kg) was without effect, while higher (9 mg/kg) but not lower (4.5 mg/kg) doses of methylphenidate impaired PAL performance. Likewise, higher but not lower doses of amphetamine (0.4; 0.8 mg/kg) and MK-801 (0.08; 0.12 mg/kg) decreased PAL performance. Impaired PAL performance induced by methylphenidate, amphetamine, and MK801 most likely reflects compromised cognitive function, e.g., retrieval of learned paired associates. Our data suggest that stimulant drugs such as methylphenidate and modafinil might not facilitate performance in hippocampus-related cognitive tasks., (© 2016 Roschlau et al.; Published by Cold Spring Harbor Laboratory Press.)

Rationale: New pharmacological treatments for the cognitive deficits in schizophrenia are needed. Tetrahydroprotoberberines, such as govadine, are one class of compounds with dopaminergic activities that may be useful in treating some aspects of the cognitive symptoms of the disorder., Objective: The objective of the present studies was to test the effects of the D- and L-enantiomers of govadine on the impairment in a paired-associate learning (PAL) task produced by acute MK-801 in rats. We also assessed effects of the typical antipsychotic haloperidol as a comparator compound., Methods: MK-801 (0.05, 0.1, 0.15, and 0.2 mg/kg), D- and L-govadine (0.3, 1.0, and 3.0 mg/kg), and haloperidol (0.05, 0.1, and 0.25 mg/kg) were administered acutely to rats well trained on the PAL task in touchscreen-equipped operant conditioning chambers., Results: Acute MK-801 impaired performance of PAL in a dose-dependent manner by reducing accuracy and increasing correction trials. L-Govadine (1.0 mg/kg), but not D-govadine, blocked the disruptive effects of MK-801 (0.15 mg/kg) on PAL. Haloperidol failed to affect the MK-801-induced disruption of PAL. Higher doses of L-govadine and haloperidol dramatically impaired performance of the task which confounded interpretation of cognitive outcomes., Conclusion: L-Govadine appears unique in its ability to improve performance of the MK-801-induced impairment in the PAL task. This behavioral effect may relate the ability of L-govadine to antagonize dopamine D2 receptors while also promoting dopamine efflux. Future research should further characterize the role of the dopamine system in the rodent PAL task to elucidate the mechanisms of its pro-cognitive effects.

Rationale: Paired associates learning (PAL) has been suggested to be predictive of functional outcomes in first episode psychosis and of conversion from mild cognitive impairment to Alzheimer's disease. An automated touch screen-based rodent PAL (rPAL) task has been developed and is sensitive to manipulations of the dopaminergic and glutamatergic system. Accordingly, rPAL when used with pharmacological models of schizophrenia, like NMDA receptor blockade with MK-801 or dopaminergic stimulation with amphetamine, may have utility as a translational model of cognitive impairment in schizophrenia., Objective: The purpose of this study was to determine if amphetamine- and MK-801-induced impairment represent distinct models of cognitive impairment by testing their sensitivity to common antipsychotics and determine the relative contributions of D1 versus D2 receptors on performance of PAL., Method: Rats were trained in rPAL and were then treated with MK-801, amphetamine, risperidone, haloperidol, quinpirole, SK-82958, or SCH-23390 alone and in combination., Results: While both amphetamine and MK-801 caused clear impairments in accuracy, MK-801 induced a profound "perseverative" type behavior that was more pronounced when compared to amphetamine. Moreover, amphetamine-induced impairments, but not the effects of MK-801, could be reversed by antipsychotics as well as the D1 receptor antagonist SCH-23390, suggesting a role for both the D1 and D2 receptor in the amphetamine impairment model., Conclusions: These data suggest that amphetamine and MK-801 represent dissociable models of impairment in PAL, dependent on different underlying neurobiology. The ability to distinguish dopaminergic versus glutamatergic effects on performance in rPAL makes it a unique and useful tool in the modeling of cognitive impairments in schizophrenia.

Rationale: The CANTAB object-location paired-associate learning (PAL) test can detect cognitive deficits in schizophrenia and Alzheimer's disease. A rodent version of touch screen PAL (dPAL) has been developed, but the underlying neural mechanisms are not fully understood. Although there is evidence that inactivation of the hippocampus following training leads to impairments in rats, this has not been tested in mice. Furthermore, it is not known whether acquisition, as opposed to performance, of the rodent version depends on the hippocampus. This is critical as many mouse models may have hippocampal dysfunction prior to the onset of task training., Objectives: The objectives of this study are to examine the effects of dorsal hippocampal (dHp) dysfunction on both performance and acquisition of mouse dPAL and to determine if hippocampal task sensitivity could be increased using a newly developed context-disambiguated PAL (cdPAL) paradigm., Methods: In experiment 1, C57Bl/6 mice received post-acquisition dHp infusions of the GABA agonist muscimol. In experiment 2, C57Bl/6 mice received excitotoxic dHp lesions prior to dPAL/cdPAL acquisition., Results: Post-acquisition muscimol dose-dependently impaired dPAL and cdPAL performance. Pre-acquisition dHp lesions had only mild effects on both PAL tasks. Behavioural challenges including addition of objects and degradation of the visual stimuli with noise did not reveal any further impairments., Conclusions: dPAL and cdPAL performance is hippocampus-dependent in the mouse, but both tasks can be learned in the absence of a functional dHp.

Rationale: Many studies suggest that glucose can temporarily enhance hippocampal-dependent memories. As the hippocampus plays a key role in associative learning, we examined the influence of glucose on verbal paired associate memory., Objective: This study examines how glucose modifies performance on a relational memory task by examining its influence on learning, subsequent forgetting and relearning., Methods: A selective reminding procedure was used to show high and low imagability paired associates to 80 participants, who were seen twice. On the first session, they received 25 g glucose pre-learning, 25 g glucose post-learning or placebo. On the second session, 1 week later, they received 25 g glucose or placebo. Cued-recall was evaluated after each learning trial, 1 week later to assess forgetting and after an opportunity to relearn the material forgotten., Results: Glucose did not influence paired associate acquisition. Those given glucose pre-learning tended to forget less material the following week, and independently, glucose at retrieval facilitated cued-recall. Both forms of facilitation were equally apparent on low and high imagability pairs. The benefit of glucose pre-learning was eliminated once the paired associates had been seen again, but the benefit of glucose at retrieval extended into the second relearning trial., Conclusions: The discussion considers the cognitive processes and hippocampal basis for paired associate learning and retention and the implications for glucose's mode of action. It is proposed that glucose during encoding serves to make the delayed memories initially more available, whereas its influence during delayed retrieval makes available memories temporarily more accessible.

The use of touch-screen equipped operant boxes is an increasingly popular approach for modeling human cognition in the rodent. However little data is currently available describing the effects of pharmacological manipulations on touch-screen based tasks. Owing to the relationship between performance on visual-spatial paired associates learning (PAL) with schizophrenia and Alzheimer's disease one task of specific interest is the touch-screen PAL task developed for rodents (J. Talpos et al., 2009). The goal of this study was to profile a range of the commonly used pharmacological models of schizophrenia and Alzheimer's disease to investigate the sensitivity of PAL to these models of disease. Male Lister hooded rats were trained on PAL until stable performance was obtained. The effects of PCP, ketamine, amphetamine, LSD, scopolamine, and biperiden (recently proposed as an alternative to scopolamine) were then tested on animals performing the PAL task. While all compounds influenced responding during PAL, only PCP and amphetamine impaired performance with minimal changes in secondary measures (response latencies, trials completed). Surprisingly ketamine did not cause a change in percent correct despite being an NMDA antagonist, indicating that not all NMDA antagonists are equal in the touch-screen platform. This finding is in agreement with existing literature showing differential effects of NMDA antagonists on a wide variety of behavioral assays include tasks of attention, memory, and cognitive flexibility (Gilmour et al., 2009; Dix et al., 2010; Smith et al., 2011). Moreover biperiden showed no benefit when compared to scopolamine, highlighting the current lack of an effective pharmacological model of cholinergic dysfunction in the touch-screen platform. These data demonstrate that performance on PAL can be disrupted by common pharmacological disease models, suggesting that PAL may have the sensitivity to serve as a translational test for the study of cognition in humans., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The prevalence of cognitive abnormalities in children has partly been ascribed to environmental chemical exposure. Appropriate animal models and tools for evaluating higher brain function are required to examine this problem. A recently developed behavioral test in which rats learn six unique flavor-location pairs in a test arena was used to evaluate paired-associate learning, a hallmark of the higher cognitive function that is essential to language learning in humans. Pregnant Long-Evans rats were dosed by gavage with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) at a dose of 0, 200, or 800 ng/kg (referred as Control, TCDD-200, TCDD-800, TBDD-200, or TBDD-800, hereafter) on gestational day 15, and the offspring was tested during adulthood. Paired-associate learning was found to be impaired in the TCDD-200 and TBDD-200 groups, but not in either group exposed to 800 ng/kg, the observations of which were ensured by non-cued trials. As for the emotional aspect, during habituation, the TCDD-200 and TBDD-200 groups showed significantly longer latencies to enter the test arena from a start box than the Control, TCDD-800, and TBDD-800 groups, suggesting that the TCDD-200 and TBDD-200 groups manifested anxiety-like behavior. Thus, both the chlorinated dioxin and its brominated congener affected higher brain function to a similar extent in a nearly identical manner. Use of the behavioral test that can evaluate paired-associate learning in rats demonstrated that in utero and lactational exposure to not only TCDD but also TBDD perturbed higher brain function in rat offspring in a nonmonotonic manner.

Manganese (Mn) is an essential trace metal nutrient, however, excess Mn can be neurotoxic. The degree to which chronic environmental or occupational exposures to Mn in adults cause neuropsychological dysfunction is of considerable interest. Descriptions of neuropsychological dysfunction following chronic Mn exposure have been somewhat inconsistent though, likely owing to different measures of exposure in different populations, complicated by factors of mixed exposures and differences in neuropsychological tests administered. We previously described up-regulation of the mRNA expression for amyloid-beta (A-beta) precursor-like protein 1 (APLP1) and the presence of A-beta diffuse plaques in frontal cortex of Mn-exposed monkeys. The present study examined Mn-induced changes in performance on a paired associate learning (PAL) task that has been suggested as a marker for preclinical Alzheimer's disease. Aspects of performance of this task were affected early following initiation of Mn exposure. Thus, PAL performance may be a sensitive and valuable tool for the early, preclinical detection of incipient dementia and it may also be a sensitive tool for detecting cognitive dysfunction from Mn exposure. The current cognitive data, combined with our previous findings, suggest that frontal cortex may be a particularly sensitive target for the effects of Mn on cognition and that chronic Mn exposure may initiate or accelerate a process that could lead to or predispose to Alzheimer's like pathology and cognitive dysfunction., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Rationale: Use of cross-species neuropsychological paradigms such as visual-spatial paired associate learning (PAL) may allow for a better understanding of underlying neural substrates of memory. Such paradigms, which are often used to guide models of memory in animals, can then be carried forward into humans to provide a basis for evaluation of pharmacologic compounds designed to ameliorate learning and memory impairments in neurologic and psychiatric morbidities., Objectives: This double-blind, randomized, crossover trial investigated effects of donepezil, an acetylcholinesterase (AChE) inhibitor, in attenuating scopolamine-induced cognitive impairment using a novel, "process-based" computerized measure of visual-spatial PAL., Results: In healthy male volunteers, scopolamine (0.6 mg) induced a time-dependent reduction in visual-spatial PAL, with the greatest impairment (Cohen's d = 1.37) observed 2 h after dosing. Cotreatment with donepezil (10 mg) significantly ameliorated scopolamine-induced impairment at the 2-h time point (Cohen's d = 0.66). Process-based analyses revealed a significant impairment in both memory (Cohen's d = 1.37 to 0.50) and executive (Cohen's d = 1 .21 to 0.62) aspects of visual-spatial PAL performance following acute scopolamine challenge, and these reductions were ameliorated by donepezil., Conclusions: Acute scopolamine challenge can produce large and robust deficits in visual-spatial PAL, which reflect impairments in both memory and executive processes. Coadministration of a single dose of donepezil can ameliorate these deficits. These results provide support for the use of a visual-spatial PAL test as a pharmacodynamic cognitive marker of central nervous system (CNS)-mediating compounds in humans.

Background/aims: AL-108-211 was a placebo-controlled, ascending-dose study that explored the safety, tolerability and efficacy of 12 weeks of treatment with AL-108 in subjects with amnestic mild cognitive impairment., Methods: A total of 144 subjects were randomized in a 2:1 drug:placebo ratio. Subjects were enrolled into the low-dose group or placebo and then to the high-dose group or placebo. Pooling of the placebo groups yielded 3 groups (approx. 48/group) whose baseline demographics and disease characteristics were well matched., Results: AL-108 was generally safe and well tolerated. Analyses of efficacy data failed to detect a statistically significant difference between the treatment groups on the composite cognitive memory score. Analyses of the individual cognitive tasks identified signals of potential efficacy in 2 tests of memory and attention., Conclusion: These data suggest that AL-108 was generally safe, well tolerated and merits additional investigation as a treatment for Alzheimer's disease., (Copyright © 2013 S. Karger AG, Basel.)

Aims: Alcohol and marijuana are the most widely used intoxicants among adolescents, yet their potential unique and interactive influences on the developing brain are not well established. Brain regions subserving learning and memory undergo continued maturation during adolescence, and may be particularly susceptible to substance-related neurotoxic damage. In this study, we characterize brain response during verbal learning among adolescent users of alcohol and marijuana., Design: Participants performed a verbal paired associates encoding task during functional magnetic resonance imaging (fMRI) scanning., Setting: Adolescent subjects were recruited from local public schools and imaged at a university-based fMRI center., Participants: Participants were 74 16-18-year-olds, divided into four groups: (i) 22 controls with limited alcohol and marijuana experience, (ii) 16 binge drinkers, (iii) eight marijuana users and (iv) 28 binge drinking marijuana users., Measurements: Diagnostic interview ensured that all teens were free from neurological or psychiatric disorders; urine toxicology and breathalyzer verified abstinence for 22-28 days before scanning; a verbal paired associates task was administered during fMRI., Findings: Groups demonstrated no differences in performance on the verbal encoding task, yet exhibited different brain response patterns. A main effect of drinking pointed to decreased inferior frontal but increased dorsal frontal and parietal fMRI response among binge drinkers (corrected P < 0.05). There was no main effect of marijuana use. Binge drinking × marijuana interactions were found in bilateral frontal regions (corrected P < 0.05), where users of either alcohol or marijuana showed greater response than non-users, but users of both substances resembled non-users., Conclusions: Adolescent substance users demonstrated altered fMRI response relative to non-using controls, yet binge drinking appeared to be associated with more differences in activation than marijuana use. Alcohol and marijuana may have interactive effects that alter these differences, particularly in prefrontal brain regions., (© 2010 Society for the Study of Addiction. No claim to original US government works.)

Rationale: Performance on the Cambridge Neuropsychological Test Automated Battery touchscreen paired-associates learning (PAL) test is predictive of Alzheimer's disease and impaired in schizophrenia and chronic drug users. An automated computer touchscreen PAL task for rats has been previously established. A pharmacologically validated PAL task for mice would be a highly valuable tool, which could be useful for a number of experimental aims including drug discovery., Objectives: This study sought to investigate the effects of systemic administration of cholinergic agents on task performance in C57Bl/6 mice., Methods: Scopolamine hydrobromide (0.02, 0.2, and 2.0 mg/kg), dicyclomine hydrochloride (M(1) receptor antagonist; 2.0, 4.0, and 8.0 mg/kg), and donepezil hydrochloride (cholinesterase inhibitor; 0.03, 0.1, and 0.3 mg/kg) were administered post-acquisition in C57Bl/6 mice performing the PAL task., Results: Scopolamine (0.2 and 2.0 mg/kg) and dicyclomine (at all administered doses) significantly impaired PAL performance. A significant facilitation in PAL was revealed in mice following donepezil administration (0.3 mg/kg)., Conclusions: The present study shows that mice can acquire the rodent PAL task and that the cholinergic system is important for PAL task performance. M(1) receptors in particular are likely implicated in normal performance of PAL. The finding that mouse PAL can detect both impairments and improvements indicates that this task could prove to be a highly valuable tool for a number of experimental aims including drug discovery.

Background: Factors of error and effort in study conditions play a crucial role in the intervention for memory-impaired individuals. In the present study, efficacy of four study conditions was compared in order to elucidate the optimal study conditions: errorless/errorful and effortless/effortful., Methods: A total of 18 patients with Alzheimer's disease and 12 patients with amnesic syndrome received study-test sessions under four different study conditions: errorless/errorful and effortless/effortful., Results: The errorless learning advantage was confirmed for both Alzheimer's disease and amnesic syndrome on both free recall and cued recall tests. In contrast, effortful learning was effective only for amnesic syndrome on a free recall test., Conclusion: Despite the overall advantage of errorless learning, the effortful process was effective in circumscribed situations., (© 2010 The Authors. Psychogeriatrics © 2010 Japanese Psychogeriatric Society.)

Rationale: Patients with obsessive compulsive disorder (OCD) demonstrate impaired cognition in some selected domains. Although serotoninergic dysfunction has been implicated in OCD, recent evidence suggests that dopamine may play a role as well., Objective: The aim of the study was to evaluate learning and working memory in OCD and to determine the effects of dopaminergic manipulations on these capacities., Methods: Visuospatial associative memory and spatial and verbal working memory were examined in 18 nondepressed patients with OCD and 18 matched healthy controls. The study further investigated whether acute administration of dopamine D2/D3 receptor agonist and antagonist would differentially modulate cognition in OCD. Each participant underwent the cognitive battery three times in a randomized double-blind, placebo-controlled crossover design., Results: Significant impairments in patients compared with controls were noted on the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning (PAL) and a measure of sustained attention (rapid visual information processing, RVIP) that persisted across all sessions, with deficient strategy in the CANTAB spatial working memory task in the first session alone. Although the dopamine D2/D3 agonist, pramipexole, led to poorer performance on the PAL and RVIP tasks, no differential effects were noted between the two groups. No significant effects were noted for the D2/D3 antagonist, amisulpride., Conclusions: The results are consistent with a specific associative memory deficit in OCD that remained robust despite possible practice effects and compensatory strategies and point to abnormal medial temporal lobe involvement in OCD in addition to the previously implicated frontostriatal loops, with no clear evidence of D2 receptor mediation.

Previous studies on inhibitory mechanisms assessed by negative priming (NP) paradigms in patients suffering from Parkinson's disease (PD) have yielded highly ambiguous results. The present study examined two possible reasons for this heterogeneity: general slowing and anti-Parkinsonian medication. Their effects on identity and location NP and positive priming (PP) were investigated. Twenty medicated PD patients and 20 PD patients after drug withdrawal were compared to 20 sex- and age-matched healthy controls. The influence of PD patients' general slowing on priming effects was statistically controlled. Location NP was found not to be affected by PD, whereas identity NP was reduced in medicated PD patients compared to non-medicated PD patients and healthy controls. At first, identity and location PP appeared to be enhanced in both PD groups. After controlling for general slowing, however, differences between PD patients and healthy controls disappeared. These findings endorse the notion that uncontrolled effects of both, PD-related general slowing and anti-Parkinsonian medication may have contributed to previously conflicting results on priming effects in PD patients.

Rationale: Paired-associate learning (PAL), as part of the Cambridge Neuropsychological Test Automated Battery, is able to predict who from an at-risk population will develop Alzheimer's disease. Schizophrenic patients are also impaired on this same task. An automated rodent model of PAL would be extremely beneficial in further research into Alzheimer's disease and schizophrenia., Objective: The objective of this study was to develop a PAL task using touchscreen-equipped operant boxes and test its sensitivity to manipulations of the hippocampus, a brain region of interest in both Alzheimer's disease and schizophrenia., Materials and Methods: Previous work has shown that spatial and non-spatial memory can be tested in touchscreen-equipped operant boxes. Using this same apparatus, rats were trained on two variants of a PAL task differing only in the nature of the S- (the unrewarded stimuli, a combination of image and location upon the screen). Rats underwent cannulation of the dorsal hippocampus, and after recovery were tested under the influence of intra-hippocampally administered glutamatergic and cholinergic antagonists while performing the PAL task., Results: Impairments were seen after the administration of glutamatergic antagonists, but not cholinergic antagonists, in one of the two versions of PAL., Conclusions: De-activation of the hippocampus caused impairments in a PAL task. The selective nature of this effect (only one of the two tasks was impaired), suggests the effect is specific to cognition and cannot be attributed to gross impairments (changes in visual learning). The pattern of results suggests that rodent PAL may be suitable as a translational model of PAL in humans.

Caffeine's effects on recall of word lists were investigated using the Deese-Roediger-McDermott (DRM) paradigm. College students were administered either 200 mg of caffeine or a 250-mg lactose placebo; after 30 min., they were tested on recall using six word lists. Words of each list were semantically related to a single word (a "critical lure") that was not presented in the list. Participants administered caffeine recalled more list words and more critical lures than participants administered lactose. Recall of list words was negatively correlated with recall of critical lures. Caffeine appears to intensify the strength of connections among list words and critical lures, thereby enhancing both true and false memory.

Context: Cannabis sativa use can impair verbal learning, provoke acute psychosis, and increase the risk of schizophrenia. It is unclear where C. sativa acts in the human brain to modulate verbal learning and to induce psychotic symptoms., Objectives: To investigate the effects of 2 main psychoactive constituents of C. sativa, Delta9-tetrahydrocannabinol (Delta9-THC) and cannabidiol, on regional brain function during verbal paired associate learning., Design: Subjects were studied on 3 separate occasions using a block design functional magnetic resonance imaging paradigm while performing a verbal paired associate learning task. Each imaging session was preceded by the ingestion of Delta9-THC (10 mg), cannabidiol (600 mg), or placebo in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject design., Setting: University research center., Participants: Fifteen healthy, native English-speaking, right-handed men of white race/ethnicity who had used C. sativa 15 times or less and had minimal exposure to other illicit drugs in their lifetime., Main Outcome Measures: Regional brain activation (blood oxygen level-dependent response), performance in a verbal learning task, and objective and subjective ratings of psychotic symptoms, anxiety, intoxication, and sedation., Results: Delta9-Tetrahydrocannabinol increased psychotic symptoms and levels of anxiety, intoxication, and sedation, whereas no significant effect was noted on these parameters following administration of cannabidiol. Performance in the verbal learning task was not significantly modulated by either drug. Administration of Delta9-THC augmented activation in the parahippocampal gyrus during blocks 2 and 3 such that the normal linear decrement in activation across repeated encoding blocks was no longer evident. Delta9-Tetrahydrocannabinol also attenuated the normal time-dependent change in ventrostriatal activation during retrieval of word pairs, which was directly correlated with concurrently induced psychotic symptoms. In contrast, administration of cannabidiol had no such effect., Conclusion: The modulation of mediotemporal and ventrostriatal function by Delta9-THC may underlie the effects of C. sativa on verbal learning and psychotic symptoms, respectively.

Although the roles of both the hippocampus and the medial prefrontal cortex (mPFC) have been suggested in a spatial paired-associate memory task, both areas were investigated separately in prior studies. The current study investigated the relative contributions of the hippocampus and mPFC to spatial paired-associate learning within a single behavioral paradigm. In a novel behavioral task, a pair of different objects appeared repeatedly across trials, but in different arms in a radial maze, and different rules were associated with those arms for reward. Specifically, in an "object-in-place" arm, the rat was required to choose a particular object associated with the arm. In a "location-in-place" arm, the animal was required to choose a certain within-arm location (ignoring the object occupying the location). Compared to normal animals, rats with ibotenic acid-based lesions in the hippocampus showed an irrecoverable impairment in performance in both object-in-place and location-in-place arms. When the mPFC was inactivated by muscimol (GABA(A) receptor agonist) in the normal animals with intact hippocampi, they showed the same severe impairment as seen in the hippocampal lesioned rats only in object-in-place arms. The results confirm that the hippocampus is necessary for a biconditional paired-associate task when space is a critical component. The mPFC, however, is more selectively involved in the object-place paired-associate task than in the location-place paired-associate task. The current task powerfully demonstrates an experimental situation in which both the hippocampus and mPFC are required and may serve as a useful paradigm for investigating the neural mechanisms of object-place association.

Background: There is emerging evidence from behavioural studies in humans for nicotinic modulation of inhibitory control. Administration of nicotine, however, also increases general arousal, and this may be responsible for the cognitive enhancing effects of nicotine., Discussion: To test an arousal explanation of nicotine's effects on cognitive inhibition, this study compared the separate and combined effects of an acute dose of nicotine and an arousal manipulation on inhibitory processes associated with the retrieval-induced forgetting (RIF) paradigm., Results: In a double blind placebo controlled design, 1.0 mg of nicotine delivered via nasal spray to non-smoking healthy young adults significantly increased the retrieval-induced forgetting observed in episodic list learning, relative to the placebo condition. In contrast, negative arousal evoked by an unsolvable anagram task had no effect either separately or in combination with nicotine., Conclusion: This result argues against the attribution of nicotine-induced changes in RIF performance to non-specific arousal effects. It suggests, furthermore, that pharmacological manipulation of the RIF produces effects that are qualitatively distinct from mood-induced effects. We consider these changes to relate to the direct modulation of information processing by nicotine.

Background: Multiple studies have documented deficits in verbal declarative memory function in depression that improve with resolution of symptoms; imaging studies show deficits in anterior cingulate function in depression, a brain area that mediates memory. No studies to date have examined neural correlates of emotionally valenced declarative memory using affectively negative (sad) verbal material that is clinically relevant to understanding depression. Also no studies have examined the effects of treatment on neural correlates of verbal declarative memory. The purpose of this study was to examine the effects of treatment with antidepressants on verbal declarative memory in patients with depression., Methods: Subjects with (N=18) and without (N=9) mid-life major depression underwent positron emission tomography (PET) imaging during verbal declarative memory tasks with both neutral paragraph encoding compared to a control condition, and emotional (sad) word pair retrieval compared to a control condition. Imaging was repeated in 13 subjects with depression after treatment with antidepressants., Results: Patients with untreated depression had a failure of anterior cingulate activation relative to controls during retrieval of emotional word pairs. Antidepressant treatment resulted in increased anterior cingulate function compared to the untreated baseline for both neutral and emotional declarative memory., Limitations: Limitations include a small sample size and variety of antidepressants used., Conclusions: These results are consistent with alterations in anterior cingulate function that are reversible with treatment in patients with depression. These findings may have implications for understanding the mechanism of action of antidepressants in the treatment of depression.

Disturbed comprehension of complex noncanonical sentences in Parkinson's disease (PD) has been linked to dopamine depletion and delayed lexical retrieval. The aim of the present study was to replicate findings of delayed lexical activation in PD patients with noncanonical sentence processing difficulties, and investigate the influence of dopamine depletion on these changes to lexical access. In the first experiment, 20 patients with PD (tested whilst 'on' dopaminergic medication) and 23 controls participated in a list priming experiment. In this paradigm, stimuli are presented as a continuous list of words/nonwords, and semantic priming effects were measured across inter-stimulus intervals (ISIs) of 500 ms, 1000 ms and 1500 ms, with data analyzed using multivariate analyses of variance. The results revealed longer delays in lexical activation for PD patients with poor comprehension of noncanonical sentences, suggesting that the speed of lexical access may be compromised in PD, and that this feature may contribute to certain sentencecomprehension difficulties. In the second experiment, 7 patients with PD who participated in the first experiment, performed the same lexical decision task while 'off' their dopaminergic medication. Semantic priming effects were measured across ISIs of 500 ms and 1500 ms. Within group comparisons revealed a different pattern of semantic priming for the PD patients when 'on' compared to 'off' medication, providing further support for a dopaminergic influence on the speed of information processing and lexical activation.

Background: Semantic priming is a function related to prefrontal cortical (PFC) networks and is lateralized. There is evidence that semantic priming underlies dopaminergic modulation. It is known that the D1-receptor is more abundant in prefrontal networks; however, until now there have been no studies investigating the selective modulation of semantic priming with dopamine agonists. Furthermore, D1 receptor dysfunction has been described in schizophrenia, and patients with formal thought disorder seem to have disturbed focusing of associations and increased indirect priming., Methods: With a subtraction design, we compared the influence of pergolide (D1/D2 agonist) with bromocriptine (D2 agonist) and placebo, in a randomized, double-blind, crossover design in 40 healthy male volunteers. Subjects performed a lateralized lexical decision task including direct and indirect related prime-target pairs (stimulus onset asynchrony = 750 msec)., Results: Only on pergolide a decrease of the indirect priming in the left hemisphere presentations was found., Conclusions: These findings point to a potential selective modulation of agonists with a D1 component on the focusing of semantic associations. The clinical relevance of this study is that it might help the development of therapeutic strategies for treating cognitive deficits in schizophrenia and Parkinson's disease, which are highly relevant to the functional outcome.

Research has suggested that semantic processing deficits in Parkinson's disease (PD) are related to striatal dopamine deficiency. As an investigation of the influence of dopamine on semantic activation in PD, 7 participants with PD performed a lexical-decision task when on and off levodopa medication. Seven healthy controls matched to the participants with PD in terms of sex, age, and education also participated in the study. By use of a multipriming paradigm, whereby 2 prime words were presented prior to the target word, semantic priming effects were measured across stimulus onset asynchronies (SOAs) of 250 ms and 1,200 ms. The results revealed a similar pattern of priming across SOAs for the control group and the PD participants on medication. In contrast, within-group comparisons revealed that automatic semantic activation was compromised in PD participants when off medication. The implications of these results for the neuromodulatory influence of dopamine on semantic processing in PD are discussed., (Copyright (c) 2006 APA, all rights reserved.)

Background: Ketamine is used acutely as a model of schizophrenia. It has been suggested that chronic ketamine may also mimic aspects of this disorder, in particular impaired cognitive function. As semantic processing deficits are considered central to cognitive impairments in schizophrenia, this study aimed to characterize semantic impairments following both acute and chronic ketamine., Methods: We examined the acute effects of two doses of ketamine (Experiment 1) using a double-blind, placebo-controlled, independent group design with 48 volunteers. Ketamine's chronic effects (Experiment 2) were explored in 16 ketamine users and 16 poly-drug controls. A semantic priming task with a frequency (high and low) and stimulus onset asynchrony (SOA: short-200 msec, long-750 msec) manipulation was used., Results: In Experiment 1, acute ketamine produced inverse priming at the long SOA. In Experiment 2, ketamine users showed inverse priming for low-frequency words at the long SOA compared to poly-drug controls., Conclusions: The inverse priming effect at the long SOA induced by acute ketamine was indicative of controlled processing impairments. In ketamine users, there was also an indication of controlled processing impairments. Decreased priming for low-frequency words suggested that long-term ketamine abuse results in damage to the semantic store.

Rationale: Attentional bias for drug-related cues has been reported with a wide range of drugs, but to date the extent to which caffeine consumers show similar biases for caffeine-related stimuli has not been tested. The present study therefore examined this issue in terms of differences in attentional bias for caffeine-related words in High, Moderate and Non-caffeine consumers using a dot-probe word task following overnight caffeine abstinence., Objectives: This study was conducted to test whether caffeine consumers show an attentional bias for caffeine-related words, and whether such biases relate to habitual levels of caffeine use., Methods: Sixteen High, Moderate and Non-consumers of caffeine were asked to complete a modified dot-probe task in order to measure attentional bias for caffeine-related relative to neutral control word groups. The task was completed following overnight caffeine abstinence, and participants also completed mood and caffeine-craving measures., Results: The High consumer group showed a significant attentional bias for the caffeine-related words, but no such bias was seen in Moderate or Non-consumer groups. As expected, craving for caffeine was strongest in the High consumers and weakest in the Non-consumers. Attentional bias in the High group correlated with self-reported caffeine consumption and with craving for caffeine, but neither effect was significant in the Moderate group., Conclusions: These data confirm that High caffeine consumers show attentional bias for caffeine-related stimuli, consistent with current theories of drug addiction.

Rationale/objectives: Research has revealed associative learning deficits among users of ecstasy; the present study explored the component processes underlying these deficits., Methods: Thirty-five ecstasy users and 62 non-ecstasy users completed a computer-based, verbal paired-associates learning task. Participants attempted to learn eight sequentially presented word pairs. After all eight had been presented, the first member of each pair was displayed and participants attempted to recall the second. Eight trials were administered. Correct responses on each trial, forgetting at various levels of learning, perseveration errors and the rate at which the associations were learned (trials to completion) were all recorded., Results: MANOVA revealed that ecstasy users performed worse overall and subsequent ANOVAs showed that users performed significantly worse on virtually all measures. Regression analysis revealed that over half of the ecstasy-group related variance in trials to completion was attributable to group differences in initial learning and forgetting. In relation to forgetting, it appears that cannabis use may be an important determinant. In relation to rate of learning (trials to completion) and initial learning, both ecstasy and cannabis may be implicated., Conclusions: There appears to be abundant evidence of associative learning deficits among ecstasy users. However, it appears that a range of illicit drugs including cannabis and ecstasy may contribute to these deficits.

Background: Previous research has been inconclusive regarding the impact of glucose ingestion and gluco-regulatory control on cognitive performance in healthy older adults. The aim of this research was to determine whether glucose specifically enhanced episodic memory in an older population. In addition, the link between individual differences in glucose regulation and the magnitude of the enhancement effect was examined., Design and Subjects: A within subjects, counterbalanced, crossover design was used with 20 participants (60-80 year olds), each serving as his/her control., Methods: Episodic memory was tested by presenting unrelated paired associates followed by immediate and delayed cued recall, and delayed recognition, under single and dual task conditions. In addition, a battery of cognitive tests was administered, including tests of semantic memory, working memory and speed of processing., Results: Glucose ingestion was found to largely facilitate performance of episodic memory. Furthermore, subsidiary analyses found that gluco-regulatory efficiency predicted episodic memory performance in both control and glucose conditions., Conclusions: A boost in performance after glucose ingestion was particularly seen in the episodic memory domain. Notably, strong evidence was provided for the utility of gluco-regulatory control measures as indicators of cognitive decline in the elderly.

The present study evaluates the effects of one year of discontinuation and one year of growth hormone (GH) treatment on quality of life (QoL) in young adults with childhood-onset growth hormone deficiency (CO-GHD). Twenty-two subjects (14 males, 8 females; 11 isolated growth hormone deficient [IGHD], 11 multiple pituitary hormone deficient [MPHD]), aged between 15 and 22 years, on ongoing GH treatment were assessed during one year of discontinuation. Thereafter, 9 of these patients, who were found to be still GH deficient (GHD), added by 11 newly recruited GHD patients who also were not treated in the preceding year (in total 10 males and 10 females, aged between 17 and 27, 5 IGHD, 15 MPHD), restarted GH treatment for one year. During discontinuation and restart of GH treatment somatic and psychological assessments took place every 6 months. In the first 6 months of the GH discontinuation period insulin-like growth factor I (IGF-I) level significantly declined whereas no further decrease in IGF-I was seen after month 6. The number of psychological complaints and depression increased only during the first 6 months of discontinuation. Across the 12-month of discontinuation tension increased in MPHD and decreased in IGHD patients. Only in the first 6 months of GH treatment IGF-I level increased, anxiety decreased and QoL improved. Depression scores tended to decrease across the 12 month treatment period. During the 2-year discontinuation and treatment period intra-subject IGF-I level was negatively correlated with depression, fatigue, tension and anxiety and positively with vigor and memory. At the end of the treatment period all psychometric parameters were similar or even improved compared to those at the start of the discontinuation period. It is concluded that one year discontinuation of GH treatment leads to a decrease in QoL within 6 months which effect is counteracted within 6 months after restart of GH treatment.

Prominent theories of implicit memory (D. Schacter, B. Church, & J. Treadwell, 1994) emphasize the dominant role of perceptual processing in mediating priming on perceptual implicit memory tests. Examinations of the effects of conceptual processing on perceptual implicit memory tests have produced ambiguous results. Although a number of investigations (e.g., J. Toth & R. Hunt, 1990) have demonstrated that variations in conceptual processing affect priming on perceptual implicit memory tests, these effects may arise because of the contaminating effects of explicit memory. The current experiment examined this controversy using midazolam, a benzodiazepine that produces a dense, albeit temporary, anterograde amnesia when injected prior to study. The experiment examined whether the effects of generation found on the implicit memory test of perceptual identification were affected by a midazolam injection prior to study. Results demonstrated that midazolam substantially diminished generation effects in free and cued recall, as well as overall performance on these tests, but had no detectable effect on the generation effect in perceptual identification.

Rationale: Tyrosine depletion has been shown to reduce dopamine over activity in animal and human investigations. However, the effects on basal dopamine function have not been explored. Such information could establish tyrosine depletion as an effective probe of dopamine function in healthy volunteers and would also have relevance for future therapeutic applications of this manipulation., Objective: The present study investigated the effect of acute tyrosine depletion on dopamine function in healthy volunteers using a combination of neuroendocrine, neuropsychological and subjective measures., Methods: On one occasion, volunteers received an amino acid drink selectively lacking tyrosine and phenylalanine (TYR-free), whilst on the other they received a balanced (BAL) amino acid drink. Plasma prolactin, amino acid levels and subjective state were monitored over 6 h following the two drinks, and volunteers also completed a battery of tests from the CANTAB, including measures of spatial memory previously found to be sensitive to changes in dopamine function., Results: Plasma prolactin levels rose following the TYR-free drink relative to the balanced mixture, indicative of decreased dopamine neurotransmission within the hypothalamus. Following the TYR-free drink, volunteers were impaired at spatial recognition memory and spatial working memory. Volunteers also tended to report that they felt less good following the TYR-free than the BAL mixture., Conclusion: Tyrosine depletion in healthy volunteers affected baseline dopamine function on the different measures employed in this study. Tyrosine depletion would thereby seem valuable as a probe of dopamine function in human volunteers. Ratings of depression and other aspects of cognitive function were unaffected, suggesting that this manipulation may be free of significant side effects when used as a treatment for conditions characterised by dopamine over activity, such as acute mania and schizophrenia.

Background: While some cognitive accounts of disorganized speech, or thought disorder, in schizophrenia have emphasized failures in working memory/discourse planning or selective attention, we have suggested that thought disorder resides in the semantic system. In this study we assessed the effect of neuroleptic medication on thought disorder and semantic processing., Methods: Seventeen patients with schizophrenia were assessed while receiving neuroleptic medications and in crossover fashion, placebo. A number of measures were obtained: clinically rated thought disorder (using the Thought, Language and Communication Scale); working memory letter number span); lexical integrity (naming and receptive vocabulary); and, semantic priming of intracategorical word pairs., Results: Semantic priming measures improved with neuroleptic medication, as did clinically rated thought disorder. No other measure changed significantly. Priming selectively covaried with changes in thought disorder., Conclusion: Changes in spreading semantic activation, measured in a semantic priming paradigm and presumably brought about by neuroleptics' influence on dopaminergic neuromodulatory systems, might reflect changes in the biases of pre-existing associative networks that favour or increase the accessibility of representations related by shared features. This study also has implications for the architecture of normal language in that a dissociation between the lexical and semantic levels was observed, due to the selective compromise of tasks demanding semantic processing.

The effects of smoking a cigarette or wearing a transdermal nicotine patch on mood and lexical decision-making were tested in eight smokers. Each participant was tested after 4 hours of smoking abstinence, under 4 conditions: placebo (very low nicotine) cigarette, nicotine cigarette, placebo patch, and nicotine patch. Relative to placebo, wearing the nicotine patch reduced Profile of Mood States (POMS) Total Mood Disturbance and Fatigue/Inertia scores, while increasing the speed of some types of lexical decisions. Smoking a nicotine cigarette did not affect reaction times, but unexpectedly decreased the accuracy of Word/ Nonword lexical decisions. Thus, transdermal nicotine may improve mood and facilitate longterm memory search and/or attentional processes in nicotine-deprived smokers.

Prior to anesthesia with propofol for gastrointestinal endoscopy, sets of pictures were presented to 20 children and adolescents (M age = 12 years). Word pairs (e.g., "hiking-woods") were presented via earphones after the children were anesthetized. Upon regaining consciousness, the children were tested for explicit memory of both the picture sets and word pairs by free recall, cued recall, and yes/no recognition. Implicit memory was tested by free association to category cues for the pictures and by word association for the word pairs. Postoperative testing revealed retrograde memory for material presented preoperatively but total amnesia for material presented intraoperatively. There was no evidence of implicit memory for material not available explicitly. The finding of uninterrupted ability to retain and retrieve information presented prior to anesthesia despite total anterograde amnesia has implications for preoperative communication directed toward pediatric patients as well as for intraoperative communication among surgical staff.

We have reported that physostigmine, a reversible cholinesterase inhibitor, enhances verbal memory in patients with Alzheimer disease (AD). To elucidate the mechanism of cognition enhancement, plasma hormones were measured during high-dose acute and low-dose chronic steady-state intravenous infusions of physostigmine in nine subjects with AD. High-dose hormone responses were measured during and for 24 h after the infusion of physostigmine 1-1.5 mg over 45-60 min. Chronic responses were measured during continuous intravenous infusions of physostigmine at doses (0.5-25 mg/day) that escalated over 2 weeks, and then during 1 week infusion of the dose that optimized cognition (2-12 mg/day) or placebo administered in a randomized, double-blind, cross-over design. A replicable improvement in verbal memory was found in five subjects. High-dose physostigmine infusion that produced noxious side effects resulted in significant elevation above baseline in plasma levels of adrenocorticotrophic hormone (ACTH) (p = 0.0001), cortisol (p = 0.0001), and beta-endorphin (p = 0.0001). Chronic physostigmine administration, in the absence of adverse effects, produced no significant elevation in ACTH (p = 0.08), cortisol (p = 0.70), or beta-endorphin (p = 0.82). These results indicate that high-dose physostigmine activates the hypothalamic-pituitary-adrenal (HPA) axis, likely representing a "stress response." In contrast, cognition-enhancing doses do not produce a peripheral corticosteroid response. Thus, physostigmine-induced memory improvement is independent of the activation of the HPA axis.

We ascertained nonsteroidal anti-inflammatory drug (NSAID) use in 2,651 participants in the UK MRC treatment trial of hypertension in older adults and measured change in cognitive function over the subsequent 54 months. There was a significant, although modest, association between change in the Paired Associate Learning Test score over time and NSAID use, which was modified by age. NSAID users showed less decline, with younger subjects seeming to benefit more than older. We found no relationship between NSAID use and time taken to complete the Trail Making Test and also no relationship between anti-indigestion drug use and either cognitive outcome. These analyses highlight the need for larger studies with prospective classification of NSAID use and adequate control of confounding, including exposure to other medications. A randomized controlled trial of NSAIDs, in those known to be at risk of cognitive decline or dementia, may be indicated in the future.

Journeymen painters were evaluated with a comprehensive battery of neuropsychological tests and compared to demographically similar nonexposed controls. For painters, a cumulative exposure to solvents was estimated from a structured interview that derived an index based on lifetime exposure and exposure in the past year. Painters were tested either shortly after having painted or after an exposure-free interval. Significant between-group differences were found on a cluster of tests measuring learning and memory. Within the painter group, scores on the learning and memory tests were significantly related to the interaction of condition and exposure. That is, those painters who were tested soon after painting and who also had a higher overall lifetime exposure, performed worst on tests of learning and memory. These results are consistent with the view that neuropsychological function--particularly learning and memory--may be compromised in active workers with a history of chronic solvent exposure. Furthermore, both the chronicity of solvent exposure, as well as the acuteness of the exposure, are significant factors in cognitive performance.

Semantic priming in word pronunciation was examined at 5 stimulus onset asynchronies (SOAs) in 75 medicated and 25 unmedicated people with schizophrenia (SCZ) and in 10 depressed and 28 normal controls. At SOAs < 950 ms, SCZ displayed priming similar to that of normal and depressed controls. At the 950-ms SOA, SCZ displayed less priming than controls. Medication dosage, but not conceptual disorganization scores, was positively associated with priming at SOAs < 950 ms. These results suggest that prior reports of enhanced priming in schizophrenia may have been confounded by methodological problems and that automatic priming processes operate normally in SCZ. The failure of SCZ to display significant priming at the 950-ms SOA is consistent with a hypothesized disturbance in higher level processes.

In order to examine the effect of dopamine on semantic processing, we performed a double-blind, placebo-controlled study. Healthy volunteers (n = 31) were tested in a lexical decision paradigm after ingestion of either L-dopa 100 mg with benserazide 25 mg or placebo. While direct semantic priming was influenced only marginally by L-dopa, the indirect priming effects was reduced significantly. These data support the hypothesis that dopamine increases the signal-to-noise ratio in semantic networks by reducing the spread of semantic processing, thereby leading to a focussing of activation.

Sustained attentional deficits have been widely reported in groups of medicated schizophrenic patients, but less is known about sequential attentional processes in patients withdrawn from medication. The attentional performance of 12 medication-withdrawn schizophrenic outpatients was compared with that of 16 matched normal volunteers on a Stroop negative priming task. This task allowed examination of both within-trial and between-trial attentional effects. Compared with the volunteers, the medication-withdrawn schizophrenic patients showed normal within-trial attentional effects as measured by standard Stroop interference and facilitation. Across trials, however, the schizophrenics exhibited reduced negative priming compared with the volunteers and in some cases a complete reversal of sustained inhibitory processes. The findings suggest that a normal inhibitory tag occurred during initial selection in the patient group, but it did not influence a subsequent act of selection as was the case for the normal volunteers. Either inhibition decayed at an abnormally fast rate in the patient group or a separate facilatory tag dominated. In either case, priming effects linked to attentional selection were clearly abnormal in the medication-withdrawn patient group.

The Paired Associate Recognition Test (PART) was developed to measure declarative memory using Wisconsin Card Sorting Test (WCST) stimuli, so that both tasks could be administered during functional neuroimaging to differentiate memory and executive function, and associated frontal and temporal lobe activation in schizophrenia. The current study was designed to compare PART and WCST performance in schizophrenic patients and to examine effects of medication and symptomatology. The PART, WCST, and standard declarative memory tasks were administered to 30 chronic schizophrenic patients and 30 matched healthy control subjects. Supporting task validity was the finding that patients were equally impaired on the PART and the WCST. Neuroleptics did not appear to affect performance. The effect of anticholinergic medication correlated negatively with WCST performance in a small subsample. Severity of schizophrenia-specific symptoms measured at intake on the Brief Psychiatric Rating Scale correlated negatively with performance on the WCST. These results support the application of the PART and WCST in future functional neuroimaging studies.

Visuospatial information processing has been shown to be particularly sensitive to acute alcohol intoxication and chronic alcohol abuse. This study extended previous studies by determining if recently detoxified alcoholics recover visuospatial processing after long-term abstinence. If visuospatial function returns to the level displayed by intoxicated alcoholics, then the deficit displayed by recently detoxified alcoholics may represent a short-term adjustment due to the removal of alcohol. However, if the visuospatial deficit remains in long-term abstinent alcoholics, then the superior processing of the intoxicated alcoholic could reflect a normalization of processing produced by alcohol ingestion. Twenty active and 40 recovering alcoholic male volunteers participated. The active alcoholics were seen intoxicated at the time of admission into a 21-day alcohol detoxification and treatment program. Of the recovering alcoholics, 20 were designated as recently detoxified alcoholics and had just completed the same treatment program. The remaining 20 long-term abstinent alcoholics had completed alcohol treatment several years previously with no relapse. Participants selected were similar in general demographic status, alcohol treatment histories, and psychomotor ability. Two main effects emerged from the results: First, the intoxicated alcoholics displayed visuospatial learning that was superior to the learning of alcoholics recently detoxified or abstinent for several years; a second principal finding was nearly identical visuospatial learning displayed by recently detoxified and long-term abstinent alcoholics.

Objective: This study was developed to offer direct support for the Josephs and Steele attention-allocation model. The model suggests that alcohol consumption limits attentional resources to the most salient environmental cue., Method: Forty men participated in a study designed to test the model using measures of memory and attention during ethanol intoxication. Twenty completed memory tests in the presence of a background distractor and 20 completed the tests without a distractor, in two sessions: once while intoxicated (80 mg/dl BAC) and once while sober., Results: A significant Distraction x Intoxication interaction indicated that ethanol-related differences in recall occurred only in the absence of distraction. Distraction impaired subjects only when they were sober., Conclusions: Results support the Josephs and Steele attention-allocation model. Findings are discussed in broad terms of an individual's cognitive capabilities when intoxicated and in terms of risk for later alcoholism.

In this five-period randomised double-blind crossover study, 12 healthy volunteers inhaled mixtures of nitrous oxide at concentrations of 0% (placebo); 5%, 10%; 20% and 40% in oxygen. Each concentration was inhaled for about 1 h, each period being on a separate day. The effects of nitrous oxide were measured using a comprehensive battery of performance tests including measures of attention, psychomotor function, memory and cognition. Mood was assessed with visual analogue scales. All tests except critical flicker fusion showed substantial effects at the highest does (40%). No measure showed evidence of change at the lowest concentration (5%). Several measures showed significant impairment at 10%, viz: digit-symbol substitution, choice reaction time (latency and total), tapping, and continuous attention. Subjects felt dizzy and muzzy on nitrous oxide, but no significant effect was seen on the Alert-Drowsy VAS. The dose-response profiles of the various tests showed substantial differences. Thus tapping was virtually linear, while choice reaction motor time and body sway showed steeply accelerating impairment with increasing dose. These results indicate that comparisons of profiles of drug-induced change must take into account the variable effects of dose before interpretations in terms of specific drug effects can be made.

A clinic-referred population of 116 children with attentional problems was classified by DSM-III [attention deficit disorder (ADD)] with respect to inattention, impulsivity, and hyperactivity. The sample proved to subdivide into three groups: inattentive, impulsive, and hyperactive (HII), n = 60; inattentive and impulsive (II), n = 26; and inattentive (I), n = 30. The distinction between II and I resolves the confounding of impulsivity and inattention in previous studies of children who have ADD but are not hyperactive. The three groups were found to be similar in mean age, gender ratio, prevalence, and pattern of associated learning disabilities, family history of psychopathology, and probability of favorable response to methylphenidate. Group I differed from Groups HII and II in the frequency of externalizing relative to internalizing comorbid psychopathology. A group that is hyperactive and impulsive but not inattentive was not found. The preponderance of similarities in associated characteristics suggests that the three groups are differing clinical presentations of an ADD spectrum.

The present investigation examined the effects of methylphenidate on impulsivity in children with attention-deficit hyperactivity disorder (ADHD). A task was designed to measure empirically the ADHD child's proclivity to blurt out incorrect answers before giving a final and/or correct response. Twenty-six ADHD children referred for double-blind placebo-controlled assessment of medication responsiveness and 14 non-ADHD controls were given a visual search word-matching task to assess impulsive responding. An analysis of covariance showed that ADHD children on methylphenidate made fewer impulsive errors than ADHD children on placebo. The control group made fewer impulsive errors than the ADHD children in the placebo condition, but the performance of the ADHD children on medication approximated the performance of the children without ADHD. These preliminary findings suggest that the word-matching task may be a useful tool for assessing impulsive responding and determining the benefits of stimulant medication on impulsivity.