Interactions between 192-IgG saporin and intraseptal cholinergic and GABAergic drugs: Role of cholinergic medial septal neurons in spatial working memory.

Rats were administered 192-IgG saporin (SAP) or vehicle into the medial septum-vertical limb of the diagonal band (MS-vDB). Starting 1 week later, the effects of intraseptal scopolamine, oxotremorine, and muscimol were tested in a T-maze alternation task. Choice accuracy in the absence of infusions did not differ between control and SAP-treated rats. Intraseptal scopolamine or muscimol impaired the choice accuracy of SAP-treated but not control rats. Oxotremorine impaired accuracy similarly in control and SAP-treated rats. The enhanced effects of scopolamine and muscimol produced by SAP are consistent with the hypothesis that cholinergic MS-vDB neurons are used in spatial working memory. The finding that SAP alone did not alter choice accuracy provides further evidence that cholinergic MS-vDB neurons are not necessary for spatial working memory. Thus, cholinergic MS-vDB neurons are involved in but not necessary for spatial working memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Longitudinal deficits to attention, executive, and working memory in subtypes of mild cognitive impairment.

Objective: Mild cognitive impairment (MCI) has emerged as a classification for a prodromal phase of cognitive decline that may precede the emergence of Alzheimer's disease (AD). Recent research suggests that attention, executive, and working memory deficits may appear much earlier in the progression of AD than traditionally conceptualized, and may be more consistently associated with the later development of AD than memory processing deficits. The present study longitudinally tracked attention, executive and working memory functions in subtypes of MCI. Method: In a longitudinal study, 52 amnestic MCI (a-MCI), 29 nonamnestic MCI (na-MCI), and 25 age- and education-matched controls undertook neuropsychological assessment of visual and verbal memory, attentional processing, executive functioning, working memory capacity, and semantic language at 10 month intervals. Results: Analysis by repeated measures ANOVA indicate that the a-MCI and na-MCI groups displayed a decline in simple sustained attention (ηp2 = .054) with a significant decline on a task of divided attention (ηp2 = .053) being evident in the a-MCI group. Stable deficits were found on other measures of attention, working memory and executive function in the a-MCI and na-MCI groups. The a-MCI group displayed stable impairments to visual and verbal memory. Conclusions: The results indicate that a-MCI and na-MCI display a stable pattern of deficits to attention, working memory, and executive function. The decline in simple sustained attention in a-MCI and n-MCI groups and to divided attention in a-MCI may be early indicators of possible transition to dementia from MCI. However, further research is required to determine this. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Attention, learning, and memory performances and intellectual resources in Vietnam veterans: PTSD and no disorder comparisons.

Attention, learning, memory, and estimated intellectual potential were examined in 26 Vietnam veterans diagnosed with posttraumatic stress disorder (PTSD) and in 21 Vietnam veterans without mental disorders. Results revealed PTSD-associated cognitive deficits on tasks of sustained attention, working memory, initial learning, and estimated premorbid intelligence but not on measures of focus of attention, shift of attention, or memory savings. Cognitive task performances adjusted for estimated native intelligence remained negatively correlated with PTSD severity. An intellectual measure adjusted for cognitive task performances was negatively correlated with PTSD severity, even after the authors statistically controlled the level of combat exposure. Results suggested that although intellectual resources may constitute a vulnerability-protective factor for PTSD development, PTSD was associated with cognitive impairment independent of intellectual functioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pyruvate infusions into the septal area attenuate spontaneous alternation impairments induced by intraseptal morphine injections.

Glucose infusions into the medial septal area attenuate memory impairments produced by concurrent intraseptal morphine injections. One possible explanation for these effects of glucose on memory is that the treatment modulates regional energy metabolism. As a test of this hypothesis, the present experiment determined whether intraseptal pyruvate injections could attenuate a spontaneous alternation impairment seen after intraseptal morphine injections. Intraseptal injections of morphine (4.0 nmol) 30 min prior to testing produced spontaneous alternation scores significantly lower than those in control groups. Morphine injections near, but outside, the septal region did not impair spontaneous alternation performance. The morphine induced impairment was similarly reversed by coadministration of either glucose (18 nmol) or pyruvate (18 nmol) into the septum. These findings suggest that glucose may act through the tricarboxylic acid cycle by increasing the availability of ATP, augmenting the synthesis of certain neurotransmitters, or both. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spatial and object working memory deficits in Parkinson's disease are due to impairment in different underlying processes.

Working memory maintenance processes for visual-spatial and visual-object information were evaluated in patients with Parkinson's disease (PD). PD patients and controls performed a working memory task with two conditions that differed only in the aspect of the stimuli that the participant was instructed to remember: their locations or shapes. Maintenance processes were investigated by measuring accuracy over 1-s, 5-s, and 10-s delays. Results indicated that patients were impaired in maintaining object information over the delay. In contrast, the patients showed impairment on the spatial condition only when the to-be-remembered stimulus was highly similar in location to the probe, but this impairment was equivalent across the delays, suggesting that this deficit was not due to maintenance impairment. These results suggest that deficits in working memory for spatial and object information are mediated by distinct cognitive processes in nondemented patients with PD and may differ in their pathophysiological basis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of opioid microinjections into the medial septal area on spatial memory in rats.

Recent work has demonstrated that posttraining systemic opioid antagonist administration facilitates the acquisition of a radial arm maze task in new spatial environments. In this study, we examined the effect of posttraining naloxone and β-endorphin microinjections into the medial septal area on the acquisition of a radial maze task in new spatial environments. The results of these experiments demonstrated that posttraining intraseptal naloxone administration facilitated, whereas posttraining intraseptal β-endorphin administration impaired, the acquisition of criterion performance on a maze task performed in new spatial environments. Further, intraventricular β-endorphin administration did not produce effects that were comparable to those observed following intraseptal β-endorphin administration, which indicates that the septal region is a brain site that is sensitive to the effects of opioids on spatial memory in new environments. Further, posttraining intraseptal β-endorphin administration had no effect on working memory in a familiar spatial environment, whereas pretraining intraseptal β-endorphin administration had no effect on the performance of a previously acquired spatial task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ethanol and spatial localization.

Water (Exp 1) and radial maze (Exp 2) tasks permitted an evaluation of the relative degree of impairment imposed by ethanol (0, 0.75, 1.5, and 2.0 g/kg) on cognitive mapping vs. cued place learning. The tasks did not require working memory. A strong tendency emerged for ethanol-treated rats to persist in cognitive mapping strategies after the strategies were no longer useful, but there was no indication of a mapping impairment per se. When performance deficits appeared, they were equivalent across mapping and cued place tasks and may have reflected motivational effects of ethanol. In most instances neither mapping nor cued place tasks were difficult for ethanol-treated animals unless the tasks required abandoning one strategy for another. The tenacity of ethanol-treated rats to use cognitive mapping strategies, particularly rats receiving the highest dose, proved consistent and theoretically decisive. The behavioral invariance of ethanol-treated rats is not caused by a cognitive mapping deficit. Rather, mapping is another domain in which ethanol reduces flexibility. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Further evidence for a deficit in switching attention in schizophrenia.

In this study, sustained, selective, divided, and switching attention, and reloading of working memory were investigated in schizophrenia by using a newly developed Visual Attention Battery (VAB). Twenty-four outpatients with schizophrenia and 24 control participants were studied using the VAB. Performance on VAB components was correlated with performance of standard tests. Patients with schizophrenia were significantly impaired on VAB tasks that required switching of attention and reloading of working memory but had normal performance on tasks involving sustained attention or attention to multiple stimulus features. Switching attention and reloading of working memory were highly correlated with Trails (B–A) score for patients. The decline in performance on the switching-attention task in patients with schizophrenia met criteria for a differential deficit in switching attention. Future research should examine the neurophysiological basis of the switching deficit and its sensitivity and specificity to schizophrenia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dose effects of triazolam and alcohol on cognitive performance in healthy volunteers.

Benzodiazepines and alcohol are widely used psychoactive substances that have performance-impairing effects. Research suggests that the impairment profiles for benzodiazepines and alcohol differ, although few cognitive psychopharmacological studies have directly compared these drugs. This double-blind, double-dummy, placebo-controlled, repeated measures study directly compared the acute dose effects of triazolam (0.125, 0.25 mg/70 kg) and alcohol (0.40, 0.80 g/kg) in 20 social drinkers. At doses that produced comparable psychomotor impairment, triazolam was more likely to impair several objective measures of cognitive performance (e.g., episodic memory, divided attention) and to slow performance across several measures. However, only alcohol impaired accuracy on the digit symbol substitution and semantic memory tasks. In addition to objective measures, both drugs impaired awareness of performance impairments (i.e., metacognition) such that participants overestimated impairment, and the magnitude of this effect was generally larger for alcohol. Only triazolam impaired other measures of metacognition (e.g., error detection on a choice reaction time task). Future research might examine the clinical implications of the performance impairments reported here given the widespread use of benzodiazepines and alcohol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Different cognitive profiles for single compared with recurrent fallers without dementia.

Relationships between self-reported retrospective falls and cognitive measures (executive function, reaction time [RT], processing speed, working memory, visual attention) were examined in a population based sample of older adults (n = 658). Two of the choice RT tests involved inhibiting responses to either targets of a specific color or location with hand and foot responses. Potentially confounding demographic variables, medical conditions, and postural sway were controlled for in logistic regression models, excluding participants with possible cognitive impairment. A factor analysis of cognitive measures extracted factors measuring RT, accuracy and inhibition, and visual search. Single fallers did not differ from nonfallers in terms of health, sway or cognitive function, except that they performed worse on accuracy and inhibition. In contrast, recurrent fallers performed worse than nonfallers on all measures. Results suggest that occasional falls in late life may be associated with subtle age-related changes in the prefrontal cortex leading to failures of executive control, whereas recurrent falling may result from more advanced brain ageing that is associated with generalized cognitive decline. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Attention and verbal learning in patients with chronic fatigue syndrome

Former neuropsychological studies with Chronic Fatigue Syndrome (CFS) patients evaluated a broad range of cognitive functions. Several, but not all, reported subtle attentional and memory impairments suggesting possible mild cerebral involvement. In this study, a battery of attentional tests and a verbal memory task were administered to 20 CFS patients and 22 healthy controls (HC) in order to clarify the specific nature of attention and memory impairment in these patients. The results provide evidence for attentional dysfunction in patients with CFS as compared to HC. CFS patients performed more poorly on a span test measuring attentional capacity and working memory. Speeded attentional tasks with a more complex element of memory scanning and divided attention seem to be a sensitive measure of reduced attentional capacity in these patients. Focused attention, defined as the ability to attend to a single stimulus while ignoring irrelevant stimuli, appears not to be impaired. CFS patients were poorer on recall of verbal information across learning trials, and poor performance on delayed recall may be due to poor initial learning and not only to a retrieval failure.     

Executive Functioning, Memory, and Learning in Phenylketonuria.

The executive deficit hypothesis of treated phenylketonuria (PKU) suggests that dopaminergic depletion in the lateral prefrontal cortex leads to selective executive impairment. This was examined by comparing adults with PKU on a lifelong diet with a matched healthy control group. Those with PKU were impaired on selective and sustained attention, working memory (Self-Ordered Pointing), and letter fluency. However, they failed to show differential sensitivity to increased cognitive load on the attentional and working memory tasks, and they did not differ significantly on the remaining executive tasks (rule finding, inhibition, and multitasking). Nor did they differ significantly on recall or recognition memory. Overall, the findings provided little support for the executive deficit hypothesis. A possible explanation in terms of slowed information processing speed is explored. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cholinergic and GABAergic modulation of medial septal area: Effect on working memory.

The role of the septohippocampal pathway in working memory was investigated by direct microinfusion of compounds into the medial septal area (MSA). Behavior was measured by performance in a continuous spatial alteration task in a T maze, and hippocampal theta rhythm was also recorded. Intraseptal saline had no effect on choice accuracy or hippocampal theta rhythm. Tetracaine decreased choice accuracy and theta rhythm 10 min, but not 9 min, after infusion. Likewise, muscimol and scopolamine produced a transient, dose-dependent suppression of hippocampal theta rhythm and a simultaneous dose-dependent impairment in choice accuracy. A significant correlation (r?=?.78) emerged between a compound's influence on theta rhythm and its effect on choice accuracy. The data support a role for the septohippocampal projection in working memory and suggest that γ-aminobutyric acid and acetylcholine may have opposing influences on neurons in the MSA. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Central cholinergic involvement in working memory: Effects of scopolamine on continuous nonmatching and discrimination performance in the rat.

In 4 experiments, male Sprague-Dawley rats (N?=?37) were trained to stable baselines of leverpressing on a variable intertrial interval continuous nonmatching-to-sample schedule (CNM) or on an analogous discrimination schedule. Scopolamine HBr (0.125, 0.25, and 0.50 mg/kg) reduced the accuracy of CNM performance to a similar extent over the 3 intertrial (retention) intervals: 2.5, 5, and 10 sec, indicating that the drug did not affect the time-dependent process of retention in working memory. When baseline levels of performance accuracy were similar in the CNM and discrimination tasks (but stimulus discriminability was greater in the CNM task), scopolamine reduced accuracy equally in the 2 procedures. The effects of scopolamine on the accuracy of noncorrection trial CNM performance were simulated by reducing stimulus discriminability; however, scopolamine disrupted CNM correction trial performance much more than did reductions in stimulus discriminability. It is concluded that scopolamine's effects on working memory are not limited to the possible effects on stimulus discrimination—scopolamine may also affect the retrieval of response rules from reference memory. (52 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lymphomas of the urinary tract

Lesioning the ventral hippocampus of neonatal rats has been proposed as an experimental model of schizophrenia. This lesion causes a syndrome of hyperresponsivity to the stimulant effects of amphetamine, impaired grooming and disrupted social interactions, effects that emerge during adolescence, much like schizophrenia. Persisting cognitive effects of neonatal ventral hippocampal lesions were assessed in the current study, because the hippocampus is critically important for a variety of cognitive functions and cognitive impairment and because it is an important feature of schizophrenia. Spatial learning and working memory were assessed in the radial-arm maze, which is sensitive to the adverse effects of hippocampal lesions made in adults. Lesioned rats showed pronounced deficits in radial-arm maze choice accuracy that persisted throughout training. Deficits were seen during the prepubertal period as well as in adulthood. Even though the lesioned rats performed more poorly, they were significantly less sensitive to the amnestic effects of the nicotinic antagonist mecamylamine and the muscarinic antagonist scopolamine. No significant effects of nicotine or amphetamine were seen in either the lesioned or control groups. The long-lasting deficits in spatial learning and working memory resulting from neonatal ventral hippocampal lesions show that, unlike frontal cortical lesions during the same age, the effects of hippocampal lesions are not overcome during development. The resistance to the amnestic effects of nicotinic and muscarinic acetylcholine (ACh) antagonists suggests that the hippocampus is a critical site for the action of these drugs. Neonatal hippocampal lesions may provide a good model of the cognitive impairments of schizophrenia and may be useful to assess novel drug effects to counteract the cognitive deficits in schizophrenia.     

The Effects of Nicotine on Attention and Working Memory in Never-Smokers.

The subjective and physiological effects of nicotine in nicotine-naive individuals are consistent across studies, though the cognitive effects are variable: Positive, negative, or no effects have been reported. Assessing specific cognitive processes (e.g., alerting, orienting, executive function, and phonological and visuospatial working memory) may help reduce this variability. This within-subject study (N = 20) was designed to assess the effect of nicotine gum (0, 2, or 4 mg) on subjective, physiological, and cognitive measures. Dose-dependent increases in dysphoria and heart rate were observed, though nicotine did not influence any aspect of attention or working memory. Future studies should take into account the difference in effect sizes for cognitive versus physiological/subjective measures and maximize power (e.g., increase sample size) accordingly. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intramuscular osteoinduction and bone marrow formation by the implantation of rhBMP-2 with atelopeptide type I collagen

The atypical neuroleptic, clozapine, has been shown to have encouraging, but mixed, effects on prefrontal cortical (PFC) cognitive deficits in schizophrenia, a stress-exacerbated disorder involving dopamine (DA) dysregulation. The current study examined the effects of acute clozapine pretreatment on the spatial working memory deficits induced by the pharmacological stressor, FG7142, in monkeys. Previous research has shown that FG7142 impairs spatial working memory in rats and monkeys through excessive DA receptor stimulation in the PFC (Murphy et al. 1996). Lower clozapine doses (1-3 mg/kg p.o.) reversed the FG7142-induced spatial working memory deficits, whereas doses in the clinical range (e.g., 6 mg/kg, p.o.) did not improve cognitive function in most animals. Clozapine alone produced a dose-related impairment in delayed response performance. These results from nonhuman primates suggest that the clozapine doses commonly used to treat schizophrenia may not be optimal for treating the PFC cognitive deficits associated with this illness.     

Noradrenergic DSP-4 lesions aggravate impairment of working memory produced by hippocampal muscarinic blockade in rats

To clarify the interactions between hippocampal cholinergic and adrenergic systems in working memory function of rats, the effects of hippocampal muscarinic receptor blockade combined with noradrenaline depletion on this behavior were examined with a three-panel runway task. Intrahippocampal administration of the muscarinic receptor antagonist scopolamine at a dose of 3.2 micrograms/side significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in the working memory task, whereas the 0.32 microgram/side dose of scopolamine did not affect working memory errors. Administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) at 50 mg/kg IP caused a marked reduction in hippocampal noradrenaline concentration, but it had no effect on working memory errors. Intrahippocampal administration of 0.32 microgram/side scopolamine, the behaviorally ineffective dose in intact rats, significantly increased the number of working memory errors in the noradrenaline-depleted animals. These results suggest that hippocampal muscarinic/noradrenergic interactions are involved in neural processes mediating working memory function of rats.     

Behavioral approaches to the assessment of attention in animals

Increasing awareness that disorders of attention may underlie cognitive dysfunctions associated with intoxication and neurodegenerative disease has stimulated research into the neural bases of attention. Because attention comprises a constellation of hypothetical cognitive processes, it can only be inferred from behavior, of either human or non-human subjects, under appropriate experimental conditions. Many behavioral procedures have been proposed for modeling attention in animals, but not all of these procedures have been systematically associated with specific attentional processes. This review endeavors to evaluate critically the construct validity of these procedures (i.e., to determine the degree to which a given procedure assesses a particular process) and to suggest experiments to improve the conceptual links between these procedures and the processes they purport to assess. Five categories of processes have been identified from the animal literature: orienting, expectancy, stimulus differentiation (including stimulus salience, discrimination of a critical stimulus from its context, and selection among stimuli), sustained attention, and parallel processing. The review discusses the strengths and weaknesses of specific behavioral procedures for assessing these categories of attentional processes and, given the conceptual uncertainties involved, it attempts to summarize the present state of knowledge of the pharmacology and neurobiology of attention.     

Reversible inactivation of the medial septum or nucleus basalis impairs working memory in rats: a dissociation of memory and performance

Lidocaine-induced inactivation of the medial septum immediately after training or prior to testing in a delay radial-arm maze task produced deficits in spatial working memory that reflected impaired acquisition of the task. Injection of lidocaine into the nucleus basalis magnocellularis produced a profile of behavioral changes that indicated that temporary inactivation of this structure impaired the behavioral expression of information already stored in working memory. This appears to reflect an impairment in processes that are required for performance (i.e., attention, motivation, sensorimotor function) of the task but not for retrieval of stored information. Site-specific inactivation of the basal forebrain should help to reveal the involvement of its component structures in different aspects of cognitive function.