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Neuropsychological predictors of BOLD response during a spatial working memory task in adolescents: what can performance tell us about fMRI response patterns?

The relationship between standardized neuropsychological test performance and functional magnetic resonance imaging (fMRI) response during cognitive tasks is largely unknown. This exploratory investigation examined the relationship between neuropsychological test performance and fMRI response to a spatial working memory (SWM) task among 49 typically developing adolescents. Participants were administered a variety of neuropsychological tests in the domains of working memory, visuospatial skills, executive functioning, attention, learning and memory, visuomotor skills and processing speed, and language functioning. Neuropsychological domain scores were used to predict fMRI response during a SWM task. Results suggest that in many brain regions, neuropsychological performance negatively predicts fMRI response, suggesting that those teens with better neuropsychological abilities required fewer neural resources to adequately perform the task. This study provides further understanding of how neuropsychological abilities relate to neural activity during fMRI tasks, and provides an important link between neuropsychological and fMRI research.

Adolescent↗

Nicotinic antagonist administration into the ventral hippocampus and spatial working memory in rats.

Nicotinic acetylcholine receptors are important for maintaining optimal memory performance. In order to more fully characterize the involvement of nicotinic systems in memory, the contributions of nicotinic acetylcholine receptor subtypes were investigated. This study targeted the alpha 7 and alpha 4 beta 2 nicotinic receptors in the ventral hippocampus, an area known to be important for spatial working memory. Antagonists of alpha 7 and alpha 4 beta 2 receptors were locally infused into the ventral hippocampus of rats and the effects on memory were examined with the radial-arm maze. The subtype-specific competitive antagonists infused into separate groups of rats were methyllycaconitine citrate (an alpha 7 antagonist) and dihydro-beta-erythroidine hydrobromide (an alpha 4 beta 2 antagonist). Their effects on radial-arm maze performance were contrasted with the non-specific competitive antagonist, D-tubocurarine chloride. Significant deficits in radial-arm maze choice accuracy performance were found at 78.7 micrograms/side for methyllycaconitine and at 106.9 micrograms/side for dihydro-beta-erythroidine. Increased response latency was also seen at these doses. Tubocurarine induced seizures at doses previously reported to have no effect. Wet dog shakes were seen in most rats at 0.1 microgram/side with tubocurarine, 26.3 micrograms/side with methyllycaconitine and 106.9 micrograms/side with dihydro-beta-erythroidine. This study suggests that both alpha 7 and alpha 4 beta 2 nicotinic acetylcholine receptor subtypes are involved in working memory formation and that the hippocampus is a critical site for nicotinic cholinergic involvement in memory function, though the high doses of antagonists needed to produce the memory impairment may have had less than completely specific effects.

Aconitine↗

Reversible hippocampal lesions disrupt water maze performance during both recent and remote memory tests.

Conventional lesion methods have shown that damage to the rodent hippocampus can impair previously acquired spatial memory in tasks such as the water maze. In contrast, work with reversible lesion methods using a different spatial task has found remote memory to be spared. To determine whether the finding of spared remote spatial memory depends on the lesion method, we reversibly inactivated the hippocampus with lidocaine either immediately (0-DAY) or 1 mo (30-DAY) after training in a water maze. For both the 0-DAY and 30-DAY retention tests, rats that received lidocaine infusions exhibited impaired performance. In addition, when the 0-DAY group was retested 2 d later, (when the drug was no longer active), the effect was reversed. That is, rats that had previously received lidocaine performed as well as control rats did. These findings indicate that the rodent hippocampus is important for both recent and remote spatial memory, as assessed in the water maze. What determines whether remote spatial memory is preserved or impaired following disruption of hippocampal function appears to be the type of task used to assess spatial memory, not the method used to disrupt the hippocampus.

Anesthetics, Local↗

A low dose of the alpha2 agonist clonidine ameliorates the visual attention and spatial working memory deficits produced by phencyclidine administration to rats.

RATIONALE: Psychotomimetic N-methyl-D-aspartate/glutamate receptor antagonists, such as phencyclidine (PCP), have been shown to produce a spectrum of behavioral, neurochemical and anatomical changes in rats that are relevant to aspects of schizophrenia, including impairments of working memory and visual attention. The alpha(2) noradrenergic receptor agonist clonidine prevents some of the behavioral effects of NMDA antagonists, suggesting that monoaminergic systems mediate some aspects of these deficits. OBJECTIVES: We sought to determine the ability of clonidine to modify the PCP-induced deficits of visual attention and spatial working memory in rats. RESULTS: In a lateralized reaction time task, a lower dose of clonidine (10 microg/kg) ameliorated the impairment of choice accuracy produced by PCP (2.5 mg/kg, IP), while the higher dose of clonidine (50 microg/kg) slowed response times and induced a deficit of choice accuracy on its own. The high dose of clonidine effectively prevented the motor impulsivity produced by PCP. In addition, clonidine (10 microg/kg) prevented PCP-induced performance deficits in a delayed non-match to sample task. CONCLUSIONS: These data indicate that clonidine may attenuate deficits of attention and working memory produced by PCP, perhaps in part by preventing some of the downstream neurochemical and anatomical effects of this psychotomimetic drug.

Adrenergic alpha-2 Receptor Agonists↗

The promnesic neurosteroid pregnenolone sulfate increases paradoxical sleep in rats.

The effect of systemic administration of the neurosteroid pregnenolone sulfate (PREG-S) on sleep-wakefulness cycle and on spatial memory performances was investigated in male Sprague-Dawley rats. In the first experiment, the effect of PREG-S administration (saline, 4.75, 47.5 mg/kg, i.p.) on 24 h EEG recording was evaluated. In the second experiment, spatial memory performance in a two-trial memory task was evaluated after post-acquisition administration of similar doses of PREG-S as in the first experiment. Results show that PREG-S increases paradoxical sleep and improves the performance on the memory task yielding similar dose response curves. Starting 4 h after administration of 47.5 mg/kg PREG-S, paradoxical sleep is increased for 10 h. The PREG-S effect on spatial memory lasts for at least 24 h after injection. These results suggest that an enhancement of paradoxical sleep may be involved in the promnesic effects of this neurosteroid.

Animals↗

Electroconvulsive shock and lidocaine reveal rapid consolidation of spatial working memory in the water maze.

Head trauma leading to concussion and electroconvulsive shock (ECS) in humans causes amnesia for events that occurred shortly before the injury (retrograde amnesia). The present experiment investigated the amnesic effect of lidocaine and ECS in 25 rats trained on a working memory version of the Morris water task. Each day, the escape platform was moved to a new location; learning was evidenced by a decrease in the latency to find the platform from the first to the second trial. "Consolidation" of this newly encoded spatial engram was disrupted by bilateral inactivation of the dorsal hippocampus with 1 microliter of 4% lidocaine applied as soon as possible after the first trial. When trial 2 was given after recovery from the lidocaine (30 min after the injection), a normal decrease in latency indicated that the new engram was not disrupted. When trial 2 was given under the influence of lidocaine (5 min after injection), absence of latency decrease demonstrated both the success of the inactivation and the importance of hippocampus for the task. To examine the role of events immediately after learning, ECS (30 or 100 mA, 50 Hz, 1.2 sec) was applied 0 sec to 45 sec after a single escape to the new platform location. A 2-h delay between ECS and trial 2 allowed the effects of ECS to dissipate. ECS applied 45 sec or 30 sec after trial 1 caused no retrograde amnesia: escape latencies on trial 2 were the same as in control rats. However, ECS applied 0 sec or 15 sec after trial 1 induced clear retrograde amnesia: escape latencies on trial 2 were no shorter than on trial 1. It is concluded that the consolidation of a newly formed memory for spatial location can only be disrupted by ECS within 30 sec after learning.

Amnesia↗

Memory in early adolescents born prematurely: a functional magnetic resonance imaging investigation.

This study employed functional magnetic resonance imaging to examine the functional neuroanatomy of the hippocampus and head of the caudate nucleus during 2 different types of memory tasks in a sample of 9 early adolescent children who were born preterm (neonatal intensive care unit [NICU] sample) and a group of 9 age-matched control children who were born at term. The investigation employed delayed match to sample (DMS), delayed nonmatch to sample (DNMS), and spatial memory span tasks, as well as 2 analogous perceptuomotor tasks that placed no demands on memory. The general question examined was whether preterm children show different levels of hippocampal and caudate activation during these tasks when compared to children born at term. The findings indicated that the 2 groups did not differ in functional activation of the hippocampus during the DMS and DNMS tasks. During the encoding phase of the spatial memory span task, the DMS perceptuomotor task, and the spatial memory span perceptuomotor task, the NICU sample showed greater activation change in the right caudate nucleus, and less right caudate activation change during the test phase. During the spatial span perceptuomotor task, the preterm group showed reduced activation change in the left caudate nucleus during both the encoding and test phase. Also, during the DMS perceptuomotor task, the NICU group showed increased activation change in the left caudate nucleus during encoding and decreased activation change at test. The implications of these findings for understanding the functional neuroanatomy of memory deficits are discussed, as is the potential for distinguishing the effects of neural plasticity from those of typical brain maturational processes.

Adolescent↗

Donepezil primarily attenuates scopolamine-induced deficits in psychomotor function, with moderate effects on simple conditioning and attention, and small effects on working memory and spatial mapping.

RATIONALE: Alzheimer's dementia (AD) patients have profound deficits in cognitive and social functions, mediated in part by a decline in cholinergic function. Acetylcholinesterase inhibitors (AChEI) are the most commonly prescribed treatment for the cognitive deficits in AD patients, but their therapeutic effects are small, and it is still not clear if they primarily affect attention, memory, or some other cognitive/behavioral functions. OBJECTIVES: The objective of the present experiments was to explore the effects of donepezil (Aricepttrade mark), an AChEI, on behavioral deficits related exclusively to cholinergic dysfunction. MATERIALS AND METHODS: The effects of donepezil were assessed in Sprague-Dawley rats with scopolamine-induced deficits in a battery of cognitive/behavioral tests. RESULTS: Scopolamine produced deficits in contextual and cued fear conditioning, the 5-choice serial reaction time test, delayed nonmatching to position, the radial arm maze, and the Morris water maze. Analyses of the pattern and size of the effects revealed that donepezil produced very large effects on scopolamine-induced deficits in psychomotor function (approximately 20-50% of the variance), moderate-sized effects on scopolamine-induced deficits in simple conditioning and attention (approximately 3-10% of the variance), but only small effects on scopolamine-induced deficits in higher cognitive functions of working memory and spatial mapping (approximately 1% of the variance). CONCLUSIONS: These results are consistent with the limited efficacy of donepezil on higher cognitive function in AD patients, and suggest that preclinical behavioral models could be used not only to determine if novel treatments have some therapeutic potential, but also to predict more precisely what the pattern and size of the effects might be.

Animals↗

Toward clinical application of neuropsychological activation probes with SPECT: a spatial working memory task.

UNLABELLED: The concept of working memory is central to theories of human cognition, because it is essential to human skills such as decision making and deductive reasoning. Although PET and functional MRI have provided robust data on the recruitment of specific pathways in working memory tasks, the experimental settings of these studies may not be transferable to a clinical situation. Hence, to develop neuropsychological SPECT activation probes that are suitable for daily clinical practice, this study reports on a neuropsychological activation task of spatial working memory under classical neuropsychological test conditions in healthy subjects. METHODS: Reaction times and accuracy were measured as behavioral parameters and functional imaging data were analyzed with statistical parametric mapping to determine significant voxel-wise changes between the perception task and the memory task. RESULTS: Subjects reacted more slowly and performed less accurately during the memory task compared with the perception task, findings that are in keeping with other neuropsychological studies. Also, the overall pattern of brain activations revealed in our experiment is consistent with the data of the literature, thereby validating our test probe. CONCLUSION: From a practical viewpoint, the close resemblance of the test conditions of the SPECT procedure with those of the investigation room and the relative simplicity of the task under study probably constitute major advantages for future clinical application of the SPECT procedure in patients with cognitive impairments.

Adult↗

The role of the amygdala and the hippocampus in working memory for spatial and non-spatial information.

Male rats received either electrolytic or sham lesions bilaterally into the amygdala, hippocampus or amygdala plus hippocampus, or were assigned to an unoperated control group. After the postoperative recovery period all lesioned and control animals were tested for the ability to master a spatial delayed non-matching-to-sample (DNMS), a visual DNMS and a visuo-tactile DNMS. Retention of these paradigms was evaluated 24 h after the last respective training session. Bilateral lesions of the amygdala severely disrupted the acquisition and retention of a DNMS paradigm with visual and visuo-tactile cues as discriminative stimuli and had no effect on the acquisition and retention of a spatial DNMS. On the contrary, bilateral lesions of the hippocampus impaired the acquisition and retention of spatial DNMS, but the animals with these lesions showed an acquisition and retention of the visual and visuo-tactile DNMS paradigms significantly better than those of animals with amygdala lesions. Combined lesions of the amygdala and hippocampus severely disrupted the acquisition and retention of the 3 paradigms. The contribution of the amygdala and the hippocampus in the working memory for spatial and non-spatial information is discussed.

Amygdala↗

The effect of repeated isoflurane anesthesia on spatial and psychomotor performance in young and aged mice.

UNLABELLED: Exposure to general anesthesia may contribute to postoperative cognitive impairment in elderly patients, but the relationship remains poorly understood. We investigated whether aged mice, 18-19 mo, are more susceptible to postanesthetic cognitive impairment than young mice, 3-4 mo, using spatial memory (Barnes maze) and psychomotor (rotarod) tasks. Initially we studied the effect of a single anesthetic episode on asymptotic maze performance. We then tested whether repeated anesthesia would impair spatial memory and psychomotor performance to a greater extent in aged mice. Mice were anesthetized with isoflurane (1.4% atm) for 30 min; controls received 90% oxygen. Anesthesia, administered during the asymptotic period of maze learning, did not impair performance tested the following day (P > 0.05). Repeated anesthesia, 2-3 h after each session, did not impair overall maze or rotarod performance in young or aged mice (P > 0.05). Spatial learning appeared to be facilitated by anesthesia, F(1,204) = 7.97, P < 0.01 for pooled results. Asymptotic performance-when learning had stabilized-remained unimpaired in both the maze and rotarod tasks. These results suggest that an age-related risk of anesthetic-induced impairment appears to be limited to acquisition of a novel motor skill and that anesthesia alone does not lead to prolonged cognitive impairments in aged mice. IMPLICATIONS: This study demonstrates that repeated isoflurane general anesthesia impaired psychomotor performance in aged mice during the initial learning period; however, spatial learning improved and, overall, spatial memory and psychomotor performance were unimpaired. Thus, general anesthesia alone does not appear to result in prolonged cognitive deficits in aged mice.

Aging↗

Impaired spatial reference memory in aromatase-deficient (ArKO) mice.

Previous studies indicate an important role for estrogen in memory and learning. Aromatase-knockout (ArKO) mice are unable to produce estrogen because they lack a functional Cyp 19 gene that encodes for aromatase, the enzyme that converts testosterone into estrogen. Using a Y-maze test for short-term spatial reference memory, we found that both male and female ArKO mice performed significantly worse than wildtype controls. Gonadectomy reduced Y-maze responses in male and female wildtype controls, but had no effect in ArKO mice. After gonadectomy, there was no significant difference between wildtype and ArKO mice. For the first time using ArKO mice, our findings confirm the importance of estrogen in memory in both males and females.

Animals↗

Huperzine A ameliorates the spatial working memory impairments induced by AF64A.

Huperzine A, a novel, potent, reversible, and selective acetylcholinesterase (AChE) inhibitor has been expected to be superior to other AChE inhibitors now for the treatment of memory deficits in patients with Alzheimer's disease. We have assessed the effects of huperzine A on performance of AF64A-treated rats in the radial maze. AF64A (2 nmol per side, i.c.v.) caused significant impairment in rats' ability to perform the spatial working memory task. This behavioural impairment was associated with a significant decrease in the activity of choline acetyltransferase (ChAT) in the hippocampus. Huperzine A (0.4-0.5 mg kg-1, i.p.) significantly ameliorated the AF64A-induced memory deficit. These results suggest that AF64A is a useful agent for disrupting working memory processes by altering hippocampal cholinergic function, and such impairment can be effectively ameliorated by huperzine A.

Alkaloids↗

Prolonged memory impairment in the absence of hippocampal cell death following traumatic brain injury in the rat.

Prolonged neurological dysfunction that results from an insult to the brain is often attributed to irreversible structural damage such as loss of neurons or axonal degeneration. For example, following cerebral ischemia even partial hippocampal CA1 neuronal loss has been proposed to be sufficient to result in deficits in hippocampal dependent spatial memory. This study examined if hippocampal CA1 neuronal loss and/or axonal injury was necessary to produce prolonged spatial memory deficits resulting from traumatic brain injury (TBI). Prior to TBI Sprague-Dawley rats were trained on an 8-arm radial maze, a task sensitive to detecting specific lesions of the hippocampus or its extrinsic connections. Following a mild, moderate, or sham injury, rats were tested for working and reference memory for 25 days. After 25 days of maze testing, histological cell counts were made from consistent coronal sections of the mid-dorsal hippocampus. Rats subjected to mild or moderate TBI manifested working memory deficits for 5 and 15 days, respectively, after injury in the absence of overt (all brain regions) or quantitative (CA1 only) evidence of neuronal death. The number of CA1 pyramidal neurons of representative sections of the mid-dorsal hippocampi for injured maze-deficit rats and sham control rats were: 1626 (S.E.M. = +/- 66) and 1693 (S.E.M. = +/- 69) per 10(6) micron2, respectively. Additionally, no overt evidence of axonal injury was observed in any forebrain structure including major intrinsic or extrinsic connecting hippocampal pathways. These data strongly suggest that mild to moderate TBI is capable of producing prolonged spatial memory deficits in the rat without evidence of either neuronal cell death in the intrinsic hippocampus or overt axonal injury in hippocampal pathways.

Animals↗

Memory for object locations in young and elderly adults.

The spatial memory of elderly and young adults was compared in two conditions: one in which common objects were displayed on a map, and one in which the objects were displayed in an actual environment (a large room) represented by the map. In the map condition, elderly adults had lower spatial memory scores than did young adults. In the room condition, however, the performance of elderly adults was not different from that of young adults. It was hypothesized that differences in the visual distinctiveness of the two contexts, map and room, were responsible for the interaction of age and task setting. An experiment using models of the map-room structures, models that differed in the visual distinctiveness of their components, confirmed this hypothesis.

Adolescent↗

Synaptic mechanisms and network dynamics underlying spatial working memory in a cortical network model.

Single-neuron recordings from behaving primates have established a link between working memory processes and information-specific neuronal persistent activity in the prefrontal cortex. Using a network model endowed with a columnar architecture and based on the physiological properties of cortical neurons and synapses, we have examined the synaptic mechanisms of selective persistent activity underlying spatial working memory in the prefrontal cortex. Our model reproduces the phenomenology of the oculomotor delayed-response experiment of Funahashi et al. (S. Funahashi, C.J. Bruce and P.S. Goldman-Rakic, Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. J Neurophysiol 61:331-349, 1989). To observe stable spontaneous and persistent activity, we find that recurrent synaptic excitation should be primarily mediated by NMDA receptors, and that overall recurrent synaptic interactions should be dominated by inhibition. Isodirectional tuning of adjacent pyramidal cells and interneurons can be accounted for by a structured pyramid-to-interneuron connectivity. Robust memory storage against random drift of the tuned persistent activity and against distractors (intervening stimuli during the delay period) may be enhanced by neuromodulation of recurrent synapses. Experimentally testable predictions concerning the neural basis of working memory are discussed.

Animals↗

Planning and spatial working memory in Parkinson's disease.

The higher level cognitive function of planning was studied in a group of medicated Parkinson's disease patients and a group of matched control subjects, using a computerised version of Shallice's Tower of London task. Baseline measurement of the ability to execute a given plan of action, to generate low level strategies required for efficient searching, and spatial working memory capacity, all of which contribute to performance on the planning task, established that the Parkinson's disease group was unimpaired on any of these measures. On the Tower of London task, the Parkinson's disease group was also unimpaired in terms of the average number of moves required to solve a problem. However, a specific planning deficit was evident when "thinking" times were analysed, and this was after the confounding influence of motor initiation and execution times had been carefully extracted from total performance times. This finding is discussed in relation to putative functions of the frontal lobes and basal ganglia, and an attention-switching hypothesis is developed to account for it.

Aged↗

Implanted cannula-mediated repetitive administration of Abeta25-35 into the mouse cerebral ventricle effectively impairs spatial working memory.

Amyloid beta (Abeta) is closely related to the onset of Alzheimer's disease (AD). To construct AD animal models, a bolus administration of a large dose of toxic Abeta into the cerebral ventricles of rodents has been performed in earlier studies. In parallel, a continuous infusion system via an osmotic pump into the cerebral ventricle has been developed to make a rat AD model. In this study, we developed a mouse AD model by repetitive administration of Abeta25-35 via a cannula implanted into the cerebral ventricle. Using this administration system, we reproducibly constructed a mouse with impaired spatial working memory. In accordance with the occurrence of the abnormal mouse behavior, we found that the number of choline acetyltransferase (ChAT)-positive neurons was reduced in paraventricular regions of brains of Abeta25-35-administered mice in a dose-dependent manner. Considering that the repetitive administration of a small dose of toxic Abeta via an implanted cannula leads to a brain status more resembling that of the AD patients than a bolus injection of a large dose of Abeta, and therapeutic as well as toxic agents are able to be repeatedly and reliably administered via an implanted cannula, we concluded that the implanted cannula-bearing AD mouse model is useful for development of new AD therapy.

Alzheimer Disease↗