Remote Effects of Hippocampal Sclerosis on Effective Connectivity during Working Memory Encoding: A Case of Connectional Diaschisis?

Accumulating evidence suggests a role for the medial temporal lobe (MTL) in working memory (WM). However, little is known concerning its functional interactions with other cortical regions in the distributed neural network subserving WM. To reveal these, we availed of subjects with MTL damage and characterized changes in effective connectivity while subjects engaged in WM task. Specifically, we compared dynamic causal models, extracted from magnetoencephalographic recordings during verbal WM encoding, in temporal lobe epilepsy patients (with left hippocampal sclerosis) and controls. Bayesian model comparison indicated that the best model (across subjects) evidenced bilateral, forward, and backward connections, coupling inferior temporal cortex (ITC), inferior frontal cortex (IFC), and MTL. MTL damage weakened backward connections from left MTL to left ITC, a decrease accompanied by strengthening of (bidirectional) connections between IFC and MTL in the contralesional hemisphere. These findings provide novel evidence concerning functional interactions between nodes of this fundamental cognitive network and sheds light on how these interactions are modified as a result of focal damage to MTL. The findings highlight that a reduced (top-down) influence of the MTL on ipsilateral language regions is accompanied by enhanced reciprocal coupling in the undamaged hemisphere providing a first demonstration of “connectional diaschisis.”

Efficiency at Rest: Magnetoencephalographic Resting-State Connectivity and Individual Differences in Verbal Working Memory

Inter-individual differences in cognitive performance are based on an efficient use of task-related brain resources. However, little is known yet on how these differences might be reflected on resting-state brain networks. Here we used Magnetoencephalography resting-state recordings to assess the relationship between a behavioral measurement of verbal working memory and functional connectivity as measured through Mutual Information. We studied theta (4?8 Hz), low alpha (8?10 Hz), high alpha (10?13 Hz), low beta (13?18 Hz) and high beta (18?30 Hz) frequency bands. A higher verbal working memory capacity was associated with a lower mutual information in the low alpha band, prominently among right-anterior and left-lateral sensors. The results suggest that an efficient brain organization in the domain of verbal working memory might be related to a lower resting-state functional connectivity across large-scale brain networks possibly involving right prefrontal and left perisylvian areas.

Age-Related Effects in Working Memory Recognition Modulated by Retroactive Interference

One of the main causes for age-related declines in working memory is a higher vulnerability to retroactive interference due to a reduced ability to suppress irrelevant information. However, the underlying neural correlates remain to be established. Magnetoencephalography was used to investigate differential neural patterns in young and older adults performing an interference-based memory task with two experimental conditions, interrupting and distracting, during successful recognition. Behaviorally, both types of retroactive interference significantly impaired accuracy at recognition more in older adults than in young adults with the latter exhibiting greater disruptions by interrupters. Magnetoencephalography revealed the presence of differential age-related neural patterns. Specifically, time-modulated activations in temporo-occipital and superior parietal regions were higher in young adults compared with older adults for the interrupting condition. These results suggest that age-related deficits in inhibitory mechanisms that increase vulnerability to retroactive interference may be associated with neural under-recruitments in a high-interference task.

Functional neuroanatomical double dissociation of mnemonic and executive control processes contributing to working memory performance

We used event-related functional MRI to investigate the neural bases of two categories of mental processes believed to contribute to performance of an alphabetization working memory task: memory storage and memory manipulation. Our delayed-response tasks required memory for the identity and position-in-the-display of items in two- or five-letter memory sets (to identify load-sensitive regions) or memory for the identity and relative position-in-the-alphabet of items in five-letter memory sets (to identify manipulation-sensitive regions). Results revealed voxels in the left perisylvian cortex of five of five subjects showing load sensitivity (as contrasted with alphabetization-sensitive voxels in this region in only one subject) and voxels of dorsolateral prefrontal cortex in all subjects showing alphabetization sensitivity (as contrasted with load-sensitive voxels in this region in two subjects). This double dissociation was reliable at the group level. These data are consistent with the hypothesis that the nonmnemonic executive control processes that can contribute to working memory function are primarily prefrontal cortex-mediated whereas mnemonic processes necessary for working memory storage are primarily posteriorly mediated. More broadly, they support the view that working memory is a faculty that arises from the coordinated interaction of computationally and neuroanatomically dissociable processes.

Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia

Antipsychotic drug treatment of schizophrenia may be complicated by side effects of widespread dopaminergic antagonism, including exacerbation of negative and cognitive symptoms due to frontal cortical hypodopaminergia. Atypical antipsychotics have been shown to enhance frontal dopaminergic activity in animal models. We predicted that substitution of risperidone for typical antipsychotic drugs in the treatment of schizophrenia would be associated with enhanced functional activation of frontal cortex. We measured cerebral blood oxygenation changes during periodic performance of a verbal working memory task, using functional MRI, on two occasions (baseline and 6 weeks later) in two cohorts of schizophrenic patients. One cohort (n = 10) was treated with typical antipsychotic drugs throughout the study. Risperidone was substituted for typical antipsychotics after baseline assessment in the second cohort (n = 10). A matched group of healthy volunteers (n = 10) was also studied on a single occasion. A network comprising bilateral dorsolateral prefrontal and lateral premotor cortex, the supplementary motor area, and posterior parietal cortex was activated by working memory task performance in both the patients and comparison subjects. A two-way analysis of covariance was used to estimate the effect of substituting risperidone for typical antipsychotics on power of functional response in the patient group. Substitution of risperidone increased functional activation in right prefrontal cortex, supplementary motor area, and posterior parietal cortex at both voxel and regional levels of analysis. This study provides direct evidence for significantly enhanced frontal function in schizophrenic patients after substitution of risperidone for typical antipsychotic drugs, and it indicates the potential value of functional MRI as a tool for longitudinal assessment of psychopharmacological effects on cerebral physiology.

The roles of prefrontal brain regions in components of working memory: Effects of memory load and individual differences

Using an event-related functional MRI design, we explored the relative roles of dorsal and ventral prefrontal cortex (PFC) regions during specific components (Encoding, Delay, Response) of a working memory task under different memory-load conditions. In a group analysis, effects of increased memory load were observed only in dorsal PFC in the encoding period. Activity was lateralized to the right hemisphere in the high but not the low memory-load condition. Individual analyses revealed variability in activation patterns across subjects. Regression analyses indicated that one source of variability was subjects’ memory retrieval rate. It was observed that dorsal PFC plays a differentially greater role in information retrieval for slower subjects, possibly because of inefficient retrieval processes or a reduced quality of mnemonic representations. This study supports the idea that dorsal and ventral PFC play different roles in component processes of working memory.

The neural basis of task-switching in working memory: Effects of performance and aging

We studied the performance of young and senior subjects on a well known working memory task, the Operation Span. This is a dual-task in which subjects perform a memory task while simultaneously verifying simple equations. Positron-emission tomography scans were taken during performance. Both young and senior subjects demonstrated a cost in accuracy and latency in the Operation Span compared with performing each component task alone (math verification or memory only). Senior subjects were disproportionately impaired relative to young subjects on the dual-task. When brain activation was examined for senior subjects, we found regions in prefrontal cortex that were active in the dual-task, but not in the component tasks. Similar results were obtained for young subjects who performed relatively poorly on the dual-task; however, for young subjects who performed relatively well in the dual-task, we found no prefrontal regions that were active only in the dual-task. Results are discussed as they relate to the executive component of task switching.

Effect of nicotine on brain activation during performance of a working memory task

Nicotine influences cognition and behavior, but the mechanisms by which these effects occur are unclear. By using positron emission tomography, we measured cognitive activation (increases in relative regional cerebral blood flow) during a working memory task [2-back task (2BT)] in 11 abstinent smokers and 11 ex-smokers. Assays were performed both after administration of placebo gum and 4-mg nicotine gum. Performance on the 2BT did not differ between groups in either condition, and the pattern of brain activation by the 2BT was consistent with reports in the literature. However, in the placebo condition, activation in ex-smokers predominated in the left hemisphere, whereas in smokers, it occurred in the right hemisphere. When nicotine was administered, activation was reduced in smokers but enhanced in ex-smokers. The lateralization of activation as a function of nicotine dependence suggests that chronic exposure to nicotine or withdrawal from nicotine affects cognitive strategies used to perform the memory task. Furthermore, the lack of enhancement of activation after nicotine administration in smokers likely reflects tolerance.

The fractionation of working memory

In performing many complex tasks, it is necessary to hold information in temporary storage to complete the task. The system used for this is referred to as working memory. Evidence for the need to postulate separable memory systems is summarized, and one particular model of working memory is described, together with its fractionation into three principal subsystems. The model has proved durable and useful and, with the development of electrophysiological and positive emission tomography scanning measures, is proving to map readily onto recent neuroanatomical developments.

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.

Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys.

The selective activation of the prefrontal cortical dopamine system by mild stress can be mimicked by anxiogenic beta-carbolines such as FG7142. To investigate the functional relevance of elevated levels of dopamine turnover in the prefrontal cortex, the current study examined the effects of FG7142 on the performance of spatial working memory tasks in the rat and monkey. FG7142 selectively increased prefrontal cortical dopamine turnover in rats and significantly impaired performance on spatial working memory tasks in both rats and monkeys. Spatial discrimination, a task with similar motor and motivational demands (rats), or delayed response performance following zero-second delays (monkeys) was unaffected by FG7142. Further, biochemical analysis in rats revealed a significant positive correlation between dopamine turnover in the prefrontal cortex and cognitive impairment on the delayed alternation task. The cognitive deficits in both rats and monkeys were prevented by pretreatment with the benzodiazepine receptor antagonist, RO15-1788, which blocked the increase in dopamine turnover and by the dopamine receptor antagonists, haloperidol, clozapine, and SCH23390. These findings indicate that excessive dopamine activity in the prefrontal cortex is detrimental to cognitive functions mediated by the prefrontal cortex.

Event-related potential correlates of impaired visuospatial working memory in schizophrenia

Previous studies have reported that patients with schizophrenia demonstrate impaired performance during working memory (WM) tasks. The current study aimed to determine whether WM impairments in schizophrenia are accompanied by reduced slow wave (SW) activity during on-line maintenance of mnemonic information. Event-related potentials were obtained from patients with schizophrenia and well controls as they performed a visuospatial delayed response task. On 50% of trials, a distractor stimulus was introduced during the delay. Compared with controls, patients with schizophrenia produced less SW memory negativity, particularly over the right hemisphere, together with reduced frontal enhancement of SW memory negativity in response to distraction. The results indicate that patients with schizophrenia generate less maintenance phase neuronal activity during WM performance, especially under conditions of distraction.

The concurrent validity and test-retest reliability of a visuospatial working memory task

To determine whether the visuospatial n-back working memory task is a reliable and valid measure of cognitive processes believed to underlie intelligence, this study compared the reaction times and accuracy of perforniance of 70 participants, with performance on the Multidimensional Aptitude Battery (MAB). Testing was conducted over two sessions separated by 1 week. Participants completed the MAB during the second test session. Moderate testretest reliability for percentage accuracy scores was found across the four levels of the n-back task, whilst reaction times were highly reliable. Furthermore, participants' performance on the MAB was negatively correlated with accuracy of performance at the easier levels of the n-back task and positively correlated with accuracy of performance at the harder task levels. These findings confirm previous research examining the cognitive basis of intelligence, and suggest that intelligence is the product of faster speed of information processing, as well as superior working memory capacity. (C) 2004 Elsevier Inc. All rights reserved.