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Working memory (WM) capacity is an important factor for a wide range of cognitive skills. This capacity has generally been assumed to be fixed. However, recent studies have suggested that WM can be improved by intensive, computerized training [Klingberg T, Fernell E, Olesen P, Johnson M, Gustafsson P, Dahlström K, et al. Computerized training of working memory in children with ADHD--a randomized, controlled trial. J Am Acad Child Adolesc Psych 2005;44:177--86]. A recent study by Olesen, Westerberg and Klingberg [Olesen P, Westerberg H, Klingberg T. Increased prefrontal and parietal brain activity after training of working memory. Nat Neurosci 2004;7:75--9] showed that group analysis of brain activity data show increases in prefrontal and parietal cortices after WM training. In the present study we performed single-subject analysis of the changes in brain activity after five weeks of training. Three young, healthy adults participated in the study. On two separate days before practice and during one day after practice, brain activity was measured with functional magnetic resonance imaging (fMRI) during performance of a WM and a baseline task. Practice on the WM tasks gradually improved performance and this effect lasted several months. The effect of practice also generalized to improve performance on a non-trained WM task and a reasoning task. After training, WM-related brain activity was significantly increased in the middle and inferior frontal gyrus. The changes in activity were not due to activations of any additional area that was not activated before training. Instead, the changes could best be described by small increases in the extent of the area of activated cortex. The effect of training of WM is thus in several respects similar to the changes in the functional map observed in primate studies of skill learning, although the physiological effect in WM training is located in the prefrontal association cortex.

The cellular maturational processes behind cognitive development during childhood, including the development of working memory capacity, are still unknown. By using the most standard computational model of visuospatial working memory, we investigated the consequences of cellular maturational processes, including myelination, synaptic strengthening, and synaptic pruning, on working memory-related brain activity and performance. We implemented five structural developmental changes occurring as a result of the cellular maturational processes in the biophysically based computational network model. The developmental changes in memory activity predicted from the simulations of the model were then compared to brain activity measured with functional magnetic resonance imaging in children and adults. We found that networks with stronger fronto-parietal synaptic connectivity between cells coding for similar stimuli, but not those with faster conduction, stronger connectivity within a region, or increased coding specificity, predict measured developmental increases in both working memory-related brain activity and in correlations of activity between regions. Stronger fronto-parietal synaptic connectivity between cells coding for similar stimuli was thus the only developmental process that accounted for the observed changes in brain activity associated with development of working memory during childhood.

In order to retain information in working memory (WM) during a delay, distracting stimuli must be ignored. This important ability improves during childhood, but the neural basis for this development is not known. We measured brain activity with functional magnetic resonance imaging in adults and 13-year-old children. Data were analyzed with an event-related design to isolate activity during cue, delay, distraction, and response selection. Adults were more accurate and less distractible than children. Activity in the middle frontal gyrus and intraparietal cortex was stronger in adults than in children during the delay, when information was maintained in WM. Distraction during the delay evoked activation in parietal and occipital cortices in both adults and children. However, distraction activated frontal cortex only in children. The larger frontal activation in response to distracters presented during the delay may explain why children are more susceptible to interfering stimuli.

Persistent neural activity constitutes one neuronal correlate of working memory, the ability to hold and manipulate information across time, a prerequisite for cognition. Yet, the underlying neuronal mechanisms are still elusive. Here, we design a visuo- spatial delayed-response task to identify the relationship between the cue-distractor spatial distance and mnemonic accuracy. Using a shared experimental and computational test protocol, we probe human subjects in computer experiments, and subsequently we evaluate different neural mechanisms underlying persistent activity using an in silico prefrontal network model. Five modes of action of the network were tested: weak or strong synaptic interactions, wide synaptic arborization, cellular bistability and reduced synaptic NMDA component. The five neural mechanisms and the human behavioral data, all exhibited a significant deterioration of the mnemonic accuracy with decreased spatial distance between the distractor and the cue. A subsequent computational analysis revealed that the firing rate and not the neural mechanism per se, accounted for the positive correlation between mnemonic accuracy and spatial distance. Moreover, the computational modeling predicts an inverse correlation between accuracy and distractibility. In conclusion, any pharmacological modulation, pathological condition or memory training paradigm targeting the underlying neural circuitry and altering the net population firing rate during the delay is predicted to determine the amount of influence of a visual distraction.

We report on a study that investigates the relationship between visual working memory and verbal working memory and a performance measure in endoscopic instrument navigation in MIST and GI Mentor II (a simulator for gastroendoscopy). Integrated cognitive neuroscience in state-of-the-art simulator training curriculum will take safety science in health care one step ahead. Current simulator validation focuses on how to train. In the light of recent research it is now prime time to ask why in search of mechanisms rather than to repeatedly show that training has effect. This will help tailor training to maximize individual output in procedures that require a high level of dexterity. WM training is a unique learning aid in simulator training and should be used alongside clinical practice in order to improve the quality of complex clinical intervention in the field of image guided surgical simulation.

Working memory capacity increases throughout childhood and adolescence, which is important for the development of a wide range of cognitive abilities, including complex reasoning. The spatial-span task, in which subjects retain information about the order and position of a number of objects, is a sensitive task to measure development of spatial working memory. This review considers results from previous neuroimaging studies investigating the neural correlates of this development. Older children and adolescents, with higher capacity, have been found to have higher brain activity in the intraparietal cortex and in the posterior part of the superior frontal sulcus, during the performance of working memory tasks. The structural maturation of white matter has been investigated by diffusion tensor magnetic resonance imaging (DTI). This has revealed several regions in the frontal lobes in which white matter maturation is correlated with the development of working memory. Among these is a superior fronto-parietal white matter region, located close to the grey matter regions that are implicated in the development of working memory. Furthermore, the degree of white matter maturation is positively correlated with the degree of cortical activation in the frontal and parietal regions. This suggests that during childhood and adolescence, there is development of networks related to specific cognitive functions, such as visuo-spatial working memory. These networks not only consist of cortical areas but also the white matter tracts connecting them. For visuo-spatial working memory, this network could consist of the superior frontal and intraparietal cortex.

Hypoxic-ischemic encephalopathy (HIE) is graded with three levels of severity-mild, moderate and severe. The outcome of individuals with mild and severe grades can be reliably predicted from this scheme. Individuals with moderate degree are divided in outcome between those who suffer major neurologic problems (e.g., cerebral palsy) and those who are assumed to recover from the incident. It is however not clear if the recovery is complete and unquestionable. A group of adolescents who had been born at term, diagnosed with moderate HIE but had not developed cerebral palsy, were investigated with diffusion tensor imaging. Fractional anisotropy maps were used as a basis of comparison to a group of controls of the same age and gender distribution. In several white matter areas fractional anisotrophy was lower in the group of individuals with a history of moderate HIE. These areas include the internal capsules (bilaterally in the posterior limb and on the right in the anterior limb), the posterior and anterior corpus callosum as well as frontal inferior white matter areas. These results indicate that even in the absence of such major neurologic impairments as cerebral palsy, moderate HIE causes long term white matter disturbances which are not repaired by adolescence.

Objective: Deficits in executive functioning, including working memory (WM) deficits, have been suggested to be important in attention-deficit/hyperactivity disorder (ADHD). During 2002 to 2003, the authors conducted a multicenter, randomized, controlled, double-blind trial to investigate the effect of improving WM by computerized, systematic practice of WM tasks., Method: Included in the trial were 53 children with ADHD (9 girls; 15 of 53 inattentive subtype), aged 7 to 12 years, without stimulant medication. The compliance criterion (>20 days of training) was met by 44 subjects, 42 of whom were also evaluated at follow-up 3 months later. Participants were randomly assigned to use either the treatment computer program for training WM or a comparison program. The main outcome measure was the span-board task, a visuospatial WM task that was not part of the training program., Results: For the span-board task, there was a significant treatment effect both post-intervention and at follow-up. In addition, there were significant effects for secondary outcome tasks measuring verbal WM, response inhibition, and complex reasoning. Parent ratings showed significant reduction in symptoms of inattention and hyperactivity/impulsivity, both post-intervention and at follow-up., Conclusions: This study shows that WM can be improved by training in children with ADHD. This training also improved response inhibition and reasoning and resulted in a reduction of the parent-rated inattentive symptoms of ADHD.

Working memory (WM) has been hypothesised to be impaired in attention-deficit/hyperactivity disorder (ADHD). However, there are few studies reported on tests measuring visuo-spatial WM (VSWM) in ADHD. Some of these studies used paradigms including episodic memory, others only used low memory loads. In the present study we used a VSWM test that has not been used previously in ADHD research. The sensitivity of the VSWM test and a choice reaction time (CRT) test was evaluated in a pilot study by comparing them to two commonly used tests in ADHD-research; the Continuous Performance Test (CPT) and a Go/no-go test, in children with and without ADHD. The groups differed significantly in performance on the VSWM test (P < .01) and CRT (P < .05) but not on the CPT (P > .1) or on the Go/no-go test (P > .1). The results from the VSWM and CRT tests were replicated in a larger sample of participants (80 boys; 27 boys with ADHD and 53 controls, mean age 11.4 years). The difference between the groups was significant for both the VSWM test (P < .01) and the CRT test (P < .01). The effect size (ES) of the VSWM test was 1.34. There was a significant age-by-group interaction on the VSWM test, with larger group differences for the older children (P < .01). Our results show that the VSWM test is a sensitive measure of cognitive deficits in ADHD and it supports the hypothesis that deficits in VSWM is a major component of ADHD.

In the human brain, myelination of axons continues until early adulthood and is thought to be important for the development of cognitive functions during childhood. We used diffusion tensor MR imaging and calculated fractional anisotropy, an indicator of myelination and axonal thickness, in children aged between 8 and 18 years. Development of working memory capacity was positively correlated with fractional anisotropy in two regions in the left frontal lobe, including a region between the superior frontal and parietal cortices. Reading ability, on the other hand, was only correlated with fractional anisotropy in the left temporal lobe, in the same white matter region where adults with reading disability are known to have lower fractional anisotropy. Both the temporal and the frontal regions were also correlated with age. These results show that maturation of white matter is an important part of brain maturation during childhood, and that maturation of relatively restricted regions of white matter is correlated with development of specific cognitive functions.

Working memory capacity has traditionally been thought to be constant. Recent studies, however, suggest that working memory can be improved by training. In this study, we have investigated the changes in brain activity that are induced by working memory training. Two experiments were carried out in which healthy, adult human subjects practiced working memory tasks for 5 weeks. Brain activity was measured with functional magnetic resonance imaging (fMRI) before, during and after training. After training, brain activity that was related to working memory increased in the middle frontal gyrus and superior and inferior parietal cortices. The changes in cortical activity could be evidence of training-induced plasticity in the neural systems that underlie working memory.

The aim of this study was to explore whether there are networks of regions where maturation of white matter and changes in brain activity show similar developmental trends during childhood. In a previous study, we showed that during childhood, grey matter activity increases in frontal and parietal regions. We hypothesized that this would be mediated by maturation of white matter. Twenty-three healthy children aged 8-18 years were investigated. Brain activity was measured using the blood oxygen level-dependent (BOLD) contrast with functional magnetic resonance imaging (fMRI) during performance of a working memory (WM) task. White matter microstructure was investigated using diffusion tensor imaging (DTI). Based on the DTI data, we calculated fractional anisotropy (FA), an indicator of myelination and axon thickness. Prior to scanning, WM score was evaluated. WM score correlated independently with FA values and BOLD response in several regions. FA values and BOLD response were extracted for each subject from the peak voxels of these regions. The FA values were used as covariates in an additional BOLD analysis to find brain regions where FA values and BOLD response correlated. Conversely, the BOLD response values were used as covariates in an additional FA analysis. In several cortical and sub-cortical regions, there were positive correlations between maturation of white matter and increased brain activity. Specifically, and consistent with our hypothesis, we found that FA values in fronto-parietal white matter correlated with BOLD response in closely located grey matter in the superior frontal sulcus and inferior parietal lobe, areas that could form a functional network underlying working memory function.

Preterm birth frequently involves white matter injury and affects long-term neurologic and cognitive outcomes. Diffusion tensor imaging has been used to show that the white matter microstructure of newborn, preterm children is compromised in a regionally specific manner. However, until now it was not clear whether these lesions would persist and be detectible on long-term follow-up. Hence, we collected diffusion tensor imaging data on a 1.5-T scanner, and computed fractional anisotropy and coherence measures to compare the white matter integrity of children born preterm to that of control subjects. The subjects for the preterm group (10.9 +/- 0.29 y; n = 9; birth weight or= 2500; gestational age, >or= 37 wk). We found that the preterm group had lower fractional anisotropy values in the posterior corpus callosum and bilaterally in the internal capsules. In the posterior corpus callosum this difference in fractional anisotropy values may partially be related to a difference in white matter volume between the groups. An analysis of the coherence measure failed to indicate a group difference in the axonal organization. These results are in agreement with previous diffusion tensor imaging findings in newborn preterm children, and indicate that ex-preterm children with attention deficits have white matter disturbances that are not compensated for or repaired before 11 y of age.

Working memory (WM) capacity is the ability to retain and manipulate information during a short period of time. This ability underlies complex reasoning and has generally been regarded as a fixed trait of the individual. Children with attention deficit hyperactivity disorder (ADHD) represent one group of subjects with a WM deficit, attributed to an impairment of the frontal lobe. In the present study, we used a new training paradigm with intensive and adaptive training of WM tasks and evaluated the effect of training with a double blind, placebo controlled design. Training significantly enhanced performance on the trained WM tasks. More importantly, the training significantly improved performance on a nontrained visuo-spatial WM task and on Raven's Progressive Matrices, which is a nonverbal complex reasoning task. In addition, motor activity--as measured by the number of head movements during a computerized test--was significantly reduced in the treatment group. A second experiment showed that similar training-induced improvements on cognitive tasks are also possible in young adults without ADHD. These results demonstrate that performance on WM tasks can be significantly improved by training, and that the training effect also generalizes to nontrained tasks requiring WM. Training improved performance on tasks related to prefrontal functioning and had also a significant effect on motor activity in children with ADHD. The results thus suggest that WM training potentially could be of clinical use for ameliorating the symptoms in ADHD.

The aim of this study was to identify changes in brain activity associated with the increase in working memory (WM) capacity that occurs during childhood and early adulthood. Functional MRI (fMRI) was used to measure brain activity in subjects between 9 and 18 years of age while they performed a visuospatial WM task and a baseline task. During performance of the WM task, the older children showed higher activation of cortex in the superior frontal and intraparietal cortex than the younger children did. A second analysis found that WM capacity was significantly correlated with brain activity in the same regions. These frontal and parietal areas are known to be involved in the control of attention and spatial WM. The development of the functionality in these areas may play an important role in cognitive development during childhood.

When people perform two tasks simultaneously, the tasks are often executed slower and with more errors than when they are carried out as single tasks. This is called dual task interference. With functional magnetic resonance imaging (fMRI), we show that concurrently performed visual and somatosensory reaction time (RT) tasks engage almost identical volumes of cortical and subcortical motor structures. Moreover, dual RT tasks engaged additional cortical regions that are not activated by the component RT tasks had they been performed as single tasks. When the inter-stimulus interval was <300 ms, the first task interfered with the second, and a field in the right inferior frontal gyrus (RIFG) appeared with activity correlated with the increased RT to the second stimulus. This activation was spatially distinct from the cortical activity of the main effect of dual task performance. Thus, the performance of single RT tasks, dual RT tasks and dual RT tasks that interfere differ psychophysically and in the brain structures subserving these tasks. A short occupancy of the common motor structures can explain the interference effect. The increased activity of the RIFG correlated with the interference effect is very likely to be a specific outcome of situations where two concurrent tasks interfere with each other. The brain appears to recruit the RIFG for a subsequent (delayed) response when there is interference between dual tasks.

Episodic memory for simple commands is better following enacted than verbal encoding. This has been proposed to be due to the possibility to base retrieval on motor information. Here we used PET to test the hypothesis that motor brain areas show increased retrieval-related activity following enacted compared to verbal encoding. Brain activity was also monitored during retrieval after imaginary enactment during encoding. It was found that activity in the right motor cortex was maximal following encoding enactment, intermediate following imaginary encoding enactment, and lowest following verbal encoding. These findings provide support that one basis for the facilitating effect on memory performance of overt, and to a lesser degree covert, encoding enactment is the possibility to base retrieval on motor information.

Working memory (WM) refers to the temporary storage and processing of goal-relevant information. WM is thought to include domain-specific short-term memory stores and executive processes, such as coordination, that operate on the contents of WM. To examine the neural substrates of coordination, we acquired functional magnetic resonance imaging data while subjects performed a WM span test designed specifically to measure executive WM. Subjects performed two tasks (sentence reading and short-term memory for five words) either separately or concurrently. Dual-task performance activated frontal-lobe areas to a greater extent than performance of either task in isolation, but no new area was activated beyond those activated by either component task. These findings support a resource theory of WM executive processes in the frontal lobes.

Diffusion tensor magnetic resonance imaging (MRI) was used to study the microstructural integrity of white matter in adults with poor or normal reading ability. Subjects with reading difficulty exhibited decreased diffusion anisotropy bilaterally in temporoparietal white matter. Axons in these regions were predominantly anterior-posterior in direction. No differences in T1-weighted MRI signal were found between poor readers and control subjects, demonstrating specificity of the group difference to the microstructural characteristics measured by diffusion tensor imaging (DTI). White matter diffusion anisotropy in the temporo-parietal region of the left hemisphere was significantly correlated with reading scores within the reading-impaired adults and within the control group. The anisotropy reflects microstructure of white matter tracts, which may contribute to reading ability by determining the strength of communication between cortical areas involved in visual, auditory, and language processing.

Interference between two concurrent tasks can be measured as an increased reaction time during simultaneous performance compared to when each task is performed alone. We tested the hypothesis that two tasks interfere because they require activation of overlapping areas of the cerebral cortex. With positron emission tomography we measured cortical activation as fields with significant increase in regional cerebral blood flow during single task performance of an auditory and a visual go/no-go task and an auditory and a visual short-term memory (STM) task. In a separate experiment we measured the degree of interference between the two go/no-go tasks and between the two STM tasks during dual task performance. Both the two go/no-go tasks and the two STM tasks activated overlapping parts of the cortex and interfered significantly during dual task performance. The two STM tasks had a larger volume of overlap and also significantly larger increase in reaction time during dual task performance, compared to the go/no-go tasks. The results thus indicate that two concurrent tasks interfere, with a resulting increase in reaction time, if they require activation of overlapping parts of the cortex.

We wanted to examine whether there are cortical fields active in short-term retention of sensory information, independent of the sensory modality. To control for selective attention, response selection and motor output, the cortical activity during short-term memory (STM) tasks was compared with that during detection (DT) tasks. Using positron emission tomography and [15O]-butanol as a tracer, we measured the regional cerebral blood flow in ten subjects during three STM tasks in which the subjects had to keep in mind: (i) the pitch of tones; (ii) frequencies of a vibrating stylus; and (iii) luminance levels of a monochrome light. Another group of ten subjects undertook three tasks in which subjects detected changes in similar stimuli. Six cortical fields were significantly more activated during STM than during DT. These fields were activated irrespective of sensory modality, and were located in the left inferior frontal gyrus, right superior frontal gyrus, right inferior parietal cortex, anterior cingulate, left frontal operculum and right ventromedial prefrontal cortex. Since the DT tasks and the STM tasks differed only with respect to the STM component, we conclude that the neuronal activity specifically related to retention of the stimuli during the delays was located in these six multi-modal cortical areas. Since no differences were observed in the sensory-specific association cortices, the results indicate further that the activity in the sensory-specific association cortices due to selective attention is not different from the activity underlying short-term retention of sensory information.

The primary motor area (M1) of mammals has long been considered to be structurally and functionally homogeneous. This area corresponds to Brodmann's cytoarchitectural area 4. A few reports showing that arm and hand are doubly represented in M1 of macaque monkeys and perhaps man, and that each subarea has separate connections from somatosensory areas, have, with a few exceptions, gone largely unnoticed. Here we show that area 4 in man can be subdivided into areas '4 anterior' (4a) and '4 posterior' (4p) on the basis of both quantitative cytoarchitecture and quantitative distributions of transmitter-binding sites. We also show by positron emission tomography that two representations of the fingers exist, one in area 4a and one in area 4p. Roughness discrimination activated area 4p significantly more than a control condition of self-generated movements. We therefore suggest that the primary motor area is subdivided on the basis of anatomy, neurochemistry and function.

Animal studies have shown that lesions of the parahippocampal cortex impair learning of visual stimulus-stimulus associations. We tested the hypothesis that recall of paired associates, in contrast to recall of non-associated items, activates the parahippocampal cortex in humans. Ten volunteers had their regional cerebral blood flow measured with positron emission tomography during non-associative recall, and during two conditions with associative recall of visual stimuli. Compared with non-associative recall, associative recall specifically increased the blood flow in a field located in the entorhinal cortex, extending into the presubiculum. Our results demonstrate functional differences between the human hippocampal and parahippocampal cortex, and show that the entorhinal cortex is engaged in associative memory.