Neural correlates of training-related working-memory gains in old age.

Working memory (WM) functioning declines in old age. Due to its impact on many higher-order cognitive functions, investigating whether training can modify WM performance has recently been of great interest. We examined the relationship between behavioral performance and neural activity following five weeks of intensive WM training in 23 healthy older adults (M=63.7 years). 12 participants received adaptive training (i.e. individually adjusted task difficulty to bring individuals to their performance maximum), whereas the others served as active controls (i.e. fixed low-level practice). Brain activity was measured before and after training, using fMRI, while subjects performed a WM task under two difficulty conditions. Although there were no training-related changes in WM during scanning, neocortical brain activity decreased post training and these decreases were larger in the adaptive training group than in the controls under high WM load. This pattern suggests intervention-related increases in neural efficiency. Further, there were disproportionate gains in the adaptive training group in trained as well as in non-trained (i.e. attention, episodic memory) tasks assessed outside the scanner, indicating the efficacy of the training regimen. Critically, the degree of training-related changes in brain activity (i.e. neocortical decreases and subcortical increases) was related to the maximum gain score achieved during the intervention period. This relationship suggests that the decreased activity, but also specific activity increases, observed were functionally relevant.

Increased prefrontal and parietal activity after training of working memory.

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.

Changes in cortical activity after training of working memory--a single-subject analysis.

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.

Computerized training of working memory in children with ADHD--a randomized, controlled trial.

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.

Combined analysis of DTI and fMRI data reveals a joint maturation of white and grey matter in a fronto-parietal network.

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.

Visuo-spatial working memory span: a sensitive measure of cognitive deficits in children with 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.

Working-memory training in younger and older adults: training gains, transfer, and maintenance.

Working memory (WM), a key determinant of many higher-order cognitive functions, declines in old age. Current research attempts to develop process-specific WM training procedures, which may lead to general cognitive improvement. Adaptivity of the training as well as the comparison of training gains to performance changes of an active control group are key factors in evaluating the effectiveness of a specific training program. In the present study, 55 younger adults (20-30 years of age) and 45 older adults (60-70 years of age) received 5 weeks of computerized training on various spatial and verbal WM tasks. Half of the sample received adaptive training (i.e., individually adjusted task difficulty), whereas the other half-worked on the same task material but on a low task difficulty level (active controls). Performance was assessed using criterion, near-transfer, and far-transfer tasks before training, after 5 weeks of intervention, as well as after a 3-month follow-up interval. Results indicate that (a) adaptive training generally led to larger training gains than low-level practice, (b) training and transfer gains were somewhat greater for younger than for older adults in some tasks, but comparable across age groups in other tasks, (c) far-transfer was observed to a test on sustained attention and for a self-rating scale on cognitive functioning in daily life for both young and old, and (d) training gains and transfer effects were maintained across the 3-month follow-up interval across age.

Preliminary evidence that allelic variation in the LMX1A gene influences training-related working memory improvement.

LMX1A is a transcription factor involved in the development of dopamine (DA)-producing neurons in midbrain. Previous research has shown that allelic variations in three LMX1A single nucleotide polymorphisms (SNPs) were related to risk of Parkinson's disease (PD), suggesting that these SNPs may influence the number of mesencephalic DA neurons. Prompted by the established link between striatal DA functions and working memory (WM) performance, we examined two of these SNPs in relation to the ability to benefit from 4 weeks of WM training. One SNP (rs4657412) was strongly associated with the magnitude of training-related gains in verbal WM. The allele linked to larger gains has previously been suggested to be associated with higher dopaminergic nerve cell density. No differential gains of either SNP were observed for spatial WM, and the genotype groups were also indistinguishable in tests of attention, interference control, episodic memory, perceptual speed, and reasoning for both SNPs. This pattern of data is in agreement with previous findings from our group, suggesting that cognitive effects of DA-related genes may be more easily detected in a training context than for single-assessment performance scores.

Working memory plasticity modulated by dopamine transporter genotype.

Dopamine (DA) is implicated in working memory (WM) functioning. Variations in the DA transporter (DAT1) gene (SLC6A3) regulate DA availability in striatum. Compared to DAT1 9/10-repeat carriers, homozygosity of the DAT1 10-repeat allele has been related to less active dopaminergic pathways. A group of younger adults received 4 weeks of computerized adaptive training on several WM tasks. All participants improved their performance as a function of training. However, DAT1 9/10-repeat carriers showed larger training-related gains than DAT1 10-repeat carriers in visuospatial WM. By contrast, the two groups were indistinguishable in baseline WM performance as well as in a variety of tasks assessing different cognitive abilities. This pattern of results provides novel evidence that WM plasticity is a more sensitive indicator of DAT1 gene-related cognitive differences than single-assessment performance scores.

Diffusion tensor imaging on teenagers, born at term with moderate hypoxic-ischemic encephalopathy.

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.

Training of working memory in children with ADHD.

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.

Maturation of white matter is associated with the development of cognitive functions during childhood.

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.

Increased brain activity in frontal and parietal cortex underlies the development of visuospatial working memory capacity during childhood.

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.

Preterm children have disturbances of white matter at 11 years of age as shown by diffusion tensor imaging.

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.