Brain function and behaviour related to development and training of working memory

Training of working memory (WM) is a research field that could result in new therapeutic breakthroughs for people with impaired WM functions. In support of this view, research in our group has previously shown that WM training could increase WM capacity in children with attention deficits and in healthy adults. Apart from that study, there had been no previous literature on WM training presenting clear evidence for a clinically relevant change on WM capacity or brain activity following WM training. Study II and III were designed to investigate these issues. Only a few previous studies have investigated the development of brain activity related to WM. The results from those previous studies indicate that the development of WM is related to changes in activity in the frontal and parietal cortex. The aim of the developmental studies in this thesis (Study I and IV) was to extend those previous findings using two new approaches: 1) integration of data on brain function and brain structure and 2) investigation of a critical WM function i.e. the ability to ignore distraction. Previous research in our group showed that increased brain activity in prefrontal and parietal areas underlie the development of WM. In Study I, we sought to investigate how this development is related to the development of brain connectivity. Our aim was to present a network of brain structure and function underlying development of WM, which has previously never been shown. Consistently, the results from Study I showed that development of WM was related to a frontoparietal network of brain regions where brain activity and connectivity showed a similar developmental trend. The published research on brain activity related to training of WM is very scarce. Therefore, Study II aimed at investigating the long-term effects of WM training on brain activity using a training paradigm that was designed to optimise the training effects for each individual. For the first time we were able to show that training of a cognitive function, WM, could result in changes in brain activity in the adult human brain in task-related areas. In Study III the aim was to establish whether WM training could result in clinically relevant effects on performance and behaviour such that it could be used as a new therapy for groups of people with attention deficits. The resulting analyses included data from 44 children, diagnosed with ADHD, who had participated in a five week WM training program. Performance on executive functions, including WM, and behavioural ratings of ADHD symptoms, improved significantly as an effect of WM training. In Study IV we investigated the development of brain activity related to the ability to ignore distraction. This ability is central to WM since distracting stimuli must be ignored in order to keep information in WM. There is no previous published research on the neural mechanisms underlying the development of this important ability. The unravelling of those mechanisms would add to the understanding of the neurobiology related to disorders affecting attention and impulsivity, in addition to increasing our knowledge about WM functions. Furthermore, Study IV was designed to analyse developmental changes in brain activity related to each phase of a WM task. Importantly, we found that development of WM was related to increased brain activity in frontal and parietal areas during maintenance of information in WM. The ability to ignore distraction was related to brain activity in the prefrontal cortex in adults. In children another part of the prefrontal cortex was related to the presence of distraction and this area corresponded to the area where information was maintained. To conclude, this thesis demonstrates previously unknown data on the capacity of the human brain in relation to the healthy and deficient WM system and identifies brain areas that are crucial for the development of this system

Brain Activity Related to Working Memory and Distraction in Children and Adults

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

Temporal Lobe Atrophy and White Matter Lesions are Related to Major Depression over 5 years in the Elderly

The influence of organic brain changes on the development of depression in the elderly is uncertain. Cross-sectional studies, most often from clinical samples, report associations with brain atrophy and cerebrovascular disease, while longitudinal population studies have given mixed results. Our aim was to investigate whether cortical atrophy and white matter lesions (WMLs) on computed tomography (CT) predict occurrence of depression in the elderly. This is a prospective population-based study with 5-year follow-up. The baseline sample included 525 elderly subjects, aged 70–86 years, without dementia or major depression, with a score on the Mini-Mental State Examination above 25, and without dementia at follow-up. Cortical atrophy and WMLs were evaluated at baseline using CT. The main outcome measure was development of major or minor depression at follow-up according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition, as evaluated using neuropsychiatric examinations and hospital discharge registers. Logistic regression was used to estimate risk. Over the period of 5 years, 20 individuals developed major and 63 minor depression. Presence of temporal lobe atrophy (odds ratio (OR)=2.81, 95% confidence interval (CI) 1.04–7.62) and moderate-to-severe WMLs (OR=3.21, 95% CI 1.00–10.26) independently predicted major, but not minor, depression after controlling for various confounders. Other brain changes did not predict occurrence of depression. Our findings suggest that temporal lobe atrophy and WMLs represent relatively independent and complementary pathways to major depression in the elderly. This may have implications for prevention, as both neurodegeneration and cerebrovascular disease have been related to preventable factors

Quantification of parenchymal calcifications in chronic pancreatitis: relation to atrophy, ductal changes, fibrosis and clinical parameters

OBJECTIVES: Parenchymal calcifications are considered a hallmark finding of chronic pancreatitis (CP), but little is known about its relation to the clinical presentation and other morphological features such as atrophy, fibrosis and ductal changes. The aim was to quantify the number and maximal size of parenchymal calcifications assessed on computed tomography (CT) and to explore the association with other CT and magnetic resonance imaging (MRI)-based pancreatic features and clinical parameters.METHODS: A well-characterised cohort of 54 CP patients was included. CT measurements included number and size of parenchymal calcifications, gland diameter and ductal diameter. MRI measurements included gland volume, ductal diameter, fibrosis (diffusion) and fatty infiltration (Dixon). Clinical parameters included body mass index (BMI), CP duration and aetiology, M-ANNHEIM clinical stage, tobacco use, alcohol consumption, the presence of diabetes, faecal elastase, clinical pain score and quality of life.RESULTS: There were no correlations between the number and size of parenchymal calcifications and any of the other morphological CT and MRI parameters (all p &gt; .05), except for larger size of calcifications in patients with high number of calcifications (p &lt; .001). The number of parenchymal calcifications was negatively correlated with BMI (r = -0.35, p = .0088). The number and size of parenchymal calcifications did not correlate with any of the other clinical parameters (all p &gt; .2).CONCLUSION: Our findings could indicate the existence of parenchymal calcifications as an independent pathophysiological process involved in the development of CP. Translational impact: Quantifications of calcifications could, in combination with other imaging biomarkers, be a useful imaging marker relevant for characterising CP.</p

Computerized training of working memory in children with ADHD—a randomized, controlled trial,”

ABSTRACT 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 (&gt;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 postintervention 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