Enrichment of rare copy number variation in children with developmental language disorder.

Developmental language disorder (DLD) is a common neurodevelopmental disorder with largely unknown etiology. Rare copy number variants (CNVs) have been implicated in the genetic architecture of other neurodevelopmental disorders (NDDs), which have led to clinical genetic testing recommendations for these disorders; however, the evidence is still lacking for DLD. We analyzed rare and de novo CNVs in 58 probands with severe DLD, their 159 family members and 76 Swedish typically developing children using high-resolution microarray. DLD probands had larger rare CNVs as measured by total length (P = .05), and average length (P = .04). In addition, the rate of rare CNVs overlapping coding genes was increased (P = .03 and P = .01) and in average more genes were affected (P = .006 and P = .03) in the probands and their siblings, respectively. De novo CNVs were found in 4.8% DLD probands (2/42) and 2.4% (1/42) siblings. Clinically significant CNVs or chromosomal anomalies were found in 6.9% (4/58) of the probands of which 2 carried 16p11.2 deletions. We provide further evidence that rare CNVs contribute to the etiology of DLD in loci that overlap with other NDDs. Based on our results and earlier literature, families with DLD should be offered molecular genetic testing as a routine in their clinical follow-up.

Interaction between striatal volume and DAT1 polymorphism predicts working memory development during adolescence.

There is considerable inter-individual variability in the rate at which working memory (WM) develops during childhood and adolescence, but the neural and genetic basis for these differences are poorly understood. Dopamine-related genes, striatal activation and morphology have been associated with increased WM capacity after training. Here we tested the hypothesis that these factors would also explain some of the inter-individual differences in the rate of WM development. We measured WM performance in 487 healthy subjects twice: at age 14 and 19. At age 14 subjects underwent a structural MRI scan, and genotyping of five single nucleotide polymorphisms (SNPs) in or close to the dopamine genes DRD2, DAT-1 and COMT, which have previously been associated with gains in WM after WM training. We then analyzed which biological factors predicted the rate of increase in WM between ages 14 and 19. We found a significant interaction between putamen size and DAT1/SLC6A3 rs40184 polymorphism, such that TC heterozygotes with a larger putamen at age 14 showed greater WM improvement at age 19. The effect of the DAT1 polymorphism on WM development was exerted in interaction with striatal morphology. These results suggest that development of WM partially share neuro-physiological mechanism with training-induced plasticity.

Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development.

A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene-brain-behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ~6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development.

Visual working memory influences the performance in virtual image-guided surgical intervention.

BACKGROUND: This study addresses for the first time the relationship between working memory and performance measures in image-guided instrument navigation with Minimally Invasive Surgical Trainer-Virtual Reality (MIST-VR) and GI Mentor II (a simulator for gastroendoscopy). In light of recent research on simulator training, it is now prime time to ask why in a search for mechanisms rather than show repeatedly that conventional curriculum for simulation training has effect. METHODS: The participants in this study were 28 Swedish medical students taking their course in basic surgery. Visual and verbal working memory span scores were assessed by a validated computer program (RoboMemo) and correlated with visual-spatial ability (MRT-A test), total flow experience (flow scale), mental strain (Borg scale), and performance scores in manipulation and diathermy (MD) using Procedicus MIST-VR and GI Mentor 11 (exercises 1 and 3). RESULTS: Significant Pearson's r correlations were obtained between visual working memory span scores for visual data link (a RoboMemo exercise) and movement economy (r = -0.417; p < 0.05), total time (r = -0.495; p < 0.01), and total score (r = -0.390; p < 0.05) using MIST-MD, as well as total time (r = -0.493; p < 0.05) and efficiency of screening (r = 0.469; p < 0.05) using GI Mentor 11 (exercise 1). Correlations also were found between visual working memory span scores in rotating data link (another RoboMemo exercise) and both total time (r = -0.467; p < 0.05) and efficiency of screening (r = -0.436; p < 0.05) using GI Mentor 11 (exercise 3). Significant Pearson's r correlations also were found between visual-spatial ability scores and several performance scores for the MIST and GI Mentor II exercises. CONCLUSIONS: Findings for the first time demonstrate that visual working memory for surgical novices may be important for performance in virtual simulator training with two well-known and validated simulators.

Computerized working memory training after stroke--a pilot study.

AIM: To examine the effects of working memory (WM) training in adult patients with stroke. METHODS: A randomized pilot study with a treatment group and a passive control group; 18 participants (12 males) in a vocational age group (mean age 54 years) were randomized to either the treatment or the control condition. The intervention consisted of computerized training on various WM tasks for five weeks. A neuropsychological test battery and self-rating on cognitive functioning in daily life (the CFQ) were administered both before and after the treatment. RESULTS: Statistically significant training effects were found on the non-trained tests for WM and attention, i.e., tests that measure related cognitive functions but are not identical to tasks in the training programme (Span board p < 0.05; PASAT p < 0.001; Ruff 2&7 p < 0.005). There was a significant decrease in symptoms of cognitive problems as measured by the CFQ (p < 0.005). CONCLUSION: More than one year after a stroke, systematic WM training can significantly improve WM and attention.

A biophysical model of multiple-item working memory: a computational and neuroimaging study.

Biophysically based computational models have successfully accounted for the persistent neural activity underlying the maintenance of single items of information in working memory. The aim of the present study was to extend previous models in order to retain multiple items, in agreement with the observed human storage capacity. This was done by implementing cellular mechanisms known to occur during the childhood development of working memory, such as an increased synaptic strength and improved contrast and specificity of the neural response. Our computational study shows that these mechanisms are sufficient to create a neural network which can store information about multiple items through sustained neural activity. Furthermore, by using functional magnetic resonance imaging, we found that the information-activity curve predicted by the model corresponds to that in the human posterior parietal cortex during performance of working memory tasks, which is consistent with previous studies of brain activity related to working memory capacity in humans.

Neural correlates of dual task interference can be dissociated from those of divided attention: an fMRI study.

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.

Activity in motor areas while remembering action events.

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.

Microstructure of temporo-parietal white matter as a basis for reading ability: evidence from diffusion tensor magnetic resonance imaging.

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.

A resource model of the neural basis of executive working memory.

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.

Myelination and organization of the frontal white matter in children: a diffusion tensor MRI study.

Myelination is critical for the functional development of the brain, but the time course of myelination during childhood is not well known. Diffusion tensor MR imaging (DTI) provides a new method for estimating myelination in vivo. Myelin restricts diffusion of water transverse to the axons, causing diffusion to be anisotropic. By quantifying the anisotropy, the progressive myelination of axons can be studied. Central white matter of the frontal lobe was studied in seven children (mean age 10 years) and five adults (mean age 27 years). Anisotropy in the frontal white matter was significantly lower in children than in adults, suggesting less myelination in children. Measurement of the coherence of white matter revealed that the right frontal lobe had a more regular organization of axons than the left frontal lobe, in both children and adults. The results demonstrate that maturation of the frontal white matter continues into the second decade of life. The time course of prefrontal maturation makes it possible that myelination is a basis for the gradual development of prefrontal functions, such as increased working memory capacity.

Concurrent performance of two working memory tasks: potential mechanisms of interference.

When two tasks are performed simultaneously, performance often deteriorates, with concomitant increases in reaction time and error rate. Three potential neurophysiological mechanisms behind this deterioration in performance have been considered here: (i) dual-task performance requires additional cognitive operations and activation of cortical areas in addition to those active during single-task performance; (ii) two tasks interfere if they require activation of the same part of cortex; and (iii) cross-modal inhibition causes interference between two tasks involving stimuli from different sensory modalities. Positron emission tomography was used to measure regional cerebral blood flow (rCBF) during performance of an auditory working memory (WM) task, a visual WM task, both WM tasks (dual task) and a control condition. Compared to the control condition, the auditory and visual WM tasks activated sensory-specific areas in the superior temporal gyrus and occipital pole respectively. Both WM tasks also activated overlapping parts of cortex in the dorsolateral prefrontal, inferior parietal and cingulate cortex. There was no separate cortical area which was activated only in the dual task, and thus no area which could be associated with any dual task specific cognitive process such as task-coordination or divided attention. Decrease in rCBF in one WM task did not overlap with the areas of rCBF increase in the other WM task. However, an inhibitory mechanism could not be ruled out, since the rCBF increase in sensory specific areas was smaller in the dual-task condition than in the single-task conditions. The cortical activity underlying WM was to a large extent organized in a non-sensory specific, or non-parallel, way, and the results are consistent with the hypothesis that concurrent tasks interfere with each other if they demand activation of the same part of cortex.

Right prefrontal activation during encoding, but not during retrieval, in a non-verbal paired-associates task.

Brain imaging studies have shown that episodic encoding into long-term memory preferentially activates the left prefrontal cortex and retrieval activates the right prefrontal cortex. However, it is unclear to what degree verbal analysis contributes to the left prefrontal activation during encoding. The present study was designed to avoid verbal analysis during encoding by using abstract pictures and computer-generated sounds which were difficult to code verbally. Sounds and pictures were grouped into six stimulus-stimulus pairs. When the sound from a pair was presented, the subjects were instructed to recall and visualize the associated picture. After 2.0 s the associated picture and another picture appeared on the screen and the subjects were required to identify the associated picture. Feedback about the choice was then given. Regional cerebral blood flow (rCBF) was measured with [15O]butanol and positron emission tomography (PET) in 10 subjects during initial training on the paired-associates task (encoding scan) and after 35 min of training (retrieval scan). Performance during the encoding scan was 59% correct and during the retrieval scan 98% correct, with a mean reaction time of 709 ms during retrieval. The rCBF was also measured during a control condition without any instruction to encode or retrieve. Compared with retrieval, encoding showed significant activation of the posterior part of the right middle frontal gyrus, the right inferior parietal cortex, the cingulate cortex, the left inferior parietal cortex and the left inferior and middle temporal gyri. The rCBF increase during encoding was strongly correlated with the rate of encoding. Retrieval was compared with both encoding and control. In none of these comparisons was there any prefrontal activation. The lack of prefrontal activation during near-perfect performance of the retrieval task suggests that the prefrontal cortex is not necessarily active when retrieval is fast and accurate, or what might be called automatic. Encoding was not associated with more activation of the left than the right prefrontal cortex. This result presents a limitation to the generality of left prefrontal activation during episodic encoding, which has been found in several previous brain imaging studies. Differences between studies in the relative activation of left and right prefrontal cortex during encoding and retrieval might be due to differences in paradigms, the type of stimulus used, and the demand for working memory and verbal analysis.

Interference between two concurrent tasks is associated with activation of overlapping fields in the cortex.

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.

Bilateral activation of fronto-parietal networks by incrementing demand in a working memory task.

Working memory (WM) is known to activate the prefrontal cortex. In the present study we hypothesized that when additional contingencies are added to the instruction of a WM task, this would increase the WM load and result in the activation of additional prefrontal areas. With positron emission tomography we measured regional cerebral blood flow in nine subjects performing a control task and two delayed matching to sample tasks, in which the subjects were matching colours and patterns to a reference picture. The second of the two delayed matching tasks had a more complex instruction than the first, with additional contingencies of how to alternate between the matching of colours and patterns. This task thus required the subjects not only to remember a stimulus to match but also to perform this matching according to a specified plan. Both delayed matching tasks activated cortical fields in the middle frontal gyrus, the frontal operculum, upper cingulate gyrus, inferior parietal cortex and cortex lining the intraparietal sulcus, all in the left hemisphere. When alternated delayed matching was compared to simple delayed matching, increases were located in the right superior and middle frontal gyrus and the right anterior inferior parietal cortex. The increased demand during alternated matching thus resulted in bilateral activation of both dorsolateral prefrontal and inferior parietal cortex. The area in the inferior parietal cortex has previously been coactivated with the dorsolateral prefrontal cortex in several WM tasks, irrespective of the sensory modality of the stimuli, and during tasks involving planning.

Activation of multi-modal cortical areas underlies short-term memory.

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.

Two different areas within the primary motor cortex of man.

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.

The human entorhinal cortex participates in associative memory.

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.