The Editor and Associate Editors would like to warmly thank the following colleagues who kindly a... more The Editor and Associate Editors would like to warmly thank the following colleagues who kindly acted as reviewers of one or more manuscripts between 1 October 2011 and 30 September 2012. Their professionalism and support for both authors and the Editorial Board are much appreciated.
Our representation of the visual world can be modulated by spatially specific attentional biases ... more Our representation of the visual world can be modulated by spatially specific attentional biases that depend flexibly on task goals. We compared searching for task-relevant features in perceived versus remembered objects. When searching perceptual input, selected task-relevant and suppressed task-irrelevant features elicited contrasting spatiotopic ERP effects, despite them being perceptually identical. This was also true when participants searched a memory array, suggesting that memory had retained the spatial organization of the original perceptual input and that this representation could be modulated in a spatially specific fashion. However, task-relevant selection and task-irrelevant suppression effects were of the opposite polarity when searching remembered compared to perceived objects. We suggest that this surprising result stems from the nature of feature- and object-based representations when stored in visual short-term memory. When stored, features are integrated into objects, meaning that the spatially specific selection mechanisms must operate upon objects rather than specific feature-level representations.
Annals of Clinical and Translational Neurology, 2015
Systematic investigation of individuals with intellectual disability after genetic diagnosis can ... more Systematic investigation of individuals with intellectual disability after genetic diagnosis can illuminate specific phenotypes and mechanisms relevant to common neurodevelopmental disorders. We report the neurological, cognitive and neuroanatomical characteristics of nine males from three families with loss-of-function mutations in ZDHHC9 (OMIM #300799). All known cases of X-linked intellectual disability (XLID) due to ZDHHC9 mutation in the United Kingdom were invited to participate in a study of neurocognitive and neuroimaging phenotypes. Seven out of nine males with ZDHHC9 mutations had been diagnosed with epilepsy, exceeding epilepsy risk in XLID comparison subjects (P = 0.01). Seizure histories and EEG features amongst ZDHHC9 mutation cases shared characteristics with rolandic epilepsy (RE). Specific cognitive deficits differentiated males with ZDHHC9 mutations from XLID comparison subjects and converged with reported linguistic and nonlinguistic deficits in idiopathic RE: impaired oromotor control, reduced verbal fluency, and impaired inhibitory control on visual attention tasks. Consistent neuroanatomical abnormalities included thalamic and striatal volume reductions and hypoplasia of the corpus callosum. Mutations in ZDHHC9 are associated with susceptibility to focal seizures and specific cognitive impairments intersecting with the RE spectrum. Neurocognitive deficits are accompanied by consistent abnormalities of subcortical structures and inter-hemispheric connectivity. The biochemical, cellular and network-level mechanisms responsible for the ZDHHC9-associated neurocognitive phenotype may be relevant to cognitive outcomes in RE.
Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual... more Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual disability (ID) and have recently been associated with neuropsychiatric risk in the non-ID population. However, it is not known whether risk for psychiatric symptoms amongst individuals with ID due to MAGUK gene mutations is higher than expected for the degree of general intellectual impairment, nor whether specific cognitive differences are associated with disruption to this gene functional network. This study addresses these two questions via behavioural questionnaires and cognitive testing, applying quantitative methods previously validated in populations with ID. We compared males with X-linked ID caused by mutations in three MAGUK genes (PAK3, DLG3, OPHN1; n = 9) to males with ID caused by mutations in other X chromosome genes (n = 17). Non-parametric and parametric analyses were applied as appropriate to data. Groups did not differ in age, global cognitive impairment, adaptive fun...
Functional connectivity is the statistical association of neuronal activity time courses across d... more Functional connectivity is the statistical association of neuronal activity time courses across distinct brain regions, supporting specific cognitive processes. This coordination of activity is likely to be highly important for complex aspects of cognition, such as the communication of fluctuating task goals from higher-order control regions to lower-order, functionally specific regions. Some of these functional connections are identifiable even when relevant cognitive tasks are not being performed (i.e. at rest). We used magnetoencephalographic recordings projected into source space to demonstrate that resting state networks in childhood have electrophysiological underpinnings that are evident in the spontaneous fluctuations of oscillatory brain activity. Using the temporal structure of these oscillatory patterns we were able to identify a number of functional resting state networks analogous to those reported in the adult literature. In a second analysis we fused this dynamic temporal information with the spatial information from a functional magnetic resonance imaging analysis of functional connectivity, to demonstrate that inter-subject variability in these electrophysiological measures of functional connectivity is correlated with individual differences in cognitive ability: the strength of connectivity between a fronto-parietal network and lower-level processing areas in inferior temporal cortex was associated with spatial working memory capacity, as measured outside the scanner with educationally relevant standardized assessments. This study represents the first exploration of the electrophysiological mechanisms underpinning resting state functional connectivity in source space in childhood, and the extent to which the strength of particular connections is associated with cognitive ability.
The Editor and Associate Editors would like to warmly thank the following colleagues who kindly a... more The Editor and Associate Editors would like to warmly thank the following colleagues who kindly acted as reviewers of one or more manuscripts between 1 October 2011 and 30 September 2012. Their professionalism and support for both authors and the Editorial Board are much appreciated.
Our representation of the visual world can be modulated by spatially specific attentional biases ... more Our representation of the visual world can be modulated by spatially specific attentional biases that depend flexibly on task goals. We compared searching for task-relevant features in perceived versus remembered objects. When searching perceptual input, selected task-relevant and suppressed task-irrelevant features elicited contrasting spatiotopic ERP effects, despite them being perceptually identical. This was also true when participants searched a memory array, suggesting that memory had retained the spatial organization of the original perceptual input and that this representation could be modulated in a spatially specific fashion. However, task-relevant selection and task-irrelevant suppression effects were of the opposite polarity when searching remembered compared to perceived objects. We suggest that this surprising result stems from the nature of feature- and object-based representations when stored in visual short-term memory. When stored, features are integrated into objects, meaning that the spatially specific selection mechanisms must operate upon objects rather than specific feature-level representations.
Annals of Clinical and Translational Neurology, 2015
Systematic investigation of individuals with intellectual disability after genetic diagnosis can ... more Systematic investigation of individuals with intellectual disability after genetic diagnosis can illuminate specific phenotypes and mechanisms relevant to common neurodevelopmental disorders. We report the neurological, cognitive and neuroanatomical characteristics of nine males from three families with loss-of-function mutations in ZDHHC9 (OMIM #300799). All known cases of X-linked intellectual disability (XLID) due to ZDHHC9 mutation in the United Kingdom were invited to participate in a study of neurocognitive and neuroimaging phenotypes. Seven out of nine males with ZDHHC9 mutations had been diagnosed with epilepsy, exceeding epilepsy risk in XLID comparison subjects (P = 0.01). Seizure histories and EEG features amongst ZDHHC9 mutation cases shared characteristics with rolandic epilepsy (RE). Specific cognitive deficits differentiated males with ZDHHC9 mutations from XLID comparison subjects and converged with reported linguistic and nonlinguistic deficits in idiopathic RE: impaired oromotor control, reduced verbal fluency, and impaired inhibitory control on visual attention tasks. Consistent neuroanatomical abnormalities included thalamic and striatal volume reductions and hypoplasia of the corpus callosum. Mutations in ZDHHC9 are associated with susceptibility to focal seizures and specific cognitive impairments intersecting with the RE spectrum. Neurocognitive deficits are accompanied by consistent abnormalities of subcortical structures and inter-hemispheric connectivity. The biochemical, cellular and network-level mechanisms responsible for the ZDHHC9-associated neurocognitive phenotype may be relevant to cognitive outcomes in RE.
Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual... more Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual disability (ID) and have recently been associated with neuropsychiatric risk in the non-ID population. However, it is not known whether risk for psychiatric symptoms amongst individuals with ID due to MAGUK gene mutations is higher than expected for the degree of general intellectual impairment, nor whether specific cognitive differences are associated with disruption to this gene functional network. This study addresses these two questions via behavioural questionnaires and cognitive testing, applying quantitative methods previously validated in populations with ID. We compared males with X-linked ID caused by mutations in three MAGUK genes (PAK3, DLG3, OPHN1; n = 9) to males with ID caused by mutations in other X chromosome genes (n = 17). Non-parametric and parametric analyses were applied as appropriate to data. Groups did not differ in age, global cognitive impairment, adaptive fun...
Functional connectivity is the statistical association of neuronal activity time courses across d... more Functional connectivity is the statistical association of neuronal activity time courses across distinct brain regions, supporting specific cognitive processes. This coordination of activity is likely to be highly important for complex aspects of cognition, such as the communication of fluctuating task goals from higher-order control regions to lower-order, functionally specific regions. Some of these functional connections are identifiable even when relevant cognitive tasks are not being performed (i.e. at rest). We used magnetoencephalographic recordings projected into source space to demonstrate that resting state networks in childhood have electrophysiological underpinnings that are evident in the spontaneous fluctuations of oscillatory brain activity. Using the temporal structure of these oscillatory patterns we were able to identify a number of functional resting state networks analogous to those reported in the adult literature. In a second analysis we fused this dynamic temporal information with the spatial information from a functional magnetic resonance imaging analysis of functional connectivity, to demonstrate that inter-subject variability in these electrophysiological measures of functional connectivity is correlated with individual differences in cognitive ability: the strength of connectivity between a fronto-parietal network and lower-level processing areas in inferior temporal cortex was associated with spatial working memory capacity, as measured outside the scanner with educationally relevant standardized assessments. This study represents the first exploration of the electrophysiological mechanisms underpinning resting state functional connectivity in source space in childhood, and the extent to which the strength of particular connections is associated with cognitive ability.
Knowledge of genetic cause in neurodevelopmental disorders can highlight molecular and cellular p... more Knowledge of genetic cause in neurodevelopmental disorders can highlight molecular and cellular processes critical for typical development. Furthermore, the relative homogeneity of neurodevelopmental disorders of known genetic origin allows the researcher to establish the subsequent neurobiological processes that mediate cognitive and behavioural outcomes. The current study investigated white matter structural connectivity in a group of individuals with intellectual disability due to mutations in ZDHHC9. In addition to shared cause of cognitive impairment, these individuals have a shared cognitive profile, involving oro-motor control difficulties and expressive language impairment. Analysis of structural network properties using graph theory measures showed global reductions in mean clustering coefficient and efficiency in the ZDHHC9 group, with maximal differences in frontal and parietal areas. Regional variation in clustering coefficient and local efficiency across cortical regions in cases and controls were significantly associated with known pattern of expression of ZDHHC9 in the normal adult human brain. The results demonstrate that a mutation in a single gene impacts upon white matter organisation across the whole-brain, but also shows regionally specific effects, according to variation in gene expression. Furthermore, these regionally specific patterns may link to specific developmental mechanisms, and correspond to specific cognitive deficits.
Knowledge of genetic cause in neurodevelopmental disorders can highlight molecular and cellular p... more Knowledge of genetic cause in neurodevelopmental disorders can highlight molecular and cellular processes critical for typical development. The current study investigated white matter structural con-nectivity in a group of individuals with mutations in ZDHHC9. These individuals have a shared cogni-tive profile, involving oro-motor control difficulties and expressive language impairment [1]. Analysis of structural network properties using graph theory measures showed global reductions in mean clustering coefficient and efficiency in the ZDHHC9 group, with maximal differences in frontal and parietal areas. Regional variation in clustering coefficient and local efficiency were associated with ZDHHC9 expression , but not expression of comparison genes (GAPDH, FMR1, GRIN2A). An inverse relationship was observed for FOXP2, another gene associated with speech and language differences. The results demonstrate that a mutation in a single gene may impact on white matter organisation across the whole-brain, but with regionally specific effects reflecting developmental mechanism and corresponding to specific cognitive deficits.
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