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 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 function or epilepsy prevalence. However, individuals with MAGUK gene mutations demonstrated significantly higher psychopathology risks, comprising elevated total problem behaviours, prominent hyperactivity and elevated scores on an autism screening checklist. Despite these overt difficulties, individuals in the MAGUK group performed more accurately than expected for age and intelligence quotient (IQ) on computerised tests of visual attention, convergent with mouse models of MAGUK loss-of-function.
Our findings support a role for MAGUK genes in influencing cognitive parameters relevant to psychiatric risk. In addition to establishing clear patterns of impairment for this group, our findings highlight the importance of careful phenotyping after genetic diagnosis, showing that gene functional network disruptions can be associated with specific psychopathological risks and cognitive differences within the context of ID.
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The online version of this article (doi:10.1186/s11689-015-9105-x) contains supplementary material, which is available to authorized users.
MAGUK; Intellectual disability; Genetics; Cognition; Psychiatric disorders; DLG3
Our ability to hold information in mind is limited, requires a high degree of cognitive control, and is necessary for many subsequent cognitive processes. Children, in particular, are highly variable in how, trial-by-trial, they manage to recruit cognitive control in service of memory. Fronto-parietal networks, typically recruited under conditions where this cognitive control is needed, undergo protracted development. We explored, for the first time, whether dynamic changes in fronto-parietal activity could account for children's variability in tests of visual short-term memory (VSTM). We recorded oscillatory brain activity using magnetoencephalography (MEG) as 9- to 12-year-old children and adults performed a VSTM task. We combined temporal independent component analysis (ICA) with general linear modeling to test whether the strength of fronto-parietal activity correlated with VSTM performance on a trial-by-trial basis. In children, but not adults, slow frequency theta (4–7 Hz) activity within a right lateralized fronto-parietal network in anticipation of the memoranda predicted the accuracy with which those memory items were subsequently retrieved. These findings suggest that inconsistent use of anticipatory control mechanism contributes significantly to trial-to-trial variability in VSTM maintenance performance.
cognitive control; cognitive development; development; executive control; magnetoencephalography
Visual search is often guided by top-down attentional templates that specify target-defining features. But search can also occur at the level of object categories. We measured the N2pc component, a marker of attentional target selection, in two visual search experiments where targets were defined either categorically (e.g., any letter), or at the item level (e.g., the letter C) by a prime stimulus. In both experiments, an N2pc was elicited during category search, in both familiar and novel contexts (Experiment 1) and with symbolic primes (Experiment 2), indicating that even when targets are only defined at the category level, they are selected at early sensory-perceptual stages. However, the N2pc emerged earlier and was larger during item-based search compared to category-based search, demonstrating the superiority of attentional guidance by item-specific templates. We discuss the implications of these findings for attentional control and category learning.
Sex chromosome trisomies (SCTs) are found on amniocentesis in 2.3–3.7 per 1000 same-sex births, yet there is a limited database on which to base a prognosis. Autism has been described in postnatally diagnosed cases of Klinefelter syndrome (XXY karyotype), but the prevalence in non-referred samples, and in other trisomies, is unclear. The authors recruited the largest sample including all three SCTs to be reported to date, including children identified on prenatal screening, to clarify this issue.
Parents of children with a SCT were recruited either via prenatal screening or via a parental support group, to give a sample of 58 XXX, 19 XXY and 58 XYY cases. Parents were interviewed using the Vineland Adaptive Behavior Scales and completed questionnaires about the communicative development of children with SCTs and their siblings (42 brothers and 26 sisters).
Rates of language and communication problems were high in all three trisomies. Diagnoses of autism spectrum disorder (ASD) were found in 2/19 cases of XXY (11%) and 11/58 XYY (19%). After excluding those with an ASD diagnosis, communicative profiles indicative of mild autistic features were common, although there was wide individual variation.
Autistic features have not previously been remarked upon in studies of non-referred samples with SCTs, yet the rate is substantially above population levels in this sample, even when attention is restricted to early-identified cases. The authors hypothesise that X-linked and Y-linked neuroligins may play a significant role in the aetiology of communication impairments and ASD.
Theories of attention-deficit/hyperactivity disorder (ADHD) posit either executive deficits and/or alterations in motivational style and reward processing as core to the disorder. Effects of motivational incentives on electrophysiological correlates of inhibitory control and relationships between motivation and stimulant medication have not been explicitly tested.
Children (9–15 years) with combined-type ADHD (n = 28) and matched typically developing children (CTRL) (n = 28) performed a go/no-go task. Electroencephalogram data were recorded. Amplitude of two event-related potentials, the N2 and P3 (markers of response conflict and attention), were measured. The ADHD children were all stimulant responders tested on and off their usual dose of methylphenidate; CTRLs were never medicated. All children performed the task under three motivational conditions: reward; response cost; and baseline, in which points awarded/deducted for inhibitory performance varied.
There were effects of diagnosis (CTRL > ADHD unmedicated), medication (on > off), and motivation (reward and/or response cost > baseline) on N2 and P3 amplitude, although the N2 diagnosis effect did not reach statistical significance (p = .1). Interactions between motivation and diagnosis/medication were nonsignificant (p > .1).
Motivational incentives increased amplitudes of electrophysiological correlates of response conflict and attention in children with ADHD, towards the baseline (low motivation) amplitudes of control subjects. These results suggest that, on these measures, motivational incentives have similar effects in children with ADHD as typically developing CTRLs and have additive effects with stimulant medication, enhancing stimulus salience and allocation of attentional resources during response inhibition.
ADHD; electrophysiology; motivation; response inhibition; stimulant medication
Previous studies have shown smaller brain volume and less gray matter in children with attention-deficit/hyperactivity disorder (ADHD). Relatively few morphological studies have examined structures thought to subserve inhibitory control, one of the diagnostic features of ADHD. We examined one such region, the pars opercularis, predicting a thinner cortex of the inferior frontal gyrus (IFG) in children with ADHD.
Structural images were obtained from 49 children (24 control; 25 ADHD combined subtype) aged 9 though 15 years. Images were processed using a volumetric pipeline to provide a fully automated estimate of regional volumes of gray and white matter. A further analysis using FreeSurfer provided measures of cortical thickness for each lobe, and for 13 regions in the frontal lobe.
Relative to controls, children with ADHD had smaller whole brain volume and lower gray matter, but not white matter, volumes in all lobes. An analysis of frontal regions showed a significant interaction of group by region. Planned contrasts showed bilateral thinner cortex in the pars opercularis in children with ADHD.
Children with ADHD showed both diffuse and regional gray matter abnormalities. Consistent with its putative role in response inhibition, the cortex of the pars opercularis was thinner in children with ADHD who, as expected, had significantly poorer inhibitory performance on a Go/No-go task. These differences held for both hemispheres raising the possibility that a developmental abnormality of IFG might drive development of inhibition difficulties.
Attention-deficit/hyperactivity disorder; MRI; Cortical thickness; Inferior frontal gyrus; Gray matter
Previous research has examined our ability to attend selectively to particular features of perceptual objects, as well as our ability to switch from attending to one type of feature to another. This is usually done in the context of anticipatory attentional-set control, comparing the neural mechanisms involved as participants prepare to attend to the same stimulus feature as on the previous trial (“task-stay” trials) with those required as participants prepare to attend to a different stimulus feature to that previously attended (“task-switch” trials). We wanted to establish how participants maintain or switch attentional set retrospectively, as they attend to features of objects held in visual short-term memory (VSTM). We found that switching, relative to maintaining attentional set retrospectively, was associated with a performance cost, which can be reduced over time. This control process was mirrored by a large parietal and frontal amplitude difference in the event-related brain potentials (ERPs) and significant differences in global field power (GFP) between switch and stay trials. However, when taking into account the switch/stay GFP differences, thereby controlling for this difference in amplitude, we could not distinguish these trial types topographically. By contrast, we found clear topographic differences between preparing an anticipatory feature-based attentional set versus applying it retrospectively within VSTM. These complementary topographical and amplitude analyses suggested that anticipatory and retrospective set control recruited a qualitatively different configuration of underlying neural generators. In contrast, switch/stay differences were largely quantitative, with them differing primarily in terms of amplitude rather than topography.
The acquisition of volitional control depends, in part, on developing the ability to countermand a planned action. Many tasks have been used to tap the efficiency of this process, but few studies have investigated how it may be modulated by participants’ motivation. Multiple mechanisms may be involved in the deliberate exercise of caution when incentives are provided. For example, control may involve modulation of the efficiency of the countermanding process, and/or inhibitory modulation of the impulse to go. One of the most commonly used paradigms to assess control of action is the Stop Signal Task, in which a primary Go stimulus is occasionally followed by a countermanding Stop signal, allowing a Stop Signal Reaction Time (SSRT) to be inferred as the outcome of a “horse race” between the go and countermanding processes. Here, we present a computational model in which high task motivation modulates proactive pre-stimulus inhibition of the go response. This allows responses to be calibrated so as to fall within a time-window that maximizes the probability of success, regardless of trial type, but does not decrease the observed SSRT. We report empirical support for the model from a sample of typically developing children, and discuss the broader implications for operationalizing measures of volitional control.
Inhibition; Motivation; Stop Signal Reaction Time; Restraint; Control of action
Fragile X syndrome (FXS) is due to the silencing of a single X-linked gene and it is associated with striking attentional difficulties. As FXS is well characterized at the cellular level, the condition provides a unique opportunity to investigate how a genetic dysfunction can impact on the development of neurocomputational properties relevant to attention. Thirteen young boys with FXS and thirteen mental-age-matched typically developing controls performed a touch-screen-based search task that manipulated the similarity between targets and distractors and their heterogeneity in size. Search speed, path and errors were recorded as multiple measures of performance. Children did not differ in overall search speed or path when searching amongst distractors, but striking error patterns distinguished children with FXS from controls. Firstly, although clear markers of previously found targets remained on screen, children with FXS perseverated on touching previous hits more than typically developing controls, consistent with the well-documented inhibitory deficits in adults with the disorder. Secondly, they could accurately discriminate single target-distractor pairs, but, when searching a complex display, they touched distractors more often than control children when distractors were similar to targets and especially so when these were infrequent, highlighting difficulties in judging relative size and allocate attentional weight independently of stimulus frequency. Thirdly, their performance was also characterized by inaccuracies in pointing, suggesting additional motor control deficits. Taken together, the findings suggest that fragile X syndrome affects the early development of multiple processes contributing to efficient attentional selection, as would be predicted from an understanding of the neurocomputational changes associated with the disorder.
atypical development; attentional control; neurocomputational changes
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.
spatial attention; visual short-term memory; working memory; ERPs; electrophysiology; task-set control
Fragile X syndrome (FXS) is due to the silencing of a single X-linked gene and it is associated with striking attentional difficulties. As FXS is well characterised at the cellular level, the condition provides a unique opportunity to investigate how a genetic dysfunction can impact on the development of neurocomputational properties relevant to attention. Thirteen young boys with FXS and 13 mental-age-matched typically developing controls performed a touch-screen-based search task that manipulated the similarity between targets and distractors and their heterogeneity in size. Search speed, path and errors were recorded as multiple measures of performance. Children did not differ in overall search speed or path when searching amongst distractors, but striking error patterns distinguished children with FXS from controls. Firstly, although clear markers of previously found targets remained on screen, children with FXS perseverated on touching previous hits more than typically developing controls, consistent with the well-documented inhibitory deficits in adults with the disorder. Secondly, they could accurately discriminate single target-distractor pairs, but, when searching a complex display, they touched distractors more often than control children when distractors were similar to targets and especially so when these were infrequent, highlighting difficulties in judging relative size and allocate attentional weight independently of stimulus frequency. Thirdly, their performance was also characterised by inaccuracies in pointing, suggesting additional motor control deficits. Taken together, the findings suggest that fragile X syndrome affects the early development of multiple processes contributing to efficient attentional selection, as would be predicted from an understanding of the neurocomputational changes associated with the disorder.
Atypical development; Attentional control; Neurocomputational changes
To review systematically the neurodevelopmental characteristics of individuals with sex chromosome trisomies (SCTs).
A bibliographic search identified English-language articles on SCTs. The focus was on studies unbiased by clinical referral, with power of at least 0.69 to detect an effect size of 1.0.
We identified 35 articles on five neonatally identified samples that had adequate power for our review. An additional 11 studies were included where cases had been identified for reasons other than neurodevelopmental concerns. Individuals with an additional X chromosome had mean IQs that were within broadly normal limits but lower than the respective comparison groups, with verbal IQ most affected. Cognitive outcomes were poorest for females with XXX. Males with XYY had normal-range IQs, but all three SCT groups (XXX, XXY, and XYY) had marked difficulties in speech and language, motor skills, and educational achievement. Nevertheless, most adults with SCTs lived independently. Less evidence was available for brain structure and for attention, social, and psychiatric outcomes. Within each group there was much variation.
Individuals with SCTs are at risk of cognitive and behavioural difficulties. However, the evidence base is slender, and further research is needed to ascertain the nature, severity, and causes of these difficulties in unselected samples.
To compare the phenotype in Klinefelter syndrome (KS) with (i) specific language impairment (SLI) and (ii) XXX and XYY trisomies.
Phenotypes of KS, XXX and XYY were based on data from a systematic review of neurodevelopmental outcomes plus a recent parent survey. Phenotype of SLI was based on a published survey of children attending a special school.
There are close similarities between the KS phenotype and SLI. Furthermore, a minority of children with KS have features of autistic spectrum disorder. Similar language and communication problems are seen in the other two sex chromosome trisomies (SCTs), XXX and XYY.
We propose the neurexin–neuroligin hypothesis, based on the observation that neuroligin genes, which occur on both X and Y chromosomes, are involved in the same synaptic networks as neurexin genes with common variants that affect risk for SLI and autism. According to our hypothesis, the effect of a triple dose of neuroligin gene product will be particularly detrimental when it occurs in conjunction with specific variants of neurexin genes on other chromosomes. This speculative proposal demonstrates the potential of illuminating the aetiology of common neurodevelopmental disorders by studying children with SCTs.
Autism; Klinefelter syndrome; Language impairment; Neurexin; Neuroligin; Sex chromosome trisomy
Background Children with attention deficit hyperactivity disorder (ADHD) are characterised by developmentally inappropriate levels of hyperactivity, impulsivity and/or inattention and are particularly impaired when performing tasks that require a high level of cognitive control. Methylphenidate (MPH) and motivational incentives may help improve cognitive control by enhancing the ability to monitor response accuracy and regulate performance accordingly.
Methods Twenty-eight children with DSM-IV ADHD (combined type) aged 9–15 years and pairwise-matched typically developing children (CTRL) performed a go/no-go task in which the incentives attached to performance on no-go trials were manipulated. The ADHD group performed the task off and on their usual dose of MPH. CTRL children performed the task twice but were never medicated. EEG data were recorded simultaneously and two electrophysiological indices of error monitoring, the error-related negativity (ERN) and error positivity (Pe) were measured. Amplitudes of each ERP were compared between diagnostic groups (CTRL, ADHD), medication days (Off MPH, On MPH) and motivational conditions (baseline – low incentive, reward, response cost).
Results Error rates were lower in the reward and response cost conditions compared with baseline across diagnostic groups and medication days. ERN and Pe amplitudes were significantly reduced in ADHD compared with CTRL, and were significantly enhanced by MPH. Incentives significantly increased ERN and Pe amplitudes in the ADHD group but had no effect in CTRL. The effects of incentives did not interact with the effects of MPH on either ERP. Effect sizes were computed and revealed larger effects of MPH than incentives on ERN and Pe amplitudes.
Conclusions The findings reveal independent effects of motivational incentives and MPH on two electrophysiological markers of error monitoring in children with ADHD, suggesting that each may be important tools for enhancing or restoring cognitive control in these children.
ADHD; electrophysiology; error monitoring; motivation; methylphenidate; stimulant medication