Natalie A. Pride

Corpus Callosum Morphology and Its Relationship to Cognitive Function in Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is associated with cognitive dysfunction and structural brain abnormalities such as an enlarged corpus callosum. This study aimed to determine the relationship between corpus callosum morphology and cognitive function in children with neurofibromatosis type 1 using quantitative neuroanatomic imaging techniques. Children with neurofibromatosis type 1 (n = 46) demonstrated a significantly larger total corpus callosum and corpus callosum index compared with control participants (n = 30). A larger corpus callosum index in children with neurofibromatosis type 1 was associated with significantly lower IQ, reduced abstract concept formation, reduced verbal memory, and diminished academic ability, specifically reading and math. Our results suggest an enlarged corpus callosum in children with neurofibromatosis type 1 is associated with cognitive impairment and may provide an early structural marker for the children at risk of cognitive difficulties. Cognitive deficits associated with structural brain abnormalities in neurofibromatosis type 1 are unlikely to be reversible and so may not respond to proposed pharmacological therapies for neurofibromatosis type 1-related cognitive impairments.

The impact of ADHD on the cognitive and academic functioning of children with NF1.

We compared cognitive functioning, academic ability, and the predictors of academic underachievement in children with neurofibromatosis type 1 (NF1) (n = 132), children with NF1 and comorbid attention deficit hyperactivity disorder (NF1 + ADHD) (n = 60), and unaffected controls (n = 52). Results indicate the presence of ADHD burdens some aspects of cognitive functioning and learning in NF1. Inattention and executive dysfunction are general characteristics of the NF1 cognitive phenotype and significantly undermine academic achievement across children with NF1.

Does attention‐deficit–hyperactivity disorder exacerbate executive dysfunction in children with neurofibromatosis type 1?

Aim  Although approximately 40% of children with neurofibromatosis type 1 (NF1) meet diagnostic criteria for attention‐deficit–hyperactivity disorder (ADHD), the impact of ADHD on the executive functioning of children with NF1 is not understood. We investigated whether spatial working memory and response inhibition are impaired in children with NF1 without a diagnosis of ADHD and whether executive deficits are exacerbated in children with a comorbid diagnosis.

The genetic and neuroanatomical basis of social dysfunction: Lessons from neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a common genetic condition associated with cognitive and social dysfunction as well as abnormal brain structure. The pathophysiology underlying social dysfunction in NF1 is poorly understood. Here, we investigate for the first time whether there is a broad deficit of social cognition in NF1 and explore the neural correlates for these deficits. Twenty‐nine adults with NF1 and 30 controls were administered an ecologically based test of social cognition, The Awareness of Social Inference Test (TASIT), to identify deficits in emotion recognition and sarcasm detection. We employed voxel‐based morphometry in a subset of NF1 patients (n = 16) and 16 additional controls to examine the neural correlates of these deficits. Results indicated that adults with NF1 were impaired in their ability to understand paradoxical sarcasm and their capacity to recognize emotion, particularly anger. TASIT performance was not associated with measures of attention, visuospatial skills or executive function. Relative to controls, gray matter (GM) volume within the right superior temporal gyrus (STG) was decreased, after controlling for total brain volume. Decreased volume in this region was significantly associated with social cognitive deficits in adults with NF1. We conclude that patients with NF1 are at high risk for a social cognitive deficit and provide evidence for a neuroanatomical basis for this deficit; GM volumetric reductions in the right STG. These findings improve our understanding of the nature of social interaction impairments in NF1 and add to the growing body of literature indicating the STG as a critical brain region for social cognition. Hum Brain Mapp 35:2372–2382, 2014.

Social functioning in adults with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common single-gene disorder characterised by a diverse range of cutaneous, neurological and neoplastic manifestations. It is well recognised that children with NF1 have poor peer interactions and are at risk for deficits in social skills. Few studies, however, have examined social functioning in adults with NF1. We aimed to determine whether adults with NF1 are at greater risk for impairment in social skills and to identify potential risk factors for social skills deficits. We evaluated social skills in 62 adults with NF1 and 39 controls using self-report and observer-report measures of social behaviour. We demonstrate that adults with NF1 exhibit significantly less prosocial behaviour than controls. This deficit was associated with social processing abilities and was more evident in males. The frequency of antisocial behaviour was comparable between the two groups, however was significantly associated with behavioural regulation in the NF1 group. These findings suggest that poor social skills in individuals with NF1 are due to deficits in prosocial behaviour, rather than an increase in antisocial behaviour. This will aid the design of interventions aimed at improving social skills in individuals with NF1.

Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome

Objective: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3. Methods: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing. Results: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures. Conclusions: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans.

Theory of mind in children with Neurofibromatosis Type 1.

OBJECTIVE Neurofibromatosis Type I (NF1) is a single gene disorder associated with cognitive and behavioral deficits. While there is clear evidence for poorer social outcomes in NF1, the factors underlying reduced social function are not well understood. This study examined theory of mind (ToM) in children with NF1 and unaffected controls. METHOD ToM was assessed in children with NF1 (n = 26) and unaffected controls (n = 36) aged 4-12 years using a nonverbal picture sequencing task. The task assessed understanding of ToM (unrealized goals, false belief, pretence, intention), while controlling for social script knowledge and physical cause-and-effect reasoning. RESULTS Children with NF1 made significantly more errors than unaffected controls on most ToM stories while demonstrating no difficulty sequencing physical cause-and-effect stories. Performance on the picture sequencing task was not related to lower intellectual function, symptoms of attention deficit-hyperactivity disorder (ADHD), or parent ratings of executive function. CONCLUSIONS Results suggest a generalized ToM deficit in children with NF1 that appears to be independent of general cognitive abilities and ADHD symptoms. The study refines understanding of the clinical presentation of NF1 and identifies psychological constructs that may contribute to the higher prevalence of social dysfunction in children with NF1. (PsycINFO Database Record

The Cognitive Profile of NF1 Children: Therapeutic Implications

Neurofibromatosis type 1 (NF1) is a complex multisystem disorder with an autosomal dominant pattern of inheritance and marked clinical variability. In the last 15 years, there have been a number of studies which have influenced our current understanding of the frequency and nature of cognitive deficits in NF1. Collectively, the studies reviewed here reveal that cognitive impairment, learning difficulties, and behavioural disturbances such as attention deficit hyperactivity disorder (ADHD) are highly prevalent and undoubtedly reflect a perturbation of central nervous system functioning. Neuroimaging studies have provided important insight into the structural and functional brain abnormalities involved which include alternations in brain organisation for language and visuospatial function and increased total brain volume, with additional areas of interest including the corpus callosum, cerebral asymmetries, thalamus, and striatum. Recent studies in animal models are also beginning to provide insights into the underlying biochemical mechanisms including abnormal activation of the Ras–MAPK pathway and alternations in neurotransmitters such as dopamine and GABA. These studies are vital to the development of targeted treatment for cognitive deficits in NF1.

Impaired engagement of the ventral attention system in neurofibromatosis type 1

Individuals with neurofibromatosis type 1 (NF1) exhibit significant impairments in attention across multiple domains. Very little is known about the contributing neural networks. We used task-based functional magnetic resonance imaging (fMRI) to examine dorsal and ventral attention networks during auditory oddball processing in children and adolescents with NF1 and typically developing controls. Significant differences in neural activation patterns were identified within brain regions supporting the ventral attention system. Children with NF1 demonstrated hypoactivation in the temporoparietal junction and the anterior cingulate cortex compared to typically developing children. Hypoactivation in the anterior cingulate cortex was associated with poorer selective attention and attentional control in children with NF1. Results indicate an abnormality in bottom-up attention networks in NF1 that may lead to inefficient and faulty suppression of stimulus-driven information outside the current attentional set that play a significant role in the NF1 behavioral phenotype.

The neural basis of deficient response inhibition in children with neurofibromatosis type 1: Evidence from a functional MRI study

Impaired response inhibition is a predominant feature of several neuropsychiatric disorders; in general the underlying aetiology of these disorders and associated impairments is unknown. The common occurrence of impaired response inhibition in a single gene disorder such as neurofibromatosis type 1 (NF1), provides a valuable opportunity to explore its mechanistic basis through the study of gene-brain-behaviour interactions. We used functional brain imaging with a Go/No-Go task to examine the neural substrates of response inhibition in children with NF1 and age and gender matched typically developing subjects. Children with NF1 were found to have abnormal activation patterns in several cortical regions, with significantly reduced activation in the inferior occipital gyrus (IOG), the fusiform gyrus/posterior cerebellum (FG/PC), the pre-supplementary motor area (pre-SMA) and the inferior frontal gyrus (IFG). Importantly, activation in the right IFG was associated with faster task reaction times and impairment in sustained attention in subjects with NF1. Our study supports the hypothesis that a network of regions typically associated with response inhibition is dysfunctional in children with NF1 and suggests this dysfunction is linked to cognitive impairment in this disorder.