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Review
Brain structure and function in neurofibromatosis type 1: current concepts and future directions
  1. Jonathan M Payne1,
  2. Mahendranath D Moharir1,
  3. Richard Webster2,
  4. Kathryn N North1,3
  1. 1Institute for Neuroscience and Muscle Research (INMR), The Children's Hospital at Westmead (Royal Alexandra Hospital for Children), Locked Bag 4001, Westmead NSW 2145, Australia
  2. 2TY Nelson Department of Neurology, The Children's Hospital at Westmead, Westmead, Sydney, Australia
  3. 3Department of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Australia
  1. Correspondence to Professor Kathryn North, Institute for Neuroscience and Muscle Research (INMR), Children's Hospital at Westmead, Locked Bag 4001, Westmead NSW 2145, Sydney, Australia; kathryn{at}chw.edu.au

Abstract

Neurofibromatosis type 1 (NF1) is a common neurogenetic condition associated with cognitive dysfunction and learning disability. Over the past decade, important and consistent findings have emerged that provide insight into the neurobiological correlates of NF1. In this review, we examine the structural and functional neuroimaging literature in individuals with NF1 and discuss findings that have emerged. Collectively, the studies reviewed here highlight structural and functional brain abnormalities as a feature of NF1 and that these abnormalities contribute to the cognitive impairments that are commonly seen. The most compelling structural finding has been an increase in total brain volume with additional areas of interest including the corpus callosum, cerebral asymmetries and differences in grey and white matter. Although the application of functional neuroimaging techniques in NF1 is in its infancy, early evidence suggests alterations in brain organisation for language and visuospatial function as well as thalamic hypometabolism. Suggestions for future research are discussed, including the importance of addressing specific hypotheses in well-defined subsamples of children with NF1 using appropriate control groups. Identifying the underlying neuropathology of NF1 will be of increased importance as targeted interventions begin to emerge.

  • Neurofibromatosis
  • MRI
  • functional imaging
  • paediatric
  • cognition

https://doi.org/10.1136/jnnp.2009.179630

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    Introduction

    Neurofibromatosis type 1 (NF1) is a common genetic condition associated with cognitive impairment and learning disability. The cognitive domains commonly affected include attention, executive function, language and visual perception.1 These cognitive deficits often undermine performance in the academic environment, with learning disabilities estimated to be present in 30–70% of children.2 The presence of cognitive deficits in NF1 has led to an interest in understanding the neurobiological basis of the NF1 cognitive profile. Important and consistent findings in the neuroimaging literature are now emerging which provide insight into the brain–behaviour relationships of this disorder. The goal of this review is to integrate research findings from existing neuroimaging studies, in order to characterise the structural and functional brain phenotype of NF1 and to provide a theoretical basis for future investigations.

    Brain morphology in NF1: structural abnormalities

    Macrocephaly, defined as a head circumference greater than the 95th percentile, occurs in about 50% of children with NF1.3 4 Although hydrocephalus and intracranial masses may cause macrocephaly in a small percentage of NF1 patients, the most common underlying reason for macrocephaly is megalencephaly (ie, large brain volume).5 6 Several MRI studies have examined the relative contributions of grey matter (GM) and white matter (WM) to increased brain size, with variable results (see table 1). Said et al examined in vivo brain volume in 22 children with NF1 compared with a control group and found that the increase in brain volume was mainly attributable to increases in WM volume; in comparison, GM contributed only 6% of the increased brain volume in the NF1 group.7 Steen et al grouped patients with NF1 according to whether they were macrocephalic or normocephalic, and demonstrated increased WM volumes in the macrocephalic group only. GM volumes in both NF1 groups were not significantly different from controls.6 Cutting et al compared brain volumes of children with NF1, both with and without attention-deficit/hyperactivity disorder (ADHD). Increased frontal and parietal WM was identified as a significant contributor to megalencephaly in the NF1 without ADHD group; however, this effect was not seen in patients with NF1 and ADHD.5 In contrast, Moore et al did not find any significant increase in WM volumes in a larger cohort, but did find an increase in GM volumes in the NF1 group when compared with controls.8 The ratio of GM to WM was found to diminish over time, so that by the age of 15 years, the ratio approached that seen in control participants.

    View this table:
    Table 1

    Summary of volumetric studies indicating percentage changes in total white matter and grey matter in children with NF1 relative to controls

    Greenwood et al measured GM and WM volumes of 16 parcellation regions (approximating lobar regions of the brain) in children with NF1.9 Right- and left-hemisphere volumes, total GM and WM volume were significantly greater in children with NF1, compared with controls. Increased GM volumes were present in regions that approximated parietal and occipital cortices, areas involved in visuospatial cognition.10 In contrast, there were increased volumes of WM in more anterior regions of the brain—approximating posterior aspects of the frontal lobes, orbitofrontal cortex and anterior temporal areas.

    There is increasing interest in the contribution of the corpus callosum to increased WM volumes, with the majority of studies reporting an NF1-related increase in total corpus callosum volume.5 6 8 11 12 One study has reported correlations between larger corpus callosum volume and the severity of learning disability.8 In contrast, smaller corpus callosum volumes have also been associated with more severe attention problems in children with NF1 and ADHD.12

    Unfortunately, many of the brain morphology studies lack strict control of confounding variables, making it difficult to compare findings. For example, studies often include large age ranges which complicate interpretation of volumetric data and make it difficult to draw conclusions from a developmental perspective. Some studies were biased by gender or included patients with brain tumours.5 8 Likewise, the nature of the control group varies between non-genetically related,6 7 partly genetically related8 12 and family-matched genetic controls.9

    Given the broad-ranging brain abnormalities in children with NF1, a number of studies have sought to determine neuroanatomical bases for the observed neuropsychological impairments.6–9 12–15 Moore et al reported that children with increased GM volumes showed greater discrepancies between their level of intelligence and academic achievement.8 In contrast, Said et al reported correlations between greater right hemisphere GM volume and superior visuospatial performance.7 Steen et al found a positive correlation between T1 relaxation values of the thalamic pulvinar and IQ scores, so that children with a lower IQ had a tendency towards shorter relaxation times.6 The authors hypothesised that shortened T1 relaxation times may reflect GM dysplasia and noted that changes in T1 are associated with maturation in the normal developing brain. Greenwood et al reported an absence of the normal positive correlations between GM volume and intelligence in their NF1 cohort.9 Taken together, these studies consistently raise evidence that GM properties influence cognitive function; however, the diverse nature of the correlations make it difficult to draw any firm conclusions concerning the role of GM properties and cognitive impairment.

    A number of studies have examined the relationship between macrocephaly and neuropsychological function, all of which have failed to find any association.1 2 6 15 16

    Two more recent studies have sought to establish a relationship between sulcal and gyral anomalies and specific neuropsychological deficits using a ‘region of interest’ approach.13 14 In their first study, the authors examined whether morphological features of the planum temporale and planum parietale were associated with learning difficulties in 24 children with NF1. The planum temporale, which lies on the superior surface of the temporal lobe within the sylvian fissure, has been hypothesised to play a role in mapping auditory phonemes onto visual graphemes, and structural imaging studies suggest a higher incidence of symmetry or reversed rightward asymmetry of the planum temporale in dyslexic populations.17 18 Compared with a control group, boys with NF1 had greater symmetry of the planum temporale, lacking the left hemisphere bias found in non-reading-impaired populations.13 19 Absence of normal planum temporale asymmetry in the NF1 group was also associated with poorer reading and maths achievement in relation to IQ scores, suggesting that abnormal development of the sylvian fissure could be a risk factor for NF1-related learning disabilities.

    Billingsley et al compared the anatomical structure of the inferior frontal gyrus (IFG) and Heschl gyrus (HG) in 38 children with NF1 and controls.14 Although IFG morphology did not differ between the groups, NF1 children with atypical right IFG morphology (extra gyrus in the frontal cortex) performed better on language and academic measures than NF1 participants with typical morphology. This result is surprising, given that the left rather than right IFG, has been implicated in linguistic functions such as phonological processing, articulation and speech motor processing.20–22 The authors suggest that the association between the right IFG and language in the NF1 population may indicate that individuals with NF1 (who experience delayed language development) are right-hemisphere dominant for language. Children with NF1 (15%) were also less likely to have a duplicate HG in the left hemisphere than controls (35%). This is also an unexpected finding, as others have reported HG duplication to be associated with greater linguistic deficits in individuals with dyslexia in the general population.18 23 It is clear that the functional organisation of language in both the left and right hemispheres needs further exploration.

    MRI T2-hyperintensities and their relationship to cognitive status

    The most commonly identified abnormalities on MRI in patients with NF1 are focal areas of hyperintensity on T2 weighted images (T2H). T2H commonly occur in the basal ganglia, cerebellum, thalamus, brain stem and subcortical WM, and are not associated with focal neurological deficits.4 24 25 The reported frequency of T2H in childhood ranges between 55 and 90%; however, with increasingly sensitive imaging techniques, the prevalence of T2H in children with NF1 is likely to approach 100%.26 Although the general consensus is that T2H tend to resolve by early adulthood,25 27 28 more recent studies investigating the evolution of T2H over time suggest their natural history to be more complex than first thought. In a large prospective study (N=103, age range 8.0 to 25.4 years), T2H in the basal ganglia, thalamus, brainstem and cerebellum were found to diminish with age (figure 1).26 Conversely, T2H occurring in the cerebral hemispheres and hippocampi did not decrease with age and, in some instances, appeared over time. A subset of these patients (n=27), followed longitudinally across an 8-year period into adulthood, showed an overall decrease in the number, size and intensity of T2H in 88% of the cohort.28 However, lesions that occurred in the cerebral cortex and deep WM did not disappear over the 8-year period, suggesting a different pathological basis. Whereas regressing lesions in the basal ganglia, thalamus, brainstem and cerebellum may represent the formation of a stable form of myelin replacing chemically abnormal myelin sheaths, stable cerebral T2H may represent areas of disordered proliferation or increased astrogliosis which have been observed in autopsy brain specimens from patients with NF1.25 26 28

    Figure 1
    Figure 1

    T2 weighted axial MRI of a boy with neurofibromatosis type 1 (NF1) (a) 7 years of age showing discrete T2 weighted images (T2H) involving the globus pallidi and left thalamus. (b) Same subject scanned five years later. Note that the right globus pallidus region of T2H is no longer evident, and the signal intensity and volume of the left globus pallidus and thalamic lesions have diminished.

    The high frequency of T2H on MRI has led to the hypothesis that these lesions are associated with the occurrence of cognitive deficits in children with NF1. This hypothesis remains controversial. Although early studies suggested no association between T2H and cognitive performance,29–33 a number of larger independent studies using clinic-based samples and quantitative neuropsychological measures found a significant association between neuropsychological status and T2H in children with NF1.3 16 34 35 A study of 40 children with NF1 found that the presence of MRI T2H was associated with significantly lower IQ scores.3 Denckla et al reported a significant correlation between patient-sibling full-scale IQ discrepancy and the number of T2H.35 While Moore et al failed to find a similar relationship between the number of T2H and neuropsychological performance in a cohort of 84 children, a relationship between IQ and the presence of thalamic T2H was reported.34 Several further studies, however, have failed to find any association between T2H and neuropsychological status.31–33 The reasons for these contradictory findings are most likely due to differences in inclusion criteria, small sample sizes, differences in subject populations and different criteria used to identify T2H.

    More recent studies have replicated the findings of Moore et al,34 highlighting a more consistent relationship between thalamic T2H and cognitive impairment.36 37 Using a large cohort of children (76 NF1, 45 unaffected siblings), Hyman et al aimed to determine whether the presence, number or location of T2H could predict intellectual functioning or specific cognitive deficits.36 T2H were classified as either discrete—with a margin distinct from normal tissue—or diffuse—having a poorly defined margin. Although the presence and number of T2H were not associated with IQ, discrete T2H located in the thalamus were associated with severe and generalised cognitive impairment. Diffuse T2H in the thalamus were also associated with reductions in IQ, but the impairments were more subtle. In a smaller cohort (N=32), Goh et al similarly reported thalamic T2H to be associated with lower intellectual function.37 The relationship between thalamic T2H and cognitive impairment is not surprising given that infarction, tumour and trauma studies have demonstrated clear links between thalamic lesions and impairments in memory, executive and visuospatial function, language and attention.38 39

    Functional neuroimaging in NF1

    To date, the literature contains only a handful of functional (f)MRI studies on patients with NF1. The first group to use this technique examined the neuronal substrate of phonological processing,40 a core component of reading. Participants were presented with an auditory and a written task to determine whether two nonsense words rhymed. Compared with controls, the NF1 group displayed greater inferior frontal activation, compared with temporoparietal activation, on the auditory task. This differential activation was more pronounced in the right hemisphere, similar to other brain imaging studies of children with dyslexia in the general population.41 The written task showed a reversed effect, with the NF1 group displaying relatively less frontal compared with posterior activity than the control group. There was a significant positive correlation between behavioural performance on these tasks and a number of reading measures, including an academic spelling test and letter–word identification. The results suggest that the increased anterior activity in the auditory task and the increased posterior activity during the written task reflect compensatory neural recruitment due to either inefficient or dysfunctional neural networks. Whether this is due to a WM disconnection syndrome, which has been well described in the general dyslexic population, is yet to be determined.42

    Two studies have investigated the functional correlates of visuospatial processing in individuals with NF1.43 44 Billingsley et al presented alphanumeric stimuli to participants in a conventional form, and inverted or rotated at varying degrees.43 In each condition, participants determined whether the presented stimulus was a letter or number. Compared with controls, NF1 participants showed a greater activity in posterior relative to anterior cortical regions during the rotation task. The authors hypothesised that the increase in posterior cortical activity is in accord with their earlier findings of morphological abnormalities in inferior frontal areas14 and may reflect an alternative resource allocation to the visual system due to functional inefficiencies in anterior regions. A more recent fMRI study used an adaptation of the Judgement of Line Orientation Task to examine the neural basis of visuospatial processing in NF1.43 The authors reported (1) greater posterior compared with anterior activation in both NF1 and control groups and (2) greater left than right hemisphere activation across anterior and posterior regions in NF1 participants. Control participants, however, showed greater right than left hemisphere activation. This left hemisphere dominance for visuospatial processing implicates a dysfunctional right hemisphere network and suggests a functional correlate for the significant visuospatial processing deficits frequently reported in this population.

    As research into the functional correlates of the NF1 cognitive phenotype moves forward, there are a number of methodological issues that need to be taken into consideration. Prior exposure to interventions such as cognitive training can have a significant impact on patterns of activation during functional neuroimaging tasks.45 46 In addition, depending on the task chosen, NF1 participants will often be impaired on the task compared with controls, making it difficult to determine whether apparent group differences in brain activation reflects actual functional differences or whether it simply represents differing levels of task performance—particularly when results suggest reduced or absent activity in the NF1 group. One way to control for this is through additional control groups matched for performance levels on the behavioural task. In addition, due to the high incidence of megalencephaly in NF1, greater amounts of displacement occur when fitting NF1 brains into a normalised template for comparison with control brains; the creation of a standard NF1 template would be welcome.44

    Positron emission tomography (PET) may be an additional useful tool to study cognitive impairment in NF1. PET with 18F-2-fluoro-2-deoxy-d-glucose can depict the patterns of glucose metabolism in various parts of the brain. Thus, PET could theoretically be utilised to determine the relationship between cerebral glucose metabolism and cognitive impairment. There are only two studies to date in the paediatric NF1 literature.47 48 Both demonstrated areas of cerebral hypometabolism in children with NF1 compared with controls, but neither study conclusively established a correlation with cognitive impairment, primarily because of small sample sizes. In addition, Kaplan et al reported thalamic hypometabolism in all patients with NF1 (n=9), suggesting delays in thalamic signal processing (figure 2).48 The adult literature contains only one recent study, exploring differences in cerebral glucose metabolism between 29 patients with NF1 and 29 age- and gender-matched controls.49 Again, there was a significant reduction in glucose uptake in the thalamus of NF1 patients compared with controls. Given the evidence for a relationship between thalamic T2H and lower intellectual function, thalamic hypometabolism in both paediatric and adult NF1 cohorts is intriguing and worthy of further study. Although a very useful research tool, the ionising radiation associated with PET is a potential risk for children with NF1, and careful consideration should be undertaken before employing it on a systematic basis.

    Figure 2
    Figure 2

    (a) 3-year-old male with neurofibromatosis type 1 (NF-1) showing bilateral thalamic hypometabolism (reduced 18F-2-fluoro-2-deoxy-d-glucose (FDG) uptake) on FDG-PET/CT. (b) 3-year-old female control with normal FDG uptake in both thalami on FDG-PET/CT.

    Future directions: diffusion tensor imaging of WM in NF1

    There is increasing acceptance of the theory that learning disabilities such as dyslexia are the consequence of a ‘disconnection syndrome’ resulting from impaired WM connectivity in the neural circuits that regulate language processing.42 50 Diffusion tensor imaging (DTI) is a type of diffusion-weighted MRI that allows non-invasive, in vivo assessment and visualisation of WM fibre tracts and their directionality on a multidimensional scale.51 52 In well-organised and intact WM tracts, diffusion of water occurs preferentially in the direction in which the axons are oriented (ie, more anisotropic diffusion). When there is lack of well-organised/aligned and structurally intact WM (eg, axonal loss or demyelination), increased water diffusion occurs perpendicular to the axis of the WM tract (ie, more isotropic diffusion). The degree of diffusion of water molecules can be quantified with the help of diffusion-weighted MRI and calculated as the apparent diffusion coefficient (ADC). The degree of WM alignment and anisotropy is calculated as the fractional anisotropy (FA), which varies considerably across brain tissue. Lower FA in any WM region suggests reduced myelin content and hence less efficient axonal conduction. DTI has shown great potential in the study of WM in relation to normal brain development and ageing, in stroke, head injury and also demyelinating and neurodegenerative diseases.53 In the field of learning disabilities, variations in WM tract measures have been associated with both general cognitive ability and specific cognitive domains.54 55 For example, FA values in the temporoparietal WM tracts correlate well with reading ability, in adults and children.42 56 57

    To the best of our knowledge, there are no published reports that explore DTI in the context of NF1 and cognitive/learning deficits, and only two published studies have used DTI to explore the integrity of WM tracts in the NF1 brain.58 Comparing DTI findings in adults with NF1 with age-matched healthy controls, there were significantly reduced FA values and elevated ADC values in the WM of every investigated anatomical brain location of NF1 patients. Significant heterogeneity of the FA values was noted in all NF1 patients, suggesting the existence of microstructural differences in the brain tissue of NF1 patients compared with normal; possibly the result of disintegration of the myelin sheaths or axonal disruption. Similar findings were reported in a study comparing diffusion characteristics of brain tissue in children with NF1.59 Elevated ADC values were found in normal appearing posterior and anterior WM, the globus pallidus and thalamus in children with NF1 compared with controls. Significantly higher ADC values were also reported in NF1 regions with T2H compared with NF1 regions without T2H, supporting the hypothesis that T2H represent disturbed microstructure of brain tissue due to the accumulation of fluid or vacuolation.

    Given the prevalence of cognitive/learning deficits, a systematic approach to the study of WM abnormalities in children with NF1 is warranted. A longitudinal analysis of WM development from childhood to adulthood is required to ascertain the influence of myelination and WM integrity in children with NF1-related cognitive and learning deficits. A prospective study of DTI in children with NF1 would be valuable to address two important issues: (1) the neural basis of cognitive and learning deficits in children with NF1, based on the assumption of ‘WM disconnection’ (eg, in language-processing circuits) and (2) the pathophysiology of T2H and their correlation with cognitive and learning deficits in children with NF1, based on the assumption of disturbed ‘WM integrity.’ Such a study would be important not only from a theoretical perspective, but also from a practical point of view, as the results could be potentially useful in the design of future clinical trials.

    Concluding remarks

    Collectively, the studies reviewed here highlight structural and functional brain abnormalities as a feature of NF1 and that these abnormalities contribute to the cognitive impairments that are commonly seen in this condition. The most compelling structural finding is the increased brain volume in individuals with NF1, primarily localised to an increase in WM volume. Conclusive findings related to specific structures do not exist, but the corpus callosum is consistently increased in size relative to brain volume, and there is also evidence of unusual cerebral symmetries in frontal and temporoparietal cortex. Longitudinal and cross-sectional analyses highlight the heterogenous nature of T2H in NF1. While most studies do not report a relationship between the general presence or number of T2H and cognitive deficits, there is evidence to suggest that T2H located in the thalamus result in cognitive impairment.

    While fMRI holds promise for elucidating the neural basis of NF1 related cognitive impairment, its application is still in its infancy. The handful of studies reviewed here should be viewed as exploratory, given the small and frequently heterogenous samples and limited normative data. These studies suggest that there are alterations in brain organisations for language and visuospatial function and should prove useful in delineating the neural basis of abnormalities in various cognitive domains affected in NF1, such as attention and executive skills, provided they are designed within a solid theoretical framework. The potential for DTI to identify abnormalities in WM pathways in children with NF1 holds great promise to better understand the neurobiological substrate of cognitive impairment in NF1, especially in combination with more sophisticated functional neuroimaging techniques.

    Given the relatively heterogeneous nature of the NF1 phenotype, it is essential that future studies address specific hypotheses in well-defined subsamples and use multiple control groups when appropriate. As pharmacological treatments for cognitive deficits are starting to be trialled in humans with NF1, fMRI and/or DTI may also provide a method of monitoring the effectiveness of therapy by demonstrating normalisation of cognitive networks. Since pharmacological therapies will only target potentially reversible cognitive deficits due to disordered biochemical pathways (such as altered ras activation), it will be important to determine the relative contribution of structural (and likely developmental) abnormalities to the NF1 cognitive phenotype, since these will be less likely to be reversible or respond to medication.

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    Footnotes

    • Funding Other Funders: Sherman Fellowship in Neurofibromatosis 1 Research, Australia.

    • Competing interests None.

    • Provenance and peer review Not commissioned; externally peer reviewed.