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Neurofibromatosis type 1 (NF1) is a common single gene disorder resulting in multi-organ involvement. In addition to physical manifestations such as characteristic pigmentary changes, nerve sheath tumors, and skeletal abnormalities, NF1 is also associated with increased rates of learning disabilities, attention deficit hyperactivity disorder, and autism spectrum disorder. While there are established NF1-related structural brain anomalies, including brain overgrowth and white matter disruptions, little is known regarding patterns of functional connectivity in NF1. Here, we sought to investigate functional network connectivity (FNC) in a well-characterized sample of NF1 participants (n = 30) vs. age- and sex-matched healthy controls (n = 30). We conducted a comprehensive investigation of both static as well as dynamic FNC and meta-state analysis, a novel approach to examine higher-dimensional temporal dynamism of whole-brain connectivity. We found that static FNC of the cognitive control domain is altered in NF1 participants. Specifically, connectivity between anterior cognitive control areas and the cerebellum is decreased, whereas connectivity within the cognitive control domain is increased in NF1 participants relative to healthy controls. These alterations are independent of IQ. Dynamic FNC analysis revealed that NF1 participants spent more time in a state characterized by whole-brain hypoconnectivity relative to healthy controls. However, connectivity strength of dynamic states did not differ between NF1 participants and healthy controls. NF1 participants exhibited also reduced higher-dimensional dynamism of whole-brain connectivity, suggesting that temporal fluctuations of FNC are reduced. Given that similar findings have been observed in individuals with schizophrenia, higher occurrence of hypoconnected dynamic states and reduced temporal dynamism may be more general indicators of global brain dysfunction and not specific to either disorder.

BackgroundNeurofibromatosis type 1 (NF1) is a monogenic disorder affecting cognitive function. About one third of children with NF1 have attentional disorders, and the cognitive phenotype is characterized by impairment in prefrontally-mediated functions. Mouse models of NF1 show irregularities in GABA release and striatal dopamine metabolism. We hypothesized that youth with NF1 would show abnormal behavior and neural activity on a task of risk-taking reliant on prefrontal-striatal circuits.MethodsYouth with NF1 (N=29) and demographically comparable healthy controls (N=22), ages 8-19, were administered a developmentally sensitive gambling task, in which they chose between low-risk gambles with a high probability of obtaining a small reward, and high-risk gambles with a low probability of obtaining a large reward. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with risky decision making, as well as age-associated changes in these behavioral and neural processes.ResultsBehaviorally, youth with NF1 tended to make fewer risky decisions than controls. Neuroimaging analyses revealed significantly reduced neural activity across multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to controls during the task. We also observed atypical age-associated changes in neural activity in patients with NF1, such that during risk taking, neural activity tended to decrease with age in controls, whereas it tended to increase with age in patients with NF1.ConclusionsFindings suggest that developmental trajectories of neural activity during risky decision-making may be disrupted in youth with NF1.

BackgroundNeurofibromatosis Type 1 (NF1) is a genetic disorder that disrupts central nervous system development and neuronal function. Cognitively, NF1 is characterized by difficulties with executive control and visuospatial abilities. Little is known about the neural substrates underlying these deficits. The current study utilized Blood-Oxygen-Level-Dependent (BOLD) functional MRI (fMRI) to explore the neural correlates of spatial working memory (WM) deficits in patients with NF1.MethodsBOLD images were acquired from 23 adults with NF1 (age M = 32.69; 61% male) and 25 matched healthy controls (age M = 33.08; 64% male) during an in-scanner visuo-spatial WM task. Whole brain functional and psycho-physiological interaction analyses were utilized to investigate neural activity and functional connectivity, respectively, during visuo-spatial WM performance. Participants also completed behavioral measures of spatial reasoning and verbal WM.ResultsRelative to healthy controls, participants with NF1 showed reduced recruitment of key components of WM circuitry, the left dorsolateral prefrontal cortex and right parietal cortex. In addition, healthy controls exhibited greater simultaneous deactivation between the posterior cingulate cortex (PCC) and temporal regions than NF1 patients. In contrast, NF1 patients showed greater PCC and bilateral parietal connectivity with visual cortices as well as between the PCC and the cerebellum. In NF1 participants, increased functional coupling of the PCC with frontal and parietal regions was associated with better spatial reasoning and WM performance, respectively; these relationships were not observed in controls.ConclusionsDysfunctional engagement of WM circuitry, and aberrant functional connectivity of 'task-negative' regions in NF1 patients may underlie spatial WM difficulties characteristic of the disorder.

ObjectiveTo assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1).MethodsA multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population.ResultsLovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = -0.15, 95% confidence interval -0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval -0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo.ConclusionsLovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population.Clinicaltrialsgov identifierThis study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493).Classification of evidenceThis study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.

ObjectiveLovastatin has been shown to reverse learning deficits in a mouse model of Neurofibromatosis Type 1 (NF1), a common monogenic disorder caused by a mutation in the Ras-MAPK pathway and associated with learning disabilities. We conducted a randomized double-blind placebo-controlled trial to assess lovastatin's effects on cognition and behavior in patients with NF1.MethodForty-four NF1 patients (mean age 25.7+/-11.6 years; 64% female) were randomly assigned to 14 weeks of lovastatin (N = 23; maximum dose of 80 mg/day for adult participants and 40 mg/day for children) or placebo (N = 21). Based on findings in the mouse model, primary outcome measures were nonverbal learning and working memory. Secondary outcome measures included verbal memory, attention, and self/parent-reported behavioral problems, as well as tolerability of medication. Participants also underwent neuroimaging assessments at baseline and 14 weeks, to determine whether neural biomarkers were associated with treatment response. Linear mixed models assessed for differential treatment effects on outcome measures.ResultsTwelve participants dropped from the study prior to completion (8 placebo, 4 lovastatin), resulting in 32 completers (15 placebo, 17 lovastatin). Lovastatin was well-tolerated, with no serious adverse events. Differential improvement favoring lovastatin treatment was observed for one primary (working memory; effect size f (2) = 0.70, P < 0.01) and two secondary outcome measures (verbal memory, f (2) = 0.19, P = 0.02, and adult self-reported internalizing problems, f (2) = 0.26, P = 0.03). Exploratory moderator analyses revealed that higher baseline neural activity in frontal regions was associated with larger treatment effects.InterpretationThese preliminary results suggest beneficial effects of lovastatin on some learning and memory functions, as well as internalizing symptoms in patients with NF1.

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin 1 gene at locus 17q11.2. Individuals with NF1 have an increased incidence of learning disabilities, attention deficits, and autism spectrum disorders. As a single-gene disorder, NF1 represents a valuable model for understanding gene-brain-behavior relationships. While mouse models have elucidated molecular and cellular mechanisms underlying learning deficits associated with this mutation, little is known about functional brain architecture in human subjects with NF1. To address this question, we used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to elucidate the intrinsic network structure of 30 NF1 participants compared with 30 healthy demographically matched controls during an eyes-open rs-fcMRI scan. Novel statistical methods were employed to quantify differences in local connectivity (edge strength) and modularity structure, in combination with traditional global graph theory applications. Our findings suggest that individuals with NF1 have reduced anterior-posterior connectivity, weaker bilateral edges, and altered modularity clustering relative to healthy controls. Further, edge strength and modular clustering indices were correlated with IQ and internalizing symptoms. These findings suggest that Ras signaling disruption may lead to abnormal functional brain connectivity; further investigation into the functional consequences of these alterations in both humans and in animal models is warranted.

Neurofibromatosis (NF1) represents the most common single gene cause of learning disabilities. NF1 patients have impairments in frontal lobe based cognitive functions such as attention, working memory, and inhibition. Due to its well-characterized genetic etiology, investigations of NF1 may shed light on neural mechanisms underlying such difficulties in the general population or other patient groups. Prior neuroimaging findings indicate global brain volume increases, consistent with neural over-proliferation. However, little is known about alterations in white matter microstructure in NF1. We performed diffusion tensor imaging (DTI) analyses using tract-based spatial statistics (TBSS) in 14 young adult NF1 patients and 12 healthy controls. We also examined brain volumetric measures in the same subjects. Consistent with prior studies, we found significantly increased overall gray and white matter volume in NF1 patients. Relative to healthy controls, NF1 patients showed widespread reductions in white matter integrity across the entire brain as reflected by decreased fractional anisotropy (FA) and significantly increased absolute diffusion (ADC). When radial and axial diffusion were examined we found pronounced differences in radial diffusion in NF1 patients, indicative of either decreased myelination or increased space between axons. Secondary analyses revealed that FA and radial diffusion effects were of greatest magnitude in the frontal lobe. Such alterations of white matter tracts connecting frontal regions could contribute to the observed cognitive deficits. Furthermore, although the cellular basis of these white matter microstructural alterations remains to be determined, our findings of disproportionately increased radial diffusion against a background of increased white matter volume suggest the novel hypothesis that one potential alteration contributing to increased cortical white matter in NF1 may be looser packing of axons, with or without myelination changes. Further, this indicates that axial and radial diffusivity can uniquely contribute as markers of NF1-associated brain pathology in conjunction with the typically investigated measures.

Background/Aims: Individuals with neurofibromatosis, including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2)–related schwannomatosis (SWN), and other forms of SWN, often experience disease manifestations and mental health difficulties for which psychosocial interventions may help. An anonymous online survey of adults with neurofibromatosis assessed their physical, social, and emotional well-being and preferences about psychosocial interventions to inform clinical trial design. Methods: Neurofibromatosis clinical researchers and patient representatives from the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration developed the survey. Eligibility criteria included age ≥ 18 years, self-reported diagnosis of NF1, NF2, or SWN, and ability to read and understand English. The online survey was distributed internationally by the Neurofibromatosis Registry and other neurofibromatosis foundations from June to August 2020. Results: Surveys were completed by 630 adults (18–81 years of age; M = 45.5) with NF1 (78%), NF2 (14%), and SWN (8%) who were mostly White, not Hispanic/Latino, female, and from the United States. The majority (91%) reported that their neurofibromatosis symptoms had at least some impact on daily life. In the total sample, 51% endorsed a mental health diagnosis, and 27% without a diagnosis believed they had an undiagnosed mental health condition. Participants indicated that neurofibromatosis affected their emotional (44%), physical (38%), and social (35%) functioning to a high degree. Few reported ever having participated in a drug (6%) or psychosocial (7%) clinical trial, yet 68% reported they "probably" or "definitely" would want to participate in a psychosocial trial if it targeted a relevant concern. Top treatment targets were anxiety, healthier lifestyle, and daily stress. Top barriers to participating in psychosocial trials were distance to clinic, costs, and time commitment. Respondents preferred interventions delivered by clinicians via individual sessions or a combination of group and individual sessions, with limited in-person and mostly remote participation. There were no significant group differences by neurofibromatosis type in willingness to participate in psychosocial trials (p = 0.27). Regarding interest in intervention targets, adults with SWN were more likely to prefer psychosocial trials for pain support compared to those with NF1 (p < 0.001) and NF2 (p < 0.001). Conclusion: This study conducted the largest survey assessing physical symptoms, mental health needs, and preferences for psychosocial trials in adults with neurofibromatosis. Results indicate a high prevalence of disease manifestations, psychosocial difficulties, and untreated mental health problems in adults with neurofibromatosis and a high degree of willingness to participate in psychosocial clinical trials. Patient preferences should be considered when designing and implementing psychosocial interventions to develop the most feasible and meaningful studies. [ABSTRACT FROM AUTHOR]

The coronavirus pandemic increased anxiety and stress and prevented access to health care worldwide; it is unclear how COVID‐19 affected adults with a multisystem genetic disorder such as neurofibromatosis (NF). An anonymous online survey was distributed through an international registry and foundations to adults with NF (June–August 2020) to assess the impact of the pandemic on mental health and NF health care. Six hundred and thirteen adults (18–81 years; M = 45.7) with NF1 (77.8%), NF2 (14.2%), and schwannomatosis (7.8%) provided complete responses. Respondents rated moderate‐to‐high amounts of worry about the impact of COVID‐19 on their emotional (46.3%) and physical health (46.7%), and 54.8% endorsed moderate‐to‐high pandemic‐related stress. Adults with diagnosed/suspected mental health disorders or moderate‐to‐severe NF symptom impact as well as females endorsed higher COVID‐19 stress (ps < 0.01). Less than half who missed a doctor's appointment for their NF care (43.4%) used telehealth. Of these, 33.3% and 46.2% reported that telehealth met their needs to a moderate or high degree, respectively. Results indicated that subgroups of adults with NF experience higher COVID‐19‐related worries and stress and may need additional support. Furthermore, telehealth is under‐utilized and could help NF providers connect with patients, although improved delivery and patient training may facilitate expanded use of these services. [ABSTRACT FROM AUTHOR]

Plexiform neurofibromas are one of the most common and disabling features of neurofibromatosis 1. Treatment options for patients with plexiform neurofibromas have been limited, with surgery being the primary option for patients with progressive lesions causing significant morbidity. Trials have evaluated other treatment approaches, including the use of antihistamines, maturation agents, and antiangiogenic agents. The design of such trials and entry criteria have been quite variable, and results have been difficult to interpret. As more is understood concerning the molecular genetic underpinnings of plexiform neurofibromas, new avenues of treatment are being explored. Evaluation of clinical trials is challenging because of the unpredictable nature of plexiform neurofibromas and difficulties in measuring objective responses. The use of innovative neuroimaging techniques and other outcome measures may greatly improve the design of trials and evaluation of potential effective agents. [ABSTRACT FROM AUTHOR]