twice-exceptional \'twis-ik-'sep-shənl\ adj(1990) having exceptional academic ability in one or more area(s) and challenged by a learning/social emotional disability or diagnosed disorder

Imagine Dan, an academically precocious 3rd grader who, on standardized tests was performing beyond 97% of his age-mates in reading, language comprehension and math. However, Dan experienced significant behavior problems in school. Emotional outbursts, defiance complying with teacher requests and, occasionally, physically agressive behaviors made it difficult for Dan to thrive in his classroom.



Twice-exceptionality affects an estimated 6% of gifted children in the U.S. alone. The University of Iowa's Belin-Blank Center and the Iowa Neuroscience Institute are joining forces to better understand the mechanisms and behaviors surrounding twice-exceptionality. Education, psychology, neuroscience, and genetics are brought to bear in an effort to understand twice-exceptionality through multiple lenses.

"We can really create a paradigm shift with regard to the neuroscience of twice-exceptionality and we're hoping to do it the Iowa way, through collaboration."
Susan Assouline

Collaborative Partners

Ted Abel, Ph.D.

Ted is director of the Iowa Neuroscience Institute and holds an endowed chair.

Susan Assouline, Ph.D.

Director of the Belin-Blank Center, Susan is a leading researcher in the field of twice-exceptionality and holds an endowed chair.

Jacob Michaelson, Ph.D.

Jacob is an associate professor of psychiatry and division director for Computational and Molecular Psychology.

Alissa Doobay, Ph.D.

Alissa is head of Psychological Services, Belin-Blank Center, a licensed psychologist, and is a leading researcher in the field of twice-exceptionality.

Megan Foley-Nicpon, Ph.D.

Megan is DEO, Psychological and Quantitative Foundations, in the College of Education, and a leading researcher in the field of twice-exeptionality.

Thomas Nickl Jockschat M.D.

Thomas is an associate professor of psychiatry in the Carver College of Medicine and specializes in neuroimaging

Brandon Lebeau, Ph.D.

Brandon is an assistant professor in the College of Education and statistician with the Belin-Blank Center.

Duhita Mahatmya, Ph.D.

Duhita is a research methodoligist for the Belin-Blank Center and College of Education.

Jon Goodwin, Ph.D.

Jon is a clinical assistant professor in the Department of Psychiatry, College of Medicine.

Interested in becoming a university collaborator?

Interested in joining the study as a participant?

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Predicting the academic achievement of gifted students with autism spectrum disorder

We are not well informed regarding the ability-achievement relationship for twice-exceptional individuals (very high cognitive ability and a diagnosed disability, e.g., autism spectrum disorder [ASD]). The research question for this investigation (N = 59) focused on the predictability of achievement among variables related to ability and education in a twice-exceptional sample of students (cognitive ability of 120 [91st percentile], or above, and diagnosed with ASD). We determined that WISC-IV Working Memory and Processing Speed Indices were both significantly positively correlated with achievement in math, reading, and written language. WISC Perceptual Reasoning Index was uniquely predictive of Oral Language test scores. Unexpected findings were that ASD diagnosis, Verbal Comprehension Index, and forms of academic acceleration were not related to the dependent variables.

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Sex Differences in Autism Spectrum Disorder: a Review

Neurodevelopmental disorders disproportionately affect males. The mechanisms underlying male vulnerability or female protection are not known and remain understudied. Determining the processes involved is crucial to understanding the etiology and advancing treatment of neurodevelopmental disorders. Here, we review current findings and theories that contribute to male preponderance of neurodevelopmental disorders, with a focus on autism.

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Profoundly gifted girls and autism spectrum disorder: A psychometric case study comparison

A case study of the psychometric characteristics of two profoundly gifted girls, one with autism spectrum disorder (ASD) and the other without ASD, is used to describe the nuances and subtleties most relevant in understanding the relationship between extreme giftedness and social difficulties. Through the presentation of the results from psychoeducational and psychosocial assessments, we demonstrate how data from a comprehensive evaluation can distinguish between the manifestation of extreme giftedness and concomitant social impairment indicative of ASD. Comparison of the assessment results highlights the relevance of cognitive and achievement information as well as the need for specific measures to diagnosis ASD. The girls demonstrated virtually identically superior cognitive and achievement performances. However, an in-depth analysis of additional measures, especially those specific to ASD, indicates that information about adaptive behavior and executive functioning can reveal important distinctions that are helpful in understanding the need for unique interventions specific to ASD.

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Cognitive and Academic Distinctions Between Gifted Students With Autism and Asperger Syndrome

The cognitive and academic profiles of high ability students with autism spectrum disorder were examined. Inclusion criteria were a diagnosis of autism (high functioning) or Asperger syndrome and at least one ability and/or achievement index standard score of 120 or above. Results indicated that despite the restricted range of cognitive abilities, students diagnosed with Asperger syndrome had significantly higher Verbal Comprehension Index scores than did students diagnosed with autism. However, students with autism had significantly higher scores on tests of math fluency and written expression than did students with Asperger syndrome. Implications for assessment, diagnosis, and intervention are discussed.

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Home-cage hypoactivity in mouse genetic models of autism spectrum disorder

Genome-wide association and whole exome sequencing studies from Autism Spectrum Disorder (ASD) patient populations have implicated numerous risk factor genes whose mutation or deletion results in significantly increased incidence of ASD. Behavioral studies of monogenic mutant mouse models of ASD-associated genes have been useful for identifying aberrant neural circuitry. However, behavioral results often differ from lab to lab, and studies incorporating both males and females are often not performed despite the significant sex-bias of ASD. In this study, we sought to investigate the simple, passive behavior of home-cage activity monitoring across multiple 24-h days in four different monogenic mouse models of ASD: Shank3b−/−, Cntnap2−/−, Pcdh10+/−, and Fmr1 knockout mice. Relative to sex-matched wildtype (WT) littermates, we discovered significant home-cage hypoactivity, particularly in the dark (active) phase of the light/dark cycle, in male mice of all four ASD-associated transgenic models. For Cntnap2−/− and Pcdh10+/− mice, these activity alterations were sex-specific, as female mice did not exhibit home-cage activity differences relative to sex-matched WT controls. These home-cage hypoactivity alterations differ from activity findings previously reported using short-term activity measurements in a novel open field. Despite circadian problems reported in human ASD patients, none of the mouse models studied had alterations in free-running circadian period. Together, these findings highlight a shared phenotype across several monogenic mouse models of ASD, outline the importance of methodology on behavioral interpretation, and in some genetic lines parallel the male-enhanced phenotypic presentation observed in human ASDs.

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Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders

Neurodevelopmental disorders, including autism spectrum disorders, are highly male biased, but the underpinnings of this are unknown. Striatal dysfunction has been strongly implicated in the pathophysiology of neurodevelopmental disorders, raising the question of whether there are sex differences in how the striatum is impacted by genetic risk factors linked to neurodevelopmental disorders. Here we report male-specific deficits in striatal function important to reward learning in a mouse model of 16p11.2 hemideletion, a genetic mutation that is strongly associated with the risk of neurodevelopmental disorders, particularly autism and attention-deficit hyperactivity disorder. We find that male, but not female, 16p11.2 deletion animals show impairments in reward-directed learning and maintaining motivation to work for rewards. Male, but not female, deletion animals overexpress mRNA for dopamine receptor 2 and adenosine receptor 2a in the striatum, markers of medium spiny neurons signaling via the indirect pathway, associated with behavioral inhibition. Both sexes show a 50% reduction of mRNA levels of the genes located within the 16p11.2 region in the striatum, including the kinase extracellular-signal related kinase 1 (ERK1). However, hemideletion males show increased activation in the striatum for ERK1, both at baseline and in response to sucrose, a signaling change associated with decreased striatal plasticity. This increase in ERK1 phosphorylation is coupled with a decrease in the abundance of the ERK phosphatase striatum-enriched protein-tyrosine phosphatase in hemideletion males. In contrast, females do not show activation of ERK1 in response to sucrose, but notably hemideletion females show elevated protein levels for ERK1 as well as the related kinase ERK2 over what would be predicted by mRNA levels. These data indicate profound sex differences in the impact of a genetic lesion linked with neurodevelopmental disorders, including mechanisms of male-specific vulnerability and female-specific resilience impacting intracellular signaling in the brain.

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Linking spatial gene expression patterns to sex-specific brain structural changes on a mouse model of 16p11.2 hemideletion

Neurodevelopmental disorders, such as ASD and ADHD, affect males about three to four times more often than females. 16p11.2 hemideletion is a copy number variation that is highly associated with neurodevelopmental disorders. Previous work from our lab has shown that a mouse model of 16p11.2 hemideletion (del/+) exhibits malespecific behavioral phenotypes. We, therefore, aimed to investigate with magnetic resonance imaging (MRI), whether del/+ animals also exhibited a sex-specific neuroanatomical endophenotype. Using the Allen Mouse Brain Atlas, we analyzed the expression patterns of the 27 genes within the 16p11.2 region to identify which gene expression patterns spatially overlapped with brain structural changes. MRI was performed ex vivo and the resulting images were analyzed using Voxel-based morphometry for T1-weighted sequences and tract-based spatial statistics for diffusion-weighted images. In a subsequent step, all available in situ hybridization (ISH) maps of the genes involved in the 16p11.2 hemideletion were aligned to Waxholm space and clusters obtained by sex-specific group comparisons were analyzed to determine which gene(s) showed the highest expression in these regions. We found pronounced sex-specific changes in male animals with increased fractional anisotropy in medial fiber tracts, especially in those proximate to the striatum. Moreover, we were able to identify gene expression patterns spatially overlapping with male-specific structural changes that were associated with neurite outgrowth and the MAPK pathway. Of note, previous molecular studies have found convergent changes that point to a sex-specific dysregulation of MAPK signaling. This convergent evidence supports the idea that ISH maps can be used to meaningfully analyze imaging data sets.

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