Probing heterogeneity to identify individualized treatment approaches in autism: Specific clusters of executive function challenges link to distinct co-occurring mental health problems.

LAY ABSTRACT: Many autistic people struggle with mental health problems like anxiety, depression, inattention, and aggression, which can be challenging to treat. Executive function challenges, which impact many autistic individuals, may serve as a risk factor for mental health problems or make treating mental health conditions more difficult. While some people respond well to medication or therapy, others do not. This study tried to understand if there are different subgroups of autistic young people who may have similar patterns of executive function strengths and challenges-like flexibility, planning, self-monitoring, and emotion regulation. Then, we investigated whether executive function subgroups were related to mental health problems in autistic youth. We found three different types of executive function subgroups in autistic youth, each with different patterns of mental health problems. This helps us identify specific profiles of executive function strengths and challenges that may be helpful with identifying personalized supports, services, and treatment strategies for mental health conditions.

Focal to bilateral tonic-clonic seizures predict pharmacoresistance in focal cortical dysplasia-related epilepsy.

OBJECTIVE: Focal cortical dysplasia (FCD) is the most common etiology of surgically-remediable epilepsy in children. Eighty-seven percent of patients with FCD develop epilepsy (75% is pharmacoresistant epilepsy [PRE]). Focal to bilateral tonic-clonic (FTBTC) seizures are associated with worse surgical outcomes. We hypothesized that children with FCD-related epilepsy with FTBTC seizures are more likely to develop PRE due to lesion interaction with restricted cortical neural networks. METHODS: Patients were selected retrospectively from radiology and surgical databases from Children's National Hospital. INCLUSION CRITERIA: 3T magnetic resonance imaging (MRI)-confirmed FCD from January 2011 to January 2020; ages 0 days to 22 years at MRI; and 18 months of documented follow-up. FCD dominant network (Yeo 7-network parcellation) was determined. Association of FTBTC seizures with epilepsy severity, surgical outcome, and dominant network was tested. Binomial regression was used to evaluate predictors (FTBTC seizures, age at seizure onset, pathology, hemisphere, lobe) of pharmacoresistance and Engel outcome. Regression was used to evaluate predictors (age at seizure onset, pathology, lobe, percentage default mode network [DMN] overlap) of FTBTC seizures. RESULTS: One hundred seventeen patients had a median age at seizure onset of 3.00 years (interquartile range [IQR] .42-5.59 years). Eighty-three patients had PRE (71%); 34 had pharmacosensitive epilepsy (PSE) (29%). Twenty patients (17%) had FTBTC seizures. Seventy-three patients underwent epilepsy surgery. Multivariate regression showed that FTBTC seizures are associated with an increased risk of PRE (odds ratio [OR] 6.41, 95% confidence interval [CI] 1.21-33.98, p = .02). FCD hemisphere/lobe was not associated with PRE. Percentage DMN overlap predicts FTBTC seizures. Seventy-two percent (n = 52) overall and 53% (n = 9) of patients with FTBTC seizures achieved Engel class I outcome. SIGNIFICANCE: In a heterogeneous population of surgical and non-operated patients with FCD-related epilepsy, the presence of FTBTC seizures is associated with a tremendous risk of PRE. This finding is a recognizable marker to help neurologists identify those children with FCD-related epilepsy at high risk of PRE and can flag patients for earlier consideration of potentially curative surgery. The FCD-dominant network also contributes to FTBTC seizure clinical expression.

Functional anomaly mapping lateralizes temporal lobe epilepsy with high accuracy in individual patients.

Mesial temporal lobe epilepsy (mTLE) is associated with variable dysfunction beyond the temporal lobe. We used functional anomaly mapping (FAM), a multivariate machine learning approach to resting state fMRI analysis to measure subcortical and cortical functional aberrations in patients with mTLE. We also examined the value of individual FAM in lateralizing the hemisphere of seizure onset in mTLE patients. Methods: Patients and controls were selected from an existing imaging and clinical database. After standard preprocessing of resting state fMRI, time-series were extracted from 400 cortical and 32 subcortical regions of interest (ROIs) defined by atlases derived from functional brain organization. Group-level aberrations were measured by contrasting right (RTLE) and left (LTLE) patient groups to controls in a support vector regression models, and tested for statistical reliability using permutation analysis. Individualized functional anomaly maps (FAMs) were generated by contrasting individual patients to the control group. Half of patients were used for training a classification model, and the other half for estimating the accuracy to lateralize mTLE based on individual FAMs. Results: Thirty-two right and 14 left mTLE patients (33 with evidence of hippocampal sclerosis on MRI) and 94 controls were included. At group levels, cortical regions affiliated with limbic and somatomotor networks were prominent in distinguishing RTLE and LTLE from controls. At individual levels, most TLE patients had high anomaly in bilateral mesial temporal and medial parietooccipital default mode regions. A linear support vector machine trained on 50% of patients could accurately lateralize mTLE in remaining patients (median AUC =1.0 [range 0.97-1.0], median accuracy = 96.87% [85.71-100Significance: Functional anomaly mapping confirms widespread aberrations in function, and accurately lateralizes mTLE from resting state fMRI. Future studies will evaluate FAM as a non-invasive localization method in larger datasets, and explore possible correlations with clinical characteristics and disease course.

Cingulate-Prefrontal Connectivity During Dynamic Cognitive Control Mediates Association Between p Factor and Adaptive Functioning in a Transdiagnostic Pediatric Sample.

BACKGROUND: Covariation among psychiatric symptoms is being actively pursued for transdiagnostic dimensions of psychopathology with predictive utility. A superordinate dimension, the p factor, reflects overall psychopathology burden and has support from genetic and neuroimaging correlates. However, the neurocognitive correlates that link an elevated p factor to maladaptive outcomes are unknown. We tested the mediating potential of dynamic adjustments in cognitive control rooted in functional connections anchored by the dorsal anterior cingulate cortex (dACC) in a transdiagnostic pediatric sample. METHODS: A multiple mediation model tested the association between the p factor (derived by principal component analysis of Child Behavior Checklist syndrome scales) and outcome measured with the Vineland Adaptive Behavior Scale-II in 89 children ages 8 to 13 years (23 female) with a variety of primary neurodevelopmental diagnoses who underwent functional magnetic resonance imaging during a socioaffective Stroop-like task with eye gaze as distractor. Mediators included functional connectivity of frontoparietal- and salience network-affiliated dACC seeds during conflict adaptation. RESULTS: Higher p factor scores were related to worse adaptive functioning. This effect was partially mediated by conflict adaptation-dependent functional connectivity between the frontoparietal network-affiliated dACC seed and the right dorsolateral prefrontal cortex. Post hoc follow-up indicated that the p factor was related to all Vineland Adaptive Behaviors Scale-II domains; the association was strongest for socialization followed by daily living skills and then communication. Mediation results remained significant for socialization only. CONCLUSIONS: Higher psychopathology burden was associated with worse adaptive functioning in early adolescence. This association was mediated by weaker dACC-dorsolateral prefrontal cortex functional connectivity underlying modulation of cognitive control in response to contextual contingencies. Our results contribute to the identification of transdiagnostic and developmentally relevant neurocognitive endophenotypes of psychopathology.

Impact of development and recent-onset epilepsy on language dominance.

OBJECTIVE: Reorganization of the language network from typically left-lateralized frontotemporal regions to bilaterally distributed or right-lateralized networks occurs in anywhere from 25%-30% of patients with focal epilepsy. In patients who have been recently diagnosed with epilepsy, an important question remains as to whether it is the presence of seizures or the underlying epilepsy etiology that leads to atypical language representations. This question becomes even more interesting in pediatric samples, where the typical developmental processes of the language network may confer more variability and plasticity in the language network. We assessed a carefully selected cohort of children with recent-onset epilepsy to examine whether it is the effects of seizures or their underlying cause that leads to atypical language lateralization. METHODS: We used functional magnetic resonance imaging (fMRI) to compare language laterality in children with recently diagnosed focal unaware epilepsy and age-matched controls. Age at epilepsy onset (age 4 to 6 years vs age 7 to 12 years) was also examined to determine if age at onset influenced laterality. RESULTS: The majority of recent-onset patients and controls exhibited left-lateralized language. There was a significant interaction such that the relationship between epilepsy duration and laterality differed by age at onset. In children with onset after age 6, a longer duration of epilepsy was associated with less left-lateralized language dominance. In contrast, in children with onset between 4 and 6 years of age, a longer duration of epilepsy was not associated with less left language dominance. SIGNIFICANCE: Our results demonstrate that although language remained largely left-lateralized in children recently diagnosed with epilepsy, the impact of seizure duration depended on age at onset, indicating that the timing of developmental and disease factors are important in determining language dominance.

Prevalence and Risk Factors for Pharmacoresistance in Children With Focal Cortical Dysplasia-Related Epilepsy.

BACKGROUND AND OBJECTIVES: Focal cortical dysplasia is the most common cause of surgically-remediable epilepsy in children. Little is known about the risk factors for the timing and development of pharmacoresistance in this population. This study sought to evaluate the prevalence and risk factors for pharmacoresistance in pediatric FCD-related epilepsy. METHODS: In this retrospective single-center cohort design, patients were identified from search of centralized radiology report database and a central epilepsy surgical database. Inclusion criteria consisted of: 3T MRI-confirmed FCD from January, 2011 to January, 2020; ages 0 days to 22 years at MRI; at least 18 months of documented follow-up after MRI, unless had single seizure or incidentally discovered FCD. Records were excluded if there was dual pathology (except for mesial temporal sclerosis), hemimegalencephaly, or tuberous sclerosis complex present in imaging or history. RESULTS: One hundred forty-three patients with confirmed FCD met inclusion criteria. One hundred twenty-four children had epilepsy (87% of FCD patients) with median age of seizure onset 2.7 years (IQR 0.75-6 years, range 0 to 17 years). Twelve children (8.5%) had a single lifetime seizure (provoked or unprovoked) or recurrent provoked seizures. Seven children (4.9%) had incidental FCD. Ninety-two patients (74%) of those with epilepsy met criteria for pharmacoresistance. Of children with epilepsy of all types, 93 children (75%) were seizure-free at the last visit; Eighty-two patients underwent epilepsy surgery, of whom 59 (72%) achieved seizure freedom. 7% (9/124) achieved seizure freedom with a second ASM, and 5.6% (7/124) with a third or more ASMs. Failure of only one antiseizure medication is associated with enormous increased incidence and earlier development of pharmacoresistance (OR 346, 95% CI 19.6-6100). Cox regression showed FCD lobar location, pathologic subtype, and age of seizure onset are not. CONCLUSIONS: Failure of one antiseizure medication is associated with substantial risk of pharmacoresistance. These data support an operational re-definition of pharmacoresistance, for surgical planning, in FCD-related epilepsy to the failure of one antiseizure medication, and support early, potentially curative surgery to improve outcomes in this patient population.

Resting-state functional MRI for motor cortex mapping in childhood-onset focal epilepsy.

BACKGROUND AND PURPOSE: Task-based functional MRI (fMRI) mapping of the motor function prior to epilepsy surgery has limitations in children with epilepsy. We present a data-driven method to automatically delineate the motor cortex using task-free, resting-state fMRI (rsfMRI) data. METHODS: We used whole-brain rsfMRI for independent component analysis (ICA). A template matching process with Discriminability Index-based Component Identification score was used for each participant to select and combine motor ICA components in their native brain space, resulting in a whole-brain ICA Motor Map (wIMM). We validated wIMM by comparing individual results with bilateral finger-tapping motor task fMRI activation, and evaluated its reproducibility in controls. RESULTS: Data from 64 patients and 12 controls were used to generate group wIMM maps. The hit rate between wIMM and motor task activation ranged from 60% to 79% across all participants. Sensitivity of wIMM for capturing the task activation peak was 87.5% among 32 patients and 100% in 12 controls with available motor task results. We also showed high similarity in repeated runs in controls. CONCLUSIONS: Our results show the sensitivity and reproducibility of an automated motor mapping method based on ICA analysis of rsfMRI in children with epilepsy. The ICA maps may provide different, but useful, information than task fMRI. Future studies will expand our method to mapping other brain functions, and may lead to a surgical planning tool for patients who cannot perform task fMRI and help predict their postsurgical function.

Networks Underlie Temporal Onset of Dysplasia-Related Epilepsy: A MELD Study.

OBJECTIVE: The purpose of this study was to evaluate if focal cortical dysplasia (FCD) co-localization to cortical functional networks is associated with the temporal distribution of epilepsy onset in FCD. METHODS: International (20 center), retrospective cohort from the Multi-Centre Epilepsy Lesion Detection (MELD) project. Patients included if >3 years old, had 3D pre-operative T1 magnetic resonance imaging (MRI; 1.5 or 3 T) with radiologic or histopathologic FCD after surgery. Images processed using the MELD protocol, masked with 3D regions-of-interest (ROI), and co-registered to fsaverage_sym (symmetric template). FCDs were then co-localized to 1 of 7 distributed functional cortical networks. Negative binomial regression evaluated effect of FCD size, network, histology, and sulcal depth on age of epilepsy onset. From this model, predictive age of epilepsy onset was calculated for each network. RESULTS: Three hundred eighty-eight patients had median age seizure onset 5 years (interquartile range [IQR] = 3-11 years), median age at pre-operative scan 18 years (IQR = 11-28 years). FCDs co-localized to the following networks: limbic (90), default mode (87), somatomotor (65), front parietal control (52), ventral attention (32), dorsal attention (31), and visual (31). Larger lesions were associated with younger age of onset (p = 0.01); age of epilepsy onset was associated with dominant network (p = 0.04) but not sulcal depth or histology. Sensorimotor networks had youngest onset; the limbic network had oldest age of onset (p values <0.05). INTERPRETATION: FCD co-localization to distributed functional cortical networks is associated with age of epilepsy onset: sensory neural networks (somatomotor and visual) with earlier onset, and limbic latest onset. These variations may reflect developmental differences in synaptic/white matter maturation or network activation and may provide a biological basis for age-dependent epilepsy onset expression. ANN NEUROL 2022;92:503-511.

Common functional connectivity alterations in focal epilepsies identified by machine learning.

OBJECTIVE: This study was undertaken to identify shared functional network characteristics among focal epilepsies of different etiologies, to distinguish epilepsy patients from controls, and to lateralize seizure focus using functional connectivity (FC) measures derived from resting state functional magnetic resonance imaging (MRI). METHODS: Data were taken from 103 adult and 65 pediatric focal epilepsy patients (with or without lesion on MRI) and 109 controls across four epilepsy centers. We used three whole-brain FC measures: parcelwise connectivity matrix, mean FC, and degree of FC. We trained support vector machine models with fivefold cross-validation (1) to distinguish patients from controls and (2) to lateralize the hemisphere of seizure onset in patients. We reported the regions and connections with the highest importance from each model as the common FC differences between the compared groups. RESULTS: FC measures related to the default mode and limbic networks had higher importance relative to other networks for distinguishing epilepsy patients from controls. In lateralization models, regions related to somatosensory, visual, default mode, and basal ganglia showed higher importance. The epilepsy versus control classification model trained using a 400-parcel connectivity matrix achieved a median testing accuracy of 75.6% (median area under the curve [AUC] = .83) in repeated independent testing. Lateralization accuracy using the 400-parcel connectivity matrix reached a median accuracy of 64.0% (median AUC = .69). SIGNIFICANCE: Machine learning models revealed common FC alterations in a heterogeneous group of patients with focal epilepsies. The distribution of the most altered regions supports the hypothesis that shared functional alteration exists beyond the seizure onset zone and its epileptic network. We showed that FC measures can distinguish patients from controls, and further lateralize focal epilepsies. Future studies are needed to confirm these findings by using larger numbers of epilepsy patients.

Atlas of lesion locations and postsurgical seizure freedom in focal cortical dysplasia: A MELD study.

OBJECTIVE: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. METHODS: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. RESULTS: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. SIGNIFICANCE: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy.

Functional Connectivity as a Potential Mechanism for Language Plasticity.

BACKGROUND AND OBJECTIVES: Task fMRI is a clinical tool for language lateralization, but has limitations, and cannot provide information about network-level plasticity. Additional methods are needed to improve the precision of presurgical language mapping. We investigate language resting-state functional connectivity (RS fMRI; FC) in typically developing children (TD) and children with epilepsy. Our objectives were to (1) understand how FC components differ between TD children and those with epilepsy; (2) elucidate how the location of disease (frontal/temporal epilepsy foci) affects FC; and (3) investigate the relationship between age and FC. METHODS: Our sample included 55 TD children (mean age 12 years, range 7-18) and 31 patients with focal epilepsy (mean age 13 years, range 7-18). All participants underwent RS fMRI. Using a bilateral canonical language map as target, vertex-wise intrahemispheric FC map and interhemispheric FC map for each participant were computed and thresholded at top 10% to compute an FC laterality index (FCLI; [(L - R)/(L + R)]) of the frontal and temporal regions for both integration (intrahemispheric FC; FCLIi) and segregation (interhemispheric FC; FCLIs) maps. RESULTS: We found FC differences in the developing language network based on disease, seizure foci location, and age. Frontal and temporal FCLIi was different between groups (t[84] = 2.82, p < 0.01; t[84] = 4.68, p < 0.01, respectively). Frontal epilepsy foci had the largest differences from TD (Cohen d frontal FCLIi = 0.84, FCLIs = 0.51; temporal FCLIi = 1.29). Development and disease have opposing influences on the laterality of FC based on groups. In the frontal foci group, FCLIi decreased with age (r = -0.42), whereas in the temporal foci group, FCLIi increased with age (r = 0.40). Within the epilepsy group, increases in right frontal integration FCLI relates to increased right frontal task activation in our mostly left language dominant group (r = 0.52, p < 0.01). Language network connectivity is associated with higher verbal intelligence in children with epilepsy (r = 0.45, p < 0.05). DISCUSSION: These findings lend preliminary evidence that FC reflects network plasticity in the form of adaptation and compensation, or the ability to recruit support and reallocate resources within and outside of the traditional network to compensate for disease. FC expands on task-based fMRI and provides complementary and potentially useful information about the language network that is not captured using task-based fMRI alone.

Neural correlates of schema-dependent episodic memory and association with behavioral flexibility in autism spectrum disorders and typical development.

BACKGROUND: Conceptual knowledge frameworks termed schemas facilitate memory formation and are posited to support flexible behavior. In adults, the medial temporal lobe (MTL) and medial prefrontal cortex (mPFC) trade-off in supporting schema-based memory formation, such that encoding of subsequently remembered schema-congruent information relies on mPFC, whereas schema-incongruent information relies on MTL. Whether this is true in the immature brain and relates to behavioral flexibility is unknown. In this preliminary investigation, we aimed to replicate the adult findings in typically developing (TD) children and to investigate the relevance to behavioral flexibility by examining a disorder with pathognomonic behavioral rigidity, autism spectrum disorder (ASD). METHODS: Children completed an associative subsequent memory paradigm, encoding object-scene pairs in an MRI scanner and subsequently completing a recognition test outside the scanner after a delay. Recognition performance was back sorted to construct remembered vs forgotten contrasts. One-way ANOVAS were conducted in MTL and mPFC masks for schema-congruency, followed by congruency by flexibility scores. Exploratory analyses were then conducted within the whole brain. RESULTS: As reported in adults, episodic memory was strongest for schema-congruent object-scene pairs, followed by intermediate pairs, and lowest for schema-incongruent pairs in both TD and ASD groups. However, the trade-off between mPFC and MTL in TD children differed from adult reports such that mPFC supported memory for intermediate schema-congruency and left anterior MTL supported memory for schema-congruent pairs. In ASD, mPFC engagement interacted with flexibility such that activation supporting memory for intermediate schema-congruency varied with parent-reported flexibility and was higher in those with more flexible behavior. A similar interaction was also observed in both the left dorsolateral and rostrolateral PFC in whole-brain analysis. CONCLUSION: Our findings provide the first preliminary evidence for the association of schema-based episodic memory formation and behavioral flexibility, an executive function impaired in multiple developmental disorders. Upon replication, this line of research holds promise for memory-based interventions addressing executive problems of behavioral rigidity.

Functional connectivity hemispheric contrast (FC-HC): A new metric for language mapping.

Development of a task-free method for presurgical mapping of language function is important for use in young or cognitively impaired patients. Resting state connectivity fMRI (RS-fMRI) is a task-free method that may be used to identify cognitive networks. We developed a voxelwise RS-fMRI metric, Functional Connectivity Hemispheric Contrast (FC-HC), to map the language network and determine language laterality through comparison of within-hemispheric language network connections (Integration) to cross-hemispheric connections (Segregation). For the first time, we demonstrated robustness and efficacy of a RS-fMRI metric to map language networks across five groups (total N = 243) that differed in MRI scanning parameters, fMRI scanning protocols, age, and development (typical vs pediatric epilepsy). The resting state FC-HC maps for the healthy pediatric and adult groups showed higher values in the left hemisphere, and had high agreement with standard task language fMRI; in contrast, the epilepsy patient group map was bilateral. FC-HC has strong but not perfect agreement with task fMRI and thus, may reflect related and complementary information about language plasticity and compensation.

Spatiotemporal distribution and age of seizure onset in a pediatric epilepsy surgery cohort with cortical dysplasia.

OBJECTIVE: Focal Cortical Dysplasias (CD) are a common etiology of refractory pediatric epilepsy and are amenable to epilepsy surgery. We investigated the association of lesion volume and location to age of seizure onset among children with CD who underwent epilepsy surgery. METHODS: A retrospective study of epilepsy surgery patients with pathologically-confirmed CD. Regions of interest (ROI) determined preoperative lesion volumes on 1.5 T and 3 T T2 and SPGR MRIs, and location in 7 distributed neural networks. Descriptive and inferential statistics were used. RESULTS: Fifty-five patients were identified: 35 girls (56.5 %). Median age of seizure onset: 19.0 months (range 0.02 months - 16.0 years). Median age of surgery: 7.8 years (range 2.89 months - 24.45 years). CD were frontal (n = 21, 38 %); temporal (n = 15, 27 %); parietal (n = 10, 18 %); occipital (n = 3, 5%); multilobar (n = 6, 11 %). Frontal FCD had seizure onset < 1-year-old (P = 0.10); temporal lobe CD seizure onset was more likely > 5-years-old (P= 0.06). Median lesion volume for CD was 23.23 cm3 (range: 1.87-591.73 cm3). Larger CD lesions were associated with earlier epilepsy (P = 0.01, r = -0.16). We did not find that lesions proximal to early maturing cortical regions were associated with earlier seizure onset. We found an association with CD location in the default mode network (DMN) and age onset < 5years old (P = 0.03). Age of seizure onset was negatively correlated with percent of CD overlapping motor cortex (P = 0.001, r =-0.794) but not with CD overlap of the visual cortex (P = 0.35). There was no effect of CD type on age of epilepsy onset. SIGNIFICANCE: Larger CD lesions are associated with earlier onset epilepsy. CD most commonly occurs within the DMN and Limbic network, and DMN is associated with seizure onset before 5-years-old. Percent of CD overlapping motor cortex correlates with earlier seizure onset. These observations may reflect patterns of brain maturation or regional differences in clinical expression of seizures.

Language lateralization from task-based and resting state functional MRI in patients with epilepsy.

We compared resting state (RS) functional connectivity and task-based fMRI to lateralize language dominance in 30 epilepsy patients (mean age = 33; SD = 11; 12 female), a measure used for presurgical planning. Language laterality index (LI) was calculated from task fMRI in frontal, temporal, and frontal + temporal regional masks using LI bootstrap method from SPM12. RS language LI was assessed using two novel methods of calculating RS language LI from bilateral Broca's area seed based connectivity maps across regional masks and multiple thresholds (p < .05, p < .01, p < .001, top 10% connections). We compared LI from task and RS fMRI continuous values and dominance classifications. We found significant positive correlations between task LI and RS LI when functional connectivity thresholds were set to the top 10% of connections. Concordance of dominance classifications ranged from 20% to 30% for the intrahemispheric resting state LI method and 50% to 63% for the resting state LI intra- minus interhemispheric difference method. Approximately 40% of patients left dominant on task showed RS bilateral dominance. There was no difference in LI concordance between patients with right-sided and left-sided resections. Early seizure onset (<6 years old) was not associated with atypical language dominance during task-based or RS fMRI. While a relationship between task LI and RS LI exists in patients with epilepsy, language dominance is less lateralized on RS than task fMRI. Concordance of language dominance classifications between task and resting state fMRI depends on brain regions surveyed and RS LI calculation method.

Data-driven identification of subtypes of executive function across typical development, attention deficit hyperactivity disorder, and autism spectrum disorders.

BACKGROUND: Impairment of executive function (EF), the goal-directed regulation of thoughts, actions, and emotions, drives negative outcomes and is common across neurodevelopmental disorders including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). A primary challenge to its amelioration is heterogeneity in symptom expression within and across disorders. Parsing this heterogeneity is necessary to attain diagnostic precision, a goal of the NIMH Research Domain Criteria Initiative. We aimed to identify transdiagnostic subtypes of EF that span the normal to impaired spectrum and establish their predictive and neurobiological validity. METHODS: Community detection was applied to clinical parent-report measures in 8-14-year-old children with and without ADHD and ASD from two independent cohorts (discovery N = 320; replication N = 692) to identify subgroups with distinct behavioral profiles. Support vector machine (SVM) classification was used to predict subgroup membership of unseen cases. Preliminary neurobiological validation was obtained with existing functional magnetic resonance imaging (fMRI) data on a subsample (N = 84) by testing hypotheses about sensitivity of EF subgroups versus DSM categories. RESULTS: We observed three transdiagnostic EF subtypes characterized by behavioral profiles that were defined by relative weakness in: (a) flexibility and emotion regulation; (b) inhibition; and (c) working memory, organization, and planning. The same tripartite structure was also present in the typically developing children. SVM trained on the discovery sample and tested on the replication sample classified subgroup membership with 77.0% accuracy. Split-half SVM classification on the combined sample (N = 1,012) yielded 88.9% accuracy (this SVM is available for public use). As hypothesized, frontal-parietal engagement was better distinguished by EF subtype than DSM diagnosis and the subgroup characterized with inflexibility failed to modulate right IPL activation in response to increased executive demands. CONCLUSIONS: The observed transdiagnostic subtypes refine current diagnostic nosology and augment clinical decision-making for personalizing treatment of executive dysfunction in children.

Cortical thickness in childhood left focal epilepsy: Thinning beyond the seizure focus.

OBJECTIVE: Structural brain differences are found in adults and children with epilepsy, yet pediatric samples have been heterogeneous regarding seizure type, magnetic resonance imaging (MRI) findings, and hemisphere of seizure focus. This study examines whether cortical thickness and surface area differ between children with left-hemisphere focal epilepsy (LHE) and age-matched typically developing (TD) peers. We examined whether age differentially moderated cortical thickness between groups and if cortical thickness was associated with duration of epilepsy, seizure frequency, or neuropsychological functioning. METHODS: Thirty-five children with LHE and 35 TD children completed neuropsychological testing and 3T MR imaging. Neuropsychological measures included general intelligence and executive functioning. All MRIs were normal. Surface-based morphometric processing and analyses were conducted using FreeSurfer 6.0. Regression analyses compared age by cortical thickness differences between groups. Correlational analyses examined associations between cortical thickness in these areas with neuropsychological functioning or epilepsy characteristics. RESULTS: Left-hemisphere focal epilepsy displayed decreased cortical thickness bilaterally compared to TD controls across 6 brain regions but no differences in surface area. Moderation analyses revealed quadratic relationships between age and cortical thickness for left frontoparietal-cingulate and right superior frontal regions. Higher performance intelligence quotient (IQ) (PIQ) and verbal IQ (VIQ) and fewer parent reported executive function problems were associated with greater cortical thickness in TD children. SIGNIFICANCE: Children with LHE displayed thinner cortex extending beyond the hemisphere of seizure focus. The nonlinear pattern of cortical thickness across age occurring in TD children is not evident in the same manner in children with LHE. These differences in cortical thickness patterns were greatest in children 8-12 years old. Greater cortical thickness was associated with higher IQ and fewer executive control problems in daily activities in TD children. Thus, differences in cortical thickness in the absence of differences in surface area, suggest cortical thickness may be a sensitive proxy of subtle neuroanatomical changes that are related to neuropsychological functioning.

Altered neural correlates of episodic memory in adolescents with severe obesity.

Negative effects of obesity on memory and associated medial temporal circuitry have been noted in animal models, but the status in humans, particularly children, is not well established. Our study is the first to examine neural correlates of successful memory encoding of visual scenes and their associated context in adolescents with severe obesity (age 14-18 years, 43% male). Despite similar subsequent memory as adolescents without obesity (BMI for age and sex <95th percentile), those with severe obesity (BMI for age and sex 120% above the 95th percentile) showed reduced hippocampal, parahippocampal, frontal, and parietal engagement during encoding of remembered visual scenes and greater lateral temporal engagement during encoding of their associated context. Standardized testing revealed a trend level group difference in memory performance, with a larger magnitude of obesity-related difference in recollection-related memory that was mediated by individual differences in lateral temporal activation during contextual encoding. The observed widespread functional alterations are concerning in light of the importance of mnemonic processing for academic achievement and feeding behavior and underscore the need for prevention and intervention initiatives for pediatric obesity.

fMRI prediction of naming change after adult temporal lobe epilepsy surgery: Activation matters.

OBJECTIVE: We aimed to predict language deficits after epilepsy surgery. In addition to evaluating surgical factors examined previously, we determined the impact of the extent of functional magnetic resonance imaging (fMRI) activation that was resected on naming ability. METHOD: Thirty-five adults (mean age 37.5 ± 10.9 years, 13 male) with temporal lobe epilepsy completed a preoperative fMRI auditory description decision task, which reliably activates frontal and temporal language networks. Patients underwent temporal lobe resections (20 left resection). The Boston Naming Test (BNT) was used to determine language functioning before and after surgery. Language dominance was determined for Broca and Wernicke area (WA) by calculating a laterality index following statistical parametric mapping processing. We used an innovative method to generate anatomic resection masks automatically from pre- and postoperative MRI tissue map comparison. This mask provided the following: (a) resection volume; (b) overlap between resection and preoperative activation; and (c) overlap between resection and WA. We examined postoperative language change predictors using stepwise linear regression. Predictors included parameters described above as well as age at seizure onset (ASO), preoperative BNT score, and resection side and its relationship to language dominance. RESULTS: Seven of 35 adults had significant naming decline (6 dominant-side resections). The final regression model predicted 38% of the naming score change variance (adjusted r2  = 0.28, P = 0.012). The percentage of top 10% fMRI activation resected (P = 0.017) was the most significant contributor. Other factors in the model included WA LI, ASO, volume of WA resected, and WA LI absolute value (extent of laterality). SIGNIFICANCE: Resection of fMRI activation during a word-definition decision task is an important factor for postoperative change in naming ability, along with other previously reported predictors. Currently, many centers establish language dominance using fMRI. Our results suggest that the amount of the top 10% of language fMRI activation in the intended resection area provides additional predictive power and should be considered when planning surgical resection.

Interactive effect of 5-HTTLPR and BDNF polymorphisms on amygdala intrinsic functional connectivity and anxiety.

The serotonin transporter (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) gene polymorphisms have been associated with risk for affective disorders and functional variability of the amygdala. We examined whether the two genotypes interactively influence intrinsic functional connectivity (FC) of the amygdala and whether FC mediates the genetic association with anxiety. Eighty genotyped healthy adults underwent resting state fMRI and completed the self-reported State-Trait Anxiety Inventory. Interactive genetic association with anxiety was observed such that effects of 5-HTTLPR depended on the BDNF Val66Met polymorphism (rs6265 variant), with higher anxiety scores in short and Met carriers compared to the other allelic groups. Voxel-wise FC with left and right amygdala seeds identified regions that were sensitive to variability in anxiety scores. A significant moderated mediation model demonstrated that the effect of 5-HTTLPR genotype on anxiety, moderated by BDNF Val66Met genotype, was fully mediated by FC between the left amygdala and the right dorsolateral prefrontal cortex, a cognitive control-related region, during a task-free state. FC was highest in carriers of the 5-HTTLPR short allele and BDNF Met allele. These findings establish intrinsic amygdala-prefrontal functional connectivity as a potential intermediate phenotype for anxiety, an important step toward identification of causal pathways for vulnerability to affective disorders.