Madison M. Berl

Atypical language in lesional and nonlesional complex partial epilepsy

Objective: We investigated the relationship between partial epilepsy, MRI findings, and atypical language representation. Methods: A total of 102 patients (4 to 55 years) with left hemisphere epileptogenic zones were evaluated using three fMRI language tasks obtained at 1.5 or 3T with EPI BOLD techniques: verbal fluency, reading comprehension, and auditory comprehension. fMRI maps were visually interpreted at a standard threshold and rated as left or atypical language. Results: Atypical language dominance occurred in 30 patients (29%) and varied with MRI type (p < 0.01). Atypical language representation occurred in 36% (13/36) with normal MRI, 21% (6/29) with mesial temporal sclerosis, 14% (4/28) with focal cortical lesions (dysplasia, tumor, vascular malformation), and all (6/6) with a history of stroke. Multivariate logistic regression analysis found handedness, seizure onset, and MRI type accounted for much of the variance in language activation patterns (χ2 = 24.09, p < 0.01). Atypical language was more prevalent in patients with early seizure onset (43.2%, p < 0.05) and atypical handedness (60%, p < 0.01). None of the three clinical factors were correlated with each other (p > 0.40). Patients with atypical language had lower verbal abilities (F = 6.96, p = 0.01) and a trend toward lower nonverbal abilities (F = 3.58, p = 0.06). There were no differences in rates of atypical language across time, age groups, or MRI scanner. Conclusion: Early seizure onset and atypical handedness, as well as the location and nature of pathologic substrate, are important factors in language reorganization. GLOSSARY: FOV = field of view; MTS = mesial temporal sclerosis; RRN = read response naming; TE = echo time; TR = repetition time; WAIS = Wechsler Adult Intelligence Scale; WISC = Wechsler Intelligence Scale for Children.

Seizure focus affects regional language networks assessed by fMRI.

Objective: To investigate the degree of language dominance in patients with left and right hemisphere seizure foci compared to normal volunteers using a fMRI reading comprehension task. Methods: Fifty patients with complex partial epilepsy, aged 8 to 56 years and 33 normal volunteers, aged 7 to 34 had fMRI (1.5 T) and neuropsychological testing. Participants silently named an object described by a sentence compared to a visual control. Data were analyzed with region of interest (ROI) analysis based on t maps for inferior frontal gyrus (IFG), midfrontal gyrus (MFG), and Wernicke area (WA). Regional asymmetry indices (AIs) were calculated [(L − R)/(L + R)]; AI >0.20 was deemed left dominant and AI <0.20 as atypical language. Results: Left hemisphere focus patients had a higher likelihood of atypical language than right hemisphere focus patients (21% vs 0%, χ2 < 0.002). Left hemisphere focus patients, excluding those with atypical language, had lower regional AI in IFG, MFG, and WA than controls. Right hemisphere focus patients were all left language dominant and had a lower AI than controls in WA and MFG, but not for IFG. AI in MFG and WA were similar between left hemisphere focus/left language patients and right hemisphere focus patients. Patients activated more voxels than healthy volunteers. Lower AIs were attributable to greater activation in right homologous regions. Less activation in the right-side WA correlated with better verbal memory performance in right focus/left hemisphere-dominant patients, whereas less strongly lateralized activation in IFG correlated better with Verbal IQ in left focus/left hemisphere-dominant patients. Conclusions: Patients had lower asymmetry indices than healthy controls, reflecting increased recruitment of homologous right hemisphere areas for language processing. Greater right hemisphere activation may reflect greater cognitive effort in patient populations, the effect of epilepsy, or its treatment. Regional activation patterns reflect adaptive efforts at recruiting more widespread language processing networks that are differentially affected based on hemisphere of seizure focus.

The fMRI Success Rate of Children and Adolescents: Typical Development, Epilepsy, Attention Deficit/Hyperactivity Disorder, and Autism Spectrum Disorders

Functional magnetic resonance imaging (fMRI) in children is increasingly used in clinical application and in developmental research; however, little is known how pediatric patient and typically developing populations successfully complete studies. We examined pediatric success rates with epilepsy, attention deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and typically developing children (TYP). We also examined the affect of age, and, for ADHD populations, medication status on success rates. We defined a successful fMRI individual run when the data were interpretable and included in group statistics. For unsuccessful runs, datasets with excessive motion or floor task performance were categorized when possible. All clinical groups scanned less successfully than controls; medication status did not affect ADHD success (epilepsy, 80%; ADHD (off methylphenidate), 77%; ADHD (on methylphenidate), 81%; ASD, 70%; TYP, 87%). Ten to 18‐year‐old had a significantly greater scan success rate than 4‐ to 6‐year‐old; adolescents (13‐ to 18‐year‐old) demonstrated greater scan success rates than 7‐ to 9‐year‐old. Success rate for completing an entire battery of experimental runs (n = 2–6), varied between 50–59% for patient populations and 69% for TYP (79% when excluding 4‐ to 6‐year‐old). Success rate for completing one run from a battery was greater than 90% for all groups, except for ASD (81%). These data suggest 20–30% more children should be recruited in these patient groups, but only 10–20% for TYP for research studies. Studies with 4‐ to 6‐year‐olds may require 20–40% additional participants; studies with 10‐ to 18‐year‐olds may require 10–15% additional participants. Hum Brain Mapp, 2009.

Limitations to plasticity of language network reorganization in localization related epilepsy

Neural networks for processing language often are reorganized in patients with epilepsy. However, the extent and location of within and between hemisphere re-organization are not established. We studied 45 patients, all with a left hemisphere seizure focus (mean age 22.8, seizure onset 13.3), and 19 normal controls (mean age 24.8) with an fMRI word definition language paradigm to assess the location of language processing regions. Individual patient SPM maps were compared to the normal group in a voxel-wise comparison; a voxel was considered to be significant if its z-value exceeded mid R:2mid R:. Subsequently, we used principal component analysis with hierarchical clustering of variance patterns from individual difference maps to identify four patient sub-groups. One did not differ from normal controls; one had increased left temporal activation on the margin of regions activated in controls; two others had recruitment in right inferior frontal gyrus, middle frontal gyrus and temporal cortex. Right hemisphere activation in these two groups occurred in homologues of left hemisphere regions that sustained task activation. Our study used novel data driven methods to find evidence for constraints on inter-hemispheric reorganization of language in recruitment of right homologues, and, in a subpopulation of patients, evidence for intra-hemispheric reorganization of language limited to the margins of typical left temporal regional activation. These methods may be applied to investigate both normal and pathological variance in other developmental disorders and cognitive domains.

Functional imaging of developmental and adaptive changes in neurocognition

Characterization of brain-behavior relationships through functional magnetic imaging (fMRI) within typically or atypically developing populations poses methodological and interpretational challenges. We consider theoretical, methodological, and artifactual factors that influence characterization of developmental and adaptive changes in childhood. Findings from anatomical and physiological brain development studies are highlighted as they may influence functional imaging results. Then, we consider several patterns of functional activation within the context of developmental processes as well as neurologic disease. Hypotheses regarding the development of cognitive networks are proposed to account for the individual differences seen in normal and atypical development. We also identify potential sources of unwanted variability related to experimental design and task performance and suggest possible solutions to help minimize these effects. Lastly, a challenge for current studies is a lack of group and individual analysis methods that can be reliably applied to capture and quantify factors that contribute to variability introduced by developmental and disease processes. We review current methods and propose potential solutions.

Pediatric functional magnetic resonance imaging (fMRI): issues and applications.

Functional magnetic resonance imaging (fMRI) represents a useful tool for studying brain functions and the neural basis of cognition in healthy children and in those in disease states. Functional magnetic resonance imaging is a relatively new use of existing magnetic resonance imaging technology that allows scientists and practitioners to observe the brain at work. It is based on the observation that local increases in blood flow are related to neural activity. This review considers principles of functional magnetic resonance imaging, issues relevant to imaging children, and research using functional magnetic resonance imaging to examine cognitive processing in pediatric populations. The focus is specifically on language studies to review strengths, limitations, and practical applications of this technology with children. Future directions for functional magnetic resonance imaging are presented.

Interhemispheric and intrahemispheric language reorganization in complex partial epilepsy

Objective: To investigate interhemispheric and intrahemispheric reorganization in patients with localization-related epilepsy. Method: We studied 50 patients with a left hemispheric focus and 20 normal right-handed controls with a 3T echoplanar imaging blood oxygen level dependent functional MRI auditory-based word definition decision task. Data were analyzed using SPM 2. Using region of interest for Broca and Wernicke areas and an asymmetry index (AI), patients were categorized as left language (LL; AI ≥0.20) or atypical language (AL; AI <0.20) for region. The point maxima activation for normal controls (p <0.05 corrected FDR) was identified in Broca and midtemporal regions and then used as a point of reference for individual point maxima identified at p < 0.001, uncorrected. Results: Patient groups showed increased frequency of having activation in right homologues. Activation in AL groups occurred in homologous right regions; distances for point maxima activation in homologous regions were the same as point maxima distances in normal control activation in left regions. Distances for LL patient in left regions showed a trend for differences for midtemporal gyrus (6 mm posterior, 3 mm superior) but variability around mean difference distance was significant. There was no effect of age at epilepsy onset, duration, or pathology on activation maxima. Conclusions: Right hemisphere language regions in patients with left hemispheric focus are homologues of left hemisphere Broca and broadly defined Wernicke areas. We found little evidence for intrahemispheric reorganization in patients with left hemisphere epilepsy who remain left language dominant by these methods.

Sub-patterns of language network reorganization in pediatric localization related epilepsy: A multisite study

To study the neural networks reorganization in pediatric epilepsy, a consortium of imaging centers was established to collect functional imaging data. Common paradigms and similar acquisition parameters were used. We studied 122 children (64 control and 58 LRE patients) across five sites using EPI BOLD fMRI and an auditory description decision task. After normalization to the MNI atlas, activation maps generated by FSL were separated into three sub‐groups using a distance method in the principal component analysis (PCA)‐based decisional space. Three activation patterns were identified: (1) the typical distributed network expected for task in left inferior frontal gyrus (Brocas) and along left superior temporal gyrus (Wernickes) (60 controls, 35 patients); (2) a variant left dominant pattern with greater activation in IFG, mesial left frontal lobe, and right cerebellum (three controls, 15 patients); and (3) activation in the right counterparts of the first pattern in Brocas area (one control, eight patients). Patients were over represented in Groups 2 and 3 (P < 0.0004). There were no scanner (P = 0.4) or site effects (P = 0.6). Our data‐driven method for fMRI activation pattern separation is independent of a priori notions and bias inherent in region of interest and visual analyses. In addition to the anticipated atypical right dominant activation pattern, a sub‐pattern was identified that involved intensity and extent differences of activation within the distributed left hemisphere language processing network. These findings suggest a different, perhaps less efficient, cognitive strategy for LRE group to perform the task. Hum Brain Mapp, 2011.

Regional Differences in the Developmental Trajectory of Lateralization of the Language Network

The timing and developmental factors underlying the establishment of language dominance are poorly understood. We investigated the degree of lateralization of traditional frontotemporal and modulatory prefrontal‐cerebellar regions of the distributed language network in children (n = 57) ages 4 to 12—a critical period for language consolidation. We examined the relationship between the strength of language lateralization and neuropsychological measures and task performance. The fundamental language network is established by four with ongoing maturation of language functions as evidenced by strengthening of lateralization in the traditional frontotemporal language regions; temporal regions were strongly and consistently lateralized by age seven, while frontal regions had greater variability and were less strongly lateralized through age 10. In contrast, the modulatory prefrontal‐cerebellar regions were the least strongly lateralized and degree of lateralization was not associated with age. Stronger core language skills were significantly correlated with greater right lateralization in the cerebellum. Hum Brain Mapp 35:270–284, 2014.

The benefits of a camp designed for children with epilepsy: evaluating adaptive behaviors over 3 years.

OBJECTIVE Children with epilepsy attending a condition-specific overnight camp were evaluated for behavioral changes over 3 consecutive years, using a modification of the Vineland Adaptive Behavioral Scale. METHODS Trained counselors completed pre- and postcamp assessments for each camper. Repeated-measures MANOVA was used to analyze effects of the camp experience for each year, with respect to gender and age. Repeated-measures ANOVA was conducted to evaluate long-term effects from year-to-year comparisons for return campers, following three successive camp experiences. RESULTS A significant change in social interaction was observed over 3 years. Despite some decline at the start of camp in consecutive years, the overall trend for return campers suggests a positive cumulative impact of continued camp participation, with improvements in the domains of social interaction, responsibility, and communication. CONCLUSION A condition-specific camp designed for children with epilepsy can improve adaptive behaviors and social interactions. Overall net gains appear to increase over time, suggesting additional benefits for return campers.