Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy

Targeted whole-exome sequencing (WES) is a powerful diagnostic tool for a broad spectrum of heterogeneous neurological disorders. Here, we aim to examine the impact on diagnosis, treatment and cost with early use of targeted WES in early-onset epilepsy. WES was performed on 180 patients with early-onset epilepsy (≤5 years) of unknown cause. Patients were classified as Retrospective (epilepsy diagnosis >6 months) or Prospective (epilepsy diagnosis <6 months). WES was performed on an Ion Proton™ and variant reporting was restricted to the sequences of 620 known epilepsy genes. Diagnostic yield and time to diagnosis were calculated. An analysis of cost and impact on treatment was also performed. A molecular diagnoses (pathogenic/likely pathogenic variants) was achieved in 59/180 patients (33%). Clinical management changed following WES findings in 23 of 59 diagnosed patients (39%) or 13% of all patients. A possible diagnosis was identified in 21 additional patients (12%) for whom supporting evidence is pending. Time from epilepsy onset to a genetic diagnosis was faster when WES was performed early in the diagnostic process (mean: 145 days Prospective vs. 2,882 days Retrospective). Costs of prior negative tests averaged $8,344 per patient in the Retrospective group, suggesting savings of$5,110 per patient using WES. These results highlight the diagnostic yield, clinical utility and potential cost-effectiveness of using targeted WES early in the diagnostic workup of patients with unexplained early-onset epilepsy. The costs and clinical benefits are likely to continue to improve. Advances in precision medicine and further studies regarding impact on long-term clinical outcome will be important

Overcoming Activation-Induced Registration Errors in fMRI

It has been shown that the presence of a blood oxygen level dependent (BOLD) signal in high-field (3T and higher) fMRI datasets can cause stimulus-correlated registration errors, especially when using a least-squares registration method. These errors can result in systematic inaccuracies in activation detection. The authors have recently proposed a new method to solve both the registration and activation detection least-squares problems simultaneously. This paper gives an outline of the new method, and demonstrates its robustness on simulated fMRI datasets containing various combinations of motion and activation. In addition to a discussion of the merits of the method and details on how it can be efficiently implemented, it is shown that, compared to the standard approach, the new method consistently reduces false-positive activations by two thirds and reduces false-negative activations by one third

Simultaneous registration and activation detection for fMRI

Abstract—Registration using the least-squares cost function is sensitive to the intensity fluctuations caused by the blood oxygen level dependent (BOLD) signal in functional MRI (fMRI) experiments, resulting in stimulus-correlated motion errors. These errors are severe enough to cause false-positive clusters in the activation maps of datasets acquired from 3T scanners. This paper presents a new approach to resolving the coupling between registration and activation. Instead of treating the two problems as individual steps in a sequence, they are combined into a single leastsquares problem and are solved simultaneously. Robustness tests on a variety of simulated three–dimensional EPI datasets show that the stimulus-correlated motion errors are removed, resulting in a substantial decrease in false-positive and false-negative activation rates. The new method is also shown to decorrelate the motion estimates from the stimulus by testing it on different in vivo fMRI datasets acquired from two different 3T scanners. Index Terms—Activation, fMRI, GLM, least-squares, registration. I

Cerebellar language mapping and cerebral language dominance in pediatric epilepsy surgery patients

Objective: Children with epilepsy often have reorganization of language networks and abnormal brain anatomy, making determination of language lateralization difficult. We characterized the proportion and distribution of language task activation in the cerebellum to determine the relationship to cerebral language lateralization. Methods: Forty-six pediatric epilepsy surgery candidates (aged 7–19 years) completed an fMRI auditory semantic decision language task. Distribution of activated voxels and language laterality indices were computed using: (a) Broca's and Wernicke's areas and their right cerebral homologues; and (b) left and right cerebellar hemispheres. Language task activation was anatomically localized in the cerebellum. Results: Lateralized language task activation in either cerebral hemisphere was highly correlated with lateralized language task activation in the contralateral cerebellar hemisphere (Broca vs. cerebellar: ρ = −0.54, p < 0.01). Cerebellar language activation was located within Crus I/II, areas previously implicated in non-motor functional networks. Conclusions: Cerebellar language activation occurs in homologous regions of Crus I/II contralateral to cerebral language activation in patients with both right and left cerebral language dominance. Cerebellar language laterality could contribute to comprehensive pre-operative evaluation of language lateralization in pediatric epilepsy surgery patients. Our data suggest that patients with atypical cerebellar language activation are at risk for having atypical cerebral language organization

Alterations in resting state networks following in utero SSRI exposure in the neonatal brain

Background: Selective Serotonin Reuptake Inhibitors (SSRIs) are commonly used to treat depression during pregnancy. SSRIs cross the placenta, inhibit serotonin (5HT) reuptake, thereby altering central fetal 5HT signaling. Both prenatal maternal mood disturbances and in utero SSRIs have been associated with altered fetal and infant behavior. Advances in resting-state (rs)fMRI have identified resting-state networks (RSNs) in newborns reflecting functional capacity of auditory and visual networks providing opportunities to examine the impact of early experience on neurodevelopment. We sought to examine the effect of in utero SSRI exposure on neonatal RSN functional organization, accounting for prenatal maternal mood symptoms. We hypothesized that prenatal SSRI-exposure would affect neonatal RSN development independent of prenatal maternal mood disturbances. Methods: Non-exposed (n = 33) and SSRI-exposed (n = 20) 6-day-old neonates underwent (rs)fMRI scan. Clinician-rated, maternal prenatal mood (Hamilton Rating Scales for Depression (HAM-D) and self-report Pregnancy Experiences Scale (PES) were completed during third trimester. Independent component analysis (ICA) was used to extract twenty-two RSNs. Results: SSRI-exposed neonates had higher blood oxygenation level dependent (BOLD) signal in auditory RSN compared with non-exposed neonates, P=0.033 (corrected for multiple comparisons), controlling for maternal mood disturbances and self-reported pregnancy experiences. Conclusions: Increased functional connectivity in auditory RSN in neonates with in utero SSRI exposure, independent of maternal mood disturbances and pregnancy negative experiences, may offer an insight into the functional organization origins of shifts in language perception and altered language development previously reported in infants and children with prenatal SSRI exposure.Arts, Faculty ofMedicine, Faculty ofOther UBCNon UBCPediatrics, Department ofPhysical Therapy, Department ofPopulation and Public Health (SPPH), School ofPsychology, Department ofReviewedFacultyGraduat

Hub distribution of the brain functional networks of newborns prenatally exposed to maternal depression and SSRI anti-depressant

Background : Prenatal maternal depression (PMD) and Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants are associated with increased developmental risk in infants. Reports suggest that PMD is associated with hyperconnectivity of the insula and the amygdala, while SSRI-exposure is associated with hyperconnectivity of the auditory network in the infant brain. However, associations between functional brain organization and PMD and/or SSRI exposure are not well understood. Methods : We examined the relation between PMD or SSRI exposure and neonatal brain functional organization. Infants of control (n = 17), depressed SSRI-treated (n = 20) and depressed-only (HAM-D ≥ 8) (n = 16) women, underwent resting-state (rs)-fMRI at postnatal day 6. At 6 months temperament was assessed using infant behavioral questionnaire (IBQ). We applied GTA and partial least square regression (PLSR) to the resting-state time-series to assess group differences in modularity, and connector and provincial hubs. Results : Modularity was similar across all groups. The depressed-only group showed higher connector hub values in the left anterior-cingulate, insula, and caudate as well as higher provincial hub values in the amygdala compared to the control group. The SSRI group showed higher provincial hub values in Heschl’s gyrus relative to the depressed-only group. PLSR showed that newborns’ hub values predicted 10% of the variability in infant temperament at 6 months, suggesting different developmental patterns between groups. Conclusions : Prenatal exposures to maternal depression and SSRIs have differential impacts on neonatal functional brain organization. Hub values at 6 days predict variance in temperament between infant groups at 6 months of age.Arts, Faculty ofMedicine, Faculty ofOther UBCNon UBCPediatrics, Department ofPhysical Therapy, Department ofPsychology, Department ofReviewedFacultyGraduat