Dosage Considerations for Transcranial Direct Current Stimulation in Children: A Computational Modeling Study

Transcranial direct current stimulation (tDCS) is being widely investigated in adults as a therapeutic modality for brain disorders involving abnormal cortical excitability or disordered network activity. Interest is also growing in studying tDCS in children. Limited empirical studies in children suggest that tDCS is well tolerated and may have a similar safety profile as in adults. However, in electrotherapy as in pharmacotherapy, dose selection in children requires special attention, and simple extrapolation from adult studies may be inadequate. Critical aspects of dose adjustment include 1) differences in neurophysiology and disease, and 2) variation in brain electric fields for a specified dose due to gross anatomical differences between children and adults. In this study, we used high-resolution MRI derived finite element modeling simulations of two healthy children, ages 8 years and 12 years, and three healthy adults with varying head size to compare differences in electric field intensity and distribution. Multiple conventional and high-definition tDCS montages were tested. Our results suggest that on average, children will be exposed to higher peak electrical fields for a given applied current intensity than adults, but there is likely to be overlap between adults with smaller head size and children. In addition, exposure is montage specific. Variations in peak electrical fields were seen between the two pediatric models, despite comparable head size, suggesting that the relationship between neuroanatomic factors and bioavailable current dose is not trivial. In conclusion, caution is advised in using higher tDCS doses in children until 1) further modeling studies in a larger group shed light on the range of exposure possible by applied dose and age and 2) further studies correlate bioavailable dose estimates from modeling studies with empirically tested physiologic effects, such as modulation of motor evoked potentials after stimulation

Modified Pediatric ASPECTS Correlates with Infarct Volume in Childhood Arterial Ischemic Stroke

Background and Purpose: Larger infarct volume as a percent of supratentorial brain volume (SBV) predicts poor outcome and hemorrhagic transformation in childhood arterial ischemic stroke (AIS). In perinatal AIS, higher scores on a modified pediatric version of the Alberta Stroke Program Early CT Score using acute MRI (modASPECTS) predict later seizure occurrence. The objectives were to establish the relationship of modASPECTS to infarct volume in perinatal and childhood AIS and to establish the interrater reliability of the score. Methods: We performed a cross sectional study of 31 neonates and 40 children identified from a tertiary care center stroke registry with supratentorial AIS and acute MRI with diffusion weighted imaging (DWI) and T2 axial sequences. Infarct volume was expressed as a percent of SBV using computer-assisted manual segmentation tracings. ModASPECTS was performed on DWI by three independent raters. The modASPECTS were compared among raters and to infarct volume as a percent of SBV. Results: ModASPECTS correlated well with infarct volume. Spearman rank correlation coefficients (ρ) for the perinatal and childhood groups were 0.76, p < 0.001 and 0.69, p < 0.001, respectively. Excluding one perinatal and two childhood subjects with multifocal punctate ischemia without large or medium sized vessel stroke, ρ for the perinatal and childhood groups were 0.87, p < 0.001 and 0.80, p < 0.001, respectively. The intraclass correlation coefficients for the three raters for the neonates and children were 0.93 [95% confidence interval (CI) 0.89–0.97, p < 0.001] and 0.94 (95% CI 0.91–0.97, p < 0.001), respectively. Conclusion: The modified pediatric ASPECTS on acute MRI can be used to estimate infarct volume as a percent of SBV with a high degree of validity and interrater reliability

Retention rates of rufinamide in pediatric epilepsy patients with and without Lennox-Gastaut Syndrome.

OBJECTIVE: To evaluate the effectiveness of rufinamide (RFM) in patients with Lennox–Gastaut Syndrome (LGS) compared to those with other epilepsy syndromes using time to treatment failure (retention rate) as the outcome measure. METHODS: In this retrospective cohort study, characteristics and outcomes of all patients receiving RFM in 2009 and 2010 were recorded. The primary outcome measure was RFM failure, defined as discontinuation of RFM or initiation of an additional antiepileptic therapy. The secondary outcome measure was discontinuation of RFM. Kaplan–Meier method survival curves were generated for time to RFM failure, for all patients and by the presence or absence of Lennox Gastaut Syndrome (LGS). The impact of age, seizure type, fast or slow drug titration, and concomitant therapy with valproate on retention rate were evaluated using Cox regression models. RESULTS: One hundred thirty-three patients were included, 39 (30%) of whom had LGS. For all patients, the probability of remaining on RFM without additional therapy was 45% at 12 months and 30% at 24 months. LGS diagnosis was an independent predictor of time to RFM failure (HR 0.51, 95% CI 0.31–0.83), with a median time to failure of 18 months in LGS compared to 6 months in all others (p = 0.006). CONCLUSIONS: In a broad population of children with refractory epilepsy, around half will continue taking the medication for at least a year without additional therapy. Patients with LGS are two times more likely to continue RFM without additional therapy compared to those without LGS

Neuromagnetic responses to tactile stimulation of the fingers: Evidence for reduced cortical inhibition for children with Autism Spectrum Disorder and children with epilepsy

The purpose of this study was to compare somatosensory responses from a group of children with epilepsy and a group of children with autism spectrum disorder (ASD), with age matched TD controls. We hypothesized that the magnitude of the tactile “P50m” somatosensory response would be reduced in both patient groups, possibly due to reduced GABAergic signaling as has been implicated in a variety of previous animal models and in vivo human MRS studies. We observed significant (~25%) decreases in tactile P50m dipole moment values from the source localized tactile P50m response, both for children with epilepsy and for children with ASD. In addition, the latency of the tactile P50m peak was observed to be equivalent between TD and ASD groups but was significantly delayed in children with epilepsy by ~6ms. Our data support the hypothesis of impaired GABAergic signaling in both children with ASD and children with epilepsy. Further work is needed to replicate these findings and directly relate them to both in vivo measures of GABA via e.g. magnetic resonance spectroscopy and psychophysical assessments of somatosensory function, and behavioral indices. Keywords: Autism Spectrum Disorder, Epilepsy, Magnetoencephalography (MEG), Post-excitatory inhibition, Somatosensory evoked fields (SEFS), Tactile stimulatio

Electric field plots on the cortical surface of the pediatric and adult brains for the M1-SO montage.

<p>The center of anode (red) was positioned on the motor strip and the cathode (black) was positioned over the contraletral supraorbital area (A-E). At 2 mA, the peak electric field was 0.66 V/m, 0.88 V/m, 0.72 V/m, 0.58 V/m, 0.56 V/min for P1, P2, S1, S2, and S3 respectively (A.1a,b,d- E.1a,b,d). A.2a,b,d, B.2a,b,d - show EF plots at 1 mA, for the pediatric heads. Cross-sectional coronal electric field plots were taken from the center of the anode (A.1c, A.2c, B.1c, B.2c, C.1c, D.1c, E.1c).</p

Segmented structures.

<p>Segmented tissue masks (skin, skull, CSF, gray matter, and white matter respectively) for the two children (P1, P2) and three adults (S1,S2,S3).</p

Directionality plots for the lateralized motor montage.

<p>The center of anode (red) is positioned on the motor strip and cathode (black) is positioned contralateral to the anode (M-O) (A1-A5). False color map are plotted for 2 mA. The red corresponds to current flowing inwards, the green corresponds to a net flow of zero, and the blue corresponds to current flowing outwards (B1-B5). </p

Approaches to normalize dose across populations.

<p>Top- Even in cases when individual modeling is practical for every subject in a study, criterion (based on population response) may be rewired to selected desired brain electric field parameters. Bottom: For each given montage and age range, there is a distribution of sensitivity (defines as the electric field in the brain per mA of current applied). In cases where the peak electric field is outside the nominal target (as is typical the case for sponge montages) further consideration should include both brain wide peak electric field and local electrical field maxima inside the nominal target. In the case of 4x1 HD-tDCS, the peak electric field is inside the ring so at the nominal target. When determining a normalized dose for a pediatric population is thus important to recognize scaling will be both montage and age dependent. </p

Electric field plots on the cortical surface of the pediatric and adult brains for HD-tDCS montage.

<p>For 4x1 high definition tDCS the center of the anode (red) was positioned on the motor strip and the four returns (black) were placed around the center in a circular fashion with a 5cm distance from the center of the anode to the center of the return (F-L). The peak electric field, at 2 mA, for 4x1 HD-tDCS was 0.68 V/m, 0.90 V/m, 0.88 V/m, 0.48 V/m, and 0.22 V/m in P1, P2, S1, S2, and S3, respectively, at a 5 cm separation (center of anode to center of cathode distance). An additional smaller ring (2.5 cm separation) was modeled for the adolescents (see methods) (G, I). At a 2.5 cm separation, the peak electric field was 0.42 V/m and 0.68 V/m, for P1 and P2 respectively. False color maps of 0.5 mA, 1 mA, and 1.5 mA of current are shown, respectively, in the adolescents and adults (F.1-3a, G.1-3a, H.1-3a, I.1-3a, J.1-3a, K.1-3a, L.1-3a). Cross-sectional coronal electric field plots were taken from the center of the anode (F.1-3b, G.1-3b, H.1-3b, I.1-3b, J.1-3b, K.1-3b, L.1-3b).</p

Intervening tissue thickness.

<p>Skin and skull thickness are among important factors that determine the flow of current through the brain. The region from which the measurements were taken are shown for the 8 year old case (A1,B1). The skin and skull thickness for the 8 year old was 6.0 ± 0.30 mm and 2.8 ± 0.28 mm, respectively.</p