A multi-center comparison of surgical techniques for corpus Callosotomy in pediatric drug-resistant epilepsy.

OBJECTIVES: Corpus callosotomy (CC) is used to reduce seizures, primarily in patients with generalized drug-resistant epilepsy (DRE). The invasive nature of the procedure contributes to underutilization despite its potential superiority to other palliative procedures. The goal of this study was to use a multi-institutional epilepsy surgery database to characterize the use of CC across participating centers. METHODS: Data were acquired from the Pediatric Epilepsy Research Consortium (PERC) Surgery Database, a prospective observational study collecting data on children 0-18 years referred for surgical evaluation of DRE across 22 U.S. pediatric epilepsy centers. Patient, epilepsy, and surgical characteristics were collected across multiple CC modalities. Outcomes and complications were recorded and analyzed statistically. RESULTS: Eighty-three patients undergoing 85 CC procedures at 14 participating epilepsy centers met inclusion criteria. Mean age at seizure onset was 2.3 years (0-9.4); mean age for Phase I evaluation and surgical intervention were 9.45 (.1-20) and 10.46 (.2-20.6) years, respectively. Generalized seizure types were the most common (59%). Complete CC was performed in 88%. The majority of CC procedures (57%) were via open craniotomy, followed by laser interstitial thermal therapy (LiTT) (20%) and mini-craniotomy/endoscopic (mc/e) (22%). Mean operative times were significantly longer for LiTT, whereas mean estimated blood loss was greater in open cases. Complications occurred in 11 cases (13%) and differed significantly between surgical techniques (p < .001). There was no statistically significant difference in length of postoperative stay across approaches. Mean follow-up was 12.8 months (range 1-39). Favorable Engel outcomes were experienced by 37 (78.7%) of the patients who underwent craniotomy, 10 (58.8%) with LiTT, and 12 (63.2%) with mc/e; these differences were not statistically significant. SIGNIFICANCE: CC is an effective surgical modality for children with DRE. Regardless of surgical modality, complication rates are acceptable and seizure outcomes generally favorable. Newer, less-invasive, surgical approaches may lead to increased adoption of this efficacious therapeutic option for pediatric DRE.

Hyperventilation and Seizures: Not a New Sense: A Literature Review.

Hyperventilation and seizures have a long association in the clinical literature and were known to have a relationship long before the electroencephalogram (EEG) was used to record changes in brain activity. As the use of EEG recording progressed, hyperventilation was the first activation method used to assist with diagnosis of epilepsy. Along with slowing of brain activity, hyperventilation can activate epileptiform spiking activity in patients with epilepsy. Currently, hyperventilation is used in standard practice to assist with the diagnosis of epilepsy during EEG recording. Hyperventilation activates epileptiform spiking activity more often than seizures but can trigger clinical seizures in up to 50% of patients with generalized epilepsy. It is more likely to trigger events in children with absence seizures than adults, and it acts as a trigger in patients with focal epilepsy far less often. However, while some clinicians suggest that its diagnostic value is limited, especially in adults with focal epilepsies, others suggest that it is simple, safe, and an important diagnostic tool, even in these patients. This review presents the history of hyperventilation and seizures, its use in the clinical practice, and possible mechanisms involved.

Integrating transition readiness assessment into clinical practice: Adaptation of the UNC TRXANSITION index into the Cerner electronic medical record.

PURPOSE: To describe the process of developing, and evaluating the feasibility and acceptability of, an EMR-based transition readiness assessment. DESIGN AND METHODS: A Cerner-based version of the UNC TRxANSITION Index was implemented across four pediatric subspecialty clinics: epilepsy, inflammatory bowel disease; type 1 diabetes, oncology survivorship. The feasibility was assessed by each's clinic's ability to meet form completion goals and their assessment rate. Acceptability was assessed via family refusal rate, a staff-completed feedback questionnaire, and whether the form was adopted into routine clinical care after completion of the pilot study. RESULTS: All clinics met form completion goals (N = 10/clinic). The assessment rate ranged from 66 to 100% across clinics. No families refused completion of the form. Most staff (70%) reported completing the form in <10 min. Staff reported on challenges experienced and provided recommendations to streamline administration and enhance clinical care. All staff reported the form helped them identify knowledge gaps in their patients. Two clinics continued using the form following completion of the pilot study. CONCLUSIONS: Implementation was most feasible in clinics that were well-staffed and had lengthier patient visits, however, time and staff resources were the biggest challenges to implementation across clinics. Based on staff feedback to improve efficiency and developmentally-tailor assessment, the form will be divided into Beginner Skills and Advanced Skills. PRACTICAL IMPLICATIONS: Integrating transition readiness assessment into the EMR has the potential to improve clinical care by facilitating staff's ability to efficiently identify knowledge gaps in their transition-aged patients and intervene.

Surgical evaluation in children <3 years of age with drug-resistant epilepsy: Patient characteristics, diagnostic utilization, and potential for treatment delays.

OBJECTIVE: Drug-resistant epilepsy (DRE) occurs at higher rates in children <3 years old. Epilepsy surgery is effective, but rarely utilized in young children despite developmental benefits of early seizure freedom. The present study aims to identify unique patient characteristics and evaluation strategies in children <3 years old who undergo epilepsy surgery evaluation as a means to assess contributors and potential solutions to health care disparities in this group. METHODS: The Pediatric Epilepsy Research Consortium Epilepsy Surgery Database, a multicentered, cross-sectional collaboration of 21 US pediatric epilepsy centers, collects prospective data on children <18 years of age referred for epilepsy surgery evaluation. We compared patient characteristics, diagnostic utilization, and surgical treatment between children <3 years old and those older undergoing initial presurgical evaluation. We evaluated patient characteristics leading to delayed referral (>1 year) after DRE diagnosis in the very young. RESULTS: The cohort included 437 children, of whom 71 (16%) were <3 years of age at referral. Children evaluated before the age of 3 years more commonly had abnormal neurological examinations (p = .002) and daily seizures (p = .001). At least one ancillary test was used in 44% of evaluations. Fifty-nine percent were seizure-free following surgery (n = 34), with 35% undergoing limited focal resections. Children with delayed referrals more often had focal aware (p < .001) seizures and recommendation for palliative surgeries (p < .001). SIGNIFICANCE: There are relatively few studies of epilepsy surgery in the very young. Surgery is effective, but may be disproportionally offered to those with severe presentations. Relatively low utilization of ancillary testing may contribute to reduced surgical therapy for those without evident lesions on magnetic resonance imaging. Despite this, a sizeable portion of patients have favorable outcome after focal epilepsy surgery resections.

Long-Range Temporal Correlations Reflect Treatment Response in the Electroencephalogram of Patients with Infantile Spasms.

Infantile spasms syndrome is an epileptic encephalopathy in which prompt diagnosis and treatment initiation are critical to therapeutic response. Diagnosis of the disease heavily depends on the identification of characteristic electroencephalographic (EEG) patterns, including hypsarrhythmia. However, visual assessment of the presence and characteristics of hypsarrhythmia is challenging because multiple variants of the pattern exist, leading to poor inter-rater reliability. We investigated whether a quantitative measurement of the control of neural synchrony in the EEGs of infantile spasms patients could be used to reliably distinguish the presence of hypsarrhythmia and indicate successful treatment outcomes. We used autocorrelation and Detrended Fluctuation Analysis (DFA) to measure the strength of long-range temporal correlations in 21 infantile spasms patients before and after treatment and 21 control subjects. The strength of long-range temporal correlations was significantly lower in patients with hypsarrhythmia than control patients, indicating decreased control of neural synchrony. There was no difference between patients without hypsarrhythmia and control patients. Further, the presence of hypsarrhythmia could be classified based on the DFA exponent and intercept with 92% accuracy using a support vector machine. Successful treatment was marked by a larger increase in the DFA exponent compared to those in which spasms persisted. These results suggest that the strength of long-range temporal correlations is a marker of pathological cortical activity that correlates with treatment response. Combined with current clinical measures, this quantitative tool has the potential to aid objective identification of hypsarrhythmia and assessment of treatment efficacy to inform clinical decision-making.

Optimizing automated detection of high frequency oscillations using visual markings does not improve SOZ localization.

OBJECTIVE: High frequency oscillations (HFOs) are a biomarker of the seizure onset zone (SOZ) and can be visually or automatically detected. In theory, one can optimize an automated algorithm's parameters to maximize SOZ localization accuracy; however, there is no consensus on whether or how this should be done. Therefore, we optimized an automated detector using visually identified HFOs and evaluated the impact on SOZ localization accuracy. METHODS: We detected HFOs in intracranial EEG from 20 patients with refractory epilepsy from two centers using (1) unoptimized automated detection, (2) visual identification, and (3) automated detection optimized to match visually detected HFOs. RESULTS: SOZ localization accuracy based on HFO rate was not significantly different between the three methods. Across patients, visually optimized detector settings varied, and no single set of settings produced universally accurate SOZ localization. Exploratory analysis suggests that, for many patients, detection settings exist that would improve SOZ localization. CONCLUSIONS: SOZ localization accuracy was similar for all three methods, was not improved by visually optimizing detector settings, and may benefit from patient-specific parameter optimization. SIGNIFICANCE: Visual HFO marking is laborious, and optimizing automated detection using visual markings does not improve localization accuracy. New patient-specific detector optimization methods are needed.

Interrater reliability of interictal EEG waveforms in Lennox-Gastaut Syndrome.

OBJECTIVE: Identification of EEG waveforms is critical for diagnosing Lennox-Gastaut Syndrome (LGS) but is complicated by the progressive nature of the disease. Here, we assess the interrater reliability (IRR) among pediatric epileptologists for classifying EEG waveforms associated with LGS. METHODS: A novel automated algorithm was used to objectively identify epochs of EEG with transient high power, which were termed events of interest (EOIs). The algorithm was applied to EEG from 20 LGS subjects and 20 healthy controls during NREM sleep, and 1350 EOIs were identified. Three raters independently reviewed the EOIs within isolated 15-second EEG segments in a randomized, blinded fashion. For each EOI, the raters assigned a waveform label (spike and slow wave, generalized paroxysmal fast activity, seizure, spindle, vertex, muscle, artifact, nothing, or other) and indicated the perceived subject type (LGS or control). RESULTS: Labeling of subject type had 85% accuracy across all EOIs and an IRR of κ =0.790, suggesting that brief segments of EEG containing high-power waveforms can be reliably classified as pathological or normal. Waveform labels were less consistent, with κ =0.558, and the results were highly variable for different categories of waveforms. Label mismatches typically occurred when one reviewer selected "nothing," suggesting that reviewers had different thresholds for applying named labels. SIGNIFICANCE: Classification of EEG waveforms associated with LGS has weak IRR, due in part to varying thresholds applied during visual review. Computational methods to objectively define EEG biomarkers of LGS may improve IRR and aid clinical decision-making.

Computational EEG attributes predict response to therapy for epileptic spasms.

OBJECTIVE: We set out to evaluate whether response to treatment for epileptic spasms is associated with specific candidate computational EEG biomarkers, independent of clinical attributes. METHODS: We identified 50 children with epileptic spasms, with pre- and post-treatment overnight video-EEG. After EEG samples were preprocessed in an automated fashion to remove artifacts, we calculated amplitude, power spectrum, functional connectivity, entropy, and long-range temporal correlations (LRTCs). To evaluate the extent to which each feature is independently associated with response and relapse, we conducted logistic and proportional hazards regression, respectively. RESULTS: After statistical adjustment for the duration of epileptic spasms prior to treatment, we observed an association between response and stronger baseline and post-treatment LRTCs (P = 0.042 and P = 0.004, respectively), and higher post-treatment entropy (P = 0.003). On an exploratory basis, freedom from relapse was associated with stronger post-treatment LRTCs (P = 0.006) and higher post-treatment entropy (P = 0.044). CONCLUSION: This study suggests that multiple EEG features-especially LRTCs and entropy-may predict response and relapse. SIGNIFICANCE: This study represents a step toward a more precise approach to measure and predict response to treatment for epileptic spasms.

Electrode Surface Area Impacts Measurement of High Frequency Oscillations in Human Intracranial EEG.

OBJECTIVE: High-frequency oscillations (HFOs) are a promising prognostic biomarker of surgical outcome in patients with epilepsy. Their rates of occurrence and morphology have been studied extensively using recordings from electrodes of various geometries. While electrode size is a potential confounding factor in HFO studies, it has largely been disregarded due to a lack of consistent evidence. Therefore, we designed an experiment to directly test the impact of electrode size on HFO measurement. METHODS: We first simulated HFO measurement using a lumped model of the electrode-tissue interaction. Then eight human subjects were each implanted with a high-density 8x8 grid of subdural electrodes. After implantation, the electrode sizes were altered using a technique recently developed by our group, enabling intracranial EEG recordings for three different electrode surface areas from a static brain location. HFOs were automatically detected in the data and their characteristics were calculated. RESULTS: The human subject measurements were consistent with the model. Specifically, HFO rate measured per area of tissue decreased significantly as electrode surface area increased. The smallest electrodes recorded more fast ripples than ripples. Amplitude of detected HFOs also decreased as electrode surface area increased, while duration and peak frequency were unaffected. CONCLUSION: These results suggest that HFO rates measured using electrodes of different surface areas cannot be compared directly. SIGNIFICANCE: This has significant implications for HFOs as a tool for surgical planning, particularly for individual patients implanted with electrodes of multiple sizes and comparisons of HFO rate made across patients and studies.

Determinants of successful ictal SPECT injection in phase 1 epilepsy presurgical evaluation: Findings from the pediatric epilepsy research consortium surgery database project.

OBJECTIVES: The main goal of presurgical evaluation in drug-resistant focal epilepsy is to identify a seizure onset zone (SOZ). Of the noninvasive, yet resource-intensive tests available, ictal single-photon emission computed tomography (SPECT) aids SOZ localization by measuring focal increases in blood flow within the SOZ via intravenous peri-ictal radionuclide administration. Recent studies indicate that geographic and center-specific factors impact utilization of these diagnostic procedures. Our study analyzed successful ictal SPECT acquisition (defined as peri-ictal injection during inpatient admission) using surgery-related data from the Pediatric Epilepsy Research Consortium (PERC) surgery database. We hypothesized that a high seizure burden, longer duration of video EEG monitoring (VEEG), and more center-specific hours of SPECT availability would increase the likelihood of successful ictal SPECT. METHODS: We identified study participants (≤18 years of age) who underwent SPECT as part of their phase 1 VEEG from January 2018 to June 2022. We assessed association between ictal SPECT outcomes (success vs. failure) and variables including patient demographics, epilepsy history, and center-specific SPECT practices. RESULTS: Phase 1 VEEG monitoring with ictal SPECT injection was planned in 297 participants and successful in 255 participants (85.86%). On multivariable analysis, the likelihood of a successful SPECT injection was higher in patients of non-Hispanic ethnicity (p = 0.040), shorter duration VEEG (p = 0.004), and higher hours of available SPECT services (p < 0.001). Higher seizure frequency (p = 0.033) was significant only in bivariate analysis. Patients treated at centers with more operational hours were more likely to experience pre-admission protocols prior to VEEG (p = 0.002). SIGNIFICANCE: There is inter-center variability in protocols and SPECT acquisition capabilities. Shorter duration of EEG monitoring, non-Hispanic ethnicity (when on private insurance), extended operational hours of nuclear medicine as noted on multivariate analysis and higher seizure frequency in bivariate analysis are strongly associated with successful ictal SPECT injection. PLAIN LANGUAGE SUMMARY: In pediatric patients with drug-resistant epilepsy, single-photon emission computed tomography (SPECT) scans can be helpful in localizing seizure onset zone. However, due to many logistical challenges described below, which include not only the half-life of the technetium isotope used to inject intravenously during a seizure (called the ictal SPECT scan) but also available nuclear scanner time in addition to the unpredictability of seizures, obtaining an ictal SPECT during a planned elective inpatient hospital stay is not guaranteed. Thus, as healthcare costs increase, planning a prolonged hospital stay during which an ictal SPECT scan is not feasible is not optimal. We leveraged our prospective surgery database to look at center-specific factors and patient-specific factors associated with an ictal SPECT injection in the first, pediatric-focussed, large-scale, multicenter, prospective, SPECT feasibility study. We found that longer availability of the scanner is the most important center-specific factor in assuring ictal SPECT injection. Although seizure frequency is an important patient-specific factor on bivariate analysis, this factor lost statistical significance when other factors like patient insurance status and video EEG duration were also considered in our multivariable logistical model.

Pediatric Palliative Epilepsy Surgery: A Report From the Pediatric Epilepsy Research Consortium (PERC) Surgery Database.

BACKGROUND: Epilepsy surgery is an underutilized resource for children with drug-resistant epilepsy. Palliative and definitive surgical options can reduce seizure burden and improve quality of life. Palliative epilepsy surgery is often seen as a "last resort" compared to definitive surgical options. We compare patient characteristics between palliative and definitive epilepsy surgical patients and present palliative surgical outcomes from the Pediatric Epilepsy Research Consortium surgical database. METHODS: The Pediatric Epilepsy Research Consortium Epilepsy Surgery database is a prospective registry of patients aged 0-18 years undergoing evaluation for epilepsy surgery at 20 pediatric epilepsy centers. We included all children with completed surgical therapy characterized as definitive or palliative. Demographics, epilepsy type, age of onset, age at referral, etiology of epilepsy, treatment history, time-to-referral/evaluation, number of failed anti-seizure medications (ASMs), imaging results, type of surgery, and postoperative outcome were acquired. RESULTS: Six hundred forty patients undergoing epilepsy surgery were identified. Patients undergoing palliative procedures were younger at seizure onset (median: 2.1 vs 4 years, P= 0.0008), failed more ASM trials before referral for presurgical evaluation (P=<0.0001), and had longer duration of epilepsy before referral for surgery (P=<0.0001). During presurgical evaluation, patients undergoing palliative surgery had shorter median duration of video-EEG data collected (P=0.007) but number of cases where ictal data were acquired was similar between groups. The most commonly performed palliative procedure was corpus callosotmy (31%), followed by lobectomy (21%) and neuromodulation (82% responsive neurostimulation vs 18% deep brain stimulation). Palliative patients were further categorized into traditionally palliative procedures vs traditionally definitive procedures. The majority of palliative patients had 50% reduction or better in seizure burden. Seizure free outcomes were significantly higher among those with traditional definitive surgeries, 41% (95% confidence interval: 26% to 57%) compared with traditional palliative surgeries and 9% (95% confidence interval: 2% to 17%). Rate of seizure freedom was 46% at 24 months or greater of follow-up in the traditional definitive group. CONCLUSIONS: Patients receiving palliative epilepsy surgery trialed more ASMs, were referred later after becoming drug resistant, and had longer gaps between drug resistance and epilepsy surgery compared with patients undergoing definitive epilepsy surgery. The extent of surgical evaluation is impacted if surgery is thought to be palliative. A majority of palliative surgery patients achieved >50% seizure reduction at follow-up, both in groups that received traditionally palliative and traditionally definitive surgical procedures. Palliative surgical patients can achieve greater seizure control and should be referred to an epilepsy surgery center promptly after failing two appropriate anti-seizure medications.

A novel method for dynamically altering the surface area of intracranial EEG electrodes.

Objective.Intracranial electroencephalogram (iEEG) plays a critical role in the treatment of neurological diseases, such as epilepsy and Parkinson's disease, as well as the development of neural prostheses and brain computer interfaces. While electrode geometries vary widely across these applications, the impact of electrode size on iEEG features and morphology is not well understood. Some insight has been gained from computer simulations, as well as experiments in which signals are recorded using electrodes of different sizes concurrently in different brain regions. Here, we introduce a novel method to record from electrodes of different sizes in the exact same location by changing the size of iEEG electrodes after implantation in the brain.Approach.We first present a theoretical model and anin vitrovalidation of the method. We then report the results of anin vivoimplementation in three human subjects with refractory epilepsy. We recorded iEEG data from three different electrode sizes and compared the amplitudes, power spectra, inter-channel correlations, and signal-to-noise ratio (SNR) of interictal epileptiform discharges, i.e. epileptic spikes.Main Results.We found that iEEG amplitude and power decreased as electrode size increased, while inter-channel correlation did not change significantly with electrode size. The SNR of epileptic spikes was generally highest in the smallest electrodes, but 39% of spikes had maximal SNR in larger electrodes. This likely depends on the precise location and spatial spread of each spike.Significance.Overall, this new method enables multi-scale measurements of electrical activity in the human brain that can facilitate our understanding of neurophysiology, treatment of neurological disease, and development of novel technologies.

Responsive Neurostimulation in Drug-Resistant Pediatric Epilepsy: Findings From the Epilepsy Surgery Subgroup of the Pediatric Epilepsy Research Consortium.

BACKGROUND: Responsive neurostimulation (RNS), a closed-loop intracranial electrical stimulation system, is a palliative surgical option for patients with drug-resistant epilepsy (DRE). RNS is approved by the US Food and Drug Administration for patients aged ≥18 years with pharmacoresistant partial seizures. The published experience of RNS in children is limited. METHODS: This is a combined prospective and retrospective study of patients aged ≤18 years undergoing RNS placement. Patients were identified from the multicenter Pediatric Epilepsy Research Consortium Surgery Registry from January 2018 to December 2021, and additional data relevant to this study were retrospectively collected and analyzed. RESULTS: Fifty-six patients received RNS during the study period. The mean age at implantation was 14.9 years; the mean duration of epilepsy, 8.1 years; and the mean number of previously trialed antiseizure medications, 4.2. Five patients (9%) previously trialed dietary therapy, and 19 patients (34%) underwent prior surgery. Most patients (70%) underwent invasive electroencephalography evaluation before RNS implantation. Complications occurred in three patients (5.3%) including malpositioned leads or transient weakness. Follow-up (mean 11.7 months) was available for 55 patients (one lost), and four were seizure-free with RNS off. Outcome analysis of stimulation efficacy was available for 51 patients: 33 patients (65%) were responders (≥50% reduction in seizure frequency), including five patients (10%) who were seizure free at follow-up. CONCLUSIONS: For young patients with focal DRE who are not candidates for surgical resection, neuromodulation should be considered. Although RNS is off-label for patients aged <18 years, this multicenter study suggests that it is a safe and effective palliative option for children with focal DRE.

Epilepsy surgery in children with genetic etiologies: A prospective evaluation of current practices and outcomes.

OBJECTIVE: This study assesses current practices and outcomes of epilepsy surgery in children with a genetic etiology. It explores the pre-surgical workup, types of surgeries, and post-surgical outcomes in a broad array of disorders. METHODS: Patients ≤18 years who completed epilepsy surgery and had a known genetic etiology prior to surgical intervention were extrapolated from the Pediatric Epilepsy Research Consortium (PERC) surgery database, across 18 US centers. Data were assessed univariably by neuroimaging and EEG results, genetic group (structural gene, other gene, chromosomal), and curative intent. Outcomes were based on a modified International League Against Epilepsy (ILAE) outcome score. RESULTS: Of 81 children with genetic epilepsy, 72 % had daily seizures when referred for surgery evaluation, which occurred a median of 2.2 years (IQR 0.3, 5.2) after developing drug resistance. Following surgery, 68 % of subjects had >50 % seizure reduction, with 33 % achieving seizure freedom [median follow-up 11 months (IQR 6, 17). Seizure freedom was most common in the monogenic structural group, but significant palliation was present across all groups. Presence of a single EEG focus was associated with a greater likelihood of seizure freedom (p=0.02). SIGNIFICANCE: There are meaningful seizure reductions following epilepsy surgery in the majority of children with a genetic etiology, even in the absence of a single structural lesion and across a broad spectrum of genetic causes. These findings highlight the need for expedited referral for epilepsy surgery and support of a broadened view of which children may benefit from epilepsy surgery, even when the intent is palliative.

EEG biomarkers for the diagnosis and treatment of infantile spasms.

Early diagnosis and treatment are critical for young children with infantile spasms (IS), as this maximizes the possibility of the best possible child-specific outcome. However, there are major barriers to achieving this, including high rates of misdiagnosis or failure to recognize the seizures, medication failure, and relapse. There are currently no validated tools to aid clinicians in assessing objective diagnostic criteria, predicting or measuring medication response, or predicting the likelihood of relapse. However, the pivotal role of EEG in the clinical management of IS has prompted many recent studies of potential EEG biomarkers of the disease. These include both visual EEG biomarkers based on human visual interpretation of the EEG and computational EEG biomarkers in which computers calculate quantitative features of the EEG. Here, we review the literature on both types of biomarkers, organized based on the application (diagnosis, treatment response, prediction, etc.). Visual biomarkers include the assessment of hypsarrhythmia, epileptiform discharges, fast oscillations, and the Burden of AmplitudeS and Epileptiform Discharges (BASED) score. Computational markers include EEG amplitude and power spectrum, entropy, functional connectivity, high frequency oscillations (HFOs), long-range temporal correlations, and phase-amplitude coupling. We also introduce each of the computational measures and provide representative examples. Finally, we highlight remaining gaps in the literature, describe practical guidelines for future biomarker discovery and validation studies, and discuss remaining roadblocks to clinical implementation, with the goal of facilitating future work in this critical area.

Evolution of Cortical Functional Networks in Healthy Infants.

During normal childhood development, functional brain networks evolve over time in parallel with changes in neuronal oscillations. Previous studies have demonstrated differences in network topology with age, particularly in neonates and in cohorts spanning from birth to early adulthood. Here, we evaluate the developmental changes in EEG functional connectivity with a specific focus on the first 2 years of life. Functional connectivity networks (FCNs) were calculated from the EEGs of 240 healthy infants aged 0-2 years during wakefulness and sleep using a cross-correlation-based measure and the weighted phase lag index. Topological features were assessed via network strength, global clustering coefficient, characteristic path length, and small world measures. We found that cross-correlation FCNs maintained a consistent small-world structure, and the connection strengths increased after the first 3 months of infancy. The strongest connections in these networks were consistently located in the frontal and occipital regions across age groups. In the delta and theta bands, weighted phase lag index networks decreased in strength after the first 3 months in both wakefulness and sleep, and a similar result was found in the alpha and beta bands during wakefulness. However, in the alpha band during sleep, FCNs exhibited a significant increase in strength with age, particularly in the 21-24 months age group. During this period, a majority of the strongest connections in the networks were located in frontocentral regions, and a qualitatively similar distribution was seen in the beta band during sleep for subjects older than 3 months. Graph theory analysis suggested a small world structure for weighted phase lag index networks, but to a lesser degree than those calculated using cross-correlation. In general, graph theory metrics showed little change over time, with no significant differences between age groups for the clustering coefficient (wakefulness and sleep), characteristics path length (sleep), and small world measure (sleep). These results suggest that infant FCNs evolve during the first 2 years with more significant changes to network strength than features of the network structure. This study quantifies normal brain networks during infant development and can serve as a baseline for future investigations in health and neurological disease.

Underrepresented Populations in Pediatric Epilepsy Surgery.

As awareness of pediatric epilepsy increases, accompanied by advancements in technology and research, it is important to identify certain types of patients that are overlooked for surgical management of epilepsy. Identifying these populations will allow us to study and elucidate the factors contributing to the underutilization and/or delayed application of surgical interventions. Demographically, African-American and Hispanic patients, as well as patients of certain Asian ethnicities, have relatively lower rates of undergoing epilepsy surgery than non-Hispanic and white patients. Among patients with epilepsy, those with higher odds of seizure-freedom following surgery are more likely to be referred for surgical evaluation by their neurologists, with the most common diagnosis being lesional focal epilepsy. However, patients with multifocal or generalized epilepsy, genetic etiologies, or normal (non-lesional) brain magnetic resonance imaging (MRI) are less likely be to referred for evaluation for resective surgery. With an increasing number of high-quality imaging modalities to help localize the epileptogenic zone as well as new techniques for both curative and palliative epilepsy surgery, there are very few populations of patients and/or types of epilepsy that should be precluded from evaluation to determine the suitability of epilepsy surgery. Ultimately, a clearer understanding of the populations who are underrepresented among those considered for epilepsy surgery, coupled with further study of the underlying reasons for this trend, will lead to less disparity in access to this critical treatment among patients with epilepsy.

Infant functional networks are modulated by state of consciousness and circadian rhythm.

Functional connectivity networks are valuable tools for studying development, cognition, and disease in the infant brain. In adults, such networks are modulated by the state of consciousness and the circadian rhythm; however, it is unknown if infant brain networks exhibit similar variation, given the unique temporal properties of infant sleep and circadian patterning. To address this, we analyzed functional connectivity networks calculated from long-term EEG recordings (average duration 20.8 hr) from 19 healthy infants. Networks were subject specific, as intersubject correlations between weighted adjacency matrices were low. However, within individual subjects, both sleep and wake networks were stable over time, with stronger functional connectivity during sleep than wakefulness. Principal component analysis revealed the presence of two dominant networks; visual sleep scoring confirmed that these corresponded to sleep and wakefulness. Lastly, we found that network strength, degree, clustering coefficient, and path length significantly varied with time of day, when measured in either wakefulness or sleep at the group level. Together, these results suggest that modulation of healthy functional networks occurs over ∼24 hr and is robust and repeatable. Accounting for such temporal periodicities may improve the physiological interpretation and use of functional connectivity analysis to investigate brain function in health and disease.

Computational characteristics of interictal EEG as objective markers of epileptic spasms.

OBJECTIVE: Favorable neurodevelopmental outcomes in epileptic spasms (ES) are tied to early diagnosis and prompt treatment, but uncertainty in the identification of the disease can delay this process. Therefore, we investigated five categories of computational electroencephalographic (EEG) measures as markers of ES. METHODS: We measured 1) amplitude, 2) power spectra, 3) Shannon entropy and permutation entropy, 4) long-range temporal correlations, via detrended fluctuation analysis (DFA) and 5) functional connectivity using cross-correlation and phase lag index (PLI). EEG data were analyzed from ES patients (n = 40 patients) and healthy controls (n = 20 subjects), with multiple blinded measurements during wakefulness and sleep for each patient. RESULTS: In ES patients, EEG amplitude was significantly higher in all electrodes when compared to controls. Shannon and permutation entropy were lower in ES patients than control subjects. The DFA intercept values in ES patients were significantly higher than control subjects, while DFA exponent values were not significantly different between the groups. EEG functional connectivity networks in ES patients were significantly stronger than controls when based on both cross-correlation and PLI. Significance for all statistical tests was p < 0.05, adjusted for multiple comparisons using the Benjamini-Hochberg procedure as appropriate. Finally, using logistic regression, a multi-attribute classifier was derived that accurately distinguished cases from controls (area under curve of 0.96). CONCLUSIONS: Computational EEG features successfully distinguish ES patients from controls in a large, blinded study. SIGNIFICANCE: These objective EEG markers, in combination with other clinical factors, may speed the diagnosis and treatment of the disease, thereby improving long-term outcomes.