High-gamma modulation language mapping and cognitive outcomes after epilepsy surgery.

OBJECTIVE: We evaluated changes in cognitive domains after neurosurgical lesioning of cortical sites with significant high-gamma power modulations (HGM) during a visual naming task, although these sites were found language-negative on standard-of-care electrical stimulation mapping (ESM). METHODS: In drug-resistant epilepsy patients who underwent resection/ablation after stereo-electroencephalography (SEEG), we computed reliable change indices (RCIs) from a battery of presurgical and 1-year postsurgical neuropsychological assessments. We modeled RCIs as a function of lesioning even one HGM language site, number of HGM language sites lesioned, and the magnitude of naming-related HGM. The analyses were adjusted for 1-year seizure freedom, operated hemispheres, and the volumes of surgical lesions. RESULTS: In 37 patients with 4455 SEEG electrode contacts (1839 and 2616 contacts in right and left hemispheres, respectively), no ESM language sites were lesioned. Patients with lesioning of even one HGM language site showed significantly lower RCIs for Peabody Picture Vocabulary Test (PPVT), working memory, and verbal learning immediate (VLI) scores. RCI declines with higher number of HGM language sites lesioned were seen in PPVT (slope [ß] = -.10), working memory (ß = -.10), VLI (ß = -.14), and letter-word identification (LWI; ß = -.14). No neuropsychological domains improved after lesioning of HGM language sites. Significant effects of the HGM magnitude at lesioned sites were seen on working memory (ß = -.31), story memory immediate (ß = -.27), verbal learning recognition (ß = -.18), LWI (ß = -.16), spelling (ß = -.49), and passage comprehension (ß = -.33). Because working memory was significantly affected in all three analyses, patients with maximal working memory decline were examined post hoc, revealing that all such patients had HGM naming sites lesioned in the posterior quadrants of either hemisphere. SIGNIFICANCE: HGM language mapping should be used as an adjunct to ESM in clinical practice and may help counsel patients/families about postsurgical cognitive deficits.

Diagnostic Utility of Pre-Genomic Hepatitis B RNA in the Evaluation of HBV/HIV Coinfection.

Background: Newer biomarkers of Hepatitis B virus (HBV) infection and treatment response have not been well-characterized in individuals with HBV/HIV coinfection. Methods: Pre-genomic RNA (pgRNA) and quantitative HBsAg (qHBsAg) were used to evaluate the associations with baseline characteristics. Participants included two separate groups - 236 with HBV/HIV coinfection enrolled in a cross-sectional cohort in Ghana and 47 from an HBV nucleoside/nucleotide treatment trial comparing tenofovir to adefovir in the United States. Results: In both cohorts, HBe antigenemia was highly associated with pgRNA and HBV DNA levels. In the treatment cohort, pre-treatment pgRNA serum concentration was 7.0 log10 U/mL, and mean qHBsAg was 201,297 IU/mL. The observed treatment-associated decrease in pgRNA was consistent with a biphasic decline curve that reached second-phase kinetics following treatment week 12. Changes from baseline were significantly correlated with changes in serum ALT (r = - 0.518; P = 0.023) but not with changes in HBV DNA (r = 0.132, P = NS). qHBsAg also correlated with ALT change (r = - 0.488, P = 0.034). Conclusion: pgRNA and qHBsAg represent newer biomarkers of HBV replication that may help monitor response and treatment outcomes. HBV pgRNA is highly associated with both HBeAg and ALT and may predict both active replication from the closed circular DNA (cccDNA) template as well as hepatic injury.

Impact of seizure onset zone and intracranial electroencephalography ictal characteristics on epilepsy surgery outcomes in tuberous sclerosis complex.

Ninety percent of tuberous sclerosis complex (TSC) patients have seizures, with ∼50 % developing drug refractory epilepsy. Surgical intervention aims to remove the seizure onset zone (SOZ). This retrospective study investigated the relationship of SOZ size, ictal pattern, and extent of resection with surgical outcomes. TSC patients undergoing resective/ablative surgery with >1-year follow-up and adequate imaging were included. Preoperative iEEG data were reviewed to determine ictal pattern and SOZ location. For outcomes, an ILAE score of 1-3 was defined as good and 4-6 as poor. Forty-four patients were included (age 117.4 ± 110.8 months). Of these, 59.1 % achieved a good outcome, while 40.9 % had a poor outcome. Size of SOZ was a significant factor (p = 0.009), with the poor outcome group having a larger SOZ (11.9 ± 6.7 electrode contacts) than the good outcome group (7.3 ± 7.2). SOZ number was significant (p = 0.020); >1 SOZ was associated with poor outcome. These results demonstrate extent of SOZ as a predictor of seizure freedom following epilepsy surgery in a mostly pediatric TSC cohort. We hypothesize that these features represent biomarkers of focality of the epileptogenic zone and can be used to sharpen prognosis for epilepsy surgery outcomes in this cohort.

Examining the feasibility and utility of heart rate variability on intervention outcomes targeting emotion regulation in autism: a brief report.

Autistic youth experience several behavioral and emotional characteristics that can predispose them to emotion dysregulation (ED). Current literature examining ED in autism spectrum disorder (ASD) is limited to parent- and self-reported measures, indicating a need for biological or physiological methods to better assess emotion regulation in ASD. Utilizing the autonomic nervous system, specifically heart rate variability (HRV), may be a promising method to objectively measure ED in ASD, given it is one of the body's primary means of regulating physiological arousal. Our pilot study is one of the first to examine the feasibility, utility, and construct validity of HRV along with clinical measures within an intervention targeting ED-specific symptoms in ASD. Participants included 30 autistic youth ages 8-17 years who participated in the pilot study of Regulating Together, a group-based intervention targeting emotion regulation. We demonstrate HRV is feasible, demonstrates adequate test-retest reliability, and is complimentary to clinician- and parent-reported measures. Our preliminary findings also point to certain HRV profiles being indicative of long-term outcomes after receiving treatment. HRV may be a useful, objective tool in determining differential needs of long-term follow-up care for treatment maintenance at screening or baseline stages.

Impact of Race in Missed Appointments in Pediatric Neurology Resident Clinic at a Large Tertiary Medical Center.

Missed medical appointments are a common problem across specialties. The discontinuity of care leads to unplanned health care utilization, increased costs, and poor health outcomes. Previous studies evaluating pediatric epilepsy have shown significant socioeconomic barriers to care. In several specialties, resident clinic no-show rates are higher than faculty clinics because of socioeconomic barriers. We sought to understand the relationship between race, socioeconomic factors, and missed appointments in a pediatric neurology resident clinic at a large tertiary care hospital. Resident clinic encounters for 1 year were extracted and analyzed for missed appointments, socioeconomic factors, and health care utilization. We found that missed appointments occur for 1 in 5 patients and correlate with socioeconomic factors (eg, income and insurance) and race. Race was a more significant factor than socioeconomic factors for missed appointments. These results provide areas to target and track interventions to improve health outcomes in children in pediatric neurology clinics.

Frontal Cortex Hyperactivation and Gamma Desynchrony in Fragile X Syndrome: Correlates of Auditory Hypersensitivity.

Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity (hyperacusis) is a distressing symptom in FXS, its neural basis is not well understood. It is postulated that hyperacusis may stem from temporal lobe hyperexcitability or dysregulation in top-down modulation. Studying the neural mechanisms underlying sound sensitivity in FXS using scalp electroencephalography (EEG) is challenging because the temporal and frontal regions have overlapping neural projections that are difficult to differentiate. To overcome this challenge, we conducted EEG source analysis on a group of 36 individuals with FXS and 39 matched healthy controls. Our goal was to characterize the spatial and temporal properties of the response to an auditory chirp stimulus. Our results showed that males with FXS exhibit excessive activation in the frontal cortex in response to the stimulus onset, which may reflect changes in top-down modulation of auditory processing. Additionally, during the chirp stimulus, individuals with FXS demonstrated a reduction in typical gamma phase synchrony, along with an increase in asynchronous gamma power, across multiple regions, most strongly in temporal cortex. Consistent with these findings, we observed a decrease in the signal-to-noise ratio, estimated by the ratio of synchronous to asynchronous gamma activity, in individuals with FXS. Furthermore, this ratio was highly correlated with performance in an auditory attention task. Compared to controls, males with FXS demonstrated elevated bidirectional frontotemporal information flow at chirp onset. The evidence indicates that both temporal lobe hyperexcitability and disruptions in top-down regulation play a role in auditory sensitivity disturbances in FXS. These findings have the potential to guide the development of therapeutic targets and back-translation strategies.

Accelerated Theta Burst Transcranial Magnetic Stimulation for Refractory Depression in Autism Spectrum Disorder.

PURPOSE: Major depressive disorder (MDD) disproportionately affects those living with autism spectrum disorder (ASD) and is associated with significant impairment and treatment recidivism. METHODS: We studied the use of accelerated theta burst stimulation (ATBS) for the treatment of refractory MDD in ASD (3 treatments daily x 10 days). This prospective open-label 12-week trial included 10 subjects with a mean age of 21.5 years, randomized to receive unilateral or bilateral stimulation of the dorsolateral prefrontal cortex. RESULTS: One participant dropped out of the study due to intolerability. In both treatment arms, depressive symptoms, scored on the Hamilton Depression Rating Scale scores, diminished substantially. At 12 weeks post-treatment, full remission was sustained in 5 subjects and partial remission in 3 subjects. Treatment with ATBS, regardless of the site of stimulation, was associated with a significant, substantial, and sustained improvement in depressive symptomatology via the primary outcome measure, the Hamilton Depression Rating Scale. Additional secondary measures, including self-report depression scales, fluid cognition, and sleep quality, also showed significant improvement. No serious adverse events occurred during the study. Mild transient headaches were infrequently reported, which are expected side effects of ATBS. CONCLUSION: Overall, ATBS treatment was highly effective and well-tolerated in individuals with ASD and co-occurring MDD. The findings support the need for a larger, sham-controlled randomized controlled trial to further evaluate efficacy of ATBS in this population.

MiR-324-5p inhibition after intrahippocampal kainic acid-induced status epilepticus does not prevent epileptogenesis in mice.

Background: Acquired epilepsies are caused by an initial brain insult that is followed by epileptogenesis and finally the development of spontaneous recurrent seizures. The mechanisms underlying epileptogenesis are not fully understood. MicroRNAs regulate mRNA translation and stability and are frequently implicated in epilepsy. For example, antagonism of a specific microRNA, miR-324-5p, before brain insult and in a model of chronic epilepsy decreases seizure susceptibility and frequency, respectively. Here, we tested whether antagonism of miR-324-5p during epileptogenesis inhibits the development of epilepsy. Methods: We used the intrahippocampal kainic acid (IHpKa) model to initiate epileptogenesis in male wild type C57BL/6 J mice aged 6-8 weeks. Twenty-four hours after IHpKa, we administered a miR-324-5p or scrambled control antagomir intracerebroventricularly and implanted cortical surface electrodes for EEG monitoring. EEG data was collected for 28 days and analyzed for seizure frequency and duration, interictal spike activity, and EEG power. Brains were collected for histological analysis. Results: Histological analysis of brain tissue showed that IHpKa caused characteristic hippocampal damage in most mice regardless of treatment. Antagomir treatment did not affect latency to, frequency, or duration of spontaneous recurrent seizures or interictal spike activity but did alter the temporal development of frequency band-specific EEG power. Conclusion: These results suggest that miR-324-5p inhibition during epileptogenesis induced by status epilepticus does not convey anti-epileptogenic effects despite having subtle effects on EEG frequency bands. Our results highlight the importance of timing of intervention across epilepsy development and suggest that miR-324-5p may act primarily as a proconvulsant rather than a pro-epileptogenic regulator.

Characterization of Migraine in Children and Adolescents With Generalized Joint Hypermobility: A Case-Control Study.

Background and Objectives: The prevalence of generalized joint hypermobility (GJH) is 5-65% in children and adolescents. The hypothesis of this study was to see whether there is an association between headache characteristics and GJH in children and adolescents with migraine. Methods: We performed a primary retrospective case-control analysis of an established database of patients with headache aged 5-17 years. Results: We included 5435 participants. Approximately 31.6% of participants (1,719/5,435) were diagnosed with GJH (Beighton score ≥ 6). Nausea (73.1% vs 67.5%, χ2 with 1 degree of freedom = 17.0, p < 0.0001), phonophobia (87.3% vs 78.8%, χ2 with 1 degree of freedom = 18.0, p < 0.0001), and the PedMIDAS score (48.2 ± 52.5, 95% CI 45.7-50.6 vs 41.6 ± 51.2, 95% CI 40.0-43.3, effect size = 0.13, p < 0.0001) were noted to be more severe in participants with GJH than those without GJH. Discussion: Youths with GJH and migraine were noted to have more severe migraine characteristics.

Appendicular lean mass index changes in patients with Duchenne muscular dystrophy and Becker muscular dystrophy.

INTRODUCTION: Mutations in the 79 exons of the dystrophin gene result in muscle wasting and weakness of varying clinical severity, ranging from severe/typical Duchenne muscular dystrophy (DMD) to intermediate DMD and mild Becker muscular dystrophy (BMD), depending on the frameshift of the mutation. We previously reported that males with DMD have progressively declining appendicular lean mass (ALM) and ALM index (ALMI) with age and worsening functional motor ability compared with healthy controls. These indices have not been studied in patients with intermediate DMD and BMD phenotypes and across DMD genotypes. In this study, we compared age-related trajectories of ALM and ALMI of patients who had (1) BMD without functional mobility deficits with patients who had DMD at different stages of disease and healthy controls; (2) a DMD intermediate phenotype with patients who had a typical DMD phenotype; and (3) DMD categorized by genotype. METHODS: We conducted a retrospective review of ALM and ALMI data from 499 patients (ages 5-23 years) with DMD (466 typical and 33 intermediate) and 46 patients (ages 5-21 years) with BMD (without functional mobility deficits and functional mobility score of 1). Patients were grouped according to age reflecting disease stage (ages 5 to <7, 7 to <10, 10 to <14, and 14 to <20 years) and genotype (mutations in exons 1-30, 31-44, 45-62, and 63-79). RESULTS: ALM and ALMI trajectories of patients with BMD paralleled those of healthy controls until adolescence, in contrast to patients with DMD. ALMI Z-scores of patients with BMD remained within ±2 SD without decline while those of patients with DMD fell below -2 SD around age 12 years. Patients with BMD had increasing ALM and ALMI with age, with peak accrual between ages 10 to <14 years. ALMI declined after age 14 years for those with intermediate DMD compared with 10 years for patients with typical DMD. Patients with mutations in exons 63-79 had a greater decline in ALMI as compared with those with other genotypes after age 10 years. CONCLUSIONS: Age-related changes in ALMI in patients with BMD and intermediate DMD differ from those with typical DMD, reflecting their clinical phenotypes. ALM and ALMI should be further studied in patients with BMD and DMD subtypes for their potential value as surrogate markers to characterize the severity of BMD and DMD and inform clinical care decisions and clinical trial designs.

Health Related Quality of Life in Autistic Youth and Their Families.

PURPOSE: The construct Quality of Life (QoL) involves a range of factors related to one's well-being. Individuals on the autism spectrum have been previously reported to have lower QoL. The purpose of the present study is to examine QoL in autistic individuals and their families and to evaluate associations between QoL and measures of functioning using the PedsQL 4.0. METHOD: Thirty-six autistic youth (ages 9-21 years) and their caregivers completed the PedsQL. Caregivers completed additional measures of their children's adaptive, social, behavioral, and emotional functioning. RESULTS: Parents and youth generally agreed on the PedsQL, with the exception of the Social Functioning domain, which youth rated higher. The parent rated PedsQL did not correlate with most areas of caregiver-rated functioning; however, there were significant negative correlations between irritability and family functioning. CONCLUSION: Limitations of this study included small sample size; broad range of intellectual functioning; lack of sample diversity; and likely recruiting bias for a drug treatment study. Despite limitations, HRQoL is an important feature that should be measured in addition to features of autism or symptoms of co-occurring symptoms.

Tolerability of transcranial magnetic stimulation language mapping in children.

OBJECTIVE: Transcranial Magnetic Stimulation (TMS) has emerged as a viable non-invasive method for mapping language networks. Little is known about the tolerability of transcranial magnetic stimulation language mapping in children. METHODS: Children aged 5-18 years underwent bilateral language mapping using repetitive transcranial magnetic stimulation (rTMS) to target 33 sites/hemisphere. Stimulation was delivered at 5 Hz, in 1-2 second bursts, during visual naming and auditory verb generation. Pain unpleasantness and pain intensity were assessed using an unpleasantness visual analog scale (VAS). RESULTS: 49 participants tolerated motor mapping and had repetitive transcranial magnetic stimulation. 35/49 (71%) completed visual naming and 26/49 (53%) completed both visual naming and verb generation. Mean electrical field per participant was 115 V/m. Young age and lower language ability were associated with lower completion. Visual analogue scale scores were significantly higher (6.1 vs. 2.8) in participants who withdrew early compared to those who completed at least visual naming. CONCLUSIONS: Pain measured by VAS was a major contributor to early withdrawal. However, a complete bilateral map was obtained with one paradigm in 71% of participants. Future studies designed to reduce pain during repetitive transcranial magnetic stimulation over language cortex will boost viability. SIGNIFICANCE: This study represents the first attempt to characterize tolerability of bilateral repetitive transcranial magnetic stimulation language mapping in healthy children.

Early Clinical Variables Associated With Refractory Convulsive Status Epilepticus in Children.

BACKGROUND AND OBJECTIVES: The objective of this study was to determine patient-specific factors known proximate to the presentation to emergency care associated with the development of refractory convulsive status epilepticus (RSE) in children. METHODS: An observational case-control study was conducted comparing pediatric patients (1 month-21 years) with convulsive SE whose seizures stopped after benzodiazepine (BZD) and a single second-line antiseizure medication (ASM) (responsive established status epilepticus [rESE]) with patients requiring more than a BZD and a single second-line ASM to stop their seizures (RSE). These subpopulations were obtained from the pediatric Status Epilepticus Research Group study cohort. We explored clinical variables that could be acquired early after presentation to emergency medical services with univariate analysis of the raw data. Variables with p < 0.1 were retained for univariable and multivariable regression analyses. Multivariable logistic regression models were fit to age-matched and sex-matched data to obtain variables associated with RSE. RESULTS: We compared data from a total of 595 episodes of pediatric SE. Univariate analysis demonstrated no differences in time to the first BZD (RSE 16 minutes [IQR 5-45]; rESE 18 minutes [IQR 6-44], p = 0.068). Time to second-line ASM was shorter in patients with RSE (RSE 65 minutes; rESE 70 minutes; p = 0.021). Both univariable and multivariable regression analyses revealed a family history of seizures (OR 0.37; 95% CI 0.20-0.70, p = 0.0022) or a prescription for rectal diazepam (OR 0.21; 95% CI 0.078-0.53, p = 0.0012) was associated with decreased odds of RSE. DISCUSSION: Time to initial BZD or second-line ASM was not associated with progression to RSE in our cohort of patients with rESE. A family history of seizures and a prescription for rectal diazepam were associated with a decreased likelihood of progression to RSE. Early attainment of these variables may help care for pediatric rESE in a more patient-tailored manner. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that patient and clinical factors may predict RSE in children with convulsive seizures.

Neuropsychological outcomes after epilepsy surgery: A comparison of stereo electroencephalography and subdural electrodes.

BACKGROUND AND PURPOSE: We analyzed the association of neuropsychological outcomes after epilepsy surgery with the intracranial electrode type (stereo electroencephalography [SEEG] and subdural electrodes [SDE]), and electrical stimulation mapping (ESM) of speech/language. METHODS: Drug-resistant epilepsy patients who underwent comprehensive neuropsychological evaluation before and 1 year after epilepsy surgery were included. SEEG and SDE subgroups were matched by age, handedness, operated hemisphere, and seizure freedom. Postsurgical neuropsychological outcomes (adjusted for presurgical scores) and reliable change indices were analyzed as functions of electrode type and ESM. RESULTS: Ninety-nine patients aged 6-29 years were included with similar surgical resection/ablation volumes in the SEEG and SDE subgroups. Most of the neuropsychological outcomes were comparable between SEEG and SDE subgroups; however, Working Memory and Processing Speed were significantly improved in the SEEG subgroup. Undergoing language ESM was associated with significant improvements in Spelling, Letter-Word Identification, Vocabulary, Verbal Comprehension, Verbal Learning, and Story Memory scores, but a decline in Calculation scores. CONCLUSIONS: Intracranial evaluations with SEEG and SDE are comparable in terms of long-term postsurgical neuropsychological outcomes. Our data suggest that SEEG may be associated with improvements in working memory and processing speed, representing cognitive domains served by spatially distributed networks. Our study also supports wider use of language ESM before epilepsy surgery, preferably using other language tasks in addition to visual naming. Rather than the type of electrode, postsurgical neuropsychological outcomes are driven by whether language ESM was performed or not, with beneficial effects of language mapping.

Empirical Frequency Bound Derivation Reveals Prominent Mid-Frontal Alpha Associated with Neurosensory Dysfunction in Fragile X Syndrome.

The FMR1 gene is inactive in Fragile X syndrome (FXS), resulting in low levels of FMRP and consequent neurochemical, synaptic, and local circuit neurophysiological alterations in the fmr1 KO mouse. In FXS patients, electrophysiological studies have demonstrated a marked reduction in global alpha activity and regional increases in gamma oscillations associated with intellectual disability and sensory hypersensitivity. Since alpha activity is associated with a thalamocortical function with widely distributed modulatory effects on neocortical excitability, insight into alpha physiology may provide insight into systems-level disease mechanisms. Herein, we took a data-driven approach to clarify the temporal and spatial properties of alpha and theta activity in participants with FXS. High-resolution resting-state EEG data were collected from participants affected by FXS (n = 65) and matched controls (n = 70). We used a multivariate technique to empirically classify neural oscillatory bands based on their coherent spatiotemporal patterns. Participants with FXS demonstrated: 1) redistribution of lower-frequency boundaries indicating a "slower" dominant alpha rhythm, 2) an anteriorization of alpha frequency activity, and 3) a correlation of increased individualized alpha power measurements with auditory neurosensory dysfunction. These findings suggest an important role for alterations in thalamocortical physiology for the well-established neocortical hyper-excitability in FXS and, thus, a role for neural systems level disruption to cortical hyperexcitability that has been studied primarily at the local circuit level in animal models.

Comparing electrical stimulation functional mapping with subdural electrodes and stereoelectroencephalography.

OBJECTIVE: Electrical stimulation mapping (ESM) is the clinical standard for functional localization with subdural electrodes (SDE). As stereoelectroencephalography (SEEG) has emerged as an alternative option, we compared functional responses, afterdischarges (ADs), and unwanted ESM-induced seizures (EISs) between the two electrode types. METHODS: Incidence and current thresholds for functional responses (sensory, motor, speech/language), ADs, and EISs were compared between SDE and SEEG using mixed models incorporating relevant covariates. RESULTS: We identified 67 SEEG ESM and 106 SDE ESM patients (7207 and 4980 stimulated contacts, respectively). We found similar incidence of language and motor responses between electrode types; however, more SEEG patients reported sensory responses. ADs and EISs occurred less commonly with SEEG than SDE. Current thresholds for language, face motor, and upper extremity (UE) motor responses and EIS significantly decreased with age. However, they were not affected by electrode type, premedication, or dominant hemispheric stimulation. AD thresholds were higher with SEEG than with SDE. For SEEG ESM, language thresholds remained below AD thresholds up to 26 years of age, whereas this relationship was inverse for SDE. Also, face and UE motor thresholds fell below AD thresholds at earlier ages for SEEG than SDE. AD and EIS thresholds were not affected by premedication. SIGNIFICANCE: SEEG and SDE have clinically relevant differences for functional brain mapping with electrical stimulation. Although evaluation of language and motor regions is comparable between SEEG and SDE, SEEG offers a higher likelihood of identifying sensory areas. A lower incidence of ADs and EISs, and a favorable relationship between functional and AD thresholds suggest superior safety and neurophysiologic validity for SEEG ESM than SDE ESM.

A sensitive and reproducible qRT-PCR assay detects physiological relevant trace levels of FMR1 mRNA in individuals with Fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited intellectual disability. FXS is caused by a trinucleotide repeat expansion in the 5' untranslated region of the FMR1 gene, which leads to gene methylation, transcriptional silencing, and lack of expression of Fragile X Messenger Riboprotein (FMRP). Currently available FXS therapies are inefficient, and the disease severity is highly variable, making it difficult to predict disease trajectory and treatment response. We and others have recently shown that a subset of full-mutation, fully-methylated (FM-FM) males with FXS express low amounts of FMRP which could contribute to phenotypic variability. To better understand the underlying mechanisms, we developed a sensitive qRT-PCR assay to detect FMR1 mRNA in blood. This assay reproducibly detects trace amounts of FMR1 mRNA in a subset of FM-FM males, suggesting that current Southern Blot and PCR determination of FM-FM status is not always associated with complete transcriptional silencing. The functional relevance of trace-level FMR1 mRNA is confirmed by showing a positive correlation with cognitive function; however, phenotypic variability is not fully explained by FMR1 expression. These results corroborate the need for better molecular assays for FXS diagnosis and encourage studies to elucidate the factors contributing to the phenotypic variability of FXS.

Biomarkers of tic severity in children with Tourette syndrome: Motor cortex inhibition measured with transcranial magnetic stimulation.

AIM: To compare transcranial magnetic stimulation (TMS)-derived measures of primary motor cortex (M1) physiology between children with and without Tourette syndrome, and to dimensionally analyze TMS measures with Tourette syndrome-related symptom severity. METHOD: We used a cross-sectional experimental design. Sixty 8- to 12-year-old children participated (30 with Tourette syndrome: three females, mean age 10 years 10 months, standard deviation [SD] 1 year 3 months; 30 typically developing children: seven females, mean age 10 years 7 months, SD 1 year 3 months). In the group with Tourette syndrome, 15 (one female, mean age 10 years 11 months, SD 1 year 3 months) had comorbid attention-deficit/hyperactivity disorder (ADHD), rated with the Conners, Third Edition and the parent-reported ADHD rating scales. Tic severity was rated with the Yale Global Tic Severity Scale and urge severity with the Individualized Premonitory Urge for Tics Scale. M1 short-interval cortical inhibition (SICI) and intracortical facilitation were compared between diagnostic groups and, within the group with Tourette syndrome, correlated with symptom severity using linear mixed-effects models for repeated measures. RESULTS: Accounting for ADHD, we found no difference in SICI or intracortical facilitation in those with Tourette syndrome versus typically developing children (p > 0.1). In the group with Tourette syndrome, reduced M1 SICI predicted greater total (p = 0.012) and global (p = 0.002) tic severity. There were no associations with urge severity (p > 0.5). INTERPRETATION: Reduced M1 SICI is robustly associated with increased tic, but not urge, severity. WHAT THIS PAPER ADDS: Increased tic severity is associated with reduced motor cortex short-interval cortical inhibition (SICI). Children with Tourette syndrome with increased urge severity also show increased tic severity. However, reduced motor cortex SICI is associated with tic, but not urge, severity.

Results of a phase Ib study of SB-121, an investigational probiotic formulation, a randomized controlled trial in participants with autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by core impairments in social communication as well as restricted, repetitive patterns of behavior and/or interests. Individuals with ASD, which includes about 2% of the US population, have challenges with activities of daily living and suffer from comorbid medical and mental health concerns. There are no drugs indicated for the core impairments of ASD. As such, there is a significant need for the development of new medication strategies for individuals with ASD. This first-in-human placebo-controlled, double-blind, crossover study investigated the safety (primary objective) and efficacy of oral SB-121, a combination of L. reuteri, Sephadex® (dextran microparticles), and maltose administered once daily for 28 days in 15 autistic participants. SB-121 was safe and well tolerated. SB-121-associated directional improvements in adaptive behavior measured by Vineland-3 and social preference as measured with eye tracking were noted. These results provide support for further clinical evaluation of SB-121 as a treatment in autistic patients. To evaluate the safety and tolerability of multiple doses of SB-121 in subjects with autism spectrum disorder. Single-center, randomized, placebo-controlled, double-blind, crossover trial. 15 patients with autism spectrum disorder were randomized and analyzed. Daily dosing of SB-121 or placebo for 28 days, followed by approximately a 14 day washout, then 28 days of dosing with other treatment. Incidence and severity of adverse events, presence of Limosilactobacillus reuteri and Sephadex® in stool, and incidence of bacteremia with positive L. reuteri identification. Additional outcomes include changes from baseline on cognitive and behavior tests as well as biomarker levels. Adverse event rates were similar between SB-121 and placebo, with most reported as mild. There were no severe or serious adverse events. No participants had features of suspected bacteremia or notable changes in vital signs, safety laboratory, or ECG parameters from baseline. There was a statistically significant increase from baseline in the Vineland-3 Adaptive Behavior Composite score (p = 0.03) during SB-121 treatment. There was a trend for increased social/geometric viewing ratio following SB-121 treatment compared to placebo. SB-121 was safe and well tolerated. SB-121-associated directional improvements in adaptive behavior measured by Vineland-3 and social preference as measured with eye tracking were noted.Trial registration: clinicaltrials.gov Identifier: NCT04944901.

Motor Function and Physiology in Youth With Neurofibromatosis Type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic neurocutaneous disorder commonly associated with motor and cognitive symptoms that greatly impact quality of life. Transcranial magnetic stimulation (TMS) can quantify motor cortex physiology, reflecting the basis for impaired motor function as well as, possibly, clues for mechanisms of effective treatment. We hypothesized that children with NF1 have impaired motor function and altered motor cortex physiology compared to typically developing (TD) control children and children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Children aged 8-17 years with NF1 (n = 21) were compared to children aged 8-12 years with ADHD (n = 59) and TD controls (n = 88). Motor development was assessed using the Physical and Neurological Examination for Subtle Signs (PANESS) scale. The balance of inhibition and excitation in motor cortex was assessed using the TMS measures short-interval cortical inhibition (SICI) and intracortical facilitation (ICF). Measures were compared by diagnosis and tested using bivariate correlations and regression for association with clinical characteristics. RESULTS: In NF1, ADHD severity scores were intermediate between the ADHD and TD cohorts, but total PANESS scores were markedly elevated (worse) compared to both (P < 0.001). Motor cortex ICF (excitatory) was significantly lower in NF1 than in TD and ADHD (P < 0.001), but SICI (inhibitory) did not differ. However, in NF1, better PANESS scores correlated with lower SICI ratios (more inhibition; ρ = 0.62, P = 0.003) and lower ICF ratios (less excitation; ρ = 0.38, P = 0.06). CONCLUSIONS: TMS-evoked SICI and ICF may reflect processes underlying abnormal motor function in children with NF1.