Pediatric Neurology

Aims: To describe the developmental phenotype of individuals with STXBP1-related disorders (STXBP1-RD) in a prospective natural history study using standardized outcome measures. Methods: Data were collected from 155 individuals with a mean age of 8.2 years. The Bayley Scales of Infant and Toddler Development-Fourth Edition (Bayley-4), Hand Manipulation and Eye Hand Coordination subtests of the Peabody Developmental Motor Scales-Third Edition (PDMS-3), and Gross Motor Function Measure-66 (GMFM-66) were assessed. The Gross Motor Function Classification System (GMFCS), Mini-Manual Ability Classification System (MiniMACS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS) were used to classify participants. Results: Assessments were well tolerated with 0-6.9% incomplete assessments. Floor or ceiling effects were not common with raw scores, age equivalents, or growth scales values but were frequently observed with scaled scores. Significant differences were found between the Bayley-4, GMFM-66, and PDMS-3 when participants were divided into groups by corresponding developmental domain classification scale. Strong associations (p < 0.05) were seen between all measures across Bayley-4 domains, PDMS-3 domains, and GMFM-66 total scores. Interpretation: The Bayley-4, GMFM-66, and PDMS-3 are suitable for use in clinical practice and future clinical trials in STXBP1-RD.

AIM: To evaluate whether selective motor control quantified from spontaneous infant movement recordings provides diagnostic and prognostic information for cerebral palsy (CP) beyond established movement-based assessments. METHOD: This multicenter diagnostic and prognostic accuracy study included 302 infants (151 with CP) with spontaneous movement recordings obtained between 10 and 20 weeks corrected age from cohorts in Australia and the United States. All eligible infants with CP were included, and a comparison sample without CP was randomly selected. Recordings were scored using the Baby Observational Selective Control Appraisal (BabyOSCAR), Motor Optimality Score Revised (MOS-R), and General Movements Assessment (GMA). Outcomes at 2 years or older included CP diagnosis, Gross Motor Function Classification System (GMFCS) level, and motor distribution. RESULTS: BabyOSCAR discriminated CP diagnosis (area under the curve [AUC] 0.98), including children later classified in GMFCS level I. Among infants with CP, BabyOSCAR discriminated GMFCS levels I - II from III - V (AUC 0.89). BabyOSCAR absolute asymmetry also discriminated unilateral CP from all other infants (AUC 0.90). Diagnostic discrimination was also observed for MOS-R (AUC 0.94) and GMA (AUC 0.86). INTERPRETATION: Quantifying selective motor control from brief infant movement recordings may provide complementary early information about CP diagnosis, functional level, and motor distribution.

Introduction: Functional Neurological Disorder (FND) affects women approximately three times more often than men. This disparity has largely been attributed to higher trauma prevalence and diagnostic bias, while the potential contribution of hormonal influences has received little attention. Methods: An online questionnaire was distributed through FND clinics in thirteen countries, assessing self-reported symptom change across five hormonal events: hormonal contraception, pregnancy, the menstrual cycle, menopause, and gender-affirming hormone therapy. Eligible participants were cisgender women with a diagnosis of FND, or gender minority individuals (transgender or non-binary). Perceived symptom change was rated on a five-point scale ranging from large improvement to large worsening. Results: Among 262 respondents (96% female; mean age 39 years), several hormonal contexts were associated with self-reported symptom changes. Overall, hormonal contraception and pregnancy were frequently associated with worsening of motor and cognitive symptoms, and menopause with worsening across all symptom domains. Menstrual cycle analysis revealed a phase-dependent pattern: worsening was most frequently reported during menstruation and the luteal phase, whereas improvement was most frequent during the follicular phase. Reported changes were not uniform, with a substantial proportion of participants describing no change or improvement. Conclusion: Self-reported FND symptom severity appears to vary with hormonal context, with motor and cognitive symptoms most consistently affected. Given the retrospective, self-report design, these findings are hypothesis-generating and support prospective research into the role of hormonal transitions in FND.

Purpose: This study examined whether word-based and non-word natural language sampling (NLS) measures complement standardized language scores in characterizing expressive communication among preschool children with autism with language impairment (AUT-LI), Down syndrome (DS), and fragile X syndrome (FXS). Method: Participants included 82 preschool children with AUT-LI (n = 32), DS (n = 34), or FXS (n = 16). Expressive communication was characterized using the Preschool Language Scales and 10-minute natural language samples collected during a standardized play-based protocol. NLS measures included traditional word-based metrics, such as lexical diversity, intelligibility, and word approximations, as well as tiered non-word vocalization measures, including non-speech, single-phoneme, and multi-phoneme vocalizations. Analyses examined age associations, diagnostic group differences, between group differences in variability, and exploratory communication profiles derived using principal component analysis and partitioning around medoids clustering. Results: Diagnostic groups did not significantly differ on standardized expressive language scores. Children with FXS showed higher performance than the AUT-LI and DS groups on several word-based NLS measures, whereas non-word vocalization measures primarily revealed differences in within-group variability. Word-based NLS measures were consistently associated with standardized expressive language skills, while associations for non-word vocalizations varied by vocalizations type. Cluster-validity indices factored a two-cluster solution. A hypothesis-informed three cluster solution that included non-word vocalizations suggested Higher Language, Lower Output, and High Output-Low Structure profiles. Conclusions: Standardized and NLS measures provide complementary descriptions of expressive communication in children with neurodevelopmental disorders. Non-word vocalization coding may be especially useful for describing clinical meaningful variation among children with limited expressive language. Keywords: Natural language sampling; expressive language; neurodevelopmental disorders; autism spectrum disorder; Down syndrome; Fragile X syndrome

Background Pontocerebellar hypoplasia Type 2A (PCH2A) is a rare, autosomal recessive disorder with reduced life expectancy. Clinical features include profound developmental delay, microcephaly, and a dyskinetic movement disorder. Additional symptoms frequently observed are feeding difficulties, vomiting, dystonic attacks, and seizures. Compared to parents of typically developing children, parents of children with PCH2A experience decreased health-related quality of life. The aim of this study was to provide a follow-up on survival, symptoms, and perceived disease burden. Methods Patients were primarily recruited via the German patients' organization (PCH-Familie e.V.). Inclusion required genetic confirmation of PCH2A. Data were collected from 2020-2022 using parent questionnaires and medical reports; uncertainties were clarified during semi-standardized telephone interviews. Statistical analysis was quantitative, appropriate statistical tests were used, depending on the data distribution. Results Sixty-five patients participated, with a median age of 6.4 years and balanced gender distribution. Sixteen patients (25%) died at a median age of 5.5 years. Ten-year survival rate was 71.5%. Feeding difficulties, dyskinesia, and sleep disturbances were common and persistent symptoms. Seizures increased with age, whereas vomiting and dystonic attacks decreased over time. Perceived disease burden differed among families, but most reported overall impaired quality of life. The most burdensome symptoms were restlessness, sleep disorder, and gastrointestinal issues, while seizures/epilepsy were ranked as least impactful. With increasing age, perceived burden from feeding and swallowing disorders, gastrointestinal problems, episodic abdominal pain, and overall quality of life decreased significantly. Conclusions Life expectancy in PCH2A remains limited, but survival appears to have improved in more recent birth cohorts. Most symptoms persist with age, though a few, like reflux and dystonic attacks, improve in tendency. Conversely, respiratory symptoms and seizures tend to worsen. Notably, perceived disease burden generally decreases as patients age. Restlessness proved to be the most burdensome symptom, although it has not been clearly described before.

Introduction The Brief Ataxia Rating Scale (BARS) and Scale for the Assessment and Rating of Ataxia (SARA) are used to quantify cerebellar ataxia severity. We investigated how often clinician ratings match patient reports of functional impairment, which scale items patients consider important, and whether incremental changes in item scores are meaningful to patients. Methods 30 patients with cerebellar ataxia completed BARS, SARA, FARS Functional Staging, and an Importance of Activities of Daily Living questionnaire. We studied BARS and SARA item scores for over- or underestimation in relation to patient perception of impairment. We explored patient rankings of item importance in relation to daily function, and their perception of the likely importance of 0.5- and 1-point changes in BARS gait and speech. Results Patients identified gait as most important on BARS and SARA, followed by oculomotor (BARS) and stance (SARA). Heel-to-shin was least important, with highest overestimation on both scales. Total overestimated points were similar between BARS (2.65 +/- 2.80) and SARA (2.78 +/- 2.78). 0.5-point changes in BARS gait and speech scores were rated very or extremely important by 60% and 46.6%, respectively, increasing to 83.3% and 70% for a 1-point change. Conclusion Gait is most meaningful to patients with cerebellar ataxia. BARS oculomotor and SARA stance rank second. BARS and SARA appendicular measures have limited patient-perceived clinical meaningfulness. 0.5-point increments in BARS gait and speech provide greater granularity of assessment and are considered meaningful by a substantial proportion of patients, supporting their relevance in practice and in clinical trials.

BACKGROUND Children receiving extracorporeal membrane oxygenation (ECMO) are at high risk for focal cerebral injury (FCI). There is emerging evidence that electroencephalography (EEG) may aid FCI detection. The EEG Correlate of Injury to the Nervous System (COIN) index quantifies and displays focal background asymmetries. We evaluated whether COIN is associated with FCI in pediatric ECMO. METHODS Retrospective, cross-sectional study of patients age 28 days to 21 years, on venoarterial ECMO at a tertiary children's hospital, who received EEG monitoring and neuroimaging during ECMO. COIN was calculated from all available EEG data. COIN of 0 implies a symmetric EEG and negative COIN values are observed with FCI. Median COIN values near FCI recognition time were compared to median COIN values from randomly selected control EEG batches using logistic regression. A receiver operator characteristic curve was used to identify multilevel FCI test ranges. Likelihood ratios were calculated to estimate the posttest FCI probability for each COIN range. RESULTS During the 8-year study period (2015-2023), 33 of 142 ECMO runs met study criteria for COIN analysis. Twelve patients (36%) had FCI. The COIN cutoff of -13.3 had 92% sensitivity and 67% specificity for FCI. The COIN cutoff of -27.7 had 67% sensitivity and 90% specificity. Likelihood ratios were 0.13 for COIN (0 to -13.3), 1.1 for COIN (-13.3 to -27.7), and 7.0 for COIN (< -27.7). Posttest probability was 0.02, 0.13, 0.49 in each respective range. CONCLUSION FCI on ECMO is associated with COIN-measured EEG asymmetry. COIN may support FCI risk-stratification during ECMO.

Purpose To evaluate whether two automated measures of nasality, Nasal Cognate Distinctiveness (NCD) and nasal posterior probability (NPP), provide clinically meaningful markers of hypernasality in speakers with motor speech disorders (MSDs) and to determine whether hypernasality-related information extends beyond stop consonants, which are typically targeted in cognate-based approaches. Method Sentence-level speech recordings were obtained from 561 patients, including 374 neurologically typical controls and 187 individuals with MSDs. NCD was computed for voiceless stops (/p/, /t/, /k/) using likelihood ratios between stops and their nasal cognates. NPP was extracted using a phonological feature-based neural network model and analyzed for stops, consonants, and vowels. Hypernasality severity was rated by speech-language pathologists. Group differences and associations with hypernasality severity were evaluated using linear mixed-effects models and Spearman correlations, and receiver operating characteristic (ROC) analyses were used to evaluate discrimination of absent versus present hypernasality. An additional 20 controls with repeat recordings were used to evaluate test-retest reliability and minimal detectable change (MDC). Results NCD generally decreased and NPP increased with increasing hypernasality severity, with phoneme-specific severity effects observed for NCD. Across stops, NCD and NPP were strongly inversely correlated and showed comparable discrimination of absent versus present hypernasality (AUCs = 0.796 and 0.730, respectively). Consonant and vowel NPP measures were both positively associated with hypernasality severity and demonstrated identical classification performance (AUC = 0.853). No significant differences in ROC performance were observed between NCD and NPP or between consonant and vowel NPP measures. Test-retest change exceeded the MDC threshold in 2 of 20 controls for NCD and 1 of 20 for NPP. Conclusions Both NCD and NPP provide objective markers of hypernasality in speakers with MSDs. The measures capture related aspects of nasalization and demonstrate comparable ability to identify clinically meaningful hypernasality. NPP captures hypernasality-related acoustic information across both consonants and vowels, with similar relationships to severity and classification performance across sound classes. Test-retest findings provide preliminary MDC benchmarks for interpreting longitudinal change.

Abstract: Objective: Post-traumatic epilepsy (PTE) is a common sequela of traumatic brain injury (TBI). Research indicates that individuals with PTE tend to experience greater cognitive difficulties compared to those with TBI alone. However, it is plausible that a distinct cognitive profile exists that distinguishes between TBI cases with and without PTE. We aimed to identify longitudinal changes in cognitive measures among TBI patients to better assess the changes associated with developing PTE. Setting: Outpatient. Participants: Prospective subjects who had suffered TBI within 6 months post-injury (TBI-6M, n=32), retrospective subjects with pre-existing PTE diagnoses (PTE, n=20), and healthy control subjects (HC, n=41). Design: We examined cognitive performance for TBI patients within 6 months post-injury, then again within 12 months (TBI-12M, n=26), and within 18-months (TBI-18M, n=25), and compared this with cognitive performance among HC and PTE. Main Measures: Cognitive tests administered yielded 15 test components for analysis. We utilized linear mixed effects modeling to examine cohort-level differences cognitive function. Results: 11/15 tests showed a significant performance deficit in the PTE subjects compared to HC. TBI-6M was not significantly different from the PTE subjects; with time, 9/15 tests showed some degree of recovery in TBI subjects. Tests for information processing speed/working memory and executive function showed strong recovery (TBI-6M vs. TBI-18M, SDMT written: p<0.0001, SDMT oral and COWAT: p<0.001). Tests for visual attention/working memory also showed a smaller but significant recovery (TBI-18M vs. PTE, p<0.05). By contrast, tests for verbal memory [HVLT-R Delayed Recall] showed chronic impairment in TBI (TBI-18M vs HC, p<0.0001). TBI subjects generally trend towards recovery in cognitive performance post-TBI. Conclusions: Information processing speed/working memory are strong indicators for TBI recovery, while auditory learning/memory shows chronic impairment. The stagnation of recovery in cognitive domains typically characterized by robust recovery may correlate with an elevated risk of developing PTE.

BACKGROUND: One in three adolescents with a concussion history report experiencing long-lasting somatic, sleep, emotional, and/or cognitive disturbances (persisting symptoms after concussion (PSaC)). Cognitive difficulties, such as attentional problems, are common symptoms and can interfere with ongoing development. Clinically, psychiatric symptoms also present in youth with PSaC. A concussion causes diffuse functional and microstructural alterations to neural networks. To develop targeted treatments for PSaC (e.g., neurostimulation), we need to understand how and where structural alterations and neural dysfunction intersect to cause long-lasting symptoms. OBJECTIVES: 1) Identify functional and microstructural properties in intrinsic connectivity networks, as well as neuropsychological outcomes, that differentiate adolescents with concussion with PSaC from those who do not have PSaC. 2) Determine whether neural activity within intrinsic connectivity networks mediates the relationship between network microstructure and specific neuropsychological features in adolescents with concussion. METHODS: CAMBY is a prospective study of adolescents aged 12 to 18 years with a history of concussion. Participants are allocated based on recovery status (PSaC vs. No-PSaC (recovered controls)). Advanced structural (magnetic resonance imaging; MRI) and functional (magnetoencephalography; MEG) neuroimaging and neuropsychological measures will be collected one month or more after concussion. Microstructural and functional features will be computed within intrinsic connectivity networks, then compared between PSaC and recovered control groups and related to symptom domains and neuropsychological profiles. IMPACT: This will be the first study to integrate MRI, MEG, and neuropsychology in adolescents with PSaC to identify disrupted networks underlying PSaC. This observational study is a necessary step towards future clinical trials that accurately target promising therapeutic neurostimulation protocols.

Background Elevated resting gamma power is a reproducible, robust neurophysiology marker across species in fragile X syndrome (FXS), a major known cause of autism spectrum disorders (ASD). In FXS, this neurophysiological phenotype is well described and particularly prominent in males harboring fully methylated full CGG repeat expansions. However, gamma power evaluations in idiopathic ASD have yielded variable results. As a single-gene model of ASD, FXS hold promise to biologically model some of the autism spectrum. Exaggerated gamma power in FXS is thought to reflect increased cortical excitability, a common feature of ASD, and has been shown to correlate with symptoms in both human FXS individuals and the Fmr1 knockout mouse model of FXS. A recent clinical trial of the BK channel positive modulator, Codabakalner, provided encouraging signs that normalization of gamma power in FXS may provide therapeutic benefit [14]. Interventional and biomarker studies in ASD provide support that this may also be the case in ASD. We utilized gamma band power to evaluate neurophysiological overlap between ASD and FXS seeking to determine the prevalence and clinical characteristics of those with ASD who exhibit a FXS-like elevated resting state gamma phenotype. Methods This cross-sectional resting EEG analysis included 159 individuals with non-syndromic ASD and 41 males with fully methylated full mutation FXS. Relative gamma power was calculated as 30-100 Hz power divided by 1-100 Hz power across 10-20-equivalent electrodes, excluding 55-65 Hz. We defined the cutoff for elevated resting gamma band power in ASD as relative gamma power of greater than or equal to the median minus one standard deviation of gamma power in our FXS male sample. Results A FXS-derived relative-gamma threshold of 0.185 or greater was met by 22% of participants with ASD (n=35). As expected, the mean ASD group resting state gamma was lower than the male FXS sample (p < 0.001). ASD participant threshold proportions by age group were 3/37 (8.1%) below 13 years, 9/50 (18.0%) age 13-18 years, and 23/72 (31.9%) in the 18+ years group. Within the ASD group, there were no observable clinical characteristics that readily differentiated participants with an elevated gamma phenotype from those without this phenotype. Conclusions Approximately one fifth of all participants and slightly over 30 percent of adults with ASD met the FXS-derived elevated resting gamma band power criterion. This represents the first investigation using a translational brain neurophysiology marker in a syndromic form of autism to parse a clinical idiopathic ASD sample to identify potential overlapping brain features. The results will work to support potential targeting of ASD subgroups in the future utilizing therapeutic approaches initially established in a single-gene form of developmental disability.

Gastrointestinal (GI) conditions are common among children with neurodevelopmental disabilities (NDDs), and are associated with functional impairment, behavioral symptoms, and increased health care utilization. A unique relationship between autism and GI dysfunction has been proposed, leading to a focus on autism in GI research, management guidelines, and clinical tool development. Leveraging >20 years of electronic health record data and a cohort of 42,204 cases with attention-deficit/hyperactivity disorder, autism, cerebral palsy, epilepsy, or intellectual disability and 297,402 controls without NDDs, we quantified associations between NDDs and GI conditions in children. GI conditions were more common in cases than controls across all individual NDDs; intellectual disability and cerebral palsy were most strongly associated with having a GI condition. In this work, clinically recognized GI morbidity was elevated across all NDDs and not unique to autism, suggesting that a broader, transdiagnostic approach to GI dysfunction in children with NDDs is warranted.

Background: Infants with extremely low birth weight (ELBW) are at high risk for neurodevelopmental impairment, but the relationship between cerebellar structure and later developmental outcome remains incompletely defined. Methods: In this retrospective single-center study, we examined total cerebellar volume on clinically acquired brain magnetic resonance imaging (MRI) in ELBW infants while accounting for postmenstrual age (PMA) at imaging. Results: Of 65 infants screened, 42 were included. Mean gestational age at birth was 25.54 {+/-} 1.68 weeks, mean birth weight was 733.2 {+/-} 118.7 g, and mean PMA at MRI was 43.02 {+/-} 6.53 weeks (range, 31.57--68.00). Mean cerebellar volume was 22.17 {+/-} 9.63 cm. Independently adjudicated developmental outcomes comprised normal development in 16 infants, isolated or specific impairment in 12, and moderate/severe impairment in 14. Unadjusted cerebellar volumes did not differ across developmental groups (P = 0.490) or qualitative MRI categories (P = 0.875). However, the PMA-by-developmental-category interaction was significant (P = 0.002), with estimated cross-sectional slopes of 1.72, 1.56, and 0.39 cm per week, respectively. The interaction remained significant within 36--46 weeks PMA (n = 29; P = 0.011) and after adjustment for small-for-gestational-age (SGA) status. Sensitivity analyses indicated uncertainty in the stability of the interaction. Conclusions: These findings suggest that age-informed cerebellar volumetric patterns may provide developmental information not evident from average volumes alone and support prospective validation with standardized imaging and developmental assessments. As a result, cerebellar volumes obtained early in life may hold prognostic information for ELBW infants.

Objective: To characterize the clinical, radiological, and pathological features of Neuro-Ocular Vasculopathy Associated with Fanconi Anemia (NOVA-FA). Methods: Six patients with FA and neurological symptoms were phenotyped using retrospective chart review of clinical notes, neuroimaging, fluorescein angiogram, CSF analysis, and advanced research techniques including extensive infectious testing. Biopsies were reviewed in two patients. Results: NOVA-FA is defined by neurological symptoms, retinal vasculopathy, accumulation of punctate cerebellar lesions and/or large mass-like lesions with surrounding vasogenic edema. Histopathology showed vasculopathy without inflammation. Treatments with immunosuppressants appeared largely ineffective. Imaging and pathology suggest a non-inflammatory small vessel vasculopathy as the primary pathology. Interpretation: NOVA-FA is a recently identified condition that affects a subset of patients with FA and results in significant disability, including death. The etiology remains unknown, although the condition mimics features of the syndrome retinal vasculopathy and cerebral leukodystrophy which is due to dysfunction in DNA repair mechanisms. There is currently no known effective treatment.

Objectives: Aneurysmal subarachnoid haemorrhage is a life-threatening emergency that commonly presents with a sudden, severe headache. The diagnosis is usually confirmed on CT imaging, however a small subset of patients demonstrate normal imaging, particularly if presentation is delayed - in which case spectrophotometric analysis of cerebrospinal fluid (CSF) is undertaken. Nevertheless, thunderclap headache is a common presentation and the vast majority of investigated patients do not have aneurysmal subarachnoid haemorrhage. This ten-year service evaluation at a tertiary neurosurgery centre aims to estimate the utility of lumbar puncture in the diagnostic work-up of these patients. Methods: All instances of CSF spectrophotometry between 01/01/2011 and 31/12/2020 were evaluated. Clinical records of patients with positive spectrophotometry were analysed. A second method identified all coded diagnoses of non-traumatic subarachnoid haemorrhage over the same time period, with review of clinical records in cases of negative imaging. Results: Of 2158 instances of CSF spectrophotometry performed at the tertiary neurosurgery centre, four aneurysms were identified and treated by coiling or clipping, resulting in a number needed to treat of 540 patients to diagnose one case of aneurysmal subarachnoid haemorrhage. Of 648 patients with a coded diagnosis of non-traumatic subarachnoid haemorrhage (including local patients and transfers from satellite hospitals), 27 patients displayed initial negative imaging, of which 9 were found to have aneurysms and underwent neuro-intervention. Lumbar puncture was instrumental in the diagnosis and led to intervention in three patients identified by this method. Conclusion: CSF analysis resulted in diagnosis and intervention for missed (CT-negative) aneurysmal subarachnoid haemorrhage in approximately 1/540 tested patients. The estimated yield in a real-world setting may be useful for clinicians or provide a basis for discussion when counselling patients on benefit and risk.

Purpose: In clinical trials, treatment efficacy is commonly assessed by comparing control and treatment groups. However, in large samples, even small and clinically trivial differences may achieve statistical significance. Accordingly, the Minimal Clinically Important Difference (MCID) is used as a threshold to determine whether statistically-significant effects are also clinically meaningful to patients. The objective of this study was to estimate the MCID for the Childhood Autism Rating Scale Second-Edition (CARS2) using the Patient Impression of Change (PIC) as an external anchor. Methods: Single-item PICs are not well suited to characterizing improvement in a multifaceted disorder such as ASD. Accordingly, the 77-item Autism Treatment Evaluation Checklist (ATEC) was used as a multi-item PIC. CARS2 and ATEC were administered concurrently to 62 children with ASD, aged 1.8-7.9 years, with assessments conducted six months apart. Results: The correlation between changes in CARS2 and ATEC total scores was 0.41-0.44 (p<0.0001), supporting the use of ATEC as an anchor measure. Two anchor-based methods yielded MCIDs of 2.39-2.82 CARS2 points. Two distribution-based methods produced MCIDs of 1.33-3.32. Conclusions: Taken together, these approaches suggest that a between-group difference of 2.6 CARS2 points (the midpoint of the anchor-based estimates) may serve as the MCID in children with ASD.

BackgroundPersistent postural-perceptual dizziness (PPPD) is a chronic functional dizziness disorder characterized by unsteadiness, hypersensitivity to motion and visually complex environments. Although increasingly investigated, the role of the different factors involved remains unclear. This study aims to comprehensively characterize PPPD across clinical, biological, and behavioral domains. MethodsData from 18 PPPD patients and 20 age- and sex-matched healthy control volunteers (HC) were analyzed, including clinical and psychological questionnaires, a neuropsychological battery, salivary markers, posturography under different conditions, and gait analysis under single- and dual-task demands. ResultsPatients reported greater depressive symptoms, higher perceived stress, and reduced quality of life than HC, but showed no neuropsychological deficits and comparable past psychological trauma and personality traits. Salivary stress marker levels were similar to HC. Gait analysis revealed a slower, cautious gait in patients, which worsened without vision, with no differences in automaticity (stride time variability). Postural assessments showed greater sway and enhanced low-frequency oscillations, exacerbated by absence of visual input in PPPD. Visual reliance for postural control correlated negatively with subjective symptom severity, but not other symptom-related measures. ConclusionPPPD patients have lower mood and increased perceived stress, with no increase in biological stress markers compared to HC. Cognition, personality, and exposure to past trauma might be less relevant than previously hypothesized. Patients show visual dependence for gait and postural control, likely a maladaptive compensatory mechanism. These findings support interventions targeted at reducing visual dependence and at improving mood, rather than interventions focusing on psychological trauma. SummaryO_LIWhat is already known on this topic - PPPD (Persistent Perceptual Postural Dizziness) is a functional dizziness disorder characterized by different biopsychosocial factors, often investigated in isolation. C_LIO_LIWhat this study adds - PPPD patients have higher depression and perceived stress scores, lower quality of life, but show no differences in past trauma, personality traits, and biological stress markers, compared to healthy controls. They also show a reliance on vision both for gait and for postural control, with increased low-frequency oscillations in the anteroposterior direction. Visual dependence is likely maintained by its perceived role in symptom reduction. C_LIO_LIHow this study might affect research, practice or policy - These findings support rehabilitation strategies aimed at reducing reliance on vision and increasing reliance on vestibular inputs, but not interventions focusing on past traumatic experiences. C_LI

Background The nonfluent/agrammatic (nfv) and logopenic (lv) variants of primary progressive aphasia (PPA) disrupt fluency through distinct underlying neurocognitive mechanisms. Differential diagnosis currently requires hours of cognitive-linguistic testing, with additional barriers for bilingual patients due to a shortage of bilingual service providers and a lack of well-established assessment methods. In English speakers, a promising automated approach for differentiating nfvPPA and lvPPA is to derive speech-timing measures and linguistic features from connected speech as input to machine learning (ML) classification algorithms. To our knowledge, this approach has not been evaluated in the context of bilingualism. Methods Thirty four Catalan Spanish simultaneous bilingual patients (lv = 24, nfv = 10) were asked to describe a picture (Western Aphasia Battery Picnic Scene) in both their dominant and non-dominant language. From the participant's recorded response, we derived four feature sets: speech-timing measures, derived with PRAAT; word-level parameters, derived from corpora; linguistic features, derived with the natural language processing tools SpaCy and CLAN; image-text congruence scores, derived with the vision-language encoder Multilingual-CLIP. Each feature set was fed into classification algorithms for differentiating nfv from lv in participants' non-dominant and dominant samples. Then, we combined each feature set's classifier into an ensemble model. We used the McNemar test to determine the statistical significance of differences in classification performance between responses in the non-dominant and dominant language. Results The best-performing classifier achieved F1 macro scores of 93% (word-level parameters) and 92% (ensemble) in the non-dominant and dominant language, respectively. For all feature sets and ensemble models, classification performance did not significantly differ between the non-dominant and dominant language. Ensemble modeling did not significantly improve classification performance in either language. Conclusions Taking advantage of recent advances in multilingual multimodal machine learning, we accurately differentiate Catalan-Spanish bilingual individuals with nfvPPA and lvPPA using a largely automated, time-efficient (1-2 minutes), and ecologically valid connected-speech-based approach. Future directions include evaluating this approach on larger datasets balanced by PPA subtype, using automated transcriptions of connected speech. Our study represents a step towards addressing current inequities in PPA differential diagnosis for non-English-speaking bilingual speakers. Trial registration Data from the clinical trial NCT05741853 was retrospectively analyzed

More than a third of women in the United States are estimated to experience abuse from an intimate partner, in which blows to the head, strangulation, and therefore brain injuries are common. Among 207 survivors of such physical violence, two-thirds reported a partner-inflicted brain injury. These women performed substantially worse than the general population across most cognitive measures, including memory and reaction time. Cognitive performance declined as injury count increased. Translated into cognitive age, survivors with the most partner-inflicted brain injuries performed over two decades older than the general population, and a decade older than survivors with no history of brain injury. Importantly, the cognitive assessment discards scores it judges unreliable, yet these came primarily from the most impaired women, suggesting that the true harm is likely greater than reported here. Such cognitive deficits may limit these women's capacity to live to their potential, including keeping safe from abuse. These findings underscore partner-inflicted brain injury as a major, under-recognized source of cognitive harm, potentially affecting more women than brain injury in professional football or the military while lacking comparable clinical recognition and care.

Background and Objectives: Deep sequencing of brain tissue in the research setting has established that mosaic variants are a major cause of malformations of cortical development (MCDs) and epilepsy. However, genetic testing in the clinical setting primarily detects germline variants using clinically accessible samples. We aimed to determine the diagnostic yield and clinical utility of deep sequencing in the clinical setting to identify pathogenic mosaic variants for this population. Methods: We performed a retrospective cohort analysis of individuals at Boston Children's Hospital with MCDs with or without epilepsy who received clinical deep sequencing between September 2017 and February 2026. Demographic, clinical, and genetic testing data were abstracted from the medical record. For individuals without systemic features, we classified brain tissue as an affected tissue sample. For individuals with systemic features, we classified brain or relevant non-brain tissue as affected. The primary outcome was the diagnostic yield of clinical deep sequencing performed using affected vs unaffected tissue samples. The secondary outcome was the clinical utility of genetic diagnoses. Results: Our cohort included 37 individuals (19/37 (51%) female, 18/37 (49%) male) with MCDs, of whom 35/37 (95%) had epilepsy (25 with brain tissue samples available from epilepsy surgery) and 8/37 (22%) had systemic features. Most (35/37 (95%)) had dysplasia phenotypes on MRI and 12/27 (44%) with pathology available had Focal Cortical Dysplasia Type I or II. The diagnostic yield was 53% (17/32; 16 mosaic and 1 germline variant) when clinical deep sequencing was performed using an affected tissue sample vs 0% (0/6) using an unaffected tissue sample (p=0.016). Of the diagnosed cases, 13/17 (76%) had testing performed on brain tissue (1 with systemic features) and 4/17 (24%) on non-brain tissue (3 buccal and 1 duodenal tissue, all with systemic features). All but one diagnosis involved the mTOR pathway. All diagnoses had clinical utility. Discussion: Clinical deep sequencing, when performed using an affected tissue sample, has high diagnostic yield and clinical utility for individuals with MCDs, especially dysplasia phenotypes, and epilepsy. Our findings support implementation of clinical deep sequencing for this population, especially as the genetic diagnoses have implications for emerging precision therapies.