Current Ear and Hearing Care Practices for Infants and Toddlers with Cleft Palate in the United States.

OBJECTIVE: To examine ear and hearing clinical practices across American Cleft Palate-Craniofacial Association (ACPA) approved teams in the United States. DESIGN: Multi-site prospective, observational, longitudinal study. SETTING: Seventeen Cleft Palate Teams in the United States. PATIENTS, PARTICIPANTS: Children with cleft palate, with or without cleft lip (CP ± L), born between 2015 and 2022, evaluated by 18 months (n = 1246). INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Standard of care otolaryngology and audiology appointments evaluated in the context of whether otolaryngology and audiology services were provided as embedded care within the team visit or as ancillary services. RESULTS: Over 71% of infants passed newborn hearing screening (NBHS). By age 18 months, only 40% of infants received audiologic follow-up while 93.6% of children received otolaryngology care. Follow-up was significantly better for infants served by teams with embedded providers versus those who refer families for ancillary services; the odds of seeing an audiologist by 18 months were three times as high among participants seen by teams with embedded audiology (OR = 3.25; CI = 2.0, 5.2) while those seen by teams with embedded otolaryngologists had more than double the odds of seeing an otolaryngologist by 18 months (OR = 2.2; CI = 1.5, 3.2). CONCLUSIONS: There is considerable variability across ACPA-approved centers in the US regarding the timing and completion of otolaryngology and audiologic follow-up for children with CP ± L. This study highlights the importance of following established standards of care and the impact that team composition and access to clinical services can have on equity of care.

Growth Patterns Between Ages 0 and 36 Months Among US Children With Orofacial Cleft: A Retrospective Cohort Study.

BACKGROUND: Little is known about how young children with orofacial cleft grow over time. OBJECTIVE: To characterize longitudinal growth patterns from ages 0 to 36 months in US children with an orofacial cleft. DESIGN: A retrospective cohort study. PARTICIPANTS/SETTING: Children with cleft lip, cleft lip and palate, or cleft palate who were younger than age 36 months at a hospital encounter between 2010 and 2019 (N = 1334) were included. The setting was a US tertiary care children's hospital with a cleft center that serves a 5-state region. MAIN OUTCOME MEASURE: Weight-for-age z scores (WAZ) and length-for-age z scores (LAZ). STATISTICAL ANALYSES PERFORMED: Longitudinal growth patterns were characterized using generalized linear mixed models to estimate mean WAZ and LAZ from age 0 to 36 months. RESULTS: Growth in infants with cleft slowed dramatically during the first 3 to 4 months of life, rebounded with catch-up growth until age 12 months for cleft lip and cleft palate and until age 36 months for cleft lip and palate. When comparing populations, children with any type of cleft demonstrated subpar growth compared with World Health Organization standards. Growth deficits were more common in those with cleft lip and palate and cleft palate compared with those with cleft lip. The intraclass coefficient showed that most of the variability in the WAZ (65%) was between individuals, whereas 35% was within an individual. The intraclass coefficient for LAZ showed that most of the variability in the LAZ (74%) was between individuals, whereas 26% was within an individual. The proportion of variance attributable to cleft type and/or comorbidities accounted for <5% of the variance for WAZ and LAZ. WAZ and LAZ were lower in children with comorbidities than those without comorbidities with cleft and World Health Organization standards. CONCLUSIONS: Infants with cleft lip and palate, cleft palate, and a cleft with comorbidities have higher rates of poor growth than peers with cleft lip and a cleft with no comorbidities, respectively.

Characterizing Speech Phenotype in Individuals With Craniofacial Microsomia: A Scoping Review.

INTRODUCTION: Craniofacial microsomia (CFM) is a complex congenital condition primarily affecting the ear, mandible, facial nerve and muscles, and tongue. Individuals with CFM are at increased risk of hearing loss, obstructive sleep apnea, and feeding/swallowing difficulties. The purpose of this scoping review was to summarize evidence pertaining to speech production in CFM. METHOD: All articles reporting any characteristic of speech production in CFM were included and screened by two independent reviewers by title, abstract, and full text. Data charting captured details related to study population and design, CFM diagnostic criteria, speech outcome measurement, and key findings. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist guided reporting of results. Our protocol was registered on the Open Science Framework (https://osf.io/npr94/) and published elsewhere. RESULTS: Forty-five articles were included in the detailed review. Most articles originated from the United States, were published in the past decade, and utilized case report/series study design. A speech-language pathologist authored 29%. The prevalence of velopharyngeal insufficiency ranged from 19% to 55% among studies. Oral distortion of alveolar and palatal fricatives and affricates primarily characterized articulation errors. Studies identified increased disordered speech and lower intelligibility in adolescents with CFM compared to unaffected peers. Evidence pertaining to phonatory and respiratory speech findings is limited. CONCLUSIONS: Evidence supports that individuals with CFM are at increased risk of both velopharyngeal and articulatory speech differences. Additional information is needed to develop speech screening guidelines for children with CFM. Heterogeneity in study design and outcome measurement precludes comparisons across studies. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24424555.

Characterising the speech phenotype in individuals with craniofacial microsomia: a scoping review protocol.

INTRODUCTION: Asymmetric mandibular hypoplasia, microtia, tongue and laryngeal anomalies, and soft palate and facial nerve dysfunction are clinical features observed in children with craniofacial microsomia (CFM). Despite involvement of all these structures in hearing and speech, there is limited evidence reporting speech outcomes in this population. Systematic reviews of clinical and surgical interventions related to CFM have been published, but no methodological review of speech outcomes exists. This scoping review will summarise what is known about speech production in individuals with CFM as well as illustrate gaps in the existing body of literature that will guide future research. METHODS/ANALYSIS: This review will follow the methodological framework for scoping reviews first reported by Arksey & O'Malley and revised by Levac and others. Databases searched will include Ovid MEDLINE, EMBASE, CINAHL, PsycINFO and grey literature. Articles reporting any parameter of speech production in individuals with CFM will be considered for inclusion. Articles published in a language other than English will be excluded. Articles will be screened in three stages: (1) title review, (2) abstract review and (3) full text review. Ten per cent of articles will be rescreened by a second reviewer. Reference lists will be hand reviewed to identify additional relevant articles. Data charting will capture article metadata, study population and design, CFM diagnostic criteria, speech outcome measurement and key findings. The Preferred Reporting Systems for Systematic Reviews and Meta-Analyses Protocols-Extension for Scoping Reviews checklist will guide reporting of results. Descriptive analysis and data visualisation strategies will be used. ETHICS AND DISSEMINATION: Institutional review board approval is not required for a scoping review, as it does not directly involve human subjects. Results will be disseminated through peer-reviewed publication as well as conference presentation.

An off-the-shelf otoacoustic-emission probe for hearing screening via a smartphone.

Otoacoustic emissions (OAEs) provide information about the function of the outer hair cells of the cochlea. In high-income countries, infants undergo OAE tests as part of the screening protocols for hearing. However, the cost of the necessary equipment hinders early screening for hearing in low- and middle-income countries, which disproportionately bear the brunt of disabling hearing loss. Here we report the design and clinical testing of a low-cost probe for OAEs. The device, which has a material cost of approximately US$10, uses an off-the-shelf microphone and off-the-shelf earphones connected to a smartphone through a headphone jack. It sends two pure tones through each of the headphone's earbuds and algorithmically detects the distortion-product OAEs generated by the cochlea and recorded via the microphone. In a clinical study involving 201 paediatric ears across three healthcare sites, the device detected hearing loss with 100% sensitivity and 88.9% specificity, comparable to the performance of a commercial device. Low-cost devices for OAE testing may aid the early detection of hearing loss in resource-constrained settings.

Central auditory processing disorders after mild traumatic brain injury.

Auditory processing disorders are common following mild traumatic brain injury (mTBI), but the neurocircuitry involved is not well understood. The present study used functional MRI to examine auditory cortex activation patterns during a passive listening task in a normative population and mTBI patients with and without clinical central auditory processing deficits (APD) as defined by the SCAN-3:A clinical battery. Patients with mTBI had overall patterns of lower auditory cortex activation during the listening tasks as compared to normative controls. A significant lateralization pattern (pairwise t-test; p⟨0.05) was observed in normative controls and in those with mTBI and APD during single-side stimulation. Additionally, baseline connectivity between left and right auditory cortices was lower in mTBI patients than in controls (p=0.01) and significantly reduced in the mTBI with APD group (p=0.008). Correlation was also observed between bilateral task-related activation and competing words subscore of the SCAN-3:A. These findings suggest the passive listening task is well suited to probe auditory function in military personnel with an mTBI diagnosis. Further, the study supports the use of multiple approaches for detecting and assessing central auditory deficits to improve monitoring of short- and long-term outcomes.

Reference ranges and stability of auditory and vestibular measures in a comprehensive assessment battery for traumatic brain injury.

BACKGROUND: Audiology clinics have many tools available to evaluate auditory and vestibular complaints. However, many tools lack established normative ranges across the life span. We conducted this study to establish reference ranges across the life span for audiology/vestibular measures commonly used to evaluate patients with traumatic brain injury. MATERIALS AND METHODS: In this repeated measures study, 75 adults, ages 18-65 years, without a history of traumatic brain injury, underwent robust auditory/vestibular evaluations three times over six months, including rotational chair, videonystagmography, computerized dynamic posturography, vestibular evoked myogenic potentials, and retinal fundoscopy. RESULTS: Age effect was notable for transient evoked otoacoustic emissions, pure-tone audiometry, auditory brainstem response, auditory middle latency response, and auditory-steady state response at 4000 hertz (Hz). Older participants (50-65 years) were more likely to have delayed latency horizontal saccades, positional nystagmus, slowed lower-extremity motor control responses, and delayed latency ocular vestibular evoked myogenic potentials. Low to mid-frequency horizontal (0.003-4 Hz) and mid-frequency vertical (1-3 Hz) vestibulo-ocular reflex, otolith-mediated reflexes, dynamic visual acuity and balance measures were generally not influenced by age. Females had larger static subjective visual testing offset angles, longer cervical vestibular evoked myogenic potential P1 latency, faster velocity horizontal saccades, and quicker motor control latency for large backward translations than age-matched males. CONCLUSION: These reference ranges can be used to discern impairment within the auditory and vestibular pathway following traumatic brain injury in young to middle-aged adults. ID: TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01925963.

Hidden hearing deficits in military service members with persistent post concussive symptoms.

INTRODUCTION: Individuals with persistent symptoms after mild traumatic brain injury (mTBI) often have auditory complaints. In this study, we used the auditory brainstem response (ABR) to determine whether cochlear synaptopathy could explain auditory symptoms. METHODS: 69 adult military service members with mTBI and 25 adults without brain injury (NCT01611194 and NCT01925963) completed pure-tone audiometry, ABR, and central auditory processing tests. All participants were male, ages 21-50. RESULTS: 37/69 mTBI participants had measurable hearing loss, while another 20%-30% had hearing complaints or tinnitus. While mTBI participants with measurable hearing loss had reduced wave I and III amplitude and decreased III-V interpeak latency, those with no measurable hearing loss did not significantly differ from controls on any ABR parameter. Those with measurable hearing loss were also more likely to have abnormal central auditory processing. mTBI participants with no measurable hearing loss but who reported hearing concerns had some ABR findings (III-V interpeak latency, I and V amplitudes, V/I amplitude ratio) more like the measurable hearing loss mTBI group than normative controls. CONCLUSION: Cochlear synaptopathy may have contributed to some of the auditory impairment in service members with mTBI with measurable hearing loss. However, these results are likely confounded by cochlear hair cell damage.

Prospective study of anxiety, post-traumatic stress and depression on postural control, gait, otolith and visuospatial function in military service members with persistent post-concussive symptoms.

PURPOSE: Military service members often report both affective and vestibular complaints after mild traumatic brain injury (mTBI), but associations between symptoms and vestibular deficits can be subtle and inconsistent. METHODS: From two complementary studies, one of military service members with persistent post-concussive symptoms after mTBI (NCT01611194) and the other of adult volunteers with no history of brain injury (NCT01925963), affective symptoms were compared to postural control, gait, otolith and visuospatial function. RESULTS: The studies enrolled 71 participants with mTBI and 75 normative controls. Participants with mTBI had significantly reduced postural equilibrium on the sensory organization test (SOT), and more so in those with high anxiety or post-traumatic stress. Cervical and ocular vestibular evoked myogenic potentials (cVEMP; oVEMP) showed prolonged latencies in mTBI participants compared to controls; oVEMPs were significantly delayed in mTBI participants with high anxiety, post-traumatic stress or depression. A subset of the mTBI group had abnormal tandem gait and high anxiety. Anxiety, post-traumatic stress, and depression did not correlate with performance on the 6-Minute Walk Test, visuospatial neuropsychological measures, and the Satisfaction with Life Scale in the mTBI group. CONCLUSION: In this study military service members with mTBI reported affective symptoms, concurrently with vestibular-balance concerns. Worse scores on affective measures were associated with abnormal findings on measures of postural control, gait and otolith function.

Longitudinal study of hyperbaric oxygen intervention on balance and affective symptoms in military service members with persistent post-concussive symptoms.

BACKGROUND: Dizziness and imbalance are common after mild traumatic brain injury (mTBI). Hyperbaric oxygen (HBO2) has been proposed for persistent post-concussive symptoms after mTBI, but its effect on vestibular function is unknown. OBJECTIVE: To describe balance function in military service-members before and after intervention, and to explore the influence of post-traumatic stress disorder (PTSD), anxiety, and depression on vestibular outcomes. METHODS: Seventy-one participants with mTBI and seventy-five healthy adults without brain injury were enrolled (NCT01611194 and NCT01925963). mTBI participants were randomized to 40 HBO2 sessions or 40 sham chamber sessions over 12 weeks. Normative controls received no intervention. Balance and neuropsychological function were measured at baseline, 13 weeks, and 6 months. RESULTS: The mTBI cohort performed worse than healthy controls on balance and gait measures and reported more affective symptoms. Some within-group improvements were noted at 13 weeks and 6 months. Significant between-intervention differences on balance measures were minimal but effects on postural control generally favored HBO2. Those with affective symptoms, particularly PTSD, had the most improvement in postural control and otolith function following 13 weeks of HBO2. CONCLUSION: HBO2 may influence balance function after mTBI, particularly in those with affective symptoms.

Hyperbaric oxygen for post-concussive symptoms in United States military service members: a randomized clinical trial.

BACKGROUND: In prior military randomized trials, participants with persistent symptoms after mild traumatic brain injury (TBI) reported improvement regardless of receiving hyperbaric oxygen (HBO2) or sham intervention. This study's objectives were to identify outcomes for future efficacy trials and describe changes by intervention. METHODS: This Phase II, randomized, double-blind, sham-controlled trial enrolled military personnel with mild TBI and persistent post-concussive symptoms. Participants were randomized to receive 40 HBO2 (1.5 atmospheres absolute (ATA), ⟩99% oxygen, 60 minutes) or sham chamber sessions (1.2 ATA, room air, 60 minutes) over 12 weeks. Participants and evaluators were blinded to allocation. Outcomes assessed at baseline, 13 weeks and six months included symptoms, quality of life, neuropsychological, neurological, electroencephalography, sleep, auditory, vestibular, autonomic, visual, neuroimaging, and laboratory testing. Participants completed 12-month questionnaires. Intention-to-treat results are reported. RESULTS: From 9/11/2012 to 5/19/2014, 71 randomized participants received HBO2 (n=36) or sham (n=35). At baseline, 35 participants (49%) met post-traumatic stress disorder (PTSD) criteria. By the Neurobehavioral Symptom Inventory, the HBO2 group had improved 13-week scores (mean change -3.6 points, P=0.03) compared to sham (+3.9 points). In participants with PTSD, change with HBO2 was more pronounced (-8.6 vs. +4.8 points with sham, P=0.02). PTSD symptoms also improved in the HBO2 group, and more so in the subgroup with PTSD. Improvements regressed at six and 12 months. Hyperbaric oxygen improved some cognitive processing speed and sleep measures. Participants with PTSD receiving HBO2 had improved functional balance and reduced vestibular complaints at 13 weeks. CONCLUSIONS: By 13 weeks, HBO2 improved post-concussive and PTSD symptoms, cognitive processing speed, sleep quality, and balance function, most dramatically in those with PTSD. Changes did not persist beyond six months. Several outcomes appeared sensitive to change; additional studies are warranted.

Comprehensive Evaluation of Healthy Volunteers Using Multi-Modality Brain Injury Assessments: An Exploratory, Observational Study.

Introduction: Even though mild traumatic brain injury is common and can result in persistent symptoms, traditional measurement tools can be insensitive in detecting functional deficits after injury. Some newer assessments do not have well-established norms, and little is known about how these measures perform over time or how cross-domain assessments correlate with one another. We conducted an exploratory study to measure the distribution, stability, and correlation of results from assessments used in mild traumatic brain injury in healthy, community-dwelling adults. Materials and Methods: In this prospective cohort study, healthy adult men and women without a history of brain injury underwent a comprehensive brain injury evaluation that included self-report questionnaires and neurological, electroencephalography, sleep, audiology/vestibular, autonomic, visual, neuroimaging, and laboratory testing. Most testing was performed at 3 intervals over 6 months. Results: The study enrolled 83 participants, and 75 were included in the primary analysis. Mean age was 38 years, 58 were male, and 53 were civilians. Participants did not endorse symptoms of post-concussive syndrome, PTSD, or depression. Abnormal neurological examination findings were rare, and 6 had generalized slowing on electroencephalography. Actigraphy and sleep diary showed good sleep maintenance efficiency, but 21 reported poor sleep quality. Heart rate variability was most stable over time in the sleep segment. Dynavision performance was normal, but 41 participants had abnormal ocular torsion. On eye tracking, circular, horizontal ramp, and reading tasks were more likely to be abnormal than other tasks. Most participants had normal hearing, videonystagmography, and rotational chair testing, but computerized dynamic posturography was abnormal in up to 21% of participants. Twenty-two participants had greater than expected white matter changes for age by MRI. Most abnormal findings were dispersed across the population, though a few participants had clusters of abnormalities. Conclusions: Despite our efforts to enroll normal, healthy volunteers, abnormalities on some measures were surprisingly common. Trial Registration: This study was registered at www.clinicaltrials.gov, trial identifier NCT01925963.

Individual Development and Adaptation (IDA): A Life-Span Longitudinal Program Suited for Person-Oriented Research.

In this article, we give a presentation of the longitudinal research program Individual Development and Adaptation (IDA) that can be helpful as a template for researchers considering to launch their own longitudinal studies, and that opens the door to IDA for researchers looking for suitable data to be analyzed within their own project or in collaboration with IDA. We also introduce the holistic-interactionistic theoretical framework of IDA and the associated person-oriented approach - an approach that is especially suited for analyzing the rich IDA data set with its broad coverage of different areas of adjustment and related factors. The paper provides an overview of the essential features of the IDA database, as well as of ongoing and planned IDA research.

Baseline vestibular and auditory findings in a trial of post-concussive syndrome

Previous studies have reported high rates of auditory and vestibular-balance deficits immediately following head injury. This study uses a comprehensive battery of assessments to characterize auditory and vestibular function in 71 U.S. military service members with chronic symptoms following mild traumatic brain injury that did not resolve with traditional interventions. The majority of the study population reported hearing loss (70%) and recent vestibular symptoms (83%). Central auditory deficits were most prevalent, with 58% of participants failing the SCAN3:A screening test and 45% showing abnormal responses on auditory steady-state response testing presented at a suprathreshold intensity. Only 17% of the participants had abnormal hearing (⟩25 dB hearing loss) based on the pure-tone average. Objective vestibular testing supported significant deficits in this population, regardless of whether the participant self-reported active symptoms. Composite score on the Sensory Organization Test was lower than expected from normative data (mean 69.6 ±vestibular tests, vestibulo-ocular reflex, central auditory dysfunction, mild traumatic brain injury, post-concussive symptoms, hearing15.6). High abnormality rates were found in funduscopy torsion (58%), oculomotor assessments (49%), ocular and cervical vestibular evoked myogenic potentials (46% and 33%, respectively), and monothermal calorics (40%). It is recommended that a full peripheral and central auditory, oculomotor, and vestibular-balance evaluation be completed on military service members who have sustained head trauma.

Seletracetam enhances short term depression in vitro.

Seletracetam (SEL), an analog of the antiepileptic drug levetiracetam (LEV), decreases seizure activity in a number of epilepsy models and binds to the synaptic vesicle protein SV2A with a higher affinity than LEV. Experiments were performed to determine if SEL, like LEV, reduces the later EPSPs in long trains of stimuli in a manner dependent upon access to the interior of synaptic vesicles and SV2A binding. When hippocampal slices were incubated in 3-30µM SEL for 3h, but not 30 min, the relative amplitude of the CA1 field excitatory synaptic potentials decreased over the course of a train of high frequency stimuli more than for control slices. This short term depression was frequency and dose dependent and largely disappeared when the spontaneous activity during the loading period was removed by cutting the Schaffer collaterals. The SEL effect was also observed in slices loaded during prolonged stimulation at 1Hz, but not 10Hz. Hippocampal slices loaded with both SEL and FM1-43 to visualize synaptic boutons released the FM1-43 in response to prolonged stimulation much more slowly than control slices during prolonged stimulation. Like LEV, SEL produced a frequency-dependent decrement of synaptic transmission that was dependent upon the drug entering recycling synaptic vesicles and compatible with SV2A binding. Previous observations of SV2A binding affinity correlated with the current effect of SEL and the previously reported effect of LEV on synaptic transmission validate SV2A as an extremely attractive target for future antiepileptic drug development.

Levetiracetam has an activity-dependent effect on inhibitory transmission.

PURPOSE: Previous work has shown that levetiracetam (LEV) binds the vesicular protein SV2A and reduces excitatory neurotransmitter release during trains of high-frequency activity, most likely by accessing its binding site through vesicular endocytosis into excitatory synaptic terminals. Because there are differences in excitatory and inhibitory transmitter release mechanisms, and there are suggestions that neurons differ in their SV2A expression, we were curious whether LEV also reduces inhibitory transmission. METHODS: We used patch-clamp recording from CA1 neurons in rat brain slices to quantify the effects of LEV on inhibitory postsynaptic currents (IPSCs). We were able to elicit pure IPSCs by stimulating inhibitory terminals close to neuronal soma and blocking excitatory postsynaptic currents with specific antagonists. KEY FINDINGS: We found that LEV reduces inhibitory currents in a frequency-dependent manner, with the largest relative effect on the later IPSCs in the highest frequency trains. However, in contrast to excitatory postsynaptic currents (EPSCs), LEV reduced IPSC trains after a briefer, 30 min incubation. When spontaneous activity during incubation was blocked with antagonists of excitatory transmission, LEV no longer reduced IPSCs. If slices were returned to LEV-free artificial cerebrospinal fluid (ACSF) after LEV incubation, but prior to recording, the IPSC reduction failed to appear. However, if synaptic activity was limited by treating with excitatory transmitter antagonists, after the initial LEV exposure, LEV still diminished trains of IPSC. The concentration required to diminish IPSC trains was lower than for EPSCs. SIGNIFICANCE: LEV exerts a qualitatively similar, frequency-dependent effect on both IPSCs and EPSCs. The much shorter latency for IPSC reduction is consistent with the greater levels of spontaneous inhibition in brain slices, supporting the hypothesis that vesicular uptake is necessary for the entry of LEVs into terminals. The vesicular entry of LEV resembles the cell entry pathways for tetanus and botulinum neurotoxins, but is unique for small, neuroactive drugs. Although the reduction of IPSC trains by LEV initially seems counterintuitive for an antiepileptic drug, there are multiple reasons that disruption of γ-aminobutyric acid (GABA) release could ultimately attenuate pathologic discharges.

A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam.

Levetiracetam (LEV) is one of the most commonly prescribed antiepileptic drugs, but its mechanism of action is uncertain. Based on prior information that LEV binds to the vesicular protein synaptic vesicle protein 2A and reduces presynaptic neurotransmitter release, we wanted to more rigorously characterize its effect on transmitter release and explain the requirement for a prolonged incubation period for its full effect to manifest. During whole cell patch recordings from rat hippocampal pyramidal neurons in vitro, we found that LEV decreased synaptic currents in a frequency-dependent manner and reduced the readily releasable pool of vesicles. When we manipulated spontaneous activity and stimulation paradigms, we found that synaptic activity during LEV incubation alters the time at which LEV's effect appears, as well as its magnitude. We believe that synaptic activity and concomitant vesicular release allow LEV to enter recycling vesicles to reach its binding site, synaptic vesicle protein 2A. In support of this hypothesis, a vesicular "load-unload" protocol using hypertonic sucrose in the presence of LEV quickly induced LEV's effect. The effect rapidly disappeared after unloading in the absence of LEV. These findings are compatible with LEV acting at an intravesicular binding site to modulate the release of transmitter and with its most marked effect on rapidly discharging neurons. Our results identify a unique neurobiological explanation for LEV's highly selective antiepileptic effect and suggest that synaptic vesicle proteins might be appropriate targets for the development of other neuroactive drugs.