Faculty Bibliography

Differential mRNA translation efficiency (mTE) of codons is important in regulating protein synthesis and cellular states and can change in response to amino acid availability. While the mTE of codons is canonically associated with their corresponding transfer RNA (tRNA) isoacceptors, its regulation by amino acids in mammalian cells remains unexplored. We found that ELAC2, a 3' tRNA maturation endonuclease, decreases the mTE of UC[C/U] serine (Ser) codons in response to Ser limitation. Ablation of ELAC2 restored UC[C/U] mTE but reduced the mTE of AG[U/C] Ser codons. Among the tRNA^Ser isoacceptors, tRNA^Ser(GCU) decreased the most in ELAC2-deficient cells. Unexpectedly, tRNA^Ser(GCU) delivery restored AG[U/C] mTE and reduced UC[C/U] mTE in ELAC2-deficient cells. Last, we deciphered the effects of Ser-sensitive codons on mRNA translation and the human proteome. Our study revealed that in response to Ser limitation, regulation of tRNA^Ser(GCU) levels fine-tune the mTE of UC[C/U] or AG[U/C] Ser-sensitive codons and shapes the proteome.

Understanding consciousness remains a significant challenge in science. What distinguishes conscious beings from unconscious systems, such as organoids, artificial intelligence or other non-sentient entities? Research on consciousness often focuses on identifying brain activity associated with conscious and non-conscious states, primarily in neurotypical human adults. However, this approach is limited in scope when applied to entities with developmental or evolutionary trajectories different from our own. How do we investigate consciousness in infants, whose brains are still maturing or in non-human animals, shaped by diverse ecological and evolutionary pressures? This opinion piece encourages consciousness studies to adopt a neuroethological perspective, drawing on Tinbergen's framework for studying behaviour. By examining the (1) mechanisms, (2) development, (3) adaptive functions and (4) evolutionary origins of consciousness, we can move beyond a human-centric focus to explore its diversity across life forms. Most investigators now accept that consciousness is not confined to humans alone but that some other animals have it, and it is a continuum shaped by evolutionary pressures. By adopting this broader approach, consciousness studies can better investigate and understand consciousness in its various forms and contexts, with significant scientific, ethical and societal implications.This article is part of the theme issue 'Evolutionary functions of consciousness'.

Chronic progressive external ophthalmoplegia (CPEO), a genetic syndrome characterized by slowly progressive paresis of extraocular muscles, is often due to single large-scale deletions of the mitochondrial genome (mtDNA). Owing to heteroplasmy, mtDNA variants are often not uniformly expressed across tissues. This genetic variability affects clinical presentation and diagnostic testing. We report a case of a 34-year-old woman who presented with symptoms suspicious for a genetic myopathy: chronic asymmetric ptosis, slowly progressive asymmetric weakness, and external ophthalmoplegia. After initial nondiagnostic peripheral genetic testing, whole-exome and mitochondrial genome sequencing of muscle revealed a single large-scale mtDNA deletion, consistent with a diagnosis of mtDNA deletion-associated CPEO. Of interest, electrophysiologic studies showed myotonia in select muscles, a rarely reported finding. We discuss the clinical presentation and diagnostic approach in suspected CPEO, with an emphasis on common pitfalls in genetic testing for mitochondrial myopathies and the need for appropriate tissue and genetic testing modality selection.

IntroductionTraumatic intracranial aneurysms (TICAs) are rare, potentially fatal complications of traumatic brain injury (TBI) or iatrogenic insult. Often forming as pseudoaneurysms, TICAs result from direct arterial wall disruption. Their unique pathophysiology, delayed presentation, and high rupture risk pose diagnostic and therapeutic challenges. This review synthesizes current evidence on TICA pathogenesis, diagnosis, and treatment, with particular emphasis on the evolving role of angiographic diagnosis and endovascular intervention.MethodsA structured PubMed search was conducted, supplemented by manual citation screening. All study designs were considered with no date restrictions. Articles were included if they reported traumatic intracranial aneurysms in patients of any age and discussed diagnostic or therapeutic approaches. Data were synthesized thematically across epidemiology, pathophysiology, imaging, treatment (endovascular and surgical), and surveillance.ResultsTICAs typically arise at sites of direct injury or at fixed vessel segments (e.g., distal ACA, peripheral MCA, cavernous/supraclinoid ICA). Their delayed and subtle appearance necessitates high clinical suspicion and serial imaging. Digital subtraction angiography is the diagnostic gold standard, though immediate or early post-trauma studies may be negative. Endovascular techniques, particularly flow diversion, are increasingly favored for their minimally invasive nature and ability to achieve parent vessel reconstruction. Open surgery retains a role for lesions complicated by mass effect, intracerebral hematoma, or anatomy unsuitable for endovascular repair. Outcomes vary with aneurysm location, treatment timing, modality, and TBI severity.ConclusionTICAs represent a distinct, high-risk entity requiring timely diagnosis and individualized, multidisciplinary management. Endovascular approaches are increasingly favored. Further research is needed to guide optimal surveillance imaging protocols.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). In CTE, hyperphosphorylated tau (p-tau) aggregates are found in neurons at the depth of cortical sulci close to the gray matter/white matter (GM/WM) boundary. To date, CTE can only be diagnosed postmortem by neuropathological examination. Traumatic encephalopathy syndrome (TES) is the clinical syndrome purported to be associated with CTE pathology. The aim of this study is to investigate microstructural properties at the GM/WM boundary in individuals with a history of exposure to RHI and clinical features of CTE (i.e., TES). Diffusion magnetic resonance imaging (dMRI), TES diagnoses, and cerebrospinal fluid (CSF) biomarkers were acquired from 165 male former American football players (age: 57.29 ± 8.23 years) from the DIAGNOSE CTE Research Project, a multicenter, observational cohort study. Fractional anisotropy (FA) was measured at the GM/WM boundary of the whole brain. In addition, a widely used method (tract-based spatial statistics [TBSS]) was applied to measure FA of central WM. We used analyses of covariance to test associations between FA and TES. Furthermore, we used linear regressions to test associations between FA and nine CSF biomarkers (i.e., p-tau-181, -217, -231, total tau, amyloid β [Aβ]_1-40, Aβ_1-42, glial fibrillary acidic protein [GFAP], neurofilament light [NfL], and soluble triggering receptor expressed on myeloid cells-2 [sTREM2]). We report an association between higher FA at the GM/WM boundary and higher levels of certainty for CTE pathology (F(1, 147) = 5.781, 95% confidence interval (CI) = 0.0003-0.003, p = 0.035) as well as neurobehavioral dysregulation (F(1, 148) = 7.559, 95% CI = 0.001-0.009, p = 0.020), and functional dependence/dementia (F(1, 148) = 5.046, 95% CI = 0.0004-0.006, p = 0.039). In addition, we report an association between higher FA at the GM/WM boundary and higher CSF p-tau-181 (β = 0.272, 95% CI = 0.078-0.466, p = 0.029) and p-tau-217 (β = 0.295, 95% CI = 0.102-0.488, p = 0.027). FA of the central WM was not associated with TES diagnoses. Taken together, these findings suggest that dMRI at the GM/WM boundary could be used to investigate microstructural alterations suggestive of tau pathology-associated neurodegeneration in individuals with TES, the clinical presentation of CTE. Future studies are needed to validate this approach and to identify clinically useful cutoff values for dMRI metrics.

Epilepsy in the Child-Bearing Ages through Menopause is an international consortium of clinicians dedicated to improving the health of women with epilepsy across the lifespan. Epilepsy in the Child-Bearing Ages through Menopause's Adolescent and Young Adult Committee addresses quality of care for female youth with epilepsy. The Committee developed a literature review and expert opinion guidance for child neurologists on performing optimal counseling about epilepsy and reproductive health for female youth with epilepsy. To do so, we identified and voted on key topics essential for this counseling, then conducted comprehensive literature reviews for each topic, iteratively developed key statements about counseling content and style for each topic and voted on final content for inclusion. The included topics were teratogenesis, folic acid supplementation, pregnancy and fertility, contraception, heritability of epilepsy, menstrual and hormonal disorders, catamenial epilepsy, and taking a sexual history. This review provides a clear, novel framework for pediatric neurologists to counsel adolescent and young adult women with epilepsy about their reproductive health, supporting improvement in practices recommended by professional organization such as the American Academy of Neurology and Child Neurology Foundation.

OBJECTIVE:People with migraine have a higher prevalence and severity of insomnia. We examined the relationship between insomnia severity and migraine-related disability (MIDAS) and migraine-specific quality of life (MSQv2.1). METHODS:We conducted a post-hoc analysis of a pilot randomized controlled study assessing the RELAXaHEAD application in those with insomnia and comorbid migraine. Descriptive statistics were used to summarize demographic and clinical characteristics. Linear mixed model analysis was conducted to evaluate Insomnia Severity Index (ISI) as a predictor of each MSQv2.1 domain and MIDAS. RESULTS:Forty-two participants completed baseline and at least one follow-up survey. Mean age was 43.8 years (SD 12.6) and the majority (85.7%) were female. Most participants (81.0%) had severe migraine-related disability (median baseline MIDAS, 32 (IQR 52)). Over half (54.8%) of participants had moderate clinical insomnia (mean baseline ISI, 18.5 (SD 4.6)). Baseline median MSQv2.1 scores were 44.3 (IQR 31.4) for Role Function-Restrictive (RFR), 65.0 (IQR 45.0) for Role Function-Preventive (RFP), and 46.7 (IQR 46.7) for Emotional Function (EF). The effect of ISI on MIDAS was statistically significant (rate ratio (RR)=1.10, p < 0.05, 95%CI [1.028, 1.171], meaning each one-point increase in ISI was associated with a 10% higher MIDAS score). Additionally, a 1-point increase in ISI was associated with a decrease of 1.2 points in MSQ-RFR (B=-1.205, p = 0.001),1.0 point in MSQ-RFP (B=-0.981, p = 0.020), and 1.4 points in MSQ-EF (B=-1.66, p = 0.001). CONCLUSIONS:Our study revealed significant associations between insomnia severity and migraine-related disability and quality of life, highlighting the importance of prevention and sleep intervention for patients with migraine.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Trans-sonolucent cranioplasty ultrasonography (TCUS) has been explored as a noninvasive tool for evaluating superficial temporal artery (STA)-middle cerebral artery (MCA) bypass patency. Previous research has focused on early postoperative feasibility. Data on its long-term utility and correlation with formal angiography remain scarce. We aimed to evaluate TCUS' role in postoperative STA-MCA bypass graft monitoring and its concordance with formal angiography. METHODS:This retrospective study included 46 consecutive direct STA-MCA anastomoses in 40 patients (March 2021-May 2024), all with sonolucent polymethyl methacrylate cranioplasty. Patient records were reviewed for demographics, disease and surgical characteristics, and outcomes. Postoperative TCUS was performed outpatient to monitor anastomotic patency. Formal follow-up angiography was also conducted, and radiographic data were reviewed for graft patency assessment and qualitative correlation with TCUS. RESULTS:Follow-up angiography was performed for 41 of 46 anastomoses (digital subtraction angiography, n = 34; computed tomography angiography, n = 4; magnetic resonance angiography, n = 3) at a median of 1.1 years, demonstrating 97.6% patency (40/41). Outpatient TCUS was performed in 32 of 46 bypasses (69.6%) with 100% patency at first scan (median 28.5 days). A second TCUS (n = 19, 41.3%) at a median of 8.4 months (3.9-13.6 months) showed robust flow in 94.7% of cases. One bypass had asymptomatic slow flow with a narrowed anastomosis, and another showed a severely stenosed STA correlating with later digital subtraction angiography. In the broader cohort, third (n = 5, median 1.2 years) and fourth (n = 1, 1.4 years) TCUS assessments demonstrated 100% patency. Among bypasses undergoing both TCUS and angiography (n = 31, 67.4%), findings were concordant in all cases. CONCLUSION/CONCLUSIONS:TCUS demonstrated complete agreement with formal angiography in assessing bypass patency, supporting TCUS as a reliable, noninvasive monitoring tool. Future research should explore quantitative TCUS flow measurements and their relationship to intraoperative flow and long-term graft remodeling.

BACKGROUND AND PURPOSE/OBJECTIVE:Mild traumatic brain injury (MTBI) is a common public health concern with potential long-term consequences, yet its underlying pathophysiology remains poorly understood. Clinical heterogeneity of individuals having diverse extent and array of symptoms has impeded the identification of reliable imaging biomarkers. Traditional group-level analyses may obscure biologically meaningful subtypes. This study uses latent class analysis (LCA) to classify MTBI subjects into symptom-defined subgroups and examines corresponding WM microstructural alterations using advanced diffusion MRI. MATERIALS AND METHODS/METHODS:Sixty-one MTBI patients within one month of injury completed the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). LCA was used to identify symptom-based subgroups. Of these, 54 MTBI patients underwent multi-shell diffusion MRI and were compared with 31 controls. WM changes were assessed across subgroups using ROI-based diffusion analyses. RESULTS:LCA identified three distinct MTBI subgroups: those with minimal to no symptoms (31.5%), the cognitively symptomatic (38.9%), and the more globally symptomatic (29.6%). The three groups were associated with different patterns of diffusion MRI differences compared with controls. The cognitively symptomatic subgroup showed predominantly central WM differences, the globally symptomatic subgroup exhibited more peripheral differences with right-hemisphere predominance and sparing the corpus callosum, marked by reduced fractional anisotropy and kurtosis and elevated diffusivities, the less symptomatic subgroup demonstrated focal differences in the callosal genu, with increased fractional anisotropy and kurtosis and decreased diffusivity measures. CONCLUSIONS:MTBI comprises biologically distinct phenotypes with subgroup-specific WM signatures on diffusion MRI. Even individuals with minimal to no symptoms show WM differences compared with controls, underscoring the limitations of symptom reporting alone. Integrating symptom-based classification with advanced diffusion MRI may improve diagnostic precision to help risk stratification and provide insight into mechanisms of injury. ABBREVIATIONS/BACKGROUND:LCA = latent class analysis; MTBI = mild traumatic brain injury; RPQ = Rivermead post-concussion symptoms questionnaire.

OBJECTIVE:To assess real-world effectiveness of switching disease-modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity. METHODS:Of 2615 pediatric-onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders. RESULTS:A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety-three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52-1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20-0.57; rate ratio: 0.38, 95% CI = 0.21-0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09-0.37; rate ratio: 0.21, 95% CI = 0.10-0.44) (p < 0.001). Adjusted number needed to treat in person-years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03-8.69) and infusion over injectable 1.43 (95% CI = 1.00-3.88). INTERPRETATION/CONCLUSIONS:Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long-term safety data are required. ANN NEUROL 2025.