Faculty Bibliography

OBJECTIVE:The application of transcranial direct current stimulation (tDCS) at home for the treatment of depression and other neuropsychiatric disorders presents both significant opportunities and inherent challenges. Ensuring safety and maintaining high-quality stimulation are paramount for the efficacy and safety of at-home tDCS. This study investigates tDCS quality based on its technical parameters as well as safety of at-home and in-clinic tDCS applications comparing the data from two randomized controlled trials in patients with major depressive disorder. METHODS:We analyzed 229 active stimulation sessions from the HomeDC study (at-home tDCS) and 835 sessions from the DepressionDC study (in-clinic tDCS). Notably, five adverse events (skin lesions) were reported exclusively in the at-home cohort, highlighting the critical need for enhanced safety protocols in unsupervised environments. RESULTS:= .097). The at-home tDCS sessions exhibited higher impedance variability (M = 837, SD = 328) compared to in-clinic sessions (M = 579, SD = 309). Furthermore, at-home tDCS sessions resulting in adverse events (AEs) were associated with significantly higher average impedances than sessions without such issues. CONCLUSION/CONCLUSIONS:The study demonstrates that monitoring the technical parameters of at-home tDCS used in this study is essential. However, it may be not sufficient for ensuring safety and promptly detecting or preventing adverse events. Quality control protocols including digital training and monitoring techniques should be systematically developed and tested for a reliable and safe application of at-home tDCS therapies.

The ability to connect the form and meaning of a concept, known as word retrieval, is fundamental to human communication. While various input modalities could lead to identical word retrieval, the exact neural dynamics supporting this process relevant to daily auditory discourse remain poorly understood. Here, we recorded neurosurgical electrocorticography (ECoG) data from 48 patients and dissociated two key language networks that highly overlap in time and space, critical for word retrieval. Using unsupervised temporal clustering techniques, we found a semantic processing network located in the middle and inferior frontal gyri. This network was distinct from an articulatory planning network in the inferior frontal and precentral gyri, which was invariant to input modalities. Functionally, we confirmed that the semantic processing network encodes word surprisal during sentence perception. These findings elucidate neurophysiological mechanisms underlying the processing of semantic auditory inputs ranging from passive language comprehension to conversational speech.

INTRODUCTION/BACKGROUND:While revascularization rates have improved for mechanical thrombectomy (MT) in acute ischemic stroke, advancements in aspiration pumps have been limited. The ALGO Smart Pump (Von Vascular, Sunrise, FL) is a small on-field, operator-driven pump offering two aspiration modes: Adaptive Pulsatile Aspiration (APA™) Mode and a continuous 'Static' mode. This study evaluates the performance of the ALGO Smart Pump's Static Mode compared to a commercially available aspiration pump. METHODS:Operators performed aspiration thrombectomy in a flow model with ALGO and the Penumbra ENGINE (Penumbra, Alameda, CA) using medium (ID.036-.057") to large (ID.068-.071) bore aspiration catheters. Primary endpoint was complete clot ingestion (CCI), defined as the full ingestion of the clot within the catheter or pump's canister, without any clot at the catheter tip or evidence of embolization to new territories (ENT). Secondary endpoints included first pass recanalization, ENT and total aspiration time. RESULTS:When comparing all catheters, ALGO Smart Pump achieved CCI in 154 of 180 thrombectomies (85.6 %) compared to Penumbra ENGINE achieving CCI in 136 of 180 thrombectomies (75.6 %). The CCI rate between pump types across all catheters was statistically significant (p = 0.008), favoring ALGO pump. There was no difference between pump type on aspiration time. CONCLUSION/CONCLUSIONS:The ALGO Smart Pump may represent an alternative in MT, with potential higher effectiveness compared to existing available aspiration pumps with additional user-friendly benefits including a sterile, smaller, on-field apparatus.

Gliomas are a major cause of cancer-related deaths in adolescents and young adults (AYAs; ages 15-39 years). Different molecular alterations drive gliomas in children and adults, leading to distinct biology and clinical consequences, but the implications of pediatric- versus adult-type alterations in AYAs are unknown. Our population-based analysis of 1,456 clinically and molecularly characterized gliomas in patients aged 0-39 years addresses this gap. Pediatric-type alterations were found in 31% of AYA gliomas and conferred superior outcomes compared to adult-type alterations. AYA low-grade gliomas with specific RAS-MAPK alterations exhibited senescence, tended to arise in different locations and were associated with superior outcomes compared to gliomas in children, suggesting different cellular origins. Hemispheric IDH-mutant, BRAF p.V600E and FGFR-altered gliomas were associated with the risk of malignant transformation, having worse outcomes with increased age. These insights into gliomagenesis may provide a rationale for earlier intervention for certain tumors to disrupt the typical behavior, leading to improved outcomes.

Hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) brain tissue is a complex mix of multiple tau species that are variably phosphorylated. The emerging studies suggest that phosphorylation of specific residues may alter the role of tau. The role of specific pTau species can be explored through protein interactome studies. The aim of this study was to analyse the interactome of tau phosphorylated at T217 (pT217), which biomarker studies suggest is one of the earliest accumulating tau species in AD. pT217 interactors were identified in fresh-frozen human brain tissue from 10 cases of advanced AD using affinity purification-mass spectrometry. The cases included a balanced cohort of APOE ε3/ε3 and ε4/ε4 genotypes (n = 5 each) to explore how apolipoprotein E altered phosphorylated tau interactions. The results were compared to our previous interactome dataset that profiled the interactors of PHF1-enriched tau to determine if individual pTau species have different interactomes. 23 proteins were identified as bona fide pT217 interactors, including known pTau interactor SQSTM1. pT217 enriched tau was phosphorylated at fewer residues compared to PHF1-enriched tau, suggesting an earlier stage of pathology development. Notable pT217 interactors included five subunits of the CTLH E3 ubiquitin ligase (WDR26, ARMC8, GID8, RANBP9, MAEA), which has not previously been linked to AD. In APOE ε3/ε3 cases pT217 significantly interacted with 46 proteins compared to 28 in APOE ε4/ε4 cases, but these proteins were significantly overlapped. CTLH E3 ubiquitin ligase subunits significantly interacted with phosphorylated tau in both APOE genotypes. pT217 interactions with SQSTM1, WDR26 and RANBP9 were validated using co-immunoprecipitation and immunofluorescent microscopy of post-mortem human brain tissue, which showed colocalisation of both protein interactors with tau pathology. Our results report the interactome of pT217 in human Alzheimer's disease brain tissue for the first time and highlight the CTLH E3 ubiquitin ligase complex as a significant novel interactor of pT217 tau.

The loss of maternal UBE3A causes Angelman syndrome whereas its duplication is associated with a heterogeneous neurodevelopmental disorder. Here, we describe two affected brothers who possess a novel UBE3A^L734S variant that is not present in two neurotypical siblings. The UBE3A^L734S variant was confirmed to be maternally inherited, and the affected individuals exhibited early global developmental delay, ongoing learning difficulties, and autistic features. Their phenotypes were inconsistent with Angelman syndrome. Biochemical characterization showed the UBE3A^L734S variant causes a dramatic increase in the activity of the UBE3A enzyme, suggesting that a gain in UBE3A activity is the driver of neurodevelopmental disease. Our observations document an emerging class of neurodevelopmental disorders caused by gain-of-function mutations in UBE3A.

Autoimmune encephalitis (AE), defined by clinical criteria and its frequent association with neural autoantibodies, often manifests with seizures, which usually stop with immunotherapy. However, a subset of encephalitic conditions present with recurrent seizures that are resistant to immunotherapy. Three primary neurological constellations that fall within this subset are discussed in this Perspective: temporal lobe epilepsy with antibodies against glutamic acid decarboxylase, epilepsy in the context of high-risk paraneoplastic antibodies, and epilepsy following adequately treated surface antibody-mediated AE. These entities all share a common mechanism of structural injury and potentially epileptogenic focal neural loss, often induced by cytotoxic T cells. Recently, we have proposed conceptualizing these conditions under the term autoimmune encephalitis-associated epilepsy (AEAE). Here, we discuss the new concept of AEAE as an emerging field of study. We consider the clinical characteristics of patients who should be investigated for AEAE and highlight the need for judicious use of traditional epilepsy therapeutics alongside immunotherapeutic considerations that are of uncertain and incomplete efficacy for this group of disorders. Last, we discuss future efforts needed to diagnose individuals before structural epileptogenesis has superseded inflammation and to develop improved therapeutics that target the specific immunological or functional disturbances in this entity.

This study investigated the potential of combining multiple MR parameters to enhance the characterization of myelin in the mouse brain. We collected ex vivo multiparametric MR data at 7 T from control and Gli1^-/- mice; the latter exhibit enhanced myelination at Postnatal Day 10 (P10) in the corpus callosum and cortex. The MR data included relaxivity, magnetization transfer, and diffusion measurements, each targeting distinct myelin properties. This analysis was followed by and compared to myelin basic protein (MBP) staining of the same samples. Although a majority of the MR parameters included in this study showed significant differences in the corpus callosum between the control and Gli1^-/- mice, only T₂, T₁/T₂, and radial diffusivity (RD) demonstrated a significant correlation with MBP values. Based on data from the corpus callosum, partial least square regression suggested that combining T₂, T₁/T₂, and inhomogeneous magnetization transfer ratio could explain approximately 80% of the variance in the MBP values. Myelin predictions based on these three parameters yielded stronger correlations with the MBP values in the P10 mouse brain corpus callosum than any single MR parameter. In the motor cortex, combining T₂, T₁/T₂, and radial kurtosis could explain over 90% of the variance in the MBP values at P10. This study demonstrates the utility of multiparametric MRI in improving the detection of myelin changes in the mouse brain.

Different theories explain how subjective experience arises from brain activity^1,2. These theories have independently accrued evidence, but have not been directly compared³. Here we present an open science adversarial collaboration directly juxtaposing integrated information theory (IIT)^4,5 and global neuronal workspace theory (GNWT)^6-10 via a theory-neutral consortium^11-13. The theory proponents and the consortium developed and preregistered the experimental design, divergent predictions, expected outcomes and interpretation thereof¹². Human participants (n = 256) viewed suprathreshold stimuli for variable durations while neural activity was measured with functional magnetic resonance imaging, magnetoencephalography and intracranial electroencephalography. We found information about conscious content in visual, ventrotemporal and inferior frontal cortex, with sustained responses in occipital and lateral temporal cortex reflecting stimulus duration, and content-specific synchronization between frontal and early visual areas. These results align with some predictions of IIT and GNWT, while substantially challenging key tenets of both theories. For IIT, a lack of sustained synchronization within the posterior cortex contradicts the claim that network connectivity specifies consciousness. GNWT is challenged by the general lack of ignition at stimulus offset and limited representation of certain conscious dimensions in the prefrontal cortex. These challenges extend to other theories of consciousness that share some of the predictions tested here^14-17. Beyond challenging the theories, we present an alternative approach to advance cognitive neuroscience through principled, theory-driven, collaborative research and highlight the need for a quantitative framework for systematic theory testing and building.