WashU weekly Neuroscience publications: January 26, 2025

Caregiver-child affective dynamics during preschool predict preadolescent suicidal thoughts and behaviors
(2025) Personality and Individual Differences, 237, art. no. 113048, . 

Quiñones-Camacho, L.E.^a , Gilbert, K.E.^b , Hennefield, L.^b , Hoyniak, C.^b , Thompson, R.J.^c , Tillman, R.^b , Barch, D.M.^b d , Luby, J.L.^b , Whalen, D.J.^b

^a Department of Educational Psychology, University of Texas at Austin, United States
^b Department of Psychiatry, Washington University in St. Louis, United States
^c Department of Psychological & Brain Sciences, Washington University in St. Louis, United States
^d Department of Radiology, Washington University in St. Louis, United States

Abstract
While previous research highlights the significance of parenting and family dynamics in adolescent suicidal thoughts and behavior (STBs), there has been a limited focus on how early caregiver-child affective patterns may influence preadolescent STBs. This is important given the rise of STBs in preadolescents. This study employed a dynamic systems approach to explore the role of in-the-moment affective dynamics in caregiver-preschooler interactions on STB risk, focusing on affective variability and shared (positive, neutral, and negative) affect as risk factors for preschool and preadolescent STBs. Children (N = 135, X with a preschool depression) and their caregivers participated in a longitudinal study; STBs were assessed using clinical diagnostic interviews at preschool (ages 3–7 years) and in preadolescence (ages 8–12 years). Two groups were created to characterize history of STBs across the two periods: no/remitted-STBs and emerged/persistent STBs. During the preschool assessment, caregiver-child dyads completed two interaction tasks coded offline. State Space Grids (SSGs) were used to derive measures of dyadic affective flexibility and shared affect. Caregiver-preschooler affective dynamics were examined as predictors of STB history. Greater affective flexibility, less shared positive affect, and more shared neutral affect predicted a higher likelihood of preadolescent STBs. Follow-up analyses with all dyadic variables revealed the unique contributions of affective flexibility and less positive shared affect predicting STB status even when controlling for child psychopathology and caregiver depression. Findings suggest affective dynamics within the caregiver-preschooler relationship are associated with later STBs, suggesting a potential dyadic risk marker for poor relationship quality in this population. © 2025 Elsevier Ltd

Author Keywords
Caregiver-child interaction;  Children;  Longitudinal;  State space grids;  Suicidal ideation

Document Type: Article
Publication Stage: Final
Source: Scopus

Chronic traumatic brain injury induces neurodegeneration, neuroinflammation, and cognitive deficits in a T cell-dependent manner
(2025) Brain Research, 1850, art. no. 149446, . 

Ayerra, L.^c d , Shumilov, K.^b , Ni, A.^a , Aymerich, M.S.^c d , Friess, S.H.^a , Celorrio, M.^a

^a Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States
^c Department of Biochemistry and Genetics, University of Navarre, Pamplona, Spain
^d Gene Therapy for Neurological Diseases, CIMA-University of Navarre, Pamplona, Spain

Abstract
Traumatic brain injury (TBI) can lead to chronic neuroinflammation, and neurodegeneration associated with long-term cognitive deficits. Following TBI, the acute neuroinflammatory response involves microglial activation and the release of proinflammatory cytokines and chemokines which induce the recruitment of peripheral immune cells such as monocytes and ultimately T cells. Persistent innate and adaptive immune cell responses can lead to chronic neurodegeneration and functional deficits. Therefore, understanding the dynamic interaction between chronic immune responses and TBI-related pathogenesis and progression of the disease is crucial. We hypothesized that T cells have an essential role in TBI severity and recovery. We used generic T cell deletion mice (TCRβ−/−δ−/−) vs Wild-type mice that underwent controlled cortical impact assessing behavioral, histological, and immune system response outcomes at 3 months post-TBI. The absence of T cells reduced neurodegeneration and was associated with improved neurological outcomes 3 months post-injury. Furthermore, the absence of T cells enhanced an anti-inflammatory phenotype in peripheral myeloid cells in the injured brain. Collectively, these data indicate that T cells promote persistent neuropathology and functional impairments chronically after TBI. © 2025

Author Keywords
and Fear Memory;  Monocytes;  Neurodegeneration;  T cells;  Traumatic brain injury

Document Type: Article
Publication Stage: Final
Source: Scopus

Differential impact of lymphatic outflow pathways on cerebrospinal fluid homeostasis
(2025) The Journal of Experimental Medicine, 222 (2), . 

Papadopoulos, Z.^a b c , Smyth, L.C.D.^a b , Smirnov, I.^a b , Gibson, D.A.^a b , Herz, J.^a b , Kipnis, J.^a b c

^a Brain Immunology and Glia (BIG) Center, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^c Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Dysfunctional lymphatic drainage from the central nervous system (CNS) has been linked to neuroinflammatory and neurodegenerative disorders, but our understanding of the lymphatic contribution to CNS fluid autoregulation remains limited. Here, we studied forces that drive the outflow of the cerebrospinal fluid (CSF) into the deep and superficial cervical lymph nodes (dcLN and scLN) and tested how the blockade of lymphatic networks affects CNS fluid homeostasis. Outflow to the dcLN occurred spontaneously in the absence of lymphatic pumping and was coupled to intracranial pressure (ICP), whereas scLN drainage was driven by pumping. Impaired dcLN drainage led to elevated CSF outflow resistance and delayed CSF-to-blood efflux despite the recruitment of the nasal-to-scLN pathway. Fluid regulation was better compensated after scLN obstruction. The dcLN pathway exhibited steady, consistent drainage across conditions, while the nasal-to-scLN pathway was dynamically activated to mitigate perturbances. These findings highlight the complex physiology of CSF homeostasis and lay the groundwork for future studies aimed at assessing and modulating CNS lymphatic function. © 2025 Papadopoulos et al.

Document Type: Article
Publication Stage: Final
Source: Scopus

Real world experience with cladribine tablets for multiple sclerosis at four academic multiple sclerosis centers
(2025) Multiple Sclerosis and Related Disorders, 94, art. no. 106272, . 

Conway, D.S.^a , Nicholas, J.A.^b , Thompson, N.R.^c , Mowry, E.M.^d , Naismith, R.T.^e

^a Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, United States
^b OhioHealth Multiple Sclerosis Center, Riverside Methodist Hospital, Columbus, OH, United States
^c Department of Quantitative Health Sciences, Center for Outcomes Research and Evaluation, Cleveland Clinic, Cleveland, OH, United States
^d The Johns Hopkins Multiple Sclerosis Center, Johns Hopkins University, Baltimore, MD, United States
^e John L Trotter Multiple Sclerosis Center, Washington University, St. Louis, MO, United States

Abstract
Background: Cladribine tablets (CladT) are a multiple sclerosis (MS) disease-modifying therapy (DMT) with safety and efficacy established in the CLARITY trial and extension. A better understanding of the role of CladT in real-world populations is needed, including the clinical and radiographic trajectories of persons with MS (PwMS) treated with CladT and how CladT compares to other MS DMTs. Methods: PwMS receiving CladT at 4 tertiary MS centers were identified and characterized. A validated electronic neuroperformance test adapted from the Multiple Sclerosis Functional Composite was administered at each visit, which provides z-scores for the Walking Speed Test (zWST), Manual Dexterity Test (zMDT), and the Processing Speed Test (zPST). The Patient Determined Disease Steps (PDDS) and NeuroQoL patient-reported outcomes are also administered. Regression modeling using generalized estimating equations was used to compare neuroperformance testing and brain MRI metrics at 6-, 12-, 18-, and 24-months to baseline. In a comparative effectiveness analysis, PwMS receiving other DMTs were propensity matched to CladT treated PwMS on variables including age, race, and disease duration. Outcomes were then compared at the same time points. Results: We identified 117 PwMS treated with CladT who had an average age of 46.7 years (SD=10.5) and average disease duration of 13.2 years (SD=5.6). Relative to baseline, there were no significant differences in zMDT and zPST at any time point. There were significant increases in zWST over the study duration, suggesting improvement in walking speed, and PDDS scores remained stable during the study period. The odds of new T2 lesions relative to baseline were lower at all time points, but this did not reach significance. There were significantly lower odds of gadolinium enhancing (GdE) lesions at 6- and 18- months relative to baseline. Twelve PwMS (11 %) started a post-CladT DMT. We matched 476 PwMS on alternative DMT (most commonly ocrelizumab, n=280, 58.8 %) to CladT-treated PwMS. zWST scores were significantly better among those receiving other CladT at 12-, 18-, and 24 months, and NeuroQoL fatigue scores also favored the CladT-treated group. Odds of new T2 and GdE lesions were higher among those receiving CladT initially, but the disparity was no longer evident at 24-months (p=0.77 and p=0.55 respectively). Conclusion: Real-world data for PwMS receiving CladT suggest it is prescribed to older patients with longer disease durations than in the pivotal trials. The pre-post analysis and the comparative effectiveness analysis suggested good performance of CladT in this broader population. There may be a delayed effect of CladT on radiographic outcomes relative to other DMTs. © 2025

Author Keywords
Cladribine tablets;  Comparative effectiveness;  Disease-modifying therapy;  Multiple sclerosis

Document Type: Article
Publication Stage: Final
Source: Scopus

Cerebrospinal fluid biomarkers as predictors of multiple sclerosis severity
(2025) Multiple Sclerosis and Related Disorders, 94, art. no. 106268, . 

Tolentino, M.^a , Pace, F.^a , Perantie, D.C.^a , Mikesell, R.^a , Huecker, J.^b , Chahin, S.^a , Ghezzi, L.^a , Piccio, L.^a , Cross, A.H.^a

^a Department of Neurology, School of Medicine, Washington University in St. Louis, 660 South Euclid Avenue, St Louis, MO 63110, United States
^b Center for Biostatistics and Data Science, School of Medicine, Washington University in St. Louis, 660 South Euclid Avenue, St Louis, MO 63110, United States

Abstract
Background: Prognostic biomarkers at multiple sclerosis (MS) onset to predict disease severity may help guide initial therapy selection for people with MS. Over 20 disease-modifying treatments (DMTs) of varying levels of risk and efficacy now exist. The ability to predict MS severity would help to identify those patients at higher risk where a highly effective, but potentially risky, therapy would be optimal. The goal of this project was to determine if cerebrospinal fluid (CSF) soluble markers obtained near time of diagnosis can predict disease severity in people with relapsing remitting MS (RRMS). Methods: We identified 42 RRMS subjects with 4 or more years of clinical follow-up at our center, 8 subjects with other inflammatory neurological diseases (OIND), and 4 subjects with non-inflammatory neurological diseases (NIND) who had donated CSF samples collected for disease diagnosis. This study evaluated soluble CSF biomarkers chosen to reflect neuroinflammation (chemokine ligand 13 – CXCL13), microglia activity (soluble triggering receptor expressed on myeloid cells 2 – sTREM2), demyelination (myelin basic protein –MBP), axon injury and loss (neurofilament light, heavy, and intermediate chains – NFL, NFH, internexin-alpha – INT-α) and neuronal loss (parvalbumin – PVALB) to determine whether any of these CSF factors might predict future MS disease severity. The main outcome measure was MS Severity Score (MSSS), which takes into account disability accumulation (expanded disability status scale – EDSS) and duration of disease. EDSS at last clinical visit was a secondary outcome measure. Univariate and multivariable regression models were used for analysis. Spearman correlations were performed to evaluate correlation between laboratory and clinical variables. Results: Forty-two RRMS patients with mean 9.4 years follow-up since lumbar puncture (LP) contributed data. Higher NFH, NFL, and sTREM2 each predicted worse MSSS using both univariate and multivariable regression models. Older age at the time of LP predicted worse MSSS both in the univariate and multivariable models. NFL correlated with NFH, and both were positively correlated with sTREM2 and CXCL13. In the combined OIND and NIND comparator group, NFH correlated with both NFL and CXCL13. Conclusion: These data support that CSF sTREM2, NFH, and NFL are predictors of MSSS, a measure of MS disease aggressiveness. This study adds to a growing literature implicating microglial activity and axonal injury in MS progression, starting from early stages of the disease. © 2025

Author Keywords
Biomarkers: cerebrospinal fluid;  Neurofilament heavy chain;  Neurofilament light chain;  Soluble TREM2

Document Type: Article
Publication Stage: Final
Source: Scopus

Momentary savoring in daily life in an adult life-span sample
(2025) Emotion (Washington, D.C.), 25 (1), pp. 93-101. Cited 1 time.

Growney, C.M.^a , Carstensen, L.L.^a , English, T.^b

^a Department of Psychology, Stanford University
^b Department of Psychological and Brain Sciences, Washington University in St. Louis

Abstract
Savoring moments can foster well-being. Older adults are theorized to prioritize emotional well-being in daily life, which directs their attention to positive aspects of life. In this study, with data collected from 2018 to 2021, 285 adults aged 25-85 completed an experience sampling procedure (six times a day for 10 days) where they reported their experienced emotions, whether they were savoring the moment, and how close they felt to their most recent social partner. They also completed a trait-level questionnaire on psychological well-being. Across the age range, individuals were more likely to savor moments when they were with close social partners. Older people were more likely than younger people to report savoring when experiencing high levels of positive affect. The tendency to savor was also tied to psychological well-being among individuals independent of their age. Findings highlight the relational aspect of savoring in daily contexts and suggest that savoring may contribute to well-being, helping to account for age advantages in well-being. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Document Type: Article
Publication Stage: Final
Source: Scopus

Successful of autologous hematopoietic stem cell mobilization with plerixafor combined with G-CSF in pediatric neuroblastoma patients, a single center experience
(2025) Transfusion and Apheresis Science, 64 (1), art. no. 104067, . 

Jafari, L.^a , Hematyar, F.^a , Karamlou, Y.^b , Alipour, N.^c , Mohseni, R.^a , Jafari, F.^a , Nikfetrat, Z.^a , Behfar, M.^a , Hamidieh, A.A.^a

^a Pediatric Cell and Gene Therapy Research Centre, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
^b Center for Gene and Cell Therapy, Washington University of St. Louis, Bone Marrow Transplantation of Washington DC, United States
^c Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract
Background: Neuroblastoma (NB) is the most common extracranial solid tumor in pediatric. In highrisk NB patients, the 5-year overall survival rate (OS) remains a stark < 50 % with conventional therapies. Autologous hematopoietic stem cell transplantation with high dose chemotherapies was used in poor prognosis and high-risk patients.Today, Plerixafor is used to increase stem cells mobilization in patients who are candidates for autologous transplantation. Objective: This study examined safety and efficacy Plerixafor is administered as a subcutaneous injection in pediatric NB patients for stem cell mobilization Study Design: A cohort of 19 pediatric neuroblastoma (NB) patients underwent autologous hematopoietic stem cell transplantation (HSCT) between February 2017 and April 2019, receiving G-CSF mobilization only. Subsequently, 37 NB patients underwent HSCT between December 2019 and October 2023, receiving both G-CSF and plerixafor for mobilization (auto-HSCT). Results: The final product CD34 cell dose /kg was evidently higher in combination group at 5.363 ± 4.243 vs. G-CSF group at 2.827 ± 3.586 × 106(P value= 0.001). Neutrophils and platelet engraftment were occurred sooner in combination group compared with G-CSF group. The 1-year overall survival (OS) rate for the G-CSF and G-CSF-and-plerixafor combination group was 70.8 % and 63.3 %, respectively (P = 0.874). No statistically significant difference in OS or disease-free survival (DFS) was observed between the two treatment groups. Conclusion: The results show that plerixafor may be safe and effective in NB pediatric patients in routine clinical practice. It was well tolerated in NB patients and no specific side effects were observed. It was not associated with improved survival. © 2025

Author Keywords
Autologous Stem Cell Transplantation;  Neuroblastoma;  Plerixafor;  Stem Cell Mobilization

Document Type: Article
Publication Stage: Final
Source: Scopus

Gene therapy ameliorates bowel dysmotility and enteric neuron degeneration and extends survival in lysosomal storage disorder mouse models
(2025) Science Translational Medicine, 17 (781), art. no. eadj1445, . 

Ziółkowska, E.A.^a , Jansen, M.J.^a , Williams, L.L.^a , Wang, S.H.^a , Eultgen, E.M.^a , Takahashi, K.^a , Le, S.Q.^a , Nelvagal, H.R.^a , Sharma, J.^a , Sardiello, M.^a , DeBosch, B.J.^a , Dickson, P.I.^a b , Anderson, J.B.^c , Sax, S.E.^c , Wright, C.M.^c , Bradley, R.P.^c , Whiteman, I.T.^d e , Makita, T.^f , Grider, J.R.^g h , Sands, M.S.^b i , Heuckeroth, R.O.^c , Cooper, J.D.^a b j

^a Department of Pediatrics, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
^b Department of Genetics, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
^c Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, United States
^d Batten Disease Support, Research and Advocacy Foundation (US), P.O. Box 30049, Gahanna, OH 43230, United States
^e Batten Disease Support and Research Association (Australia), 74 McLachlan Avenue, Shelly BeachNSW 2261, Australia
^f Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, United States
^g Department of Physiology and Biophysics, Division of Gastroenterology, VCU Program in Enteric Neuromuscular Sciences (VPENS), Virginia Commonwealth University, Richmond, VA 23298, United States
^h Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States
ⁱ Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
^j Department of Neurology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States

Abstract
Children with neurodegenerative disease often have debilitating gastrointestinal symptoms. We hypothesized that this may be due at least in part to underappreciated degeneration of neurons in the enteric nervous system (ENS), the master regulator of bowel function. To test this hypothesis, we evaluated mouse models of neuronal ceroid lipofuscinosis type 1 and 2 (CLN1 and CLN2 disease, respectively), neurodegenerative lysosomal storage disorders caused by deficiencies in palmitoyl protein thioesterase-1 and tripeptidyl peptidase-1, respectively. Both mouse lines displayed slow bowel transit in vivo that worsened with age. Although the ENS appeared to develop normally in these mice, there was a progressive and profound loss of myenteric plexus neurons accompanied by changes in enteric glia in adult mice. Similar pathology was evident in colon autopsy material from a child with CLN1 disease. Neonatal administration of adeno-associated virus–mediated gene therapy prevented bowel transit defects, ameliorated loss of enteric neurons, and extended survival in mice. Treatment after weaning was less effective than treating neonatally but still extended the lifespan of CLN1 disease mice. These data provide proof-of-principle evidence of ENS degeneration in two lysosomal storage diseases and suggest that gene therapy can ameliorate ENS disease, also improving survival. Copyright © 2025 The Authors, some rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy
(2025) Science Translational Medicine, 17 (781), art. no. eadk3690, . 

Brandao, W.^a , Jain, N.^b c d , Yin, Z.^a e , Kleemann, K.L.^a f , Carpenter, M.^a , Bao, X.^b c d , Serrano, J.R.^b c d , Tycksen, E.^g , Durao, A.^a , Barry, J.-L.^a , Baufeld, C.^a , Guneykaya, D.^a , Zhang, X.^a , Litvinchuk, A.^b c d , Jiang, H.^b c d , Rosenzweig, N.^a , Pitts, K.M.^a e , Aronchik, M.^a , Yahya, T.^a , Cao, T.^a , Takahashi, M.K.^a h , Krishnan, R.^a , Davtyan, H.ⁱ , Ulrich, J.D.^b c d , Blurton-Jones, M.ⁱ , Ilin, I.^j , Weiner, H.L.^a k , Holtzman, D.M.^b c d , Butovsky, O.^a k

^a department of neurology, Brigham and Women’s hospital, harvard Medical School, Boston, Ma, United States
^b department of neurology, Washington University School of Medicine, Mo, St. louis, United States
^c hope center for neurological disorders, Washington University School of Medicine, Mo, St. louis, United States
^d Knight alzheimer’s disease research center, Washington University School of Medicine, Mo, St. louis, United States
^e department of ophthalmology, Massachusetts eye and ear infirmary, harvard Medical School, Boston, Ma, United States
^f institute for clinical chemistry and clinical Pharmacology, University hospital Bonn, Bonn, Germany
^g Mcdonnell Genome institute, Genome Technology access center, Washington University School of Medicine, Mo, St. louis, United States
^h Faculty of Medicine, University of São Paulo (USP), São Paulo, Brazil
ⁱ department of neurobiology and Behavior, University of california, Irvine, CA, United States
^j General Biophysics llc, Boston, Ma, United States
^k Gene lay institute of immunology and inflammation, Brigham and Women’s hospital, Mass General hospital, harvard Medical School, Boston, Ma, United States

Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre–neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD. copyright © 2025 The authors, some rights reserved;

Document Type: Article
Publication Stage: Final
Source: Scopus

Engaging dystonia networks with subthalamic stimulation
(2025) Proceedings of the National Academy of Sciences of the United States of America, 122 (2), art. no. e2417617122, . 

Butenko, K.^a , Neudorfer, C.^a b , Dembek, T.A.^c , Hollunder, B.^d e f , Meyer, G.M.^a , Li, N.^d , Oxenford, S.^d , Bahners, B.H.^a g h , Al-Fatly, B.^d , Lofredi, R.^d , Gordon, E.M.ⁱ , Dosenbach, N.U.F.^i j k , Ganos, C.^l , Hallett, M.^m , Jinnah, H.A.ⁿ , Starr, P.A.^o , Ostrem, J.L.^p , Wu, Y.^q , Zhang, C.^r , Fox, M.D.^a , Horn, A.^a b d e

^a Center for Brain Circuit Therapeutics, Department of Neurology, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States
^b Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
^c Department of Neurology, Faculty of Medicine, University of Cologne, Cologne, 50937, Germany
^d Movement Disorders and Neuromodulation Unit, Department of Neurology, Charité—Universitätsmedizin Berlin, Berlin, 10117, Germany
^e Einstein Center for Neurosciences Berlin, Charité—Universitätsmedizin Berlin, Berlin, 10117, Germany
^f Berlin School of Mind and Brain, Humboldt—Universität zu Berlin, Berlin, 10117, Germany
^g Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, 40225, Germany
^h Department of Neurology, Center for Movement Disorders and Neuromodulation, Medical Faculty University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, 40225, Germany
ⁱ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^j Department of Neurology, Washington University School of Medicine, St. Louis, MO 63108, United States
^k Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^l Movement Disorder Clinic, Edmond J. Safra Program in Parkinson’s Disease, Division of Neurology, University of Toronto, Toronto Western Hospital, Toronto, ON M5T 2S6, Canada
^m Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, United States
ⁿ Department of Neurology, Emory University, Atlanta, GA 30322, United States
^o Department of Neurological Surgery, University of California, San Francisco, CA 94143, United States
^p Movement Disorders and Neuromodulation Centre, Department of Neurology, University of California, San Francisco, CA 94143, United States
^q Department of Neurology &, Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
^r Department of Neurosurgery, Rujin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China

Abstract
Deep brain stimulation is an efficacious treatment for dystonia. While the internal pallidum serves as the primary target, recently, stimulation of the subthalamic nucleus (STN) has been investigated. However, optimal targeting within this structure and its surroundings have not been studied in depth. Indeed, historical targets that have been used for surgical treatment of dystonia are directly adjacent to the STN. Further, multiple types of dystonia exist, and outcomes are variable, suggesting that not all types would profit maximally from the same target. Therefore, a thorough investigation of neural substrates underlying stimulation effects on dystonia signs and symptoms is warranted. Here, we analyze a multicenter cohort of isolated dystonia patients with subthalamic implantations (N = 58) and relate their stimulation sites to improvements of appendicular and cervical symptoms as well as blepharospasm. Stimulation of the ventral oral posterior nucleus of thalamus and surrounding regions were associated with improvements in cervical dystonia, while stimulation of the dorsolateral STN was associated with improvements in limb dystonia and blepharospasm. This dissociation was matched by structural connectivity analysis, where the cerebellothalamic, corticospinal, and pallidosubthalamic tracts were associated with improvements of cervical dystonia, while hyperdirect and subthalamopallidal pathways with alleviation of limb dystonia and blepharospasm. On the level of functional networks, improvements of limb dystonia were associated with connectivity to the corresponding somatotopic regions in the primary motor cortex, while alleviation of cervical dystonia to the cingulo-opercular network. These findings shed light on the pathophysiology of dystonia and may guide DBS targeting and programming in the future. Copyright © 2025 the Author(s).

Author Keywords
cervical dystonia;  deep brain stimulation;  limb dystonia;  structural connectivity;  sweet-spot analysis

Document Type: Article
Publication Stage: Final
Source: Scopus

Cannabis use characteristics and associations with problematic use outcomes, quitting-related factors, and mental health among US young adults
(2025) Substance Abuse Treatment, Prevention, and Policy, 20 (1), p. 1. 

Berg, C.J.^a b c , LoParco, C.R.^a , Romm, K.F.^d , Cui, Y.^a , McCready, D.M.^a , Wang, Y.^a b , Yang, Y.T.^b e , Szlyk, H.S.^f , Kasson, E.^f , Chakraborty, R.^e , Cavazos-Rehg, P.A.^f

^a Department of Prevention and Community Health, Milken Institute School of Public Health, George Washington UniversityWA, United States
^b George Washington Cancer Center, George Washington UniversityWA, United States
^c 800 22nd St NWWA 20052, United States
^d TSET Health Promotion Research Center, Stephenson Cancer Center; Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
^e Center for Health Policy and Media Engagement, School of Nursing, George Washington UniversityWA, United States
^f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
OBJECTIVE: Given the changes in trends of cannabis use (e.g., product types), this study examined latent classes of young adult use and associations with use-related outcomes. METHODS: We analyzed 2023 survey data among 4,031 US young adults (Mage=26.29, 59.4% female, 19.0% Hispanic, 13.5% Black, 13.6% Asian). Among those reporting past-month use (48.8%), latent class analysis (LCA) indicators included: days used (1-5; 6-20; 21-30), use/day (1; 2-4; ≥5), and type usually used (herb/flower; edibles; oils/vape; concentrates/other). Multivariable regressions examined class in relation to problematic use, quitting-related factors, and mental health, controlling for sociodemographics and state non-medical cannabis laws. RESULTS: LCA identified 4 classes of cannabis use frequency and types used: ‘infrequent-herb/edibles’ (41.4%), ‘frequent-herb’ (16.8%), ‘moderate-herb’ (28.0%), and ‘moderate-oil/other’ (13.8%). In multivariable analyses (referent group: ‘moderate-herb’ class), ‘frequent-herb’ reported less problematic use (B=-0.18, 95%CI=-0.30, -0.07), while ‘moderate-oil/other’ reported greater (B = 0.39, 95%CI = 0.27, 0.51). ‘Infrequent-herb/edibles’ had lower odds of driving post-use of cannabis (aOR = 0.28, 95%CI = 0.22, 0.37) and cannabis/alcohol (aOR = 0.52, 95%CI = 0.35, 0.76), whereas ‘frequent-herb’ (aOR = 1.52, 95%CI = 1.02, 2.28) and ‘moderate-oil/other’ (aOR = 3.98, 95%CI = 2.72, 5.82) reported greater odds of driving post-cannabis/alcohol use. ‘Moderate-oil/other’ reported higher quitting importance (B = 0.59, 95%CI = 0.17, 1.01), while ‘frequent-herb’ reported lower (B=-0.33, 95%CI=-0.99, -0.18). ‘Infrequent-herb/edibles’ reported higher quitting confidence (B = 0.56, 95%CI = 0.20, 0.92), whereas ‘frequent-herb’ (B=-1.01, 95%CI=-1.45, -0.57) and ‘moderate-oil/other’ (B=-1.27, 95%CI=-1.74, -0.81) reported lower. ‘Infrequent-herb/edibles’ reported fewer mental health symptoms (B=-0.55, 95%CI=-0.93, -0.17), while ‘moderate-oil/other’ reported more (B = 1.03, 95%CI = 0.53, 1.52). CONCLUSIONS: Preventing frequent and moderate use of cannabis, particularly of oils/concentrates, is crucial given the potential negative implications for problematic use, quitting, and mental health. © 2025. The Author(s).

Author Keywords
Cannabis;  Epidemiology;  Marijuana;  Problematic use;  Risk factors

Document Type: Article
Publication Stage: Final
Source: Scopus

Control of neurovascular coupling by ATP-sensitive potassium channels
(2025) Journal of Cerebral Blood Flow and Metabolism, . 

Bowen, R.M.^a b , York, N.W.^c d , Padawer-Curry, J.^e f , Bauer, A.Q.^b f , Lee, J.-M.^a b , Nichols, C.G.^c d

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO, United States
^d Center for the Investigation of Membrane Excitability and Diseases, Washington University in St. Louis, St. Louis, MO, United States
^e Imaging Sciences PhD Program, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Regional blood flow within the brain is tightly coupled to regional neuronal activity, a process known as neurovascular coupling (NVC). In this study, we demonstrate the striking role of SUR2- and Kir6.1-dependent ATP-sensitive potassium (KATP) channels in control of NVC in the sensory cortex of conscious mice, in response to mechanical stimuli. We demonstrate that either globally increased (pinacidil-activated) or decreased (glibenclamide-inhibited) KATP activity markedly disrupts NVC; pinacidil-activation is capable of completely abolishing stimulus-evoked cortical hemodynamic responses, while glibenclamide slows and reduces the response. The response is similarly slowed and reduced in SUR2 KO animals, while animals expressing gain-of-function (GOF) mutations in Kir6.1, which underlie Cantú syndrome, exhibit baseline reduction of NVC as well as increased sensitivity to pinacidil. In revealing the dramatic effects of either increasing or decreasing SUR2/Kir6.1-dependent KATP activity on NVC, whether pharmacologically or genetically induced, the study has important implications both for monogenic KATP channel diseases and for more common brain pathologies. © The Author(s) 2025.

Author Keywords
ABCC9;  Cantú syndrome;  KCNJ8;  Kir6.1;  SUR2

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Decoding brain structure to stage Alzheimer’s disease pathology in Down syndrome
(2025) Alzheimer’s and Dementia, . 

Kennedy, J.T.^a , Wisch, J.K.^a , Dincer, A.^b , Roman, J.^a , Gordon, B.A.^b c , Handen, B.^d , Benzinger, T.L.S.^b , Head, E.^e f , Mapstone, M.^g , Christian, B.T.^h i , Tudorascu, D.L.^d , Laymon, C.L.^j , Hartley, S.L.^h k , Lao, P.^l m , Brickman, A.M.^l m , Zaman, S.H.ⁿ , Ances, B.M.^a , the ABC-DS and DIAN Consortia^o

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychological & Brain Sciences, Washington University, St. Louis, MO, United States
^d Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^e Department of Pathology and Laboratory Medicine, University of California, Medical Sciences D, Irvine, CA, United States
^f Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
^g Department of Neurology, University of California, Irvine, CA, United States
^h Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI, United States
ⁱ Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, United States
^j Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
^k Department of Human Development & Family Studies, University of Wisconsin-Madison, Madison, WI, United States
^l Department of Neurology, Columbia University, New York, NY, United States
^m Gertrude H. Sergievsky Center and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, United States
ⁿ Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Cambridge, United Kingdom

Abstract
INTRODUCTION: Alzheimer’s disease (AD) in Down syndrome (DS) is associated with changes in brain structure. It is unknown if thickness and volumetric changes can identify AD stages and if they are similar to other genetic forms of AD. METHODS: Magnetic resonance imaging scans were collected for 178 DS adults (106 nonclinical, 45 preclinical, and 27 symptomatic). Cortical thickness and subcortical volumes were compared between DS groups and evaluated as a staging metric using receiver operating characteristic analyses. Thickness patterns were compared to those previously reported in autosomal-dominant AD (ADAD). RESULTS: Decreased parietal and temporal lobe thickness differentiated amyloid positivity (area under the curve [AUC] = 0.83) and impairment (AUC = 0.81), and slightly outperformed subcortical volumes (AUC = 0.8/0.74). Thickness differences in DS were more widespread, severe, and had better discriminative ability than ADAD. DISCUSSION: Cortical thickness can stage AD pathology in DS. Identification of brain regions affected by AD may aid in tracking disease course and evaluating treatment effects. Highlights: DSAD is associated with reduced temporal and parietal cortical thickness. DSAD is associated with smaller hippocampal and striatal volumes. Thickness differences can stage DSAD better than other forms of AD. DSAD thickness differences are more extensive and severe than ADAD. © 2025 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s;  amyloid;  autosomal dominant Alzheimer’s disease;  cognitive impairment;  cortical thickness;  dementia;  Down syndrome;  MRI;  subcortical volume

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Opioid use in treated and untreated obstructive sleep apnoea: remifentanil pharmacokinetics and pharmacodynamics in adult volunteers
(2025) British Journal of Anaesthesia, . 

Maharaj, A.R.^a , Montana, M.C.^b , Hornik, C.P.^c , Kharasch, E.D.^d e

^a Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada
^b Department of Anesthesiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
^c Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States
^d Department of Anesthesiology, Duke University School of Medicine, Durham, NC, United States
^e Bermaride LLC, Durham, NC, United States

Abstract
Background: Patients with obstructive sleep apnoea (OSA) are considered more sensitive to opioids and at increased risk of opioid-induced respiratory depression. Nonetheless, whether OSA treatment (continuous positive airway pressure, CPAP; or bilevel positive airway pressure, BIPAP) modifies this risk remains unknown. Greater opioid sensitivity can arise from altered pharmacokinetics or pharmacodynamics. This preplanned analysis of a previous cohort study of remifentanil clinical effects in OSA tested the null hypothesis that the pharmacokinetics, pharmacodynamics, or both of remifentanil, a representative μ-opioid agonist, are not altered in adults with treated or untreated OSA. Methods: A single-centre, prospective, open-label, cohort study administered a stepped-dose, target-controlled remifentanil infusion (target effect-site concentrations 0.5, 1, 2, 3, 4 ng ml−1) to awake adult volunteers (median age 52 yr, range 23–70) without OSA (n=20), with untreated OSA (n=33), or with treated OSA (n=21). Type III (in-home) polysomnography verified OSA. Remifentanil plasma concentrations, end-expired CO2, thermal heat tolerance, and pupil diameter (miosis) were assessed. Population pharmacokinetic (clearance, volume of distribution) and pharmacodynamic (miosis, thermal heat tolerance, end-expired CO2) models were developed. Results: Remifentanil clearance (median) was 147, 143, and 155 L h−1 (P=0.472), and volume of distribution was 19.6, 15.5, and 17.7 L (P=0.473) for subjects without OSA, untreated OSA, or treated OSA, respectively. Total body weight was an influential covariate on both remifentanil clearance and central volume of distribution. There were no statistically or clinically significant differences between the three groups in miosis EC50 or Emax, or the slopes of thermal heat tolerance or end-expired CO2 vs remifentanil concentration. At a plasma remifentanil concentration of 4 ng ml−1, in participants without OSA, with untreated OSA, or with treated OSA, respectively, model-estimated pupil area (12%, 13%, and 17% of baseline, P=0.086), thermal heat tolerance (50°C, 51°C, and 51°C, P=0.218), and end-expired CO2 (6.3 kPa, 6.4 kPa, and 6.7 kPa, P=0.257) were not statistically different between groups. Conclusions: OSA (untreated or treated) did not influence remifentanil pharmacokinetics or pharmacodynamics (miosis, analgesia, respiratory depression). Results support the null hypothesis that neither pharmacokinetics nor pharmacodynamics of remifentanil, a representative μ-opioid, are altered in adults with treated or untreated OSA. These findings provide a mechanistic explanation for the lack of influence of OSA or OSA treatment on the clinical miotic, sedative, analgesic, or respiratory depressant response to remifentanil in awake adults. The conventional notion that OSA alters sensitivity to the effects of opioids in awake adults is not supported by our findings, such that opioid dosing might not need adjustment for pharmacokinetic or pharmacodynamic considerations. Clinical trial registration: ClinicalTrials.gov, NCT02898792, https://clinicaltrials.gov/ct2/show/NCT02898792. First Posted: September 13, 2016. © 2024 British Journal of Anaesthesia

Author Keywords
analgesia;  miosis;  obstructive sleep apnoea;  opioids;  pharmacodynamics;  remifentanil;  respiratory depression

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Snoring and risk of dementia: a prospective cohort and Mendelian randomization study
(2025) Sleep, 48 (1), art. no. zsae149, . Cited 1 time.

Gao, Y.^a , Andrews, S.^b , Daghlas, I.^c , Brenowitz, W.D.^d e , Raji, C.A.^f g , Yaffe, K.^b c e h , Leng, Y.^b

^a Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
^b Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, United States
^c Department of Neurology, University of California San Francisco, San Francisco, CA, United States
^d Kaiser Permanente Center for Health Research, Portland, OR, United States
^e Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States
^f Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Neurology, Washington University in St. Louis., St. Louis, MO, United States
^h San Francisco Veterans Affairs Health System, San Francisco, CA, United States

Abstract
Study Objectives: The association between snoring, a very common condition that increases with age, and dementia risk is controversial. We aimed to investigate the observational and causal relationship between snoring and dementia, and to elucidate the role of body mass index (BMI). Methods: Using data from 451 250 participants who were dementia-free at baseline, we examined the association between self-reported snoring and incident dementia using Cox proportional-hazards models. Causal relationship between snoring and Alzheimer’s disease (AD) was examined using bidirectional two-sample Mendelian randomization (MR) analysis. Results: During a median follow-up of 13.6 years, 8325 individuals developed dementia. Snoring was associated with a lower risk of all-cause dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.89 to 0.98) and AD (HR 0.91; 95% CI 0.84 to 0.97). The association was slightly attenuated after adjusting for BMI, and was stronger in older individuals, APOE ϵ4 allele carriers, and during shorter follow-up periods. MR analyses suggested no causal effect of snoring on AD; however, genetic liability to AD was associated with a lower risk of snoring. Multivariable MR indicated that the effect of AD on snoring was primarily driven by BMI. Conclusions: The phenotypic association between snoring and lower dementia risk likely stems from reverse causation, with genetic predisposition to AD associated with reduced snoring. This may be driven by weight loss in prodromal AD. Increased attention should be paid to reduced snoring and weight loss in older adults as potential early indicators of dementia risk. © 2024 The Author(s). Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved.

Author Keywords
Alzheimer’s disease;  body mass index;  dementia;  Mendelian randomization;  multivariable Mendelian randomization;  prodrome;  sleep apnea;  snoring;  vascular dementia

Document Type: Article
Publication Stage: Final
Source: Scopus

Chronic high fat diet-induced cerebrovascular remodeling impairs recovery of blood flow after cerebral ischemia in mice
(2025) Journal of Cerebral Blood Flow and Metabolism, . 

Li, J.^a , Sun, N.^b c , Hu, S.^b c , Zuo, Z.^a

^a Department of Anesthesiology, University of Virginia, Charlottesville, VA, United States
^b Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States
^c Department of Biomedical Engineering, Washington University in St Louis, St. Louis, MO, United States

Abstract
Obesity and associated metabolic disturbances worsen brain ischemia outcome. High fat diet (HFD)-fed mice are obese and have cerebrovascular remodeling and worsened brain ischemia outcome. We determined whether HFD-induced cerebrovascular remodeling impaired reperfusion to the ischemic penumbra. Six-week-old C57BL/6J or matrix metalloprotease-9 knockout (MMP-9−/−) mice were on HFD or regular diet (RD) for 12 to 14 months before a 60-min left middle cerebral arterial occlusion (MCAO). Photoacoustic microscopy was performed at left cerebral frontal cortex. HFD increased cerebrovascular density and tortuosity in C57BL/6J mice but not in MMP-9−/− mice. Blood flow to the ischemic penumbra slowly recovered but did not reach the baseline 2 h after MCAO in RD-fed mice. Oxygen extraction fraction was increased to maintain cerebral metabolic rate of oxygen (CMRO2) throughout brain ischemia and reperfusion period. This blood flow recovery was worsened in HFD-fed mice, leading to decreased CMRO2. MMP-9−/− attenuated these HFD effects. HFD increased MMP-9 activity and interleukin 1β. Pyrrolidine dithiocarbamate, an anti-inflammatory agent, abolished the HFD effects. Interleukin 1β increased MMP-9 activity. In summary, HFD induces cerebrovascular remodeling, leading to worsened recovery of blood supply to the ischemic penumbra to contribute to poor outcome after brain ischemia. Neuroinflammation may activate MMP-9 in HFD-fed mice. © The Author(s) 2025.

Author Keywords
Cerebrovascular remodeling;  high fat diet;  matrix metalloprotease-9;  neuroinflammation;  reperfusion

Document Type: Article
Publication Stage: Article in Press
Source: Scopus