WashU weekly Neuroscience publications: July 2, 2023

Shank2 identifies a subset of glycinergic neurons involved in altered nociception in an autism model
(2023) Molecular Autism, 14 (1), art. no. 21, . 

Olde Heuvel, F.^a , Ouali Alami, N.^a b , Aousji, O.^a , Pogatzki-Zahn, E.^c , Zahn, P.K.^c d , Wilhelm, H.^a , Deshpande, D.^e , Khatamsaz, E.^a , Catanese, A.^f , Woelfle, S.^f , Schön, M.^f , Jain, S.^g , Grabrucker, S.^f , Ludolph, A.C.^a h , Verpelli, C.ⁱ , Michaelis, J.^e , Boeckers, T.M.^f h k , Roselli, F.^a h j

^a Department of Neurology, Ulm University, Ulm, Germany
^b International PhD Program, Ulm University, Ulm, Germany
^c Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
^d Clinic for Anesthesiology, Intensive Care and Pain Medicine, University Hospital Bergmannsheil Bochum, Bochum, Germany
^e Department of Biophysics, Ulm University, Ulm, Germany
^f Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany
^g Department of Internal Medicine (Renal), Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
^h German Center for Neurodegenerative Diseases (DZNE), Ulm, Germany
ⁱ Institute of Neuroscience, National Science Council, Milan, Italy
^j Center for Biomedical Research (ZBF), Helmholtzstraße 8/2, Ulm, 89081, Germany
^k Department of Anatomy and Cell Biology, Ulm University, Albert-Einstein Allee 11, Ulm, 89081, Germany

Abstract
Background: Autism Spectrum Disorders (ASD) patients experience disturbed nociception in the form of either hyposensitivity to pain or allodynia. A substantial amount of processing of somatosensory and nociceptive stimulus takes place in the dorsal spinal cord. However, many of these circuits are not very well understood in the context of nociceptive processing in ASD. Methods: We have used a Shank2−/− mouse model, which displays a set of phenotypes reminiscent of ASD, and performed behavioural and microscopic analysis to investigate the role of dorsal horn circuitry in nociceptive processing of ASD. Results: We determined that Shank2−/− mice display increased sensitivity to formalin pain and thermal preference, but a sensory specific mechanical allodynia. We demonstrate that high levels of Shank2 expression identifies a subpopulation of neurons in murine and human dorsal spinal cord, composed mainly by glycinergic interneurons and that loss of Shank2 causes the decrease in NMDAR in excitatory synapses on these inhibitory interneurons. In fact, in the subacute phase of the formalin test, glycinergic interneurons are strongly activated in wild type (WT) mice but not in Shank2−/− mice. Consequently, nociception projection neurons in laminae I are activated in larger numbers in Shank2−/− mice. Limitations: Our investigation is limited to male mice, in agreement with the higher representation of ASD in males; therefore, caution should be applied to extrapolate the findings to females. Furthermore, ASD is characterized by extensive genetic diversity and therefore the findings related to Shank2 mutant mice may not necessarily apply to patients with different gene mutations. Since nociceptive phenotypes in ASD range between hyper- and hypo-sensitivity, diverse mutations may affect the circuit in opposite ways. Conclusion: Our findings prove that Shank2 expression identifies a new subset of inhibitory interneurons involved in reducing the transmission of nociceptive stimuli and whose unchecked activation is associated with pain hypersensitivity. We provide evidence that dysfunction in spinal cord pain processing may contribute to the nociceptive phenotypes in ASD. © 2023, The Author(s).

Author Keywords
Autism spectrum disorder;  Glycinergic interneurons;  Nociception;  Shank2;  Spinal cord

Funding details
251293561, 431995586, CRC1149
PO1319/3
777500

Document Type: Article
Publication Stage: Final
Source: Scopus

Brain hubs defined in the group do not overlap with regions of high inter-individual variability
(2023) NeuroImage, 277, art. no. 120195, . 

Smith, D.M.^a b , Kraus, B.T.^a , Dworetsky, A.^a c , Gordon, E.M.^d , Gratton, C.^a c e

^a Department of Psychology, Northwestern University, Evanston, IL, United States
^b Department of Neurology, Division of Cognitive Neurology/Neuropsychology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
^c Department of Psychology, Florida State University, Tallahassee, FL, United States
^d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurology, Northwestern University, Evanston, IL, United States

Abstract
Connector ‘hubs’ are brain regions with links to multiple networks. These regions are hypothesized to play a critical role in brain function. While hubs are often identified based on group-average functional magnetic resonance imaging (fMRI) data, there is considerable inter-subject variation in the functional connectivity profiles of the brain, especially in association regions where hubs tend to be located. Here we investigated how group hubs are related to locations of inter-individual variability. To answer this question, we examined inter-individual variation at group-level hubs in both the Midnight Scan Club and Human Connectome Project datasets. The top group hubs defined based on the participation coefficient did not overlap strongly with the most prominent regions of inter-individual variation (termed ‘variants’ in prior work). These hubs have relatively strong similarity across participants and consistent cross-network profiles, similar to what was seen for many other areas of cortex. Consistency across participants was further improved when these hubs were allowed to shift slightly in local position. Thus, our results demonstrate that the top group hubs defined with the participation coefficient are generally consistent across people, suggesting they may represent conserved cross-network bridges. More caution is warranted with alternative hub measures, such as community density (which are based on spatial proximity to network borders) and intermediate hub regions which show higher correspondence to locations of individual variability. © 2023

Funding details
National Science FoundationNSF2048066
National Institutes of HealthNIHMH121276, MH124567, NS129521, R01MH118370, T32NS047987
Northwestern UniversityNU
University of WashingtonUW
Office of the Provost, University of South Carolina
Dysphonia InternationalNSDA
Office of Research, University of Georgia

Document Type: Article
Publication Stage: Final
Source: Scopus

Individual differences in T1w/T2w ratio development during childhood
(2023) Developmental Cognitive Neuroscience, 62, art. no. 101270, . 

Boroshok, A.L.^a , McDermott, C.L.^a , Fotiadis, P.^b , Park, A.T.^a , Tooley, U.A.^a b c d , Gataviņš, M.M.^a , Tisdall, M.D.^e , Bassett, D.S.^{b f g h i j k} , Mackey, A.P.^a b

^a Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States
^b Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, United States
^c Department of Psychiatry, Washington University in St. Louis, United States
^d Department of Neurology, Washington University in St. Louis, United States
^e Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^f Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, United States
^g Department of Electrical & Systems Engineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, United States
^h Department of Physics & Astronomy, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, United States
ⁱ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^j Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^k Santa Fe Institute, Santa Fe, NM, United States

Abstract
Myelination is a key developmental process that promotes rapid and efficient information transfer. Myelin also stabilizes existing brain networks and thus may constrain neuroplasticity, defined here as the brain’s potential to change in response to experiences rather than the canonical definition as the process of change. Characterizing individual differences in neuroplasticity may shed light on mechanisms by which early experiences shape learning, brain and body development, and response to interventions. The T1-weighted/T2-weighted (T1w/T2w) MRI signal ratio is a proxy measure of cortical microstructure and thus neuroplasticity. Here, in pre-registered analyses, we investigated individual differences in T1w/T2w ratios in children (ages 4–10, n = 157). T1w/T2w ratios were positively associated with age within early-developing sensorimotor and attention regions. We also tested whether socioeconomic status, cognition (crystallized knowledge or fluid reasoning), and biological age (as measured with molar eruption) were related to T1w/T2w signal but found no significant effects. Associations among T1w/T2w ratios, early experiences, and cognition may emerge later in adolescence and may not be strong enough to detect in moderate sample sizes. © 2023 The Authors

Author Keywords
Myelination;  Neurodevelopment;  Plasticity

Funding details
National Science FoundationNSFDRL 2045095
National Institute on Drug AbuseNIDA1R34DA050297-01
Canadian Institute for Advanced ResearchCIFAR
Jacobs Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Trunk control in and out of an episode of recurrent low back pain in young adults during the Balance-Dexterity Task
(2023) Journal of Electromyography and Kinesiology, 71, art. no. 102794, . 

Shih, H.-J.S.^a b , Ai, J.^a , Abe, J.^c , Tang, J.^a , Rowley, K.M.^a d , Van Dillen, L.R.^e f , Kulig, K.^a

^a Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA, United States
^b Department of Biobehavioral Sciences, Teachers College, Columbia University, New York, NY, United States
^c Department of Biological Sciences, University of Southern California, Los Angeles, CA, United States
^d Kinesiology Department, California State University East Bay, Hayward, CA, United States
^e Program in Physical Therapy, Washington University in St. Louis Medical School, St. Louis, MO, United States
^f Department of Orthopaedic Surgery, Washington University in St. Louis Medical School, St. Louis, MO, United States

Abstract
We investigated motor control strategies utilized by individuals with recurrent low back pain (rLBP) during active pain and remission periods as well as by back-healthy controls using the Balance-Dexterity Task. Nineteen young adults with rLBP were tested first when they were in pain and then again in symptom remission, and 19 matched controls were also tested. Trunk kinematic coupling and muscle co-activation were examined while participants performed the task by standing on one leg while compressing a spring with a maximum consistent force with the other leg. We found a decreased bilateral external oblique co-activation during the spring condition of the task compared to the stable block condition in people with rLBP compared to back healthy individuals. There was also reduced trunk coupling during the spring condition of the task compared to the stable block condition in both the rLBP active and remission groups, but no group difference between rLBP and back-healthy individuals. When individuals were in active pain, they exhibited more co-activation than when they were in remission, but the co-activation during active pain was not greater than in back-healthy individuals. © 2023 Elsevier Ltd

Author Keywords
Electromyography;  Motor control;  Rehabilitation;  Spine

Funding details
National Institutes of HealthNIH
National Center for Medical Rehabilitation ResearchNCMRR5 R01 HD 047709
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
International Society of BiomechanicsISB

Document Type: Article
Publication Stage: Final
Source: Scopus

Withdrawal of antiseizure medications after MRI–Guided laser interstitial thermal therapy in extra-temporal lobe epilepsy
(2023) Seizure, 110, pp. 86-92. 

Athreya, A.^a , Matthews, R.E.^a , Drane, D.L.^a b c , Bonilha, L.^a , Willie, J.T.^d e , Gross, R.E.^e , Karakis, I.^a

^a Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^b Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
^c Department of Neurology, University of Washington, Seattle, WA, United States
^d Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States

Abstract
Purpose: This study investigated the success rate of antiseizure medications (ASMs) withdrawal following MRI Guided Laser Interstitial Thermal Therapy (MRg-LITT) for extra-temporal lobe epilepsy (ETLE), and identified predictors of seizure recurrence. Methods: We retrospectively assessed 27 patients who underwent MRg-LITT for ETLE. Patients’ demographics, disease characteristics, and post-surgical outcomes were evaluated for their potential to predict seizure recurrence associated with ASMs withdrawal. Results: The median period of observation post MRg-LITT was 3 years (range 18 – 96 months) and the median period to initial ASMs reduction was 0.5 years (range 1–36 months). ASMs reduction was attempted in 17 patients (63%), 5 (29%) of whom had seizure recurrence after initial reduction. Nearly all patient who relapsed regained seizure control after reinstitution of their ASMs regimen. Pre-operative seizure frequency (p = 0.002) and occurrence of acute post-operative seizures (p = 0.01) were associated with increased risk for seizure recurrence post ASMs reduction. At the end of the observation period, 11% of patients were seizure free without drugs, 52% were seizure free with drugs and 37% still experienced seizures despite ASMs. Compared with pre-operative status, the number of ASMs was reduced in 41% of patients, unchanged in 55% of them and increased in only 4% of them. Conclusions: Successful MRg-LITT for ETLE allows for ASMs reduction in a significant portion of patients and complete ASMs withdrawal in a subset of them. Patients with higher pre-operative seizure frequency or occurrence of acute post operative seizures exhibit higher chances relapse post ASMs reduction. © 2023 British Epilepsy Association

Author Keywords
Antiepileptic drugs;  Antiseizure medications;  Epilepsy;  Epilepsy surgery;  Laser ablation

Document Type: Article
Publication Stage: Final
Source: Scopus

Blood neurofilament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: findings from the ocrelizumab randomised, double-blind phase 3 clinical trials
(2023) eBioMedicine, 93, art. no. 104662, . 

Bar-Or, A.^a , Thanei, G.-A.^b , Harp, C.^c , Bernasconi, C.^b , Bonati, U.^b , Cross, A.H.^d , Fischer, S.^c , Gaetano, L.^b , Hauser, S.L.^e , Hendricks, R.^c , Kappos, L.^f g , Kuhle, J.^f g , Leppert, D.^f g , Model, F.^b , Sauter, A.^b , Koendgen, H.^b , Jia, X.^c , Herman, A.E.^c

^a Center for Neuroinflammation and Experimental Therapeutics, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^b F. Hoffmann-La Roche Ltd., Basel, Switzerland
^c Genentech, Inc., South San Francisco, CA, United States
^d Washington University School of Medicine, St Louis, MO, United States
^e University of California, San Francisco, San Francisco, CA, United States
^f Multiple Sclerosis Centre, Neurology, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
^g Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital Basel and University of Basel, Switzerland

Abstract
Background: Neurofilament light chain (NfL), a neuronal cytoskeletal protein that is released upon neuroaxonal injury, is associated with multiple sclerosis (MS) relapsing activity and has demonstrated some prognostic ability for future relapse-related disease progression, yet its value in assessing non-relapsing disease progression remains unclear. Methods: We examined baseline and longitudinal blood NfL levels in 1421 persons with relapsing MS (RMS) and 596 persons with primary progressive MS (PPMS) from the pivotal ocrelizumab MS trials. NfL treatment-response and risk for disease worsening (including disability progression into the open-label extension period and slowly expanding lesions [SELs] on brain MRI) at baseline and following treatment with ocrelizumab were evaluated using time-to-event analysis and linear regression models. Findings: In persons from the RMS control arms without acute disease activity and in the entire PPMS control arm, higher baseline NfL was prognostic for greater whole brain and thalamic atrophy, greater volume expansion of SELs, and clinical progression. Ocrelizumab reduced NfL levels vs. controls in persons with RMS and those with PPMS, and abrogated the prognostic value of baseline NfL on disability progression. Following effective suppression of relapse activity by ocrelizumab, NfL levels at weeks 24 and 48 were significantly associated with long-term risk for disability progression, including up to 9 years of observation in RMS and PPMS. Interpretation: Highly elevated NfL from acute MS disease activity may mask a more subtle NfL abnormality that reflects underlying non-relapsing progressive biology. Ocrelizumab significantly reduced NfL levels, consistent with its effects on acute disease activity and disability progression. Persistently elevated NfL levels, observed in a subgroup of persons under ocrelizumab treatment, demonstrate potential clinical utility as a predictive biomarker of increased risk for clinical progression. Suppression of relapsing biology with high-efficacy immunotherapy provides a window into the relationship between NfL levels and future non-relapsing progression. Funding: F. Hoffmann-La Roche Ltd. © 2023 The Author(s)

Author Keywords
Biomarker;  Disease progression;  Multiple sclerosis;  NfL;  Ocrelizumab

Funding details
F. Hoffmann-La Roche

Document Type: Article
Publication Stage: Final
Source: Scopus

Measurement of relative motion of the brain and skull in the mini-pig in-vivo
(2023) Journal of Biomechanics, 156, art. no. 111676, . 

Kailash, K.A.^a , Guertler, C.A.^b , Johnson, C.L.^c , Okamoto, R.J.^b , Bayly, P.V.^a b

^a Washington University in St. Louis, Biomedical Engineering, United States
^b Washington University in St. Louis, Mechanical Engineering and Material Science, United States
^c University of Delaware, Biomedical Engineering, United States

Abstract
The mechanical role of the skull-brain interface is critical to the pathology of concussion and traumatic brain injury (TBI) and may evolve with age. Here we characterize the skull-brain interface in juvenile, female Yucatan mini-pigs from 3 to 6 months old using techniques from magnetic resonance elastography (MRE). The displacements of the skull and brain were measured by a motion-sensitive MR imaging sequence during low-amplitude harmonic motion of the head. Each animal was scanned four times at 1-month intervals. Harmonic motion at 100 Hz was excited by three different configurations of a jaw actuator in order to vary the direction of loading. Rigid-body linear motions of the brain and skull were similar, although brain rotations were consistently smaller than corresponding skull rotations. Relative displacements between the brain and skull were estimated for voxels on the surface of the brain. Amplitudes of relative displacements between skull and brain were 1–3 μm, approximately 25–50% of corresponding skull displacements. Maps of relative displacement showed variations by anatomical region, and the normal component of relative displacement was consistently 25–50% of the tangential component. These results illuminate the mechanics of the skull-brain interface in a gyrencephalic animal model relevant to human brain injury and development. © 2023 Elsevier Ltd

Author Keywords
Brain biomechanics;  Brain-skull interface;  Magnetic resonance elastography;  MRI

Funding details
R01EB027577, U01 NS112120
N00014-22-1-2198

Document Type: Article
Publication Stage: Final
Source: Scopus

Morphine and Hydromorphone Effects, Side Effects, and Variability: A Crossover Study in Human Volunteers
(2023) Anesthesiology, 139 (1), pp. 16-34. 

Meissner, K.^a b c , Dahan, A.^b , Olofsen, E.^b , Göpfert, C.^c d , Blood, J.^c , Wieditz, J.^e , Kharasch, E.D.^f

^a Department of Anesthesiology, University Medical Center Göttingen, Göttingen, Germany
^b Department of Anesthesiology, Leiden University Medical Center, Leiden, Netherlands
^c Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
^d Chronic Pain Therapy, Kliniken Ostalb, Ellwangen, Germany
^e Anesthesiology Clinic, Department of Medical Statistics, University of Medicine Göttingen, Göttingen, Germany
^f Department of Anesthesiology, Duke University, Durham, NC, United States

Abstract
Background: Balancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department, and other acute care settings. Morphine and hydromorphone are postoperative analgesic standards. Nevertheless, their comparative effects and side effects, timing, and respective variabilities remain poorly understood. This study tested the hypothesis that IV morphine and hydromorphone differ in onset, magnitude, duration, and variability of analgesic and ventilatory effects. Methods: The authors conducted a randomized crossover study in healthy volunteers. Forty-two subjects received a 2-h IV infusion of hydromorphone (0.05 mg/kg) or morphine (0.2 mg/kg) 1 to 2 weeks apart. The authors measured arterial opioid concentrations, analgesia in response to heat pain (maximally tolerated temperature, and verbal analog pain scores at discrete preset temperatures to determine half-maximum temperature effect), dark-adapted pupil diameter and miosis, end-expired carbon dioxide, and respiratory rate for 12 h after dosing. Results: For morphine and hydromorphone, respectively, maximum miosis was less (3.9 [3.4 to 4.2] vs. 4.6 mm [4.0 to 5.0], P < 0.001; median and 25 to 75% quantiles) and occurred later (3.1 ± 0.9 vs. 2.3 ± 0.7 h after infusion start, P < 0.001; mean ± SD); maximum tolerated temperature was less (49 ± 2 vs. 50 ± 2°C, P < 0.001); verbal pain scores at end-infusion at the most informative stimulus (48.2°C) were 82 ± 4 and 59 ± 3 (P < 0.001); maximum end-expired CO2was 47 (45 to 50) and 48 mmHg (46 to 51; P = 0.007) and occurred later (5.5 ± 2.8 vs. 3.0 ± 1.5 h after infusion start, P < 0.001); and respiratory nadir was 9 ± 1 and 11 ± 2 breaths/min (P < 0.001), and occurred at similar times. The area under the temperature tolerance-time curve was less for morphine (1.8 [0.0 to 4.4]) than hydromorphone (5.4°C-h [1.6 to 12.1] P < 0.001). Interindividual variability in clinical effects did not differ between opioids. Conclusions: For morphine compared to hydromorphone, analgesia and analgesia relative to respiratory depression were less, onset of miosis and respiratory depression was later, and duration of respiratory depression was longer. For each opioid, timing of the various clinical effects was not coincident. Results may enable more rational opioid selection, and suggest hydromorphone may have a better clinical profile. © 2023 Lippincott Williams and Wilkins. All rights reserved.

Funding details
National Institutes of HealthNIHK24-DA00417, R01-DA042985, R01-DA14211, UL1-TR000448
Foundation for Barnes-Jewish HospitalFBJH
Institute of Clinical and Translational SciencesICTS

Document Type: Article
Publication Stage: Final
Source: Scopus

Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E
(2023) The Journal of Clinical Investigation, 133 (12), . 

Li, C.^a , Wilborn, J.^b , Pittman, S.^a , Daw, J.^a , Alonso-Pérez, J.^c , Díaz-Manera, J.^d , Weihl, C.C.^a , Haller, G.^a b e

^a Department of Neurology and
^b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^c Neuromuscular Disease Unit, Neurology Department, Hospital Universitario Nuestra Señora de Candelaria, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Tenerife, Spain
^d John Walton Muscular Dystrophy Research Center, Newcastle University, Newcastle Upon Tyne, United Kingdom
^e Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Genetic testing is essential for patients with a suspected hereditary myopathy. More than 50% of patients clinically diagnosed with a myopathy carry a variant of unknown significance in a myopathy gene, often leaving them without a genetic diagnosis. Limb-girdle muscular dystrophy (LGMD) type R4/2E is caused by mutations in β-sarcoglycan (SGCB). Together, β-, α-, γ-, and δ-sarcoglycan form a 4-protein transmembrane complex (SGC) that localizes to the sarcolemma. Biallelic loss-of-function mutations in any subunit can lead to LGMD. To provide functional evidence for the pathogenicity of missense variants, we performed deep mutational scanning of SGCB and assessed SGC cell surface localization for all 6,340 possible amino acid changes. Variant functional scores were bimodally distributed and perfectly predicted pathogenicity of known variants. Variants with less severe functional scores more often appeared in patients with slower disease progression, implying a relationship between variant function and disease severity. Amino acid positions intolerant to variation mapped to points of predicted SGC interactions, validated in silico structural models, and enabled accurate prediction of pathogenic variants in other SGC genes. These results will be useful for clinical interpretation of SGCB variants and improving diagnosis of LGMD; we hope they enable wider use of potentially life-saving gene therapy.

Author Keywords
Genetic variation;  Genetics;  Muscle Biology;  Neuromuscular disease

Document Type: Article
Publication Stage: Final
Source: Scopus

Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease
(2023) Science Translational Medicine, 15 (700), p. eabo2984. 

Ferreiro, A.L.^a b c , Choi, J.^a , Ryou, J.^a , Newcomer, E.P.^a b , Thompson, R.^d , Bollinger, R.M.^e , Hall-Moore, C.^f , Ndao, I.M.^f , Sax, L.^f , Benzinger, T.L.S.^g h , Stark, S.L.^d e h , Holtzman, D.M.^d h i , Fagan, A.M.^d h i , Schindler, S.E.^d h , Cruchaga, C.^d i j k , Butt, O.H.^d , Morris, J.C.^d h , Tarr, P.I.^f l , Ances, B.M.^{b d g h i l} , Dantas, G.^{a b c l m}

^a Edison Family Center for Genome Sciences and Systems Biology, Washington University School of MedicineMO 63110, United States
^b Department of Biomedical Engineering, Washington University in St. LouisMO 63130, United States
^c Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of MedicineMO 63110, United States
^d Department of Neurology, Washington University School of MedicineMO 63110, United States
^e Program in Occupational Therapy, Washington University School of MedicineMO 63110, United States
^f Division of Gastroenterology, Hepatology, Nutrition, Department of Pediatrics, Washington University School of MedicineMO 63110, United States
^g Department of Radiology, Washington University School of MedicineMO 63110, United States
^h Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of MedicineMO 63110, United States
ⁱ Hope Center for Neurological Disorders, Washington University School of MedicineMO 63110, United States
^j Washington University School of MedicineMO 63110, United States
^k Department of Psychiatry, Washington University School of MedicineMO 63110, United States
^l Department of Molecular Microbiology, Washington University School of MedicineMO 63110, United States
^m Department of Pediatrics, Washington University School of MedicineMO 63110, United States

Abstract
Alzheimer’s disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with β-amyloid (Aβ) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process. We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.

Document Type: Article
Publication Stage: Final
Source: Scopus

Neurocognitive Dysfunction With Neuronal Injury in People With HIV on Long-Duration Antiretroviral Therapy
(2023) Neurology, 100 (24), pp. E2466-E2476. 

McMahan, C.^a d , Dietrich, D.K.^a , Horne, E.F.^a e , Kelly, E.^a f , Geannopoulos, K.^a g , Siyahhan Julnes, P.S.^a h , Ham, L.^i j , Santamaria, U.^k , Lau, C.-Y.^l , Wu, T.^b , Hsieh, H.-C.^m n , Ganesan, A.^m n o , Berjohn, C.^p , Kapetanovic, S.^q , Reich, D.S.^c , Nair, G.^c , Snow, J.ⁱ , Agan, B.K.^m n o , Nath, A.^a , Smith, B.R.^a

^a Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, Nih, Bethesda, MD, United States
^b National Institute of Neurological Disorders and Stroke, Nih, Bethesda, MD, United States
^c Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, Nih, Bethesda, MD, United States
^d University of Pittsburgh School of MedicinePA, United States
^e Duke University School of Medicine, Durham, NC, United States
^f Virginia Commonwealth University School of Medicine, Richmond, United States
^g Department of Neurology, Case Western Reserve University, University Hospitals Cleveland Medical CenterOH, United States
^h Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Office of the Clinical Director, National Institute of Mental Health, Nih, Bethesda, MD, United States
^j San Diego State University, University of California San Diego Joint Doctoral Program in Clinical Psychology, United States
^k Leidos Biomedical Research, Frederick, MD, United States
^l Hiv Dynamics and Replication Program, Nci, Nih, Bethesda, United States
^m Infectious Diseases Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, United States
ⁿ The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, United States
^o Department of Medicine, Uniformed Services University, Bethesda, MD, United States
^p Division of Infectious Diseases, Naval Medical Center San DiegoCA, United States
^q Department of Psychiatry and the Behavioral Sciences, University of Southern California Keck School of Medicine, Los Angeles, United States

Abstract
Background and ObjectivesNeurologic outcomes in people with HIV (PWH) on long-duration antiretroviral therapy (ART) are not fully understood, and the underlying pathophysiology is unclear. To address this, we established a cohort of such individuals and compared them with HIV-negative controls using a novel matching technique. Both groups underwent extensive cognitive testing, evaluation for psychiatric measures, and MRI and CSF analyses.MethodsParticipants underwent comprehensive neuropsychological testing and completed standardized questionnaires measuring depressive symptoms, perceptions of own functioning, and activities of daily living as part of an observational study. Brain MRI and lumbar puncture were optional. Coarsened Exact Matching was used to reduce between-group differences in age and sex, and weighted linear/logistic regression models were used to assess the effect of HIV on outcomes.ResultsData were analyzed from 155 PWH on ART for at least 15 years and 100 HIV-negative controls. Compared with controls, PWH scored lower in the domains of attention/working memory (PWH least square mean [LSM] = 50.4 vs controls LSM = 53.1, p = 0.008) and motor function (44.6 vs 47.7, p = 0.009) and a test of information processing speed (symbol search 30.3 vs 32.2, p = 0.003). They were more likely to self-report a higher number of cognitive difficulties in everyday life (p = 0.011). PWH also reported more depressive symptoms, general anxiety, and use of psychiatric medications (all with p < 0.05). PWH had reduced proportions of subcortical gray matter on MRI (β = -0.001, p < 0.001), and CSF showed elevated levels of neurofilament light chain (664 vs 529 pg/mL, p = 0.01) and tumor necrosis factor α (0.229 vs 0.156 ng/mL, p = 0.0008).DiscussionPWH, despite effective ART for over a decade, displayed neurocognitive deficits and mood abnormalities. MRI and CSF analyses revealed reduced brain volume and signs of ongoing neuronal injury and neuroinflammation. As the already large proportion of virologically controlled PWH continues to grow, longitudinal studies should be conducted to elucidate the implications of cognitive, psychiatric, MRI, and CSF abnormalities in this group. © American Academy of Neurology.

Funding details
HU0001190002
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Institute of Mental HealthNIMH
National Institute of Allergy and Infectious DiseasesNIAIDY1-AI-5072
National Institute of Neurological Disorders and StrokeNINDS
Henry M. Jackson FoundationHJF
Office of AIDS ResearchOARIDCRP-078
Uniformed Services University of the Health SciencesUSUHS

Document Type: Article
Publication Stage: Final
Source: Scopus

Brain Abscess and Stroke in Children and Adults With Hereditary Hemorrhagic Telangiectasia: Analysis of a Large National Claims Database
(2023) Neurology, 100 (23), pp. E2324-E2330. Cited 1 time.

White, A.J.^a , Marmor, I.^b , Peacock, K.M.^c , Nickel, K.B.^c , Zavadil, J.^b , Olsen, M.A.^c

^a Department of Pediatrics, Saint Louis University, School of Medicine, United States
^b Department of Pediatrics, Department of Medicine, Washington University, School of Medicine, St. Louis, MO, United States
^c Division of Infectious Diseases, Department of Medicine, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Background and ObjectivesHereditary hemorrhagic telangiectasia (HHT) is an inherited disease associated with pathogenic variants in transforming growth factor-β signaling pathway-related genes, resulting in abnormal vascular development in various organs. Brain arteriovenous malformations (AVMs) may lead to intracranial hemorrhage, and brain abscess or ischemic stroke may result from right to left shunting via pulmonary AVMs. We aimed to investigate the risk for these severe complications in both adults and children with HHT.MethodsWe conducted a case-control study among participants aged 1-64 years in the MarketScan Commercial (2006-2019) and Multistate Medicaid Databases (2011-2019). We identified cases with HHT using International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification (ICD-9/10) diagnosis codes (ICD-9-CM 448.0, ICD-10-CM I78.0). Control patients without HHT coding were frequency matched 10:1 to patients with HHT by age, duration of insurance enrollment, sex, and Medicaid status. Outcomes of interest (brain abscess, stroke, and intracranial/subarachnoid hemorrhage) were identified using the appropriate ICD-9/10 diagnosis codes. We calculated incidence and standardized rates of the various outcomes and compared rate ratios (RRs) between HHT cases and controls.ResultsA total of 5,796 patients with HHT, of whom 588 were children (age younger than 16 years), were matched with 57,960 controls. There was an increased incidence of brain abscesses in HHT cases compared with controls, with an RR of 35.6 (95% CI 15.4-82.5). No brain abscesses were recorded in children aged 15 years or younger. Hemorrhagic strokes/subarachnoid hemorrhages were more common in HHT cases, with an RR of 4.01 (95% CI 2.8-5.7) in adults and 60.2 (95% CI 7.2-500.4) in children. Ischemic strokes were also more common in cases, with an RR of 3.7 (95% CI, 3.0-4.5) in adults and 70.4 (95% CI 8.7-572.3) in children.DiscussionWe observed a much higher incidence of severe CNS vascular complications in patients with HHT, particularly in children. Although a higher incidence of brain abscesses was noted in adult patients with HHT, no brain abscesses were recorded in children, a result that may be considered when surveillance recommendations for this population are revisited. © American Academy of Neurology.

Funding details
UL1 TR002345

Document Type: Article
Publication Stage: Final
Source: Scopus

Benzodiazepine, Z-drug, and sleep medication prescriptions in male and female people with opioid use disorder on buprenorphine and comorbid insomnia: an analysis of multistate insurance claims
(2023) Sleep, 46 (6), art. no. zsad083, . 

Martin, C.E.^a , Patel, H.^b , Dzierewski, J.M.^c , Moeller, F.G.^d , Bierut, L.J.^b e , Grucza, R.A.^f , Xu, K.Y.^b

^a Department of Obstetrics and Gynecology and Vcu Institute for Drug and Alcohol Studies, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c National Sleep Foundation, Washington, DC, United States
^d Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
^e Alvin J Siteman Cancer Center, Barnes Jewish Hospital, St. Louis, MO, United States
^f Departments of Family and Community Medicine and Health and Outcomes Research, St. Louis University, St. Louis, MO, United States

Abstract
Study Objectives: In adult populations, women are more likely than men to be prescribed benzodiazepines. However, such disparities have not been investigated in people with opioid use disorder (OUD) and insomnia receiving buprenorphine, a population with particularly high sedative/hypnotic receipt. This retrospective cohort study used administrative claims data from Merative MarketScan Commercial and MultiState Medicaid Databases (2006-2016) to investigate sex differences in the receipt of insomnia medication prescriptions among patients in OUD treatment with buprenorphine. Methods: We included people aged 12-64 years with diagnoses of insomnia and OUD-initiating buprenorphine during the study timeframe. The predictor variable was sex (female versus male). The primary outcome was receipt of insomnia medication prescription within 60 days of buprenorphine start, encompassing benzodiazepines, Z-drugs, or non-sedative/hypnotic insomnia medications (e.g. hydroxyzine, trazodone, and mirtazapine). Associations between sex and benzodiazepine, Z-drug, and other insomnia medication prescription receipt were estimated using Poisson regression models. Results: Our sample included 9510 individuals (female n = 4637; male n = 4873) initiating buprenorphine for OUD who also had insomnia, of whom 6569 (69.1%) received benzodiazepines, 3891 (40.9%) Z-drugs, and 8441 (88.8%) non-sedative/hypnotic medications. Poisson regression models, adjusting for sex differences in psychiatric comorbidities, found female sex to be associated with a slightly increased likelihood of prescription receipt: benzodiazepines (risk ratio [RR], RR = 1.17 [1.11-1.23]), Z-drugs (RR = 1.26 [1.18-1.34]), and non-sedative/hypnotic insomnia medication (RR = 1.07, [1.02-1.12]). Conclusions: Sleep medications are commonly being prescribed to individuals with insomnia in OUD treatment with buprenorphine, with sex-based disparities indicating a higher prescribing impact among female than male OUD treatment patients. © 2023 The Author(s). Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved.

Author Keywords
benzodiazepines;  insomnia;  opioid use disorder;  sex differences;  sleep medication

Funding details
National Institutes of HealthNIH
National Center for Advancing Translational SciencesNCATS
Institute of Clinical and Translational SciencesICTSUL1 TR002345
Division of Bone and Mineral Diseases, John T. Milliken Department of Medicine, Washington University in St. LouisUG1 DA050207

Document Type: Article
Publication Stage: Final
Source: Scopus

Using social influence strategies to improve rates of online mental health survey participation: Results from two experiments
(2023) Journal of Behavioral and Cognitive Therapy, 33 (2), pp. 81-89. 

Rackoff, G.N.^a , Monocello, L.T.^b , Fowler, L.A.^b , Vázquez, M.M.^b , Shah, J.^b , Fitzsimmons-Craft, E.E.^b , Barr Taylor, C.^c d , Eisenberg, D.^e , Wilfley, D.E.^b , Newman, M.G.^a

^a Department of Psychology, The Pennsylvania State University, University Park, PA, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^d Center for m2Health, Palo Alto University, Palo Alto, CA, United States
^e Department of Health Policy and Management, Fielding School of Public Health, University of California at Los Angeles, Los Angeles, CA, United States

Abstract
BACKGROUND: Online surveys are routinely used in mental health screening and treatment follow-up assessment, though they can yield low response rates. We tested the effects of social psychology-informed influence strategies for increasing rates of participation in an online mental health screening survey (Experiment 1) and a treatment follow-up survey (Experiment 2). METHODS and RESULTS: In Experiment 1 (N = 45,569), embedding one or any combination of three motivational appeals (personal gain, community gain, and inclusivity) in screening survey invitation and reminder emails unexpectedly led to lower rates of survey participation compared to when the appeals were not included (overall participation rate = 12.02%, ORs = 0.75 to 0.97, ps < .001). In Experiment 2 (N = 873), a video of a TikTok influencer encouraging survey participation embedded in treatment follow-up survey invitation and reminder emails did not significantly affect survey completion compared to a humorous gif unrelated to survey participation (overall participation rate = 47.88%, OR = 1.18, p = .200). Moderator analyses revealed that the video led to higher rates of participation than the gif among White participants (OR = 1.39, p = .031) and non-Hispanic participants (OR = 1.35, p = .029) only, whereas the video led to lower rates of participation than the gif among students who did not disclose their race (OR = 0.31, p = .010). CONCLUSIONS: Efforts to improve online survey participation should be balanced with possible downsides (e.g., added email length) and should be evaluated for differential performance among population subgroups prior to widespread implementation. © 2023 Association Française de Therapie Comportementale et Cognitive

Author Keywords
Influencer;  Methodology;  Online surveys;  Recruitment;  Sampling;  Social media

Funding details
K01MD017630, K08MH120341, R01MH115128, T32HL130357

Document Type: Article
Publication Stage: Final
Source: Scopus

Oxidation Driven Reversal of PIP2-dependent Gating in GIRK2 Channels
(2023) Function, 4 (3), art. no. zqad016, . 

Lee, S.-J.^a , Maeda, S.^b , Gao, J.^a , Nichols, C.G.^a

^a Department of Cell Biology and Physiology, Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI, United States

Abstract
Physiological activity of G protein gated inward rectifier K+ (GIRK, Kir3) channel, dynamically regulated by three key ligands, phosphoinositol-4,5-bisphosphate (PIP2), G, and Na+, underlies cellular electrical response to multiple hormones and neurotransmitters in myocytes and neurons. In a reducing environment, matching that inside cells, purified GIRK2 (Kir3.2) channels demonstrate low basal activity, and expected sensitivity to the above ligands. However, under oxidizing conditions, anomalous behavior emerges, including rapid loss of PIP2 and Na+-dependent activation and a high basal activity in the absence of any agonists, that is now paradoxically inhibited by PIP2. Mutagenesis identifies two cysteine residues (C65 and C190) as being responsible for the loss of PIP2 and Na+-dependent activity and the elevated basal activity, respectively. The results explain anomalous findings from earlier studies and illustrate the potential pathophysiologic consequences of oxidation on GIRK channel function, as well as providing insight to reversed ligand-dependence of Kir and KirBac channels. © Function. All Rights Reserved.

Author Keywords
GIRK2;  kir3;  oxidation;  oxidative stress;  PIP2;  reversed gating

Funding details
National Institutes of HealthNIHHL140024, TR003670

Document Type: Article
Publication Stage: Final
Source: Scopus

Ex vivo immunocapture and functional characterization of cell-type-specific mitochondria using MitoTag mice
(2023) Nature Protocols, . 

de Mello, N.P.^a b c , Fecher, C.^a c d , Pastor, A.M.^a , Perocchi, F.^a b e , Misgeld, T.^a e f

^a Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany
^b Institute for Diabetes and Obesity, Helmholtz Zentrum München, Munich, Germany
^c Graduate School of Systemic Neurosciences, Ludwig-Maximilians Universität München, Munich, Germany
^d Department of Cell Biology & Physiology, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^e Munich Cluster for Systems Neurology, Munich, Germany
^f German Center for Neurodegenerative Diseases, Munich, Germany

Abstract
Mitochondria are key bioenergetic organelles involved in many biosynthetic and signaling pathways. However, their differential contribution to specific functions of cells within complex tissues is difficult to dissect with current methods. The present protocol addresses this need by enabling the ex vivo immunocapture of cell-type-specific mitochondria directly from their tissue context through a MitoTag reporter mouse. While other available methods were developed for bulk mitochondria isolation or more abundant cell-type-specific mitochondria, this protocol was optimized for the selective isolation of functional mitochondria from medium-to-low-abundant cell types in a heterogeneous tissue, such as the central nervous system. The protocol has three major parts: First, mitochondria of a cell type of interest are tagged via an outer mitochondrial membrane eGFP by crossing MitoTag mice to a cell-type-specific Cre-driver line or by delivery of viral vectors for Cre expression. Second, homogenates are prepared from relevant tissues by nitrogen cavitation, from which tagged organelles are immunocaptured using magnetic microbeads. Third, immunocaptured mitochondria are used for downstream assays, e.g., to probe respiratory capacity or calcium handling, revealing cell-type-specific mitochondrial diversity in molecular composition and function. The MitoTag approach enables the identification of marker proteins to label cell-type-specific organelle populations in situ, elucidates cell-type-enriched mitochondrial metabolic and signaling pathways, and reveals functional mitochondrial diversity between adjacent cell types in complex tissues, such as the brain. Apart from establishing the mouse colony (6–8 weeks without import), the immunocapture protocol takes 2 h and functional assays require 1–2 h. © 2023, Springer Nature Limited.

Funding details
390857198, EXC 2145
Seventh Framework ProgrammeFP7616791, FP/2007-2013
European Research CouncilERC
Deutsche ForschungsgemeinschaftDFGCRC870 A11-ID 118803580, Mi 694/7-1, Mi 694/8-1, Mi 694/9-1 A03-ID 428663564, TRR 274/1 B03/ C02-ID 408885537
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Helmholtz Association

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

Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals
(2023) Psychological Medicine, . 

Hinojosa, C.A.^a , Liew, A.^a , An, X.^b , Stevens, J.S.^a , Basu, A.^c , Van Rooij, S.J.H.^a , House, S.L.^d , Beaudoin, F.L.^e , Zeng, D.^f , Neylan, T.C.^g , Clifford, G.D.^h i , Jovanovic, T.^j , Linnstaedt, S.D.^b , Germine, L.T.^k l m , Rauch, S.L.^k m n , Haran, J.P.^o , Storrow, A.B.^p , Lewandowski, C.^q , Musey, P.I.^r , Hendry, P.L.^s , Sheikh, S.^s , Jones, C.W.^t , Punches, B.E.^u v , Kurz, M.C.^w x y , Swor, R.A.^z , Hudak, L.A.^aa , Pascual, J.L.^ab ac , Seamon, M.J.^ac ad , Datner, E.M.^ae af , Chang, A.M.^ag , Pearson, C.^ah , Peak, D.A.^ai , Merchant, R.C.^aj , Domeier, R.M.^ak , Rathlev, N.K.^al , Sergot, P.^am , Sanchez, L.D.^aj an , Bruce, S.E.^ao , Miller, M.W.^ap aq , Pietrzak, R.H.^ar as , Joormann, J.^at , Pizzagalli, D.A.^m au , Sheridan, J.F.^av aw , Harte, S.E.^ax ay , Elliott, J.M.^az ba bb , Kessler, R.C.^bc , Koenen, K.C.^c , McLean, S.A.^bd be , Ressler, K.J.^m au , Fani, N.^a

^a Department of Psychiatry and Behavioral Sciences, Emory University, School of Medicine, Atlanta, GA, United States
^b Department of Anesthesiology, Institute for Trauma Recovery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^c Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
^d Department of Emergency Medicine, Washington University, School of Medicine, St. Louis, MO, United States
^e Department of Emergency Medicine, Department of Health Services, Policy, and Practice, The Alpert Medical School, Brown University, Rhode Island Hospital, The Miriam Hospital, Providence, RI, United States
^f Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States
^g Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, United States
^h Department of Biomedical Informatics, Emory University, School of Medicine, Atlanta, GA, United States
ⁱ Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta, GA, United States
^j Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, United States
^k Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
^l The Many Brains Project, Belmont, MA, United States
^m Department of Psychiatry, Harvard Medical School, Boston, MA, United States
ⁿ Department of Psychiatry, McLean Hospital, Belmont, MA, United States
^o Department of Emergency Medicine, University of Massachusetts, Chan Medical School, Worcester, MA, United States
^p Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
^q Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
^r Department of Emergency Medicine, Indiana University, School of Medicine, Indianapolis, IN, United States
^s Department of Emergency Medicine, University of Florida, College of Medicine, Jacksonville, FL, United States
^t Department of Emergency Medicine, Cooper Medical School, Rowan University, Camden, NJ, United States
^u Department of Emergency Medicine, Ohio State University, College of Medicine, Columbus, OH, United States
^v Ohio State University, College of Nursing, Columbus, OH, United States
^w Department of Emergency Medicine, University of Alabama, School of Medicine, Birmingham, AL, United States
^x Department of Surgery, Division of Acute Care Surgery, University of Alabama, School of Medicine, Birmingham, AL, United States
^y Center for Injury Science, University of Alabama at Birmingham, Birmingham, AL, United States
^z Department of Emergency Medicine, Oakland University, William Beaumont School of Medicine, Rochester, MI, United States
^aa Department of Emergency Medicine, Emory University, School of Medicine, Atlanta, GA, United States
^ab Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States
^ac Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ad Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, United States
^ae Department of Emergency Medicine, Einstein Healthcare Network, Philadelphia, PA, United States
^af Department of Emergency Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
^ag Department of Emergency Medicine, Jefferson University Hospitals, Philadelphia, PA, United States
^ah Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, United States
^ai Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
^aj Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^ak Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ypsilanti, MI, United States
^al Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, United States
^am Department of Emergency Medicine, McGovern Medical School, UTHealth, Houston, TX, United States
^an Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
^ao Department of Psychological Sciences, University of Missouri, St. Louis, MO, United States
^ap Behavioral Science Division, National Center for Ptsd, Va Boston Healthcare System, Boston, MA, United States
^aq Department of Psychiatry, Boston University, School of Medicine, Boston, MA, United States
^ar Clinical Neurosciences Division, National Center for Ptsd, Va Connecticut Healthcare System, West Haven, CT, United States
^as Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
^at Department of Psychology, Yale University, New Haven, CT, United States
^au Division of Depression and Anxiety, McLean Hospital, Belmont, MA, United States
^av Division of Biosciences, Ohio State University, College of Dentistry, Columbus, OH, United States
^aw Institute for Behavioral Medicine Research, Osu Wexner Medical Center, Columbus, OH, United States
^ax Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
^ay Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, United States
^az Kolling Institute, University of Sydney, St Leonards, NSW, Australia
^ba Faculty of Medicine and Health, University of Sydney, Northern Sydney Local Health District, St. Leonards NSWNSW, Australia
^bb Physical Therapy & Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^bc Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
^bd Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^be Department of Psychiatry, Institute for Trauma Recovery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Abstract
Background Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. Methods In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant’s substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. Results Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. Conclusions Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies. Copyright © The Author(s), 2023. Published by Cambridge University Press.

Author Keywords
alcohol use;  cannabis use;  depression;  posttraumatic stress disorder

Funding details
R33AG05654
U01MH110925
R01HD079076, R03HD094577
1H79TI083101-01

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

Adaptation of a Mobile Interactive Obesity Treatment Approach for Early Severe Mental Illness: Protocol for a Mixed Methods Implementation and Pilot Randomized Controlled Trial
(2023) JMIR Research Protocols, 12, art. no. e42114, . 

Nicol, G.E.^a , Jansen, M.O.^b , Ricchio, A.R.^a , Schweiger, J.A.^a , Keenoy, K.E.^c , Miller, J.P.^d , Morrato, E.H.^e , Guo, Z.^a , Evanoff, B.A.^f , Parks, J.J.^g , Newcomer, J.W.^h

^a Department of Psychiatry, Washington University School of Medicine, Washington University in St. Louis, Saint Louis, MO, United States
^b Division of Child & Adolescent Psychiatry, Department of Psychiatry, University of California, Los Angeles, Los Angeles, CA, United States
^c Trial-CARE Division, Center for Clinical Studies, Washington University School of Medicine, St. Louis, MO, United States
^d Division of Biostatistics, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^e Parkinson School of Health Sciences and Public Health, Loyola University of Chicago, Chicago, IL, United States
^f Division of General Medical Sciences, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
^g National Council for Mental Wellbeing, Washington, DC, United States
^h Thriving Mind South Florida, Miami, FL, United States

Abstract
Background: Obesity is common in individuals with severe mental illness (SMI), contributing to a significantly shortened lifespan when compared to the general population. Available weight loss treatments have attenuated efficacy in this population, underscoring the importance of prevention and early intervention. Objective: Here, we describe a type 1 hybrid study design for adapting and pilot-testing an existing mobile health intervention for obesity prevention in individuals with early SMI and Class I or early-stage obesity, defined as a BMI of 30-35. Methods: An existing, evidence-based interactive obesity treatment approach using low-cost, semiautomated SMS text messaging was selected for adaptation. Community mental health clinics and Clubhouse settings in Eastern Missouri and South Florida were identified to participate. This study has the following 3 aims. First, using the Enhanced Framework for Reporting Adaptations and Modifications to Evidence-based interventions, contextual aspects of the clinical and digital treatment environments are identified for adaptation, considering 5 main stakeholder groups (clinical administrators, prescribing clinicians, case managers, nurses, and patients). Following a 2-week trial of unadapted SMS text messaging, Innovation Corps methods are used to discover needed intervention adaptations by stakeholder group and clinical setting. Second, adaptations to digital functionality and intervention content will be made based on themes identified in aim 1, followed by rapid usability testing with key stakeholders. A process for iterative treatment adaptation will be developed for making unplanned modifications during the aim 3 implementation pilot study. Individuals working in partner community mental health clinics and Clubhouse settings will be trained in intervention delivery. Third, in a randomized pilot and feasibility trial, adults with 5 years or less of treatment for an SMI diagnosis will be randomized 2:1 to 6 months of an adapted interactive obesity treatment approach or to an attentional control condition, followed by a 3-month extension phase of SMS text messages only. Changes in weight, BMI, and behavioral outcomes, as well as implementation challenges, will be evaluated at 6 and 9 months. Results: Institutional review board approval for aims 1 and 2 was granted on August 12, 2018, with 72 focus group participants enrolled; institutional review board approval for aim 3 was granted on May 6, 2020. To date, 52 participants have been enrolled in the study protocol. Conclusions: In this type 1 hybrid study design, we apply an evidence-based treatment adaptation framework to plan, adapt, and feasibility test a mobile health intervention in real-world treatment settings. Resting at the intersection of community mental health treatment and physical health promotion, this study aims to advance the use of simple technology for obesity prevention in individuals with early-stage mental illness. © Ginger E Nicol, Madeline O Jansen, Amanda R Ricchio, Julia A Schweiger, Katie E Keenoy, J Philip Miller, Elaine H Morrato, Zhaohua Guo, Bradley A Evanoff, Joseph J Parks, John W Newcomer. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 09.06.2023. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on https://www.researchprotocols.org, as well as this copyright and license information must be included.

Author Keywords
community mental health services;  implementation science;  mental disorders;  obesity;  primary prevention

Funding details
UL1TR002345
P30DK092950
MH118395

Document Type: Article
Publication Stage: Final
Source: Scopus

Toward a computational theory of manifold untangling: from global embedding to local flattening
(2023) Frontiers in Computational Neuroscience, 17, art. no. 1197031, . 

Li, X.^a , Wang, S.^b

^a Lane Department of Computer Science and Electrical Engineering (CSEE), West Virginia University, Morgantown, WV, United States
^b Department of Radiology, Washington University at St. Louis, St. Louis, MO, United States

Abstract
It has been hypothesized that the ventral stream processing for object recognition is based on a mechanism called cortically local subspace untangling. A mathematical abstraction of object recognition by the visual cortex is how to untangle the manifolds associated with different object categories. Such a manifold untangling problem is closely related to the celebrated kernel trick in metric space. In this paper, we conjecture that there is a more general solution to manifold untangling in the topological space without artificially defining any distance metric. Geometrically, we can either embed a manifold in a higher-dimensional space to promote selectivity or flatten a manifold to promote tolerance. General strategies of both global manifold embedding and local manifold flattening are presented and connected with existing work on the untangling of image, audio, and language data. We also discuss the implications of untangling the manifold into motor control and internal representations. Copyright © 2023 Li and Wang.

Author Keywords
blessing of dimensionality;  manifold embedding;  manifold flattening;  motor control;  object recognition

Funding details
FA9550-21-1-0088
R01MH129426
BCS-1945230, IIS-2114644

Document Type: Article
Publication Stage: Final
Source: Scopus

Managing EEG studies: How to prepare and what to do once data collection has begun
(2023) Psychophysiology, . 

Boudewyn, M.A.^a , Erickson, M.A.^b , Winsler, K.^c , Ragland, J.D.^d , Yonelinas, A.^c , Frank, M.^e , Silverstein, S.M.^f , Gold, J.^g , MacDonald, A.W., III^h , Carter, C.S.^d , Barch, D.M.ⁱ , Luck, S.J.^c

^a Department of Psychology, University of California Santa Cruz, Santa Cruz, CA, United States
^b Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
^c Department of Psychology, University of California, Davis, CA, United States
^d Department of Psychiatry and Behavioral Sciences, University of California, Davis, CA, United States
^e Department of Cognitive, Linguistics and Psychological Sciences, Brown University, Providence, RI, United States
^f Department of Psychiatry, Neuroscience and Opthamology, University of Rochester, Rochester Medical Center, Rochester, NY, United States
^g Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States
^h Department of Psychology, University of Minnesota, Minneapolis, MN, United States
ⁱ Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
In this paper, we provide guidance for the organization and implementation of EEG studies. This work was inspired by our experience conducting a large-scale, multi-site study, but many elements could be applied to any EEG project. Section 1 focuses on study activities that take place before data collection begins. Topics covered include: establishing and training study teams, considerations for task design and piloting, setting up equipment and software, development of formal protocol documents, and planning communication strategy with all study team members. Section 2 focuses on what to do once data collection has already begun. Topics covered include: (1) how to effectively monitor and maintain EEG data quality, (2) how to ensure consistent implementation of experimental protocols, and (3) how to develop rigorous preprocessing procedures that are feasible for use in a large-scale study. Links to resources are also provided, including sample protocols, sample equipment and software tracking forms, sample code, and tutorial videos (to access resources, please visit: https://osf.io/wdrj3/). © 2023 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.

Author Keywords
EEG methods;  guidelines;  large-scale;  multisite;  protocol;  recommendations

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