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Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer's disease neuropathology and atypical effects of the cholinergic antagonist atropine

Alcantara-Gonzalez, David; Chartampila, Elissavet; Criscuolo, Chiara; Scharfman, Helen E
It has been reported that hyperexcitability occurs in a subset of patients with Alzheimer's disease (AD) and hyperexcitability could contribute to the disease. Several studies have suggested that the hippocampal dentate gyrus (DG) may be an important area where hyperexcitability occurs. Therefore, we tested the hypothesis that the principal DG cell type, granule cells (GCs), would exhibit changes at the single-cell level which would be consistent with hyperexcitability and might help explain it. We used the Tg2576 mouse, where it has been shown that hyperexcitability is robust at 2-3 months of age. GCs from 2 to 3-month-old Tg2576 mice were compared to age-matched wild type (WT) mice. Effects of muscarinic cholinergic antagonism were tested because previously we found that Tg2576 mice exhibited hyperexcitability in vivo that was reduced by the muscarinic cholinergic antagonist atropine, counter to the dogma that in AD one needs to boost cholinergic function. The results showed that GCs from Tg2576 mice exhibited increased frequency of spontaneous excitatory postsynaptic potentials/currents (sEPSP/Cs) and reduced frequency of spontaneous inhibitory synaptic events (sIPSCs) relative to WT, increasing the excitation:inhibition (E:I) ratio. There was an inward NMDA receptor-dependent current that we defined here as a novel synaptic current (nsC) in Tg2576 mice because it was very weak in WT mice. Intrinsic properties were distinct in Tg2576 GCs relative to WT. In summary, GCs of the Tg2576 mouse exhibit early electrophysiological alterations that are consistent with increased synaptic excitation, reduced inhibition, and muscarinic cholinergic dysregulation. The data support previous suggestions that the DG contributes to hyperexcitability and there is cholinergic dysfunction early in life in AD mouse models.
PMID: 33484828
ISSN: 1095-953x
CID: 4766672

Determinants of using children's mental health research in policymaking: variation by type of research use and phase of policy process

Purtle, Jonathan; Nelson, Katherine L; Horwitz, Sarah Mc Cue; McKay, Mary M; Hoagwood, Kimberly E
BACKGROUND:Research use in policymaking is multi-faceted and has been the focus of extensive study. However, virtually no quantitative studies have examined whether the determinants of research use vary according to the type of research use or phase of policy process. Understanding such variation is important for selecting the targets of implementation strategies that aim to increase the frequency of research use in policymaking. METHODS:A web-based survey of US state agency officials involved with children's mental health policymaking was conducted between December 2019 and February 2020 (n = 224, response rate = 33.7%, 49 states responding (98%), median respondents per state = 4). The dependent variables were composite scores of the frequency of using children's mental health research in general, specific types of research use (i.e., conceptual, instrumental, tactical, imposed), and during different phases of the policy process (i.e., agenda setting, policy development, policy implementation). The independent variables were four composite scores of determinants of research use: agency leadership for research use, agency barriers to research use, research use skills, and dissemination barriers (e.g., lack of actionable messages/recommendations in research summaries, lack of interaction/collaboration with researchers). Separate multiple linear regression models estimated associations between determinant and frequency of research use scores. RESULTS:Determinants of research use varied significantly by type of research use and phase of policy process. For example, agency leadership for research use was the only determinant significantly associated with imposed research use (β = 0.31, p < 0.001). Skills for research use were the only determinant associated with tactical research use (β = 0.17, p = 0.03) and were only associated with research use in the agenda-setting phase (β = 0.16, p = 0.04). Dissemination barriers were the most universal determinants of research use, as they were significantly and inversely associated with frequency of conceptual (β = -0.21, p = 0.01) and instrumental (β = -0.22, p = 0.01) research use and during all three phases of policy process. CONCLUSIONS:Decisions about the determinants to target with policy-focused implementation strategies-and the strategies that are selected to affect these targets-should reflect the specific types of research use that these strategies aim to influence.
PMCID:7815190
PMID: 33468166
ISSN: 1748-5908
CID: 4798712

Synaptic processes and immune-related pathways implicated in Tourette syndrome

Tsetsos, Fotis; Yu, Dongmei; Sul, Jae Hoon; Huang, Alden Y; Illmann, Cornelia; Osiecki, Lisa; Darrow, Sabrina M; Hirschtritt, Matthew E; Greenberg, Erica; Muller-Vahl, Kirsten R; Stuhrmann, Manfred; Dion, Yves; Rouleau, Guy A; Aschauer, Harald; Stamenkovic, Mara; Schlögelhofer, Monika; Sandor, Paul; Barr, Cathy L; Grados, Marco A; Singer, Harvey S; Nöthen, Markus M; Hebebrand, Johannes; Hinney, Anke; King, Robert A; Fernandez, Thomas V; Barta, Csaba; Tarnok, Zsanett; Nagy, Peter; Depienne, Christel; Worbe, Yulia; Hartmann, Andreas; Budman, Cathy L; Rizzo, Renata; Lyon, Gholson J; McMahon, William M; Batterson, James R; Cath, Danielle C; Malaty, Irene A; Okun, Michael S; Berlin, Cheston; Woods, Douglas W; Lee, Paul C; Jankovic, Joseph; Robertson, Mary M; Gilbert, Donald L; Brown, Lawrence W; Coffey, Barbara J; Dietrich, Andrea; Hoekstra, Pieter J; Kuperman, Samuel; Zinner, Samuel H; Wagner, Michael; Knowles, James A; Jeremy Willsey, A; Tischfield, Jay A; Heiman, Gary A; Cox, Nancy J; Freimer, Nelson B; Neale, Benjamin M; Davis, Lea K; Coppola, Giovanni; Mathews, Carol A; Scharf, Jeremiah M; Paschou, Peristera; Barr, Cathy L; Batterson, James R; Berlin, Cheston; Budman, Cathy L; Cath, Danielle C; Coppola, Giovanni; Cox, Nancy J; Darrow, Sabrina; Davis, Lea K; Dion, Yves; Freimer, Nelson B; Grados, Marco A; Greenberg, Erica; Hirschtritt, Matthew E; Huang, Alden Y; Illmann, Cornelia; King, Robert A; Kurlan, Roger; Leckman, James F; Lyon, Gholson J; Malaty, Irene A; Mathews, Carol A; McMahon, William M; Neale, Benjamin M; Okun, Michael S; Osiecki, Lisa; Robertson, Mary M; Rouleau, Guy A; Sandor, Paul; Scharf, Jeremiah M; Singer, Harvey S; Smit, Jan H; Sul, Jae Hoon; Yu, Dongmei; Aschauer, Harald Aschauer Harald; Barta, Csaba; Budman, Cathy L; Cath, Danielle C; Depienne, Christel; Hartmann, Andreas; Hebebrand, Johannes; Konstantinidis, Anastasios; Mathews, Carol A; Müller-Vahl, Kirsten; Nagy, Peter; Nöthen, Markus M; Paschou, Peristera; Rizzo, Renata; Rouleau, Guy A; Sandor, Paul; Scharf, Jeremiah M; Schlögelhofer, Monika; Stamenkovic, Mara; Stuhrmann, Manfred; Tsetsos, Fotis; Tarnok, Zsanett; Wolanczyk, Tomasz; Worbe, Yulia; Brown, Lawrence; Cheon, Keun-Ah; Coffey, Barbara J; Dietrich, Andrea; Fernandez, Thomas V; Garcia-Delgar, Blanca; Gilbert, Donald; Grice, Dorothy E; Hagstrøm, Julie; Hedderly, Tammy; Heiman, Gary A; Heyman, Isobel; Hoekstra, Pieter J; Huyser, Chaim; Kim, Young Key; Kim, Young-Shin; King, Robert A; Koh, Yun-Joo; Kook, Sodahm; Kuperman, Samuel; Leventhal, Bennett L; Madruga-Garrido, Marcos; Mir, Pablo; Morer, Astrid; Münchau, Alexander; Plessen, Kerstin J; Roessner, Veit; Shin, Eun-Young; Song, Dong-Ho; Song, Jungeun; Tischfield, Jay A; Willsey, A Jeremy; Zinner, Samuel; Aschauer, Harald; Barr, Cathy L; Barta, Csaba; Batterson, James R; Berlin, Cheston; Brown, Lawrence; Budman, Cathy L; Cath, Danielle C; Coffey, Barbara J; Coppola, Giovanni; Cox, Nancy J; Darrow, Sabrina; Davis, Lea K; Depienne, Christel; Dietrich, Andrea; Dion, Yves; Fernandez, Thomas; Freimer, Nelson B; Gilbert, Donald; Grados, Marco A; Greenberg, Erica; Hartmann, Andreas; Hebebrand, Johannes; Heiman, Gary; Hirschtritt, Matthew E; Hoekstra, Pieter; Huang, Alden Y; Illmann, Cornelia; Jankovic, Joseph; King, Robert A; Kuperman, Samuel; Lee, Paul C; Lyon, Gholson J; Malaty, Irene A; Mathews, Carol A; McMahon, William M; Müller-Vahl, Kirsten; Nagy, Peter; Neale, Benjamin M; Nöthen, Markus M; Okun, Michael S; Osiecki, Lisa; Paschou, Peristera; Rizzo, Renata; Robertson, Mary M; Rouleau, Guy A; Sandor, Paul; Scharf, Jeremiah M; Schlögelhofer, Monika; Singer, Harvey S; Stamenkovic, Mara; Stuhrmann, Manfred; Sul, Jae Hoon; Tarnok, Zsanett; Tischfield, Jay; Tsetsos, Fotis; Willsey, A Jeremy; Woods, Douglas; Worbe, Yulia; Yu, Dongmei; Zinner, Samuel
Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.
PMID: 33462189
ISSN: 2158-3188
CID: 4760342

Sensing everyday activity: Parent perceptions and feasibility

Levin, Hannah I; Egger, Dominique; Andres, Lara; Johnson, Mckensey; Bearman, Sarah Kate; de Barbaro, Kaya
Mobile and wearable sensors provide a unique opportunity to capture the daily activities and interactions that shape developmental trajectories, with potential to revolutionize the study of development (de Barbaro, 2019). However, developmental research employing sensors is still in its infancy, and parents' comfort using these devices is uncertain. This exploratory report assesses parent willingness to participate in sensor studies via a nationally representative survey (N = 210) and live recruitment of a low-income, minority population for an ongoing study (N = 359). The survey allowed us to assess how protocol design influences acceptability, including various options for devices and datastream resolution, conditions of data sharing, and feedback. By contrast, our recruitment data provided insight into parents' true willingness to participate in a sensor study, with a protocol including 72 h of continuous audio, motion, and physiological data. Our results indicate that parents are relatively conservative when considering participation in sensing studies. However, nearly 41 % of surveyed parents reported that they would be at least somewhat willing to participate in studies with audio or video recordings, 26 % were willing or extremely willing, and 14 % reported being extremely willing. These results roughly paralleled our recruitment results, where 58 % of parents indicated interest, 29 % of parents scheduled to participate, and 10 % ultimately participated. Additionally, 70 % of caregivers stated their reason for not participating in the study was due to barriers unrelated to sensing while about 25 % noted barriers due to either privacy concerns or the physical sensors themselves. Parents' willingness to collect sensitive datastreams increased if data stayed within the household for individual use only, are shared anonymously with researchers, or if parents receive feedback from devices. Overall, our findings suggest that given the correct circumstances, mobile sensors are a feasible and promising tool for characterizing children's daily interactions and their role in development.
PMID: 33465730
ISSN: 1934-8800
CID: 4760492

Adapting an empirical clinic-based organizational skills training program for use in schools: Iterative development and pilot assessment

Di Bartolo, Christina A.; Abikoff, Howard; McDonald, Margaret; Gallagher, Richard
Effective organizational skills (e.g., time management, materials management, and task planning) are associated with academic success, yet some children struggle to gain these skills without intervention. While evidence-based organizational skills interventions for pediatric clinical populations exist, none target organizationally impaired general populations in a primary school setting. In Organizational Skills Training-School (OST-S), school professionals teach small groups of 4th"“5th grade organizationally impaired elementary school students skills associated with tracking assignments, managing materials, time management, and planning. This open pilot study of 33 students examined: a. the feasibility of adapting and implementing an established clinic-based, individualized treatment (OST-C) to a group format in a school setting, b. the program's acceptability among children, parents, and school partners, and c. whether participating children improved in the same functional areas that OST-C positively influenced. Results indicated that we could adapt the intervention, school partners could implement it, and participants could accept it. Pre-post improvements in organizational skills (as rated by parents, teachers, and children), homework problems, and academic performance demonstrated the potential effectiveness of OST-S, suggesting the need for further efficacy work.
SCOPUS:85104490878
ISSN: 0033-3085
CID: 4861652

Useful Untruths: A Plea for the Necessity of Pluralism in Child Analysis

Lament, Claudia
The late nineteenth century philosopher Hans Vaihinger and the preeminent contemporary philosopher, Kwame Anthony Appiah contend that in order to see a more complete picture of the world, we need a plurality of pictures with which to view it, not just one. This truth comes with epistemological burdens and with the inconvenient fact that the human mind is unable to juggle more than one picture or theory simultaneously. Thus, psychoanalytic clinicians tend to select one theory as a guide when treating patients. In this paper, I will offer ways to think about this conundrum as it appears in the child psychoanalytic setting and whether it is possible to shift from one"™s usual theoretical point of view to include alternate theoretical perspectives"“and thus, to gain a more complete "truth", as Vaihinger and Appiah suggest we should aspire to"“as the clinical situation allows.
SCOPUS:85103831857
ISSN: 0079-7308
CID: 4860922

Recent smell loss is the best predictor of COVID-19 among individuals with recent respiratory symptoms

Gerkin, Richard C; Ohla, Kathrin; Veldhuizen, Maria G; Joseph, Paule V; Kelly, Christine E; Bakke, Alyssa J; Steele, Kimberley E; Farruggia, Michael C; Pellegrino, Robert; Pepino, Marta Y; Bouysset, Cédric; Soler, Graciela M; Pereda-Loth, Veronica; Dibattista, Michele; Cooper, Keiland W; Croijmans, Ilja; Di Pizio, Antonella; Ozdener, M Hakan; Fjaeldstad, Alexander W; Lin, Cailu; Sandell, Mari A; Singh, Preet B; Brindha, V Evelyn; Olsson, Shannon B; Saraiva, Luis R; Ahuja, Gaurav; Alwashahi, Mohammed K; Bhutani, Surabhi; D'Errico, Anna; Fornazieri, Marco A; Golebiowski, Jérôme; Hwang, Liang-Dar; Öztürk, Lina; Roura, Eugeni; Spinelli, Sara; Whitcroft, Katherine L; Faraji, Farhoud; Fischmeister, Florian PhS; Heinbockel, Thomas; Hsieh, Julien W; Huart, Caroline; Konstantinidis, Iordanis; Menini, Anna; Morini, Gabriella; Olofsson, Jonas K; Philpott, Carl M; Pierron, Denis; Shields, Vonnie D C; Voznessenskaya, Vera V; Albayay, Javier; Altundag, Aytug; Bensafi, Moustafa; Bock, María Adelaida; Calcinoni, Orietta; Fredborg, William; Laudamiel, Christophe; Lim, Juyun; Lundström, Johan N; Macchi, Alberto; Meyer, Pablo; Moein, Shima T; Santamaría, Enrique; Sengupta, Debarka; Dominguez, Paloma Rohlfs; Yanik, Hüseyin; Hummel, Thomas; Hayes, John E; Reed, Danielle R; Niv, Masha Y; Munger, Steven D; Parma, Valentina
In a preregistered, cross-sectional study we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC=0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4<OR<10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable.
PMID: 33367502
ISSN: 1464-3553
CID: 4731482

Substance-induced or substance-associated primary psychoses? Continuing the discussion. a response to i.А. fedotov, et al.

Cherro, M.; Jatchavala, C.; Handuleh, D. J.I.M.; Ransing, R.; Shoib, Sh; Ori, D.; Ojeahere, M. I.; Soler-Vidal, J.; Pereira-Sanchez, V.
This letter to the editor continues the discussion about the similarities and differences between secondary psychosis and schizophrenia, which was initiated by the authors of the article «Substance-induced psychosis and schizophrenia: the interaction point» (Fedotov I.A., Quattrone D., Shustov D.I. Substance-induced psychosis and schizophrenia: the interaction point. I.P. Pavlov Russian Medical Biological Herald. 2020;28(4):593-604. doi:10.23888/PAVLOVJ2020284593-604).
SCOPUS:85121286046
ISSN: 0204-3475
CID: 5115142

Friendly Faces: Characteristics of Children and Adolescents With Repeat Visits to a Specialized Child Psychiatric Emergency Program

Marr, Mollie; Horwitz, Sarah M; Gerson, Ruth; Storfer-Isser, Amy; Havens, Jennifer F
OBJECTIVES/OBJECTIVE:Pediatric mental health emergency department (ED) visits continue to rise with 19% to 62% of youth presenting to the ED ultimately returning for a mental health-related complaint. To better understand the needs of children returning to the ED, this study examines the clinical, demographic, and environmental factors associated with revisits to a dedicated child psychiatric ED. METHODS:Clinical factors, home environment, and mental health service utilization of 885 children presenting to a dedicated child psychiatric ED over a 1-year period were abstracted by retrospective chart review. Bivariate analyses comparing demographic and clinical characteristics for children with and without revisits and a multivariable logistic regression were performed. RESULTS:Of the children presenting to the ED, 186 (21.0%) had at least 1 revisit in the subsequent 180 days. Thirty-one percent of initial visits presented as urgent, 55% presented as emergent. Children presenting with more severe symptoms at their initial visit were more likely to return within 6 months. Female gender, suicidal and disruptive behavioral symptomatology, and a diagnosis of oppositional defiant disorder were associated with repeat visits. Children with mental health system involvement were more likely to have revisits than those who were "treatment naive." CONCLUSIONS:Revisits to the ED are driven by both clinical factors, including severity and psychosocial complexity, and barriers to accessing services. Addressing the problem of return ED visits will require the development of a robust mental health service system that is accessible to children and families of all socioeconomic levels.
PMID: 29438124
ISSN: 1535-1815
CID: 2956152

9/11 Twenty Years On: Fractured Identities; Fear of the Other; Forging a New Path for Our Children Introduction to the Section

Lament, Claudia; Ismi, Naghma Mimi
This is an introduction to a collection of papers that commemorates the twentieth anniversary of 9/11. The nature of the content of the papers which follow is spurred by reflections on this anniversary from a number of domains: child and adult psychoanalysis; the healing arts of theater; the parent-child treatment of Afghani and Iraqi asylum-seeking families; the Law of the Mother and siblingships; the changes occurring in psychoanalytic views of secularism; and the confrontation of racial prejudice and othering in the workplace and its repercussions upon the self. Concepts of splitting, the bearing of ambivalence, and the capacity to reflect and resist fragmentation are illuminated.
SCOPUS:85116542930
ISSN: 0079-7308
CID: 5055702