Search

Neural activity and behavior vary within an individual (states) and between individuals (traits). However, the mapping of state-trait neural variation to behavior is not well understood. To address this gap, we quantify moment-to-moment changes in brain-wide co-activation patterns derived from resting-state functional magnetic resonance imaging. In healthy young adults, we identify reproducible spatiotemporal features of co-activation patterns at the single-subject level. We demonstrate that a joint analysis of state-trait neural variations and feature reduction reveal general motifs of individual differences, encompassing state-specific and general neural features that exhibit day-to-day variability. The principal neural variations co-vary with the principal variations of behavioral phenotypes, highlighting cognitive function, emotion regulation, alcohol and substance use. Person-specific probability of occupying a particular co-activation pattern is reproducible and associated with neural and behavioral features. This combined analysis of state-trait variations holds promise for developing reproducible neuroimaging markers of individual life functional outcome., Competing Interests: K.L. consults for Manifest Technologies. A.A. and J.D.M. hold equity with Neumora Therapeutics (formerly BlackThorn Therapeutics), Manifest Technologies, and are co-inventors on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding(N-BRIDGE), PCT International Application No.PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No.16/149,903, filed on October 2, 664 2018, U.S. Application for PCT International Application No.18/054, 009 filed on October 2, 2018. J.L.J. is an employee of Manifest Technologies, has previously worked for Neumora, and is a co-inventor on the following patent: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No.PCT/US2119/022110, filed March 13, 2019. C.F. consults for Manifest Technologies and formerly consulted for RBNC (formerly BlackThorn Therapeutics). G.R. consults for and holds equity in Neumora and Manifest Technologies. L.P. is an employee of Manifest Technologies. J.H.K. holds equity in Biohaven Pharmaceuticals, Biohaven Pharmaceuticals Medical Sciences, Clearmind Medicine, EpiVario, Neumora Therapeutics, Tempero Bio, Terran Biosciences, Tetricus, and Spring Care. J.H.K. consults for AE Research Foundation, Aptinyx, Biohaven Pharmaceuticals, Biogen, Bionomics, Limited (Australia), BioXcel Therapeutics, Boehringer Ingelheim International, Cerevel Therapeutics, Clearmind Medicine, Cybin IRL, Delix Therapeutics, Eisai, Enveric Biosciences, Epiodyne, EpiVario, Evidera, Freedom Biosciences, Janssen Research & Development, Jazz Pharmaceuticals, Leal Therapeutics, Neumora Therapeutics, Neurocrine Biosciences, Novartis Pharmaceuticals Corporation, Otsuka America Pharmaceutical, Perception Neuroscience, Praxis Precision Medicines, PsychoGenics, Spring Care, Sunovion Pharmaceuticals, Takeda Industries, Tempero Bio, Terran Biosciences, and Tetricus. All other co-authors declare no competing interests., (Copyright: © 2024 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neural activity and behavior vary within an individual (states) and between individuals (traits). However, the mapping of state-trait neural variation to behavior is not well understood. To address this gap, we quantify moment-to-moment changes in brain-wide co-activation patterns derived from resting-state functional magnetic resonance imaging. In healthy young adults, we identify reproducible spatio-temporal features of co-activation patterns at the single subject level. We demonstrate that a joint analysis of state-trait neural variations and feature reduction reveal general motifs of individual differences, encompassing state-specific and general neural features that exhibit day-to-day variability. The principal neural variations co-vary with the principal variations of behavioral phenotypes, highlighting cognitive function, emotion regulation, alcohol and substance use. Person-specific probability of occupying a particular co-activation pattern is reproducible and associated with neural and behavioral features. This combined analysis of state-trait variations holds promise for developing reproducible neuroimaging markers of individual life functional outcome., Competing Interests: Declarations. A.A. and J.D.M. hold equity with Neumora Therapeutics (formerly BlackThorn Therapeutics), Manifest Technologies, and are co-inventors on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding(N-BRIDGE), PCT International Application No.PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No.16/149,903, filed on October 2, 664 2018, U.S. Application for PCT International Application No.18/054, 009 filed on October 2, 2018. J.L.J. is an employee of Manifest Technologies, has previously worked for Neumora, and is a co-inventor on the following patent: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No.PCT/US2119/022110, filed March 13, 2019. C.F. consults for Manifest Technologies and formerly consulted for RBNC (formerly BlackThorn Therapeutics). G.R. consults for and holds equity in Neumora and Manifest Technologies. L.P. is an employee of Manifest Technologies. J.H.K. holds equity in Biohaven Pharmaceuticals, Biohaven Pharmaceuticals Medical Sciences, Clearmind Medicine, EpiVario, Neumora Therapeutics, Tempero Bio, Terran Biosciences, Tetricus, and Spring Care. J.H.K. consults for AE Research Foundation, Aptinyx, Biohaven Pharmaceuticals, Biogen, Bionomics, Limited (Australia), BioXcel Therapeutics, Boehringer Ingelheim International, Cerevel Therapeutics, Clearmind Medicine, Cybin IRL, Delix Therapeutics, Eisai, Enveric Biosciences, Epiodyne, EpiVario, Evidera, Freedom Biosciences, Janssen Research & Development, Jazz Pharmaceuticals, Leal Therapeutics, Neumora Therapeutics, Neurocrine Biosciences, Novartis Pharmaceuticals Corporation, Otsuka America Pharmaceutical, Perception Neuroscience, Praxis Precision Medicines, PsychoGenics, Spring Care, Sunovion Pharmaceuticals, Takeda Industries, Tempero Bio, Terran Biosciences, and Tetricus. All other co-authors declare no competing interests.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects., Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets., Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level., Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry., Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV)., Clinical Trial Number: NCT03842800., Competing Interests: FM, MR, CS, BA, AS, NS, CD, AK, MF, NR, TC, JX, YC, PM, ES, FV No competing interests declared, JJ J.L.J. is an employee of Manifest Technologies and has previously worked for Neumora (formerly BlackThorn Therapeutics) and is a co-inventor on the following patent: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019, JB Currently an employee of Neumora Therapeutics and consulted for BlackThorn Therapeutics in 2019, ZT, CF Consults for Manifest Technologies and previously consulted for Neumora (formerly BlackThorn Therapeutics), GR Consults for and holds equity with RBNC (formerly BlackThorn Therapeutics), SF Sarah K. Fineberg: discloses work with the pharmaceutical company Boehringer Ingelheim as site PI for a multinational clinical trial and for consulting on advisory boards (< $10,000 in 2022), JK Was a consultant for Aptinyx, Atai Life Sciences, AstraZeneca Pharmaceuticals, Biogen Idec, Biomedisyn Corporation, Bionomics, Limited, Boehringer Ingelheim International, Cadent Therapeutics, Clexio Bioscience, COMPASS Pathways, Limited, Concert Pharmaceuticals, Epiodyne, EpiVario, Greenwich Biosciences, Heptares Therapeutics, Limited (UK), Janssen Research \& Development, Jazz Pharmaceuticals, Otsuka America Pharmaceutical, Perception Neuroscience Holdings, Spring Care, Sunovion Pharmaceuticals, Takeda Industries, Taisho Pharmaceutical Co. He served on advisory boards for Biohaven Pharmaceuticals, BioXcel Therapeutics, BlackThorn Therapeutics, Cadent Therapeutics, Cerevel Therapeutics, EpiVario, Eisai, Lohocla Research Corporation, Novartis Pharmaceuticals Corporation, PsychoGenics, Tempero Bio, and Terran Biosciences. He owns stock or stock options in Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Biohaven Pharmaceuticals Medical Sciences, BlackThorn Therapeutics, EpiVario, Terran Biosciences, and Tempero Bio, and he is on the editorial board of Biological Psychiatry, JM Consults for and holds equity with RBNC (formerly BlackThorn Therapeutics) and is a coinventor on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin, WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No. 16/149,903 filed on October 2, 2018, U.S. Application or PCT International Application No. 18/054,009 filed on October 2, 2018, KP Currently an employee of by Boehringer Ingelheim GmBH \& CO KG, AA Consults for and holds equity with RBNC (formerly BlackThorn Therapeutics) and is a coinventor on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin, WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No. 16/149,903 filed on October 2, 2018, U.S. Application for PCT International Application No. 18/054,009 filed on October 2, 2018, (© 2024, Moujaes, Ji et al.)

Importance: Understanding the mechanisms of major depressive disorder (MDD) improvement is a key challenge to determine effective personalized treatments., Objective: To perform a secondary analysis quantifying neural-to-symptom relationships in MDD as a function of antidepressant treatment., Design: Double blind randomized controlled trial., Setting: Multicenter., Participants: Patients with early onset recurrent depression from the public Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study., Interventions: Either sertraline or placebo during 8 weeks (stage 1), and according to response a second line of treatment for 8 additional weeks (stage 2)., Main Outcomes and Measures: To identify a data-driven pattern of symptom variations during these two stages, we performed a Principal Component Analysis (PCA) on the variations of individual items of four clinical scales measuring depression, anxiety, suicidal ideas and manic-like symptoms, resulting in a univariate measure of clinical improvement. We then investigated how initial clinical and neural factors predicted this measure during stage 1. To do so, we extracted resting-state global brain connectivity (GBC) at baseline at the individual level using a whole-brain functional network parcellation. In turn, we computed a linear model for each brain parcel with individual data-driven clinical improvement scores during stage 1 for each group., Results: 192 patients (127 women), age 37.7 years old (standard deviation: 13.5), were included. The first PC (PC1) capturing 20% of clinical variation was similar across treatment groups at stage 1 and stage 2, suggesting a reproducible pattern of symptom improvement. PC1 patients' scores significantly differed according to treatment during stage 1, whereas no difference of response was evidenced between groups with the Clinical Global Impressions (CGI). Baseline GBC correlated to stage 1 PC1 scores in the sertraline, but not in the placebo group., Conclusions and Relevance: Using data-driven reduction of symptoms scales, we identified a common profile of symptom improvement across placebo and sertraline. However, the neural patterns of baseline that mapped onto symptom improvement distinguished between treatment and placebo. Our results underscore that mapping from data-driven symptom improvement onto neural circuits is vital to detect treatment-responsive neural profiles that may aid in optimal patient selection for future trials., Competing Interests: Declarations A.A. and J.D.M. hold equity with Neumora Therapeutics (formerly BlackThorn Therapeutics), Manifest Technologies, and are co-inventors on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding(N-BRIDGE), PCT International Application No.PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No.16/149,903, filed on October 2, 664 2018, U.S. Application for PCT International Application No.18/054, 009 filed on October 2, 2018. J.L.J. is an employee of Manifest Technologies, has previously worked for Neumora, and is a co-inventor on the following patent: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No.PCT/US2119/022110, filed March 13, 2019. C.F. consults for Manifest Technologies and formerly consulted for RBNC (formerly BlackThorn Therapeutics). Z.T. has previously consulted for Neumora and consults for Manifest Technologies. G.R. holds equity and consults in Neumora and Manifest Technologies. J.D. and A.K. consult for Neurotherapeutix Medical Services. A.K. and A.M. have previously consulted for Neumora. J.H.K. holds equity in Biohaven Pharmaceuticals, Biohaven Pharmaceuticals Medical Sciences, Clearmind Medicine, EpiVario, Neumora Therapeutics, Tempero Bio, Terran Biosciences, Tetricus, and Spring Care. J.H.K. consults for AE Research Foundation, Aptinyx, Biohaven Pharmaceuticals, Biogen, Bionomics, Limited (Australia), BioXcel Therapeutics, Boehringer Ingelheim International, Cerevel Therapeutics, Clearmind Medicine, Cybin IRL, Delix Therapeutics, Eisai, Enveric Biosciences, Epiodyne, EpiVario, Evidera, Freedom Biosciences, Janssen Research & Development, Jazz Pharmaceuticals, Leal Therapeutics, Neumora Therapeutics, Neurocrine Biosciences, Novartis Pharmaceuticals Corporation, Otsuka America Pharmaceutical, Perception Neuroscience, Praxis Precision Medicines, PsychoGenics, Spring Care, Sunovion Pharmaceuticals, Takeda Industries, Tempero Bio, Terran Biosciences, and Tetricus. All other co-authors declare no competing interests.

Each cortical area has a distinct pattern of anatomical connections within the thalamus, a central subcortical structure composed of functionally and structurally distinct nuclei. Previous studies have suggested that certain cortical areas may have more extensive anatomical connections that target multiple thalamic nuclei, which potentially allows them to modulate distributed information flow. However, there is a lack of quantitative investigations into anatomical connectivity patterns within the thalamus. Consequently, it remains unknown if cortical areas exhibit systematic differences in the extent of their anatomical connections within the thalamus. To address this knowledge gap, we used diffusion magnetic resonance imaging (dMRI) to perform brain-wide probabilistic tractography for 828 healthy adults from the Human Connectome Project. We then developed a framework to quantify the spatial extent of each cortical area's anatomical connections within the thalamus. Additionally, we leveraged resting-state functional MRI, cortical myelin, and human neural gene expression data to test if the extent of anatomical connections within the thalamus varied along the cortical hierarchy. Our results revealed two distinct corticothalamic tractography motifs: 1) a sensorimotor cortical motif characterized by focal thalamic connections targeting posterolateral thalamus, associated with fast, feed-forward information flow; and 2) an associative cortical motif characterized by diffuse thalamic connections targeting anteromedial thalamus, associated with slow, feed-back information flow. These findings were consistent across human subjects and were also observed in macaques, indicating cross-species generalizability. Overall, our study demonstrates that sensorimotor and association cortical areas exhibit differences in the spatial extent of their anatomical connections within the thalamus, which may support functionally-distinct cortico-thalamic information flow.

Introduction: Neuroimaging technology has experienced explosive growth and transformed the study of neural mechanisms across health and disease. However, given the diversity of sophisticated tools for handling neuroimaging data, the field faces challenges in method integration, particularly across multiple modalities and species. Specifically, researchers often have to rely on siloed approaches which limit reproducibility, with idiosyncratic data organization and limited software interoperability., Methods: To address these challenges, we have developed Quantitative Neuroimaging Environment & Toolbox (QuNex), a platform for consistent end-to-end processing and analytics. QuNex provides several novel functionalities for neuroimaging analyses, including a "turnkey" command for the reproducible deployment of custom workflows, from onboarding raw data to generating analytic features., Results: The platform enables interoperable integration of multi-modal, community-developed neuroimaging software through an extension framework with a software development kit (SDK) for seamless integration of community tools. Critically, it supports high-throughput, parallel processing in high-performance compute environments, either locally or in the cloud. Notably, QuNex has successfully processed over 10,000 scans across neuroimaging consortia, including multiple clinical datasets. Moreover, QuNex enables integration of human and non-human workflows via a cohesive translational platform., Discussion: Collectively, this effort stands to significantly impact neuroimaging method integration across acquisition approaches, pipelines, datasets, computational environments, and species. Building on this platform will enable more rapid, scalable, and reproducible impact of neuroimaging technology across health and disease., Competing Interests: JJ is an employee of Manifest Technologies and has previously worked for Neumora (formerly BlackThorn Therapeutics) and is a co-inventor on the following patent: AA, JM, and JJ: systems and methods for neuro-behavioral relationships in dimensional geometric embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019. AK and AM have previously consulted for Neumora (formerly BlackThorn Therapeutics). CF, JD, and ZT have previously consulted for Neumora (formerly BlackThorn Therapeutics) and consult for Manifest Technologies. MHe and LP are employees of Manifest Technologies. VZ and SS consults for Manifest Technologies. JM and AA consult for and hold equity with Neumora (formerly BlackThorn Therapeutics), Manifest Technologies, and are co-inventors on the following patents: JM, AA, and Martin, WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No. 16/149,903 filed on October 2, 2018, U.S. Application for PCT International Application No. 18/054,009 filed on October 2, 2018. GR consults for and holds equity with Neumora (formerly BlackThorn Therapeutics) and Manifest Technologies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ji, Demšar, Fonteneau, Tamayo, Pan, Kraljič, Matkovič, Purg, Helmer, Warrington, Winkler, Zerbi, Coalson, Glasser, Harms, Sotiropoulos, Murray, Anticevic and Repovš.)

The phenotype of schizophrenia, regardless of etiology, represents the most studied psychotic disorder with respect to neurobiology and distinct phases of illness. The early phase of illness represents a unique opportunity to provide effective and individualized interventions that can alter illness trajectories. Developmental age and illness stage, including temporal variation in neurobiology, can be targeted to develop phase-specific clinical assessment, biomarkers, and interventions. We review an earlier model whereby an initial glutamate signaling deficit progresses through different phases of allostatic adaptation, moving from potentially reversible functional abnormalities associated with early psychosis and working memory dysfunction, and ending with difficult-to-reverse structural changes after chronic illness. We integrate this model with evidence of dopaminergic abnormalities, including cortical D 1 dysfunction, which develop during adolescence. We discuss how this model and a focus on a potential critical window of intervention in the early stages of schizophrenia impact the approach to research design and clinical care. This impact includes stage-specific considerations for symptom assessment as well as genetic, cognitive, and neurophysiological biomarkers. We examine how phase-specific biomarkers of illness phase and brain development can be incorporated into current strategies for large-scale research and clinical programs implementing coordinated specialty care. We highlight working memory and D 1 dysfunction as early treatment targets that can substantially affect functional outcome., (© 2022 The Authors.)

Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Difficulties in advancing effective patient-specific therapies for psychiatric disorders highlight a need to develop a stable neurobiologically grounded mapping between neural and symptom variation. This gap is particularly acute for psychosis-spectrum disorders (PSD). Here, in a sample of 436 PSD patients spanning several diagnoses, we derived and replicated a dimensionality-reduced symptom space across hallmark psychopathology symptoms and cognitive deficits. In turn, these symptom axes mapped onto distinct, reproducible brain maps. Critically, we found that multivariate brain-behavior mapping techniques (e.g. canonical correlation analysis) do not produce stable results with current sample sizes. However, we show that a univariate brain-behavioral space (BBS) can resolve stable individualized prediction. Finally, we show a proof-of-principle framework for relating personalized BBS metrics with molecular targets via serotonin and glutamate receptor manipulations and neural gene expression maps derived from the Allen Human Brain Atlas. Collectively, these results highlight a stable and data-driven BBS mapping across PSD, which offers an actionable path that can be iteratively optimized for personalized clinical biomarker endpoints., Competing Interests: JJ consults for RBNC (formerly BlackThorn Therapeutics) and is a co-inventor for the following pending patent: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019. MH, BA, AS, FM, FV No competing interests declared, CF, ZT, JD consults for RBNC (formerly BlackThorn Therapeutics). JB consulted for BlackThorn Therapeutics in 2019 and is currently an employee of RBNC Therapeutics. KP is currently an employee of F.Hoffmann-La Roche AG. WM is an employee of The Janssen Pharmaceutical Companies of Johnson & Johnson and is a co-inventor for the following pending patent: Murray JD, Anticevic A, Martin, WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No. 16/149,903 filed on October 2, 2018, GR consults for and holds equity with RBNC (formerly BlackThorn Therapeutics). JM consults for and holds equity with RBNC (formerly BlackThorn Therapeutics) and is a coinventor on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin, WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No. 16/149,903 filed on October 2, 2018, U.S. Application or PCT International Application No. 18/054,009 filed on October 2, 2018. AA consults for and holds equity with RBNC (formerly BlackThorn Therapeutics) and is a coinventor on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioral Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin, WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No. 16/149,903 filed on October 2, 2018, U.S. Application for PCT International Application No. 18/054,009 filed on October 2, 2018., (© 2021, Ji et al.)

Transcranial direct current stimulation (tDCS) has been proposed as a therapeutic option for treatment-resistant auditory verbal hallucinations (AVH) in schizophrenia. In such cases, repeated sessions of tDCS are delivered with the anode over the left prefrontal cortex and the cathode over the left temporoparietal junction. Despite promising findings, the clinical response to tDCS is highly heterogeneous among patients. Here, we explored baseline differences between responders and nonresponders to frontotemporal tDCS using electric field modeling. We hypothesized that responders would display different tDCS-induced electric field strength in the brain areas involved in AVH compared to nonresponders.Using baseline structural MRI scans of 17 patients with schizophrenia and daily AVH who received 10 sessions of active frontotemporal tDCS, we constructed individual realistic whole brain models estimating electric field strength. Electric field maps were compared between responders (n = 6) and nonresponders to tDCS (n = 11) using an independent two-sample t test. Clinical response was defined as at least a 50% decrease of AVH 1 month after the last tDCS session.Results from the electric field map comparison showed that responders to tDCS displayed higher electric field strength in the left transverse temporal gyrus at baseline compared to nonresponders (T = 2.37; p = 0.016; 32 voxels).These preliminary findings suggested that the strength of the tDCS-induced electric field reaching the left transverse temporal gyrus could play an important role in the response to frontotemporal tDCS. In addition, this work suggests the interest of using electric field modeling to individualize tDCS and increase response rate.

This paper proposes an innovative method, named b-ntPET, for solving a competition model in PET. The model is built upon the state-of-the-art method called lp-ntPET. It consists in identifying the parameters of the PET kinetic model relative to a reference region that rule the steady state exchanges, together with the identification of four additional parameters defining a displacement curve caused by an endogenous neurotransmitter discharge, or by a competing injected drug targeting the same receptors as the PET tracer. The resolution process of lp-ntPET is however suboptimal due to the use of discretized basis functions, and is very sensitive to noise, limiting its sensitivity and accuracy. Contrary to the original method, our proposed resolution approach first estimates the probability distribution of the unknown parameters using Markov-Chain Monte-Carlo sampling, distributions from which the estimates are then inferred. In addition, and for increased robustness, the noise level is jointly estimated with the parameters of the model. Finally, the resolution is formulated in a Bayesian framework, allowing the introduction of prior knowledge on the parameters to guide the estimation process toward realistic solutions. The performance of our method was first assessed and compared head-to-head with the reference method lp-ntPET using well-controlled realistic simulated data. The results showed that the b-ntPET method is substantially more robust to noise and much more sensitive and accurate than lp-ntPET. We then applied the model to experimental animal data acquired in pharmacological challenge studies and human data with endogenous releases induced by transcranial direct current stimulation. In the drug challenge experiment on cats using [ 18 F]MPPF, a serotoninergic 1A antagonist radioligand, b-ntPET measured a dose response associated with the amount of the challenged injected concurrent 5-HT1A agonist, where lp-ntPET failed. In human [ 11 C]raclopride experiment, contrary to lp-ntPET, b-ntPET successfully detected significant endogenous dopamine releases induced by the stimulation. In conclusion, our results showed that the proposed method b-ntPET has similar performance to lp-ntPET for detecting displacements, but with higher resistance to noise and better robustness to various experimental contexts. These improvements lead to the possibility of detecting and characterizing dynamic drug occupancy from a single PET scan more efficiently., (Copyright © 2020 Irace, Mérida, Redouté, Fonteneau, Suaud-Chagny, Brunelin, Vidal, Zimmer, Reilhac and Costes.)

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique increasingly used to modulate neural activity in the living brain. In order to establish the neurophysiological, cognitive or clinical effects of tDCS, most studies compare the effects of active tDCS to those observed with a sham tDCS intervention. In most cases, sham tDCS consists in delivering an active stimulation for a few seconds to mimic the sensations observed with active tDCS and keep participants blind to the intervention. However, to date, sham-controlled tDCS studies yield inconsistent results, which might arise in part from sham inconsistencies. Indeed, a multiplicity of sham stimulation protocols is being used in the tDCS research field and might have different biological effects beyond the intended transient sensations. Here, we seek to enlighten the scientific community to this possible confounding factor in order to increase reproducibility of neurophysiological, cognitive and clinical tDCS studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A single transcranial direct current stimulation (tDCS) session applied over the dorsolateral prefrontal cortex (DLFPC) can be associated with procognitive effects. Furthermore, repeated DLPFC tDCS sessions are under investigation as a new therapeutic tool for a range of neuropsychiatric conditions. A possible mechanism explaining such beneficial effects is a modulation of meso-cortico-limbic dopamine transmission. We explored the spatial and temporal neurobiological effects of bifrontal tDCS on subcortical dopamine transmission during and immediately after the stimulation. In a double blind sham-controlled study, 32 healthy subjects randomly received a single session of either active (20 min, 2 mA; n = 14) or sham (n = 18) tDCS during a dynamic positron emission tomography scan using [11C]raclopride binding. During the stimulation period, no significant effect of tDCS was observed. After the stimulation period, compared with sham tDCS, active tDCS induced a significant decrease in [11C]raclopride binding potential ratio in the striatum, suggesting an increase in extracellular dopamine in a part of the striatum involved in the reward-motivation network. The present study provides the first evidence that bifrontal tDCS induces neurotransmitter release in polysynaptic connected subcortical areas. Therefore, levels of dopamine activity and reactivity should be a new element to consider for a general hypothesis of brain modulation by bifrontal tDCS.

Auditory verbal hallucinations (AVH) in patients with schizophrenia are linked to abnormalities within a large cerebral network including frontal and temporal regions. Whilst abnormalities of frontal speech production and temporal speech perception regions have been extensively studied, alterations of the dorsolateral prefrontal cortex (DLPFC), a region critically involved in the pathophysiology of schizophrenia, have rarely been studied in relation to AVH. Using 1.5 T proton magnetic resonance spectroscopy, this study examined the relationship between right and left DLPFCs N-AcetylAspartate (NAA) levels and the severity of AVH in patients with schizophrenia. Twenty-seven male patients with schizophrenia were enrolled in this study, 15 presented daily treatment-resistant AVH (AVH+) and 12 reported no AVH (no-AVH). AVH+ patients displayed higher NAA levels in the right DLPFC than no-AVH patients (p = 0.033). In AVH+ patients, NAA levels were higher in the right DLPFC than in the left (p = 0.024). No difference between the right and left DLPFC was observed in no-AVH patients. There was a positive correlation between NAA levels in the right DLPFC and the severity of AVH (r = 0.404, p = 0.037). Despite limited by magnetic field strength, these results suggest that AVH may be associated with increased NAA levels in the right DLPFC in schizophrenia.

A new approach for the elaboration of low molecular weight pressure-sensitive adhesives based on supramolecular chemistry is explored. The synthesis of model systems coupled with probe-tack tests and rheological experiments highlights the influence of the transient network formed by supramolecular bonds on the adhesion energy. The first step of our approach consists of synthesizing poly(butyl acrylate-co-glycidyl methacrylate) copolymers from a difunctional initiator able to self-associate by four hydrogen bonds between urea groups. Linear copolymers with a low dispersity (M n = 10 kg/mol, Ip < 1.4) have been synthesized via atom transfer radical polymerization. Films of the copolymers were then partially cross-linked through reaction of the epoxy functions with a diamine. The systematic variation of the average ratio of glycidyl methacrylate and diamine per copolymer shed light on the respective role played by the supramolecular interactions (between bis-urea groups and with the side chains) and by the chain extension and branching induced by the diamine/epoxy reaction. In this strategy, the adhesive performance can be optimized by modifying the strength of "stickers" (via the structure of the supramolecular initiator, for instance) and the polymer network (e.g., via the length and level of branching of the copolymer chains) in order to approach commercial PSA-like properties (high debonding energy and clean removal).

Auditory verbal hallucinations (AVH) of schizophrenia are associated with a disrupted connectivity between frontal and temporoparietal language areas. We hypothesized that this dysconnectivity is underpinned by white matter abnormalities in the left arcuate fasciculus, the main fiber bundle connecting speech production and perception areas. We therefore investigated the relationship between AVH severity and the integrity of the arcuate fasciculus measured by diffusion tensor imaging (DTI) tractography in patients with schizophrenia. Thirty-eight patients with treatment-resistant schizophrenia were included: 26 presented with daily severe treatment-resistant AVH, 12 reported prominent negative symptoms and no AVH. Fractional anisotropy (FA) was measured along the length of the left and right anterior arcuate fasciculi and severity of AVH was assessed using P3 PANSS item. FA values were significantly higher in the left arcuate fasciculus in patients with AVH than in no AVH patients (F (1,35)  = 3.86; p = 0.05). No difference was observed in the right arcuate fasciculus. There was a significant positive correlation between FA value in the left arcuate fasciculus and the severity of AVH (r = 0.36; p = 0.02). No correlation was observed between FA values and PANSS total score suggesting a specific relationship between AVH severity and the left arcuate fasciculus integrity. These results support the hypothesis of a relationship between left frontotemporal connectivity and AVH in patients with schizophrenia and suggest that whilst a disruption of frontotemporal connectivity might be present to ensure the emergence of AVH, more severe anatomical alterations may prevent the occurrence of AVH in patients with schizophrenia.

Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive brain stimulation techniques currently used as therapeutic tools in various psychiatric conditions. Applied over the dorsolateral prefrontal cortex (DLPFC), they showed their efficacy in reducing drug-resistant symptoms in patients with major depression and in patients with schizophrenia with predominantly negative symptoms. The DLPFC is a brain structure involved in the expression of these symptoms as well as in other dysfunctional functions observed in theses conditions such as emotional processes. The goal of this review is to establish whether or not a link exists between clinical improvements and modulation of emotional processes following the stimulation of the DLPFC in both conditions. The data collected show that improved emotional processes is not linked to a clinical improvement neither in patients with depression nor in patients with negative schizophrenia. Our results suggests that although sharing common brain structures, the brain networks involved in both symptoms and in emotional processes would be separate.

Attention improves the processing of specific information while other stimuli are disregarded. A good balance between bottom-up (attentional capture by unexpected salient stimuli) and top-down (selection of relevant information) mechanisms is crucial to be both task-efficient and aware of our environment. Only few studies have explored how an isolated unexpected task-irrelevant stimulus outside the attention focus can disturb the top-down attention mechanisms necessary to the good performance of the ongoing task, and how these top-down mechanisms can modulate the bottom-up mechanisms of attentional capture triggered by an unexpected event. We recorded scalp electroencephalography in 18 young adults performing a new paradigm measuring distractibility and assessing both bottom-up and top-down attention mechanisms, at the same time. Increasing task load in top-down attention was found to reduce early processing of the distracting sound, but not bottom-up attentional capture mechanisms nor the behavioral distraction cost in reaction time. Moreover, the impact of bottom-up attentional capture by distracting sounds on target processing was revealed as a delayed latency of the N100 sensory response to target sounds mirroring increased reaction times. These results provide crucial information into how bottom-up and top-down mechanisms dynamically interact and compete in the human brain, i.e. on the precarious balance between voluntary attention and distraction.

Background: Dental caries is a common disease and affects many adults worldwide. Inlay or onlay restoration is widely used to treat the resulting tooth substance loss. Two esthetic materials can be used to manufacture an inlay/onlay restoration of the tooth: ceramic or composite. Here, we present the protocol of a multicenter randomized controlled trial (RCT) comparing the clinical efficacy of both materials for tooth restoration. Other objectives are analysis of overall quality, wear, restoration survival and prognosis., Methods: The CEramic and COmposite Inlays Assessment (CECOIA) trial is an open-label, parallel-group, multicenter RCT involving two hospitals and five private practices. In all, 400 patients will be included. Inclusion criteria are adults who need an inlay/onlay restoration for one tooth (that can be isolated with use of a dental dam and has at least one intact cusp), can tolerate restorative procedures and do not have severe bruxism, periodontal or carious disease or poor oral hygiene. The decayed tissue will be evicted, the cavity will be prepared for receiving an inlay/onlay and the patient will be randomized by use of a centralized web-based interface to receive: 1) a ceramic or 2) composite inlay or onlay. Treatment allocation will be balanced (1:1). The inlay/onlay will be adhesively luted. Follow-up will be for 2 years and may be extended; two independent examiners will perform the evaluations. The primary outcome measure will be the score obtained with use of the consensus instrument of the Fédération Dentaire Internationale (FDI) World Dental Federation. Secondary outcomes include this instrument's items, inlay/onlay wear, overall quality and survival of the inlay/onlay. Data will be analyzed by a statistician blinded to treatments and an adjusted ordinal logistic regression model will be used to compare the efficacy of both materials., Discussion: For clinicians, the CECOIA trial results may help with evidence-based recommendations concerning the choice of materials for inlay/onlay restoration. For patients, the results may lead to improvement in long-term restoration. For researchers, the results may provide ideas for further research concerning inlay/onlay materials and prognosis.This trial is funded by a grant from the French Ministry of Health., Trial Registration: ClinicalTrials.gov Identifier: NCT01724827.