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  1. Article ; Online: A computational model to characterize the time-course of response to rapid antidepressant therapies.

    Nunes, Abraham / Singh, Selena

    PloS one

    2024  Volume 19, Issue 2, Page(s) e0297708

    Abstract: Our objective is to propose a method capable of disentangling the magnitude, the speed, and the duration or decay rate of the time course of response to rapid antidepressant therapies. To this end, we introduce a computational model of the time course of ...

    Abstract Our objective is to propose a method capable of disentangling the magnitude, the speed, and the duration or decay rate of the time course of response to rapid antidepressant therapies. To this end, we introduce a computational model of the time course of response to a single treatment with a rapid antidepressant. Numerical simulation is used to evaluate whether model parameters can be accurately estimated from observed data. Finally, we compare our computational modelling-based approach with linear mixed effects modelling in terms of their ability to detect changes in the magnitude and time-course of response to rapid antidepressant therapies in simulated randomized trials. Simulation experiments show that the parameters of our computational model can be accurately recovered using nonlinear least squares. Parameter estimation accuracy is stable over noise levels reaching as high as 25% of the true antidepressant effect magnitude. Comparison of our approach to mixed effects modelling using simulated randomized controlled trial data demonstrates an inability of linear mixed models to disentangle effect magnitude and time course, while our computational model accurately separates these response components. Our modelling approach may accurately identify the (A) magnitude, (B) speed, and (C) durability or decay rate of response to rapid antidepressant therapies. Future studies should fit this model to data from real clinical trials, and use resulting parameter estimates to uncover predictors and causes of different elements of the temporal course of antidepressant response.
    MeSH term(s) Antidepressive Agents/pharmacology ; Antidepressive Agents/therapeutic use ; Causality ; Computer Simulation ; Psychotherapy ; Randomized Controlled Trials as Topic
    Chemical Substances Antidepressive Agents
    Language English
    Publishing date 2024-02-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0297708
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  2. Article ; Online: Two common questions about machine learning methods in psychiatric applications.

    Nunes, Abraham

    Bipolar disorders

    2019  Volume 21, Issue 7, Page(s) 665

    Language English
    Publishing date 2019-08-26
    Publishing country Denmark
    Document type Letter
    ZDB-ID 1472242-2
    ISSN 1399-5618 ; 1398-5647
    ISSN (online) 1399-5618
    ISSN 1398-5647
    DOI 10.1111/bdi.12822
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5604: Show issues Location:
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  3. Article: Mechanisms of Sustained Increases in

    Petzi, Maximilian / Singh, Selena / Trappenberg, Thomas / Nunes, Abraham

    Brain sciences

    2023  Volume 13, Issue 11

    Abstract: Subanaesthetic doses of ketamine increase γ oscillation power in neural activity measured using electroencephalography (EEG), and this effect lasts several hours after ketamine administration. The mechanisms underlying this effect are unknown. Using a ... ...

    Abstract Subanaesthetic doses of ketamine increase γ oscillation power in neural activity measured using electroencephalography (EEG), and this effect lasts several hours after ketamine administration. The mechanisms underlying this effect are unknown. Using a computational model of the hippocampal cornu ammonis 3 (CA3) network, which is known to reproduce ketamine's acute effects on γ power, we simulated the plasticity of glutamatergic synapses in pyramidal cells to test which of the following hypotheses would best explain this sustained γ power:
    Language English
    Publishing date 2023-11-07
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2651993-8
    ISSN 2076-3425
    ISSN 2076-3425
    DOI 10.3390/brainsci13111562
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  4. Article ; Online: Granule cells perform frequency-dependent pattern separation in a computational model of the dentate gyrus.

    Singh, Selena / Becker, Suzanna / Trappenberg, Thomas / Nunes, Abraham

    Hippocampus

    2023  Volume 34, Issue 1, Page(s) 14–28

    Abstract: Mnemonic discrimination (MD) may be dependent on oscillatory perforant path input frequencies to the hippocampus in a "U"-shaped fashion, where some studies show that slow and fast input frequencies support MD, while other studies show that intermediate ... ...

    Abstract Mnemonic discrimination (MD) may be dependent on oscillatory perforant path input frequencies to the hippocampus in a "U"-shaped fashion, where some studies show that slow and fast input frequencies support MD, while other studies show that intermediate frequencies disrupt MD. We hypothesize that pattern separation (PS) underlies frequency-dependent MD performance. We aim to study, in a computational model of the hippocampal dentate gyrus (DG), the network and cellular mechanisms governing this putative "U"-shaped PS relationship. We implemented a biophysical model of the DG that produces the hypothesized "U"-shaped input frequency-PS relationship, and its associated oscillatory electrophysiological signatures. We subsequently evaluated the network's PS ability using an adapted spatiotemporal task. We undertook systematic lesion studies to identify the network-level mechanisms driving the "U"-shaped input frequency-PS relationship. A minimal circuit of a single granule cell (GC) stimulated with oscillatory inputs was also used to study potential cellular-level mechanisms. Lesioning synapses onto GCs did not impact the "U"-shaped input frequency-PS relationship. Furthermore, GC inhibition limits PS performance for fast frequency inputs, while enhancing PS for slow frequency inputs. GC interspike interval was found to be input frequency dependent in a "U"-shaped fashion, paralleling frequency-dependent PS observed at the network level. Additionally, GCs showed an attenuated firing response for fast frequency inputs. We conclude that independent of network-level inhibition, GCs may intrinsically be capable of producing a "U"-shaped input frequency-PS relationship. GCs may preferentially decorrelate slow and fast inputs via spike timing reorganization and high frequency filtering.
    MeSH term(s) Dentate Gyrus/physiology ; Neurons/physiology ; Hippocampus/physiology ; Perforant Pathway ; Synapses/physiology
    Language English
    Publishing date 2023-11-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1074352-2
    ISSN 1098-1063 ; 1050-9631
    ISSN (online) 1098-1063
    ISSN 1050-9631
    DOI 10.1002/hipo.23585
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    Zs.A 3227: Show issues Location:
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  5. Article ; Online: Familial traits of bipolar disorder: A systematic review and meta-analysis.

    Scott, Katie / Nunes, Abraham / Pavlova, Barbara / Meier, Sandra / Alda, Martin

    Acta psychiatrica Scandinavica

    2023  Volume 148, Issue 2, Page(s) 133–141

    Abstract: Background: Genetic studies of bipolar disorder (BD) have shown varied results, which is in part because of the heterogeneity of the disorder. Identifying clinical phenotypes of BD could reduce variability and benefit research. Since BD has a robust ... ...

    Abstract Background: Genetic studies of bipolar disorder (BD) have shown varied results, which is in part because of the heterogeneity of the disorder. Identifying clinical phenotypes of BD could reduce variability and benefit research. Since BD has a robust genetic component, studies can investigate clinical traits that cluster in families to identify phenotypes with a probable genetic basis.
    Methods: We conducted a systematic review of the current literature on familial clinical traits of BD. Text screening and data extraction were performed independently by two reviewers, and random effects meta-analysis was used.
    Results: Of 1117 unique records, 16 studies met inclusion criteria. These studies indicated 14 potentially familial traits of BD: age of onset (OR: 4.50; 95% CI: [3.25, 6.22]), bipolar type (OR: 2.05 [1.50, 2.79]), lithium response (OR: 3.71 [1.28, 10.82]), polarity at onset (OR: 1.17 [1.03, 1.34]), psychotic features (OR: 2.20 [1.51, 3.20]), mood-incongruent psychosis (OR: 2.52 [1.66, 3.83]), puerperal psychosis (OR: 6.54 [2.55, 16.77]), rapid cycling (OR: 4.95 [0.96, 25.40]), suicide attempt (OR: 1.04 [0.65, 1.67]), alcoholism (OR: 1.53 [1.09, 2.16]), obsessive-compulsive disorder (OR: 3.10 [1.31; 7.09]), panic disorder (OR: 2.69 [1.12; 6.48]), social anxiety disorder (OR: 1.00 [0.39, 2.55]), and specific phobia (OR: 1.94 [0.95; 3.96]). For most traits, tests of heterogeneity were significant and publication bias was likely.
    Conclusion: The results of our review and meta-analysis highlight the lack of studies investigating familial clinical traits of BD, despite the need to address heterogeneity. The large degree of variability between studies must be reduced for future research.
    MeSH term(s) Humans ; Bipolar Disorder/genetics ; Bipolar Disorder/diagnosis ; Phenotype ; Psychotic Disorders/diagnosis ; Obsessive-Compulsive Disorder ; Panic Disorder
    Language English
    Publishing date 2023-05-15
    Publishing country United States
    Document type Meta-Analysis ; Systematic Review ; Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 103-x
    ISSN 1600-0447 ; 0001-690X
    ISSN (online) 1600-0447
    ISSN 0001-690X
    DOI 10.1111/acps.13569
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  6. Article ; Online: Lessons from ecology for understanding the heterogeneity of bipolar disorder.

    Nunes, Abraham / Scott, Katie / Alda, Martin

    Journal of psychiatry & neuroscience : JPN

    2022  Volume 47, Issue 5, Page(s) E359–E365

    MeSH term(s) Humans ; Bipolar Disorder ; Genetic Predisposition to Disease
    Language English
    Publishing date 2022-10-18
    Publishing country Canada
    Document type Editorial ; Research Support, Non-U.S. Gov't
    ZDB-ID 1077443-9
    ISSN 1488-2434 ; 1180-4882
    ISSN (online) 1488-2434
    ISSN 1180-4882
    DOI 10.1503/jpn.220172
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    Zs.B 2105: Show issues Location:
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  7. Article ; Online: A scoping review and comparison of approaches for measuring genetic heterogeneity in psychiatric disorders.

    Wang, Harvey / Alda, Martin / Trappenberg, Thomas / Nunes, Abraham

    Psychiatric genetics

    2021  Volume 32, Issue 1, Page(s) 1–8

    Abstract: An improved understanding of genetic etiological heterogeneity in a psychiatric condition may help us (a) isolate a neurophysiological 'final common pathway' by identifying its upstream genetic origins and (b) facilitate characterization of the condition' ...

    Abstract An improved understanding of genetic etiological heterogeneity in a psychiatric condition may help us (a) isolate a neurophysiological 'final common pathway' by identifying its upstream genetic origins and (b) facilitate characterization of the condition's phenotypic variation. This review aims to identify existing genetic heterogeneity measurements in the psychiatric literature and provides a conceptual review of their mechanisms, limitations, and assumptions. The Scopus database was searched for studies that quantified genetic heterogeneity or correlation of psychiatric phenotypes with human genetic data. Ninety studies were included. Eighty-seven reports quantified genetic correlation, five applied genomic structural equation modelling, three evaluated departure from the Hardy-Weinberg equilibrium at one or more loci, and two applied a novel approach known as MiXeR. We found no study that rigorously measured genetic etiological heterogeneity across a large number of markers. Developing such approaches may help better characterize the biological diversity of psychopathology.
    MeSH term(s) Genetic Heterogeneity ; Genomics ; Humans ; Mental Disorders/genetics ; Phenotype
    Language English
    Publishing date 2021-10-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1067837-2
    ISSN 1473-5873 ; 0955-8829
    ISSN (online) 1473-5873
    ISSN 0955-8829
    DOI 10.1097/YPG.0000000000000304
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    Zs.A 3165: Show issues Location:
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  8. Article ; Online: Asymmetrical reliability of the Alda score favours a dichotomous representation of lithium responsiveness.

    Nunes, Abraham / Trappenberg, Thomas / Alda, Martin

    PloS one

    2020  Volume 15, Issue 1, Page(s) e0225353

    Abstract: The Alda score is commonly used to quantify lithium responsiveness in bipolar disorder. Most often, this score is dichotomized into "responder" and "non-responder" categories, respectively. This practice is often criticized as inappropriate, since ... ...

    Abstract The Alda score is commonly used to quantify lithium responsiveness in bipolar disorder. Most often, this score is dichotomized into "responder" and "non-responder" categories, respectively. This practice is often criticized as inappropriate, since continuous variables are thought to invariably be "more informative" than their dichotomizations. We therefore investigated the degree of informativeness across raw and dichotomized versions of the Alda score, using data from a published study of the scale's inter-rater reliability (n = 59 raters of 12 standardized vignettes each). After learning a generative model for the relationship between observed and ground truth scores (the latter defined by a consensus rating of the 12 vignettes), we show that the dichotomized scale is more robust to inter-rater disagreement than the raw 0-10 scale. Further theoretical analysis shows that when a measure's reliability is stronger at one extreme of the continuum-a scenario which has received little-to-no statistical attention, but which likely occurs for the Alda score ≥ 7-dichotomization of a continuous variable may be more informative concerning its ground truth value, particularly in the presence of noise. Our study suggests that research employing the Alda score of lithium responsiveness should continue using the dichotomous definition, particularly when data are sampled across multiple raters.
    MeSH term(s) Animals ; Bipolar Disorder/metabolism ; Bipolar Disorder/pathology ; Confidence Intervals ; Humans ; Lithium Compounds/adverse effects ; Probability ; Programming Languages
    Chemical Substances Lithium Compounds
    Language English
    Publishing date 2020-01-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0225353
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  9. Article ; Online: We need an operational framework for heterogeneity in psychiatric research

    Nunes, Abraham / Trappenberg, Thomas / Alda, Martin

    Journal of psychiatry & neuroscience : JPN

    2020  Volume 45, Issue 1, Page(s) 3–6

    MeSH term(s) Biomedical Research/standards ; Humans ; Psychiatry/standards ; Statistics as Topic/standards
    Language English
    Publishing date 2020-04-10
    Publishing country Canada
    Document type Editorial ; Research Support, Non-U.S. Gov't
    ZDB-ID 1077443-9
    ISSN 1488-2434 ; 1180-4882
    ISSN (online) 1488-2434
    ISSN 1180-4882
    DOI 10.1503/jpn.190198
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  10. Article ; Online: Multiplicative Decomposition of Heterogeneity in Mixtures of Continuous Distributions.

    Nunes, Abraham / Alda, Martin / Trappenberg, Thomas

    Entropy (Basel, Switzerland)

    2020  Volume 22, Issue 8

    Abstract: A system's heterogeneity ( ...

    Abstract A system's heterogeneity (
    Language English
    Publishing date 2020-08-01
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2014734-X
    ISSN 1099-4300 ; 1099-4300
    ISSN (online) 1099-4300
    ISSN 1099-4300
    DOI 10.3390/e22080858
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