Publications by authors named "Neil A Harrison"

90 Publications

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets.

Authors:
Merel C Postema Martine Hoogman Sara Ambrosino Philip Asherson Tobias Banaschewski Cibele E Bandeira Alexandr Baranov Claiton H D Bau Sarah Baumeister Ramona Baur-Streubel Mark A Bellgrove Joseph Biederman Janita Bralten Daniel Brandeis Silvia Brem Jan K Buitelaar Geraldo F Busatto Francisco X Castellanos Mara Cercignani Tiffany M Chaim-Avancini Kaylita C Chantiluke Anastasia Christakou David Coghill Annette Conzelmann Ana I Cubillo Renata B Cupertino Patrick de Zeeuw Alysa E Doyle Sarah Durston Eric A Earl Jeffery N Epstein Thomas Ethofer Damien A Fair Andreas J Fallgatter Stephen V Faraone Thomas Frodl Matt C Gabel Tinatin Gogberashvili Eugenio H Grevet Jan Haavik Neil A Harrison Catharina A Hartman Dirk J Heslenfeld Pieter J Hoekstra Sarah Hohmann Marie F Høvik Terry L Jernigan Bernd Kardatzki Georgii Karkashadze Clare Kelly Gregor Kohls Kerstin Konrad Jonna Kuntsi Luisa Lazaro Sara Lera-Miguel Klaus-Peter Lesch Mario R Louza Astri J Lundervold Charles B Malpas Paulo Mattos Hazel McCarthy Leyla Namazova-Baranova Rosa Nicolau Joel T Nigg Stephanie E Novotny Eileen Oberwelland Weiss Ruth L O'Gorman Tuura Jaap Oosterlaan Bob Oranje Yannis Paloyelis Paul Pauli Felipe A Picon Kerstin J Plessen J Antoni Ramos-Quiroga Andreas Reif Liesbeth Reneman Pedro G P Rosa Katya Rubia Anouk Schrantee Lizanne J S Schweren Jochen Seitz Philip Shaw Tim J Silk Norbert Skokauskas Juan C Soliva Vila Michael C Stevens Gustavo Sudre Leanne Tamm Fernanda Tovar-Moll Theo G M van Erp Alasdair Vance Oscar Vilarroya Yolanda Vives-Gilabert Georg G von Polier Susanne Walitza Yuliya N Yoncheva Marcus V Zanetti Georg C Ziegler David C Glahn Neda Jahanshad Sarah E Medland Paul M Thompson Simon E Fisher Barbara Franke Clyde Francks

J Child Psychol Psychiatry 2021 Mar 22. Epub 2021 Mar 22.

Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

Objective: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.

Methods: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.

Results: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing.

Conclusion: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
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http://dx.doi.org/10.1111/jcpp.13396DOI Listing
March 2021

Expression of sterile-α and armadillo motif in rheumatoid arthritis monocytes correlates with TLR2 induced IL-1β and disease activity.

Rheumatology (Oxford) 2021 Feb 19. Epub 2021 Feb 19.

Brighton and Sussex Medical School, University of Sussex, Brighton, BN1 9PS, U.K.

Objective: Cartilage and bone damage in rheumatoid arthritis (RA) are associated with elevated IL-1β. The effects of IL-1β can be reduced by biological therapies that target IL-1β or TNFα. However, the mechanisms responsible for increased IL-1β and the effect of anti-TNFα have not been fully elucidated. Recently, sterile-α and armadillo motif-containing protein (SARM) was identified as a negative regulator of toll-like receptor (TLR) induced IL-1β secretion through an interaction with the inflammasome. This study set out to investigate SARM during TLR induced IL-1β secretion in RA peripheral blood monocytes and in patients commencing anti-TNFα treatment.

Methods: Monocytes were isolated from RA patients and healthy controls; disease activity was measured by DAS28. IL-1β secretion was measured by ELISA following TLR1/2, TLR4 and TLR7/8 stimulation. The mRNA expression of SARM, IL-1β and the components of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome were measured by quantitative PCR. SARM protein expression was measured by western blotting.

Results: TLR1/2 activation induced elevated IL-1β in RA monocytes compared with heathy controls (p= 0.0009), which negatively correlated with SARM expression (p = 0.0086). Lower SARM expression also correlated with higher disease activity (p = 0.0246). Additionally, patients responding to anti-TNFα treatment demonstrated a rapid upregulation of SARM, which was not observed in non-responders.

Conclusion: Together, these data highlight a potential contribution from SARM to RA pathophysiology where decreased SARM may lead to elevated IL-1β associated with RA pathogenesis. Furthermore, the data additionally present a potential mechanism by which TNFα blockade can modify IL-1β secretion.
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http://dx.doi.org/10.1093/rheumatology/keab162DOI Listing
February 2021

Beyond bones: The relevance of variants of connective tissue (hypermobility) to fibromyalgia, ME/CFS and controversies surrounding diagnostic classification: an observational study.

Clin Med (Lond) 2021 Jan;21(1):53-58

Brighton and Sussex University Hospitals NHS Trust, Brighton, UK and Brighton and Sussex Medical School, Falmer, UK.

Background: Fibromyalgia and myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) are poorly understood conditions with overlapping symptoms, fuelling debate as to whether they are manifestations of the same spectrum or separate entities. Both are associated with hypermobility, but this remains significantly undiagnosed, despite impact on quality of life.

Objective: We planned to understand the relevance of hypermobility to symptoms in fibromyalgia and ME/CFS.

Method: Sixty-three patient participants presented with a confirmed diagnosis of fibromyalgia and/or ME/CFS; 24 participants were healthy controls. Patients were assessed for symptomatic hypermobility.

Results: Evaluations showed exceptional overlap in patients between fibromyalgia and ME/CFS, plus 81% met Brighton criteria for hypermobility syndrome (odds ratio 7.08) and 18% met 2017 hypermobile Ehlers-Danlos syndrome (hEDS) criteria. Hypermobility scores significantly predicted symptom levels.

Conclusion: Symptomatic hypermobility is particularly relevant to fibromyalgia and ME/CFS, and our findings highlight high rates of mis-/underdiagnosis. These poorly understood conditions have a considerable impact on quality of life and our observations have implications for diagnosis and treatment targets.
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http://dx.doi.org/10.7861/clinmed.2020-0743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850199PMC
January 2021

Shifting uncertainty intolerance: methylphenidate and attention-deficit hyperactivity disorder.

Transl Psychiatry 2021 01 6;11(1):12. Epub 2021 Jan 6.

Department of Psychiatry, University of Cambridge, Cambridge, UK.

Risk evaluation is a critical component of decision making. Risk tolerance is relevant in both daily decisions and pathological disorders such as attention-deficit hyperactivity disorder (ADHD), where impulsivity is a cardinal symptom. Methylphenidate, a commonly prescribed drug in ADHD, improves attention but has mixed reports on risk-based decision making. Using a double-blinded placebo protocol, we studied the risk attitudes of ADHD patients and age-matched healthy volunteers while performing the 2-step sequential learning task and examined the effect of methylphenidate on their choices. We then applied a novel computational analysis using the hierarchical drift-diffusion model to extract parameters such as threshold ('a'-amount of evidence accumulated before making a decision), drift rate ('v'-information processing speed) and response bias ('z' apriori bias towards a specific choice) focusing specifically on risky choice preference. Critically, we show that ADHD patients on placebo have an apriori bias towards risky choices compared to controls. Furthermore, methylphenidate enhanced preference towards risky choices (higher apriori bias) in both groups but had a significantly greater effect in the patient population independent of clinical scores. Thus, methylphenidate appears to shift tolerance towards risky uncertain choices possibly mediated by prefrontal dopaminergic and noradrenergic modulation. We emphasise the utility of computational models in detecting underlying processes. Our findings have implications for subtle yet differential effects of methylphenidate on ADHD compared to healthy population.
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http://dx.doi.org/10.1038/s41398-020-01118-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791121PMC
January 2021

Amplified engagement of prefrontal cortex during control of voluntary action in Tourette syndrome.

Brain Commun 2020 27;2(2):fcaa199. Epub 2020 Nov 27.

Sackler Centre for Consciousness Science, University of Sussex, Sussex, UK.

Tourette syndrome is characterized by 'unvoluntary' tics, which are compulsive, yet often temporarily suppressible. The inferior frontal gyrus is implicated in motor control, including inhibition of pre-potent actions through influences on downstream subcortical and motor regions. Although tic suppression in Tourette syndrome also engages the inferior frontal gyrus, it is unclear whether such prefrontal control of action is also dysfunctional: Tic suppression studies do not permit comparison with control groups, and neuroimaging studies of motor inhibition can be confounded by the concurrent expression or suppression of tics. Here, patients with Tourette syndrome were directly compared to control participants when performing an intentional inhibition task during functional MRI. Tic expression was recorded throughout for removal from statistical models. Participants were instructed to make a button press in response to Go cues, withhold responses to NoGo cues, and decide whether to press or withhold to 'Choose' cues. Overall performance was similar between groups, for both intentional inhibition rates (% Choose-Go) and reactive NoGo inhibition commission errors. A subliminal face prime elicited no additional effects on intentional or reactive inhibition. Across participants, the task activated prefrontal and motor cortices and subcortical nuclei, including pre-supplementary motor area, inferior frontal gyrus, insula, caudate nucleus, thalamus and primary motor cortex. In Tourette syndrome, activity was elevated in the inferior frontal gyrus, insula and basal ganglia, most notably within the right inferior frontal gyrus during voluntary action and inhibition (Choose-Go and Choose-NoGo), and reactive inhibition (NoGo-correct). Anatomically, the locus of this inferior frontal gyrus hyperactivation during control of voluntary action matched that previously reported for tic suppression. In Tourette syndrome, activity within the caudate nucleus was also enhanced during both intentional (Choose-NoGo) and reactive (NoGo-correct) inhibition. Strikingly, despite the absence of overt motor behaviour, primary motor cortex activity increased in patients with Tourette syndrome but decreased in controls during both reactive and intentional inhibition. Additionally, severity of premonitory sensations scaled with functional connectivity of the pre-supplementary motor area to the caudate nucleus, globus pallidus and thalamus when choosing to respond (Choose-Go). Together, these results suggest that patients with Tourette syndrome use equivalent prefrontal mechanisms to suppress tics and withhold non-tic actions, but require greater inferior frontal gyrus engagement than controls to overcome motor drive from hyperactive downstream regions, notably primary motor cortex. Moreover, premonitory sensations may cue midline motor regions to generate tics through interactions with the basal ganglia.
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http://dx.doi.org/10.1093/braincomms/fcaa199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772099PMC
November 2020

Correction: Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study.

Transl Psychiatry 2020 Oct 19;10(1):352. Epub 2020 Oct 19.

Stress, Psychiatry and Immunology Laboratory & Perinatal Psychiatry, King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, Maurice Wohl Clinical Neuroscience Institute, King's College London, SE5 9RT, London, UK.

We have corrected this Article post-publication, because Dr. Cattaneo's affiliation details were originally incorrect (she was affiliated with three institutions but is in fact only linked to one: Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia). These changes reflect in both the PDF and HTML versions of this Article.
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http://dx.doi.org/10.1038/s41398-020-01044-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572382PMC
October 2020

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

Authors:
Yash Patel Nadine Parker Jean Shin Derek Howard Leon French Sophia I Thomopoulos Elena Pozzi Yoshinari Abe Christoph Abé Alan Anticevic Martin Alda Andre Aleman Clara Alloza Silvia Alonso-Lana Stephanie H Ameis Evdokia Anagnostou Andrew A McIntosh Celso Arango Paul D Arnold Philip Asherson Francesca Assogna Guillaume Auzias Rosa Ayesa-Arriola Geor Bakker Nerisa Banaj Tobias Banaschewski Cibele E Bandeira Alexandr Baranov Núria Bargalló Claiton H D Bau Sarah Baumeister Bernhard T Baune Mark A Bellgrove Francesco Benedetti Alessandro Bertolino Premika S W Boedhoe Marco Boks Irene Bollettini Caterina Del Mar Bonnin Tiana Borgers Stefan Borgwardt Daniel Brandeis Brian P Brennan Jason M Bruggemann Robin Bülow Geraldo F Busatto Sara Calderoni Vince D Calhoun Rosa Calvo Erick J Canales-Rodríguez Dara M Cannon Vaughan J Carr Nicola Cascella Mara Cercignani Tiffany M Chaim-Avancini Anastasia Christakou David Coghill Annette Conzelmann Benedicto Crespo-Facorro Ana I Cubillo Kathryn R Cullen Renata B Cupertino Eileen Daly Udo Dannlowski Christopher G Davey Damiaan Denys Christine Deruelle Annabella Di Giorgio Erin W Dickie Danai Dima Katharina Dohm Stefan Ehrlich Benjamin A Ely Tracy Erwin-Grabner Thomas Ethofer Damien A Fair Andreas J Fallgatter Stephen V Faraone Mar Fatjó-Vilas Jennifer M Fedor Kate D Fitzgerald Judith M Ford Thomas Frodl Cynthia H Y Fu Janice M Fullerton Matt C Gabel David C Glahn Gloria Roberts Tinatin Gogberashvili Jose M Goikolea Ian H Gotlib Roberto Goya-Maldonado Hans J Grabe Melissa J Green Eugenio H Grevet Nynke A Groenewold Dominik Grotegerd Oliver Gruber Patricia Gruner Amalia Guerrero-Pedraza Raquel E Gur Ruben C Gur Shlomi Haar Bartholomeus C M Haarman Jan Haavik Tim Hahn Tomas Hajek Benjamin J Harrison Neil A Harrison Catharina A Hartman Heather C Whalley Dirk J Heslenfeld Derrek P Hibar Eva Hilland Yoshiyuki Hirano Tiffany C Ho Pieter J Hoekstra Liesbeth Hoekstra Sarah Hohmann L E Hong Cyril Höschl Marie F Høvik Fleur M Howells Igor Nenadic Maria Jalbrzikowski Anthony C James Joost Janssen Fern Jaspers-Fayer Jian Xu Rune Jonassen Georgii Karkashadze Joseph A King Tilo Kircher Matthias Kirschner Kathrin Koch Peter Kochunov Gregor Kohls Kerstin Konrad Bernd Krämer Axel Krug Jonna Kuntsi Jun Soo Kwon Mikael Landén Nils I Landrø Luisa Lazaro Irina S Lebedeva Elisabeth J Leehr Sara Lera-Miguel Klaus-Peter Lesch Christine Lochner Mario R Louza Beatriz Luna Astri J Lundervold Frank P MacMaster Luigi A Maglanoc Charles B Malpas Maria J Portella Rachel Marsh Fiona M Martyn David Mataix-Cols Daniel H Mathalon Hazel McCarthy Colm McDonald Genevieve McPhilemy Susanne Meinert José M Menchón Luciano Minuzzi Philip B Mitchell Carmen Moreno Pedro Morgado Filippo Muratori Clodagh M Murphy Declan Murphy Benson Mwangi Leila Nabulsi Akiko Nakagawa Takashi Nakamae Leyla Namazova Janardhanan Narayanaswamy Neda Jahanshad Danai D Nguyen Rosa Nicolau Ruth L O'Gorman Tuura Kirsten O'Hearn Jaap Oosterlaan Nils Opel Roel A Ophoff Bob Oranje Victor Ortiz García de la Foz Bronwyn J Overs Yannis Paloyelis Christos Pantelis Mara Parellada Paul Pauli Maria Picó-Pérez Felipe A Picon Fabrizio Piras Federica Piras Kerstin J Plessen Edith Pomarol-Clotet Adrian Preda Olga Puig Yann Quidé Joaquim Radua J Antoni Ramos-Quiroga Paul E Rasser Lisa Rauer Janardhan Reddy Ronny Redlich Andreas Reif Liesbeth Reneman Jonathan Repple Alessandra Retico Vanesa Richarte Anja Richter Pedro G P Rosa Katya K Rubia Ryota Hashimoto Matthew D Sacchet Raymond Salvador Javier Santonja Kelvin Sarink Salvador Sarró Theodore D Satterthwaite Akira Sawa Ulrich Schall Peter R Schofield Anouk Schrantee Jochen Seitz Mauricio H Serpa Esther Setién-Suero Philip Shaw Devon Shook Tim J Silk Kang Sim Schmitt Simon Helen Blair Simpson Aditya Singh Antonin Skoch Norbert Skokauskas Jair C Soares Noam Soreni Carles Soriano-Mas Gianfranco Spalletta Filip Spaniel Stephen M Lawrie Emily R Stern S Evelyn Stewart Yoichiro Takayanagi Henk S Temmingh David F Tolin David Tomecek Diana Tordesillas-Gutiérrez Michela Tosetti Anne Uhlmann Therese van Amelsvoort Nic J A van der Wee Steven J A van der Werff Neeltje E M van Haren Guido A van Wingen Alasdair Vance Javier Vázquez-Bourgon Daniela Vecchio Ganesan Venkatasubramanian Eduard Vieta Oscar Vilarroya Yolanda Vives-Gilabert Aristotle N Voineskos Henry Völzke Georg G von Polier Esther Walton Thomas W Weickert Cynthia Shannon Weickert Andrea S Weideman Katharina Wittfeld Daniel H Wolf Mon-Ju Wu T T Yang Kun Yang Yuliya Yoncheva Je-Yeon Yun Yuqi Cheng Marcus V Zanetti Georg C Ziegler Barbara Franke Martine Hoogman Jan K Buitelaar Daan van Rooij Ole A Andreassen Christopher R K Ching Dick J Veltman Lianne Schmaal Dan J Stein Odile A van den Heuvel Jessica A Turner Theo G M van Erp Zdenka Pausova Paul M Thompson Tomáš Paus

JAMA Psychiatry 2021 Jan;78(1):47-63

Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

Minocycline differentially modulates human spatial memory systems.

Neuropsychopharmacology 2020 12 24;45(13):2162-2169. Epub 2020 Aug 24.

Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, CF24 4HQ, UK.

Microglia play a critical role in many processes fundamental to learning and memory in health and are implicated in Alzheimer's pathogenesis. Minocycline, a centrally-penetrant tetracycline antibiotic, inhibits microglial activation and enhances long-term potentiation, synaptic plasticity, neurogenesis and hippocampal-dependent spatial memory in rodents, leading to clinical trials in human neurodegenerative diseases. However, the effects of minocycline on human memory have not previously been investigated. Utilising a double-blind, randomised crossover study design, we recruited 20 healthy male participants (mean 24.6 ± 5.0 years) who were each tested in two experimental sessions: once after 3 days of Minocycline 150 mg (twice daily), and once 3 days of placebo (identical administration). During each session, all completed an fMRI task designed to tap boundary- and landmark-based navigation (thought to rely on hippocampal and striatal learning mechanisms respectively). Given the rodent literature, we hypothesised that minocycline would selectively modulate hippocampal learning. In line with this, minocycline biased use of boundary- compared to landmark-based information (t = 3.140, p = 0.002). However, though this marginally improved performance for boundary-based objects (t = 1.972, p = 0.049), it was outweighed by impaired landmark-based navigation (t = 6.374, p < 0.001) resulting in an overall performance decrease (t = 3.295, p = 0.001). Furthermore, against expectations, minocycline significantly reduced activity during memory encoding in the right caudate (t = 2.992, p = 0.003) and five other cortical regions, with no significant effect in the hippocampus. In summary, minocycline impaired human spatial memory performance, likely through disruption of striatal processing resulting in greater biasing towards reliance on boundary-based navigation.
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http://dx.doi.org/10.1038/s41386-020-00811-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784680PMC
December 2020

Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study.

Transl Psychiatry 2020 07 23;10(1):232. Epub 2020 Jul 23.

Stress, Psychiatry and Immunology Laboratory & Perinatal Psychiatry, King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, Maurice Wohl Clinical Neuroscience Institute, King's College London, SE5 9RT, London, UK.

The mRNA expression signatures associated with the 'pro-inflammatory' phenotype of depression, and the differential signatures associated with depression subtypes and the effects of antidepressants, are still unknown. We examined 130 depressed patients (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy controls from the BIODEP study, and used whole-blood mRNA qPCR to measure the expression of 16 candidate mRNAs, some never measured before: interleukin (IL)-1-beta, IL-6, TNF-alpha, macrophage inhibiting factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, CCL2, CXCL12, c-reactive protein (CRP), alpha-2-macroglobulin (A2M), acquaporin-4 (AQP4), ISG15, STAT1 and USP-18. All genes but AQP4, ISG15 and USP-18 were differentially regulated. Treatment-resistant and drug-free depressed patients had both increased inflammasome activation (higher P2RX7 and proinflammatory cytokines/chemokines mRNAs expression) and glucocorticoid resistance (lower GR and higher FKBP5 mRNAs expression), while responsive patients had an intermediate phenotype with, additionally, lower CXCL12. Most interestingly, using binomial logistics models we found that a signature of six mRNAs (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) distinguished treatment-resistant from responsive patients, even after adjusting for other variables that were different between groups, such as a trait- and state-anxiety, history of childhood maltreatment and serum CRP. Future studies should replicate these findings in larger, longitudinal cohorts, and test whether this mRNA signature can identify patients that are more likely to respond to adjuvant strategies for treatment-resistant depression, including combinations with anti-inflammatory medications.
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http://dx.doi.org/10.1038/s41398-020-00874-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376244PMC
July 2020

Subcortical Brain Volume, Regional Cortical Thickness, and Cortical Surface Area Across Disorders: Findings From the ENIGMA ADHD, ASD, and OCD Working Groups.

Authors:
Premika S W Boedhoe Daan van Rooij Martine Hoogman Jos W R Twisk Lianne Schmaal Yoshinari Abe Pino Alonso Stephanie H Ameis Anatoly Anikin Alan Anticevic Celso Arango Paul D Arnold Philip Asherson Francesca Assogna Guillaume Auzias Tobias Banaschewski Alexander Baranov Marcelo C Batistuzzo Sarah Baumeister Ramona Baur-Streubel Marlene Behrmann Mark A Bellgrove Francesco Benedetti Jan C Beucke Joseph Biederman Irene Bollettini Anushree Bose Janita Bralten Ivanei E Bramati Daniel Brandeis Silvia Brem Brian P Brennan Geraldo F Busatto Sara Calderoni Anna Calvo Rosa Calvo Francisco X Castellanos Mara Cercignani Tiffany M Chaim-Avancini Kaylita C Chantiluke Yuqi Cheng Kang Ik K Cho Anastasia Christakou David Coghill Annette Conzelmann Ana I Cubillo Anders M Dale Sara Dallaspezia Eileen Daly Damiaan Denys Christine Deruelle Adriana Di Martino Ilan Dinstein Alysa E Doyle Sarah Durston Eric A Earl Christine Ecker Stefan Ehrlich Benjamin A Ely Jeffrey N Epstein Thomas Ethofer Damien A Fair Andreas J Fallgatter Stephen V Faraone Jennifer Fedor Xin Feng Jamie D Feusner Jackie Fitzgerald Kate D Fitzgerald Jean-Paul Fouche Christine M Freitag Egill A Fridgeirsson Thomas Frodl Matt C Gabel Louise Gallagher Tinatin Gogberashvili Ilaria Gori Patricia Gruner Deniz A Gürsel Shlomi Haar Jan Haavik Geoffrey B Hall Neil A Harrison Catharina A Hartman Dirk J Heslenfeld Yoshiyuki Hirano Pieter J Hoekstra Marcelo Q Hoexter Sarah Hohmann Marie F Høvik Hao Hu Chaim Huyser Neda Jahanshad Maria Jalbrzikowski Anthony James Joost Janssen Fern Jaspers-Fayer Terry L Jernigan Dmitry Kapilushniy Bernd Kardatzki Georgii Karkashadze Norbert Kathmann Christian Kaufmann Clare Kelly Sabin Khadka Joseph A King Kathrin Koch Gregor Kohls Kerstin Konrad Masaru Kuno Jonna Kuntsi Gerd Kvale Jun Soo Kwon Luisa Lázaro Sara Lera-Miguel Klaus-Peter Lesch Liesbeth Hoekstra Yanni Liu Christine Lochner Mario R Louza Beatriz Luna Astri J Lundervold Charles B Malpas Paulo Marques Rachel Marsh Ignacio Martínez-Zalacaín David Mataix-Cols Paulo Mattos Hazel McCarthy Jane McGrath Mitul A Mehta José M Menchón Maarten Mennes Mauricio Moller Martinho Pedro S Moreira Astrid Morer Pedro Morgado Filippo Muratori Clodagh M Murphy Declan G M Murphy Akiko Nakagawa Takashi Nakamae Tomohiro Nakao Leyla Namazova-Baranova Janardhanan C Narayanaswamy Rosa Nicolau Joel T Nigg Stephanie E Novotny Erika L Nurmi Eileen Oberwelland Weiss Ruth L O'Gorman Tuura Kirsten O'Hearn Joseph O'Neill Jaap Oosterlaan Bob Oranje Yannis Paloyelis Mara Parellada Paul Pauli Chris Perriello John Piacentini Fabrizio Piras Federica Piras Kerstin J Plessen Olga Puig J Antoni Ramos-Quiroga Y C Janardhan Reddy Andreas Reif Liesbeth Reneman Alessandra Retico Pedro G P Rosa Katya Rubia Oana Georgiana Rus Yuki Sakai Anouk Schrantee Lena Schwarz Lizanne J S Schweren Jochen Seitz Philip Shaw Devon Shook Tim J Silk H Blair Simpson Norbert Skokauskas Juan Carlos Soliva Vila Anastasia Solovieva Noam Soreni Carles Soriano-Mas Gianfranco Spalletta Emily R Stern Michael C Stevens S Evelyn Stewart Gustavo Sudre Philip R Szeszko Leanne Tamm Margot J Taylor David F Tolin Michela Tosetti Fernanda Tovar-Moll Aki Tsuchiyagaito Theo G M van Erp Guido A van Wingen Alasdair Vance Ganesan Venkatasubramanian Oscar Vilarroya Yolanda Vives-Gilabert Georg G von Polier Susanne Walitza Gregory L Wallace Zhen Wang Thomas Wolfers Yuliya N Yoncheva Je-Yeon Yun Marcus V Zanetti Fengfeng Zhou Georg C Ziegler Kathrin C Zierhut Marcel P Zwiers Paul M Thompson Dan J Stein Jan Buitelaar Barbara Franke Odile A van den Heuvel

Am J Psychiatry 2020 09 16;177(9):834-843. Epub 2020 Jun 16.

The full list of authors in the ENIGMA working groups, author affiliations, author disclosures, and acknowledgments are provided in online supplements.

Objective: Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data.

Methods: Structural T-weighted whole-brain MRI data from healthy control subjects (N=5,827) and from patients with ADHD (N=2,271), ASD (N=1,777), and OCD (N=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. The authors examined subcortical volume, cortical thickness, and cortical surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults, using linear mixed-effects models adjusting for age, sex, and site (and intracranial volume for subcortical and surface area measures).

Results: No shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood.

Conclusions: The study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.
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http://dx.doi.org/10.1176/appi.ajp.2020.19030331DOI Listing
September 2020

Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits.

Neuropsychopharmacology 2020 08 30;45(9):1482-1489. Epub 2020 May 30.

Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Brighton, UK.

Functional magnetic resonance imaging (fMRI) can be combined with drugs to investigate the system-level functional responses in the brain to such challenges. However, most psychoactive agents act on multiple neurotransmitters, limiting the ability of fMRI to identify functional effects related to actions on discrete pharmacological targets. We recently introduced a multimodal approach, REACT (Receptor-Enriched Analysis of functional Connectivity by Targets), which offers the opportunity to disentangle effects of drugs on different neurotransmitters and clarify the biological mechanisms driving clinical efficacy and side effects of a compound. Here, we focus on methylphenidate (MPH), which binds to the dopamine transporter (DAT) and the norepinephrine transporter (NET), to unravel its effects on dopaminergic and noradrenergic functional circuits in the healthy brain at rest. We then explored the relationship between these target-enriched resting state functional connectivity (FC) maps and inter-individual variability in behavioural responses to a reinforcement-learning task encompassing a novelty manipulation to disentangle the molecular systems underlying specific cognitive/behavioural effects. Our main analysis showed a significant MPH-induced FC increase in sensorimotor areas in the functional circuit associated with DAT. In our exploratory analysis, we found that MPH-induced regional variations in the DAT and NET-enriched FC maps were significantly correlated with some of the inter-individual differences on key behavioural responses associated with the reinforcement-learning task. Our findings show that main MPH-related FC changes at rest can be understood through the distribution of DAT in the brain. Furthermore, they suggest that when compounds have mixed pharmacological profiles, REACT may be able to capture regional functional effects that are underpinned by the same cognitive mechanism but are related to engagement of distinct molecular targets.
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http://dx.doi.org/10.1038/s41386-020-0724-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360745PMC
August 2020

Interferon and anti-TNF therapies differentially modulate amygdala reactivity which predicts associated bidirectional changes in depressive symptoms.

Mol Psychiatry 2020 May 26. Epub 2020 May 26.

Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex Campus, Brighton, BN1 9RY, UK.

A third of patients receiving Interferon-α (IFN-α) treatment for Hepatitis-C develop major depressive disorder (MDD). Conversely, anti-Tumor Necrosis Factor (TNF) therapies improve depression providing key empirical support for the "inflammatory theory" of depression. Heightened amygdala reactivity (particularly to negatively valanced stimuli) is a consistent finding within MDD; can predict treatment efficacy and reverses following successful treatment. However, whether IFN-α and anti-TNF enhance/attenuate depressive symptoms through modulation of amygdala emotional reactivity is unknown. Utilizing a prospective study design, we recruited 30 patients (mean 48.0 ± 10.5 years, 21 male) initiating IFN-α treatment for Hepatitis-C and 30 (mean 50.4 ± 15.7 years, 10 male) anti-TNF therapy for inflammatory arthritis. All completed an emotional face-processing task during fMRI and blood sampling before and after their first IFN-α (4-h) or anti-TNF (24-h) injection and follow-up psychiatric assessments for 3 months of treatment. IFN-α significantly increased depression symptoms (Hamilton Depression Rating Scale HAM-D) at 4 weeks (p < 0.001) but not 4-h after first dose (p > 0.1). Conversely, anti-TNF significantly improved depressive symptoms (Hospital Anxiety and Depression Rating Scale HADS) at both 24-h (P = 0.015) and 12 weeks (p = 0.018). In support of our a-priori hypothesis, both IFN-α and anti-TNF significantly modulated amygdala reactivity with IFN-α acutely enhancing right amygdala responses to sad (compared with neutral) faces (p = 0.032) and anti-TNF conversely decreasing right amygdala reactivity (across emotional valence) (p = 0.033). Furthermore, these changes predicted IFN-induced increases in HAM-D 4 weeks later (R = 0.17, p = 0.022) and anti-TNF-associated decreases in HADS at 24-h (R = 0.23, p = 0.01) suggesting that actions of systemic inflammation on amygdala emotional reactivity play a mechanistic role in inflammation-associated depressive symptoms.
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http://dx.doi.org/10.1038/s41380-020-0790-9DOI Listing
May 2020

Dissociating self-generated volition from externally-generated motivation.

PLoS One 2020 19;15(5):e0232949. Epub 2020 May 19.

Department of Psychiatry, Depression and Anxiety Center for Discovery and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.

Insight into motivational processes may be gained by examining measures of willingness to exert effort for rewards, which have been linked to neuropsychiatric symptoms of anhedonia and apathy. However, while much work has focused on the development of models of motivation based on classic tasks of externally-generated levels of effort for reward, there has been less focus on the question of self-generated motivation or volition. We developed a task that aims to capture separate measures of self-generated and externally-generated motivation, with two task variants for physical and cognitive effort, and sought to test and validate this measure in two populations of healthy volunteers (N = 27 and N = 28). Similar to previous reports, a sigmoid function represented a better overall fit to the effort-reward data than a linear or Weibull model. Individual sigmoid function shapes were governed by two free parameters: bias (the amount of reward needed for effort initiation) and reward insensitivity (the amount of increase in reward needed to accelerate effort expenditure). For both physical and cognitive effort, bias was higher in the self-generated condition, indicating reduced self-generated volitional effort initiation, compared to externally-generated effort initiation, across effort domains. Bias against initial effort initiation in the self-generated condition was related to a specific dimensional measure of anticipatory anhedonia. For physical effort only, reward insensitivity was also higher in the self-generated condition compared to the externally-generated motivation condition, indicating lower self-generated effort acceleration. This work provides a novel objective measure of self-generated motivation that may provide insights into mechanisms of anhedonia and related symptoms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232949PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236980PMC
July 2020

Peripheral Blood Cell-Stratified Subgroups of Inflamed Depression.

Biol Psychiatry 2020 07 2;88(2):185-196. Epub 2019 Dec 2.

Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom; Cambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge, United Kingdom.

Background: Depression has been associated with increased inflammatory proteins, but changes in circulating immune cells are less well defined.

Methods: We used multiparametric flow cytometry to count 14 subsets of peripheral blood cells in 206 depression cases and 77 age- and sex-matched controls (N = 283). We used univariate and multivariate analyses to investigate the immunophenotypes associated with depression and depression severity.

Results: Depression cases, compared with controls, had significantly increased immune cell counts, especially neutrophils, CD4 T cells, and monocytes, and increased inflammatory proteins (C-reactive protein and interleukin-6). Within-group analysis of cases demonstrated significant associations between the severity of depressive symptoms and increased myeloid and CD4 T-cell counts. Depression cases were partitioned into 2 subgroups by forced binary clustering of cell counts: the inflamed depression subgroup (n = 81 out of 206; 39%) had increased monocyte, CD4, and neutrophil counts; increased C-reactive protein and interleukin-6; and more severe depression than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven analysis identified 4 subgroups of depression cases, 2 of which (n = 38 and n = 100; 67% collectively) were associated with increased inflammatory proteins and more severe depression but differed in terms of myeloid and lymphoid cell counts. Results were robust to potentially confounding effects of age, sex, body mass index, recent infection, and tobacco use.

Conclusions: Peripheral immune cell counts were used to distinguish inflamed and uninflamed subgroups of depression and to indicate that there may be mechanistically distinct subgroups of inflamed depression.
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http://dx.doi.org/10.1016/j.biopsych.2019.11.017DOI Listing
July 2020

Childhood trauma, HPA axis activity and antidepressant response in patients with depression.

Brain Behav Immun 2020 07 30;87:229-237. Epub 2019 Nov 30.

Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, Kings College London, UK; National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, UK.

Childhood trauma is among the most potent contributing risk factors for depression and is associated with poor treatment response. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been linked to both childhood trauma and depression, but the underlying mechanisms are poorly understood. The present study aimed to investigate the link between childhood trauma, HPA axis activity and antidepressant response in patients with depression. As part of the Wellcome Trust NIMA consortium, 163 depressed patients and 55 healthy volunteers were included in this study. Adult patients meeting Structured Clinical Interview for Diagnostic and Statistical Manual Version-5 criteria for major depression were categorised into subgroups of treatment responder (n = 42), treatment non-responder (n = 80) and untreated depressed (n = 41) based on current depressive symptom severity measured by the 17-item Hamilton Rating Scale for Depression and exposure to antidepressant medications established by Antidepressant Treatment Response Questionnaire. Childhood Trauma Questionnaire was obtained. Baseline serum C-reactive protein was measured using turbidimetric detection. Salivary cortisol was analyzed at multiple time points during the day using the ELISA technique. Glucocorticoid resistance was defined as the coexistence of hypercortisolemia and inflammation. Our results show that treatment non-responder patients had higher exposure to childhood trauma than responders. No specific HPA axis abnormalities were found in treatment non-responder depressed patients. Untreated depressed showed increased diurnal cortisol levels compared with patients on antidepressant medication, and higher prevalence of glucocorticoid resistance than medicated patients and controls. The severity of childhood trauma was associated with increased diurnal cortisol levels only in individuals with glucocorticoid resistance. Therefore, our findings suggest that the severity of childhood trauma experience contributes to a lack of response to antidepressant treatment. The effects of childhood trauma on increased cortisol levels are specifically evident in patients with glucocorticoid resistance and suggest glucocorticoid resistance as a target for the development of personalized treatment for a subgroup of depressed patients with a history of childhood trauma rather than for all patients with resistance to antidepressant treatment.
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http://dx.doi.org/10.1016/j.bbi.2019.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327513PMC
July 2020

Disentangling the Effects of Peripheral Inflammatory Markers on Brain Functional Connectivity.

Authors:
Neil A Harrison

Biol Psychiatry 2019 07;86(2):84-86

Cardiff University Brain Research Imaging Centre, Department of Psychology, Cardiff, United Kingdom; Division of Psychological Medicine and Neuroscience, Department of Medicine, Cardiff University, Cardiff, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2019.05.013DOI Listing
July 2019

Factor analyses differentiate clinical phenotypes of idiopathic and interferon-alpha-induced depression.

Brain Behav Immun 2019 08 25;80:519-524. Epub 2019 Apr 25.

Immunopsychiatry Research Clinic, Sussex Education Centre, Sussex Partnership NHS Foundation Trust, Brighton BN3 7HZ, United Kingdom; School of Psychology, University of Sussex, Brighton BN1 9RH, United Kingdom.

The discovery that prolonged administration of interferon-alpha (a pro-inflammatory cytokine) readily precipitates depressive symptoms has played a key role in development of the inflammation theory of major depressive disorder (MDD). However, it remains unclear whether the clinical phenotype of patients with inflammation-associated depression significantly overlaps with, or can be distinguished from that of patients with 'idiopathic' depression. Here we explored the Hamilton depression scale factor structure of 172 patients undergoing interferon-alpha treatment for hepatitis-C at the point of transition to a depressive episode of DSM IV defined major depression severity. The resulting factor structure was first compared with a model derived from 6 previous studies of 'idiopathic' MDD (Cole et al., 2004). This confirmatory factor analysis revealed that the factor structure of HAMD scores in our interferon-alpha treated cohort did not plausibly fit that previously described for 'idiopathic' MDD. Instead, subsequent exploratory factor analysis revealed a distinct four factor model with a novel primary factor grouping cognitive symptoms of depression and anxiety (HAMD items 1, 2, 9, 10, 11, 15). The second sleep disorder factor (items 4, 5, 6) replicated previous findings in 'idiopathic' depression. A third and unique factor grouped somatic symptoms and function (items 7, 12, 13, 14 and item 1). The final factor (also common in idiopathic depression studies), grouped gastrointestinal symptoms and weight loss (items 12 and 16). Severe depression items (3, 8, and 17) were excluded from analysis due to very low variance. At transition, interferon-alpha induced major depressive episodes therefore appears to have more associated anxiety features that covary with depressed mood than classical or 'idiopathic' MDD and a low likelihood of severe features such as suicidal ideation. Identification of this clinical phenotype may help identify patients with an inflammatory depression etiology and support the development of more effective and personalized therapies.
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http://dx.doi.org/10.1016/j.bbi.2019.04.035DOI Listing
August 2019

Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples.

Authors:
Martine Hoogman Ryan Muetzel Joao P Guimaraes Elena Shumskaya Maarten Mennes Marcel P Zwiers Neda Jahanshad Gustavo Sudre Thomas Wolfers Eric A Earl Juan Carlos Soliva Vila Yolanda Vives-Gilabert Sabin Khadka Stephanie E Novotny Catharina A Hartman Dirk J Heslenfeld Lizanne J S Schweren Sara Ambrosino Bob Oranje Patrick de Zeeuw Tiffany M Chaim-Avancini Pedro G P Rosa Marcus V Zanetti Charles B Malpas Gregor Kohls Georg G von Polier Jochen Seitz Joseph Biederman Alysa E Doyle Anders M Dale Theo G M van Erp Jeffery N Epstein Terry L Jernigan Ramona Baur-Streubel Georg C Ziegler Kathrin C Zierhut Anouk Schrantee Marie F Høvik Astri J Lundervold Clare Kelly Hazel McCarthy Norbert Skokauskas Ruth L O'Gorman Tuura Anna Calvo Sara Lera-Miguel Rosa Nicolau Kaylita C Chantiluke Anastasia Christakou Alasdair Vance Mara Cercignani Matt C Gabel Philip Asherson Sarah Baumeister Daniel Brandeis Sarah Hohmann Ivanei E Bramati Fernanda Tovar-Moll Andreas J Fallgatter Bernd Kardatzki Lena Schwarz Anatoly Anikin Alexandr Baranov Tinatin Gogberashvili Dmitry Kapilushniy Anastasia Solovieva Hanan El Marroun Tonya White Georgii Karkashadze Leyla Namazova-Baranova Thomas Ethofer Paulo Mattos Tobias Banaschewski David Coghill Kerstin J Plessen Jonna Kuntsi Mitul A Mehta Yannis Paloyelis Neil A Harrison Mark A Bellgrove Tim J Silk Ana I Cubillo Katya Rubia Luisa Lazaro Silvia Brem Susanne Walitza Thomas Frodl Mariam Zentis Francisco X Castellanos Yuliya N Yoncheva Jan Haavik Liesbeth Reneman Annette Conzelmann Klaus-Peter Lesch Paul Pauli Andreas Reif Leanne Tamm Kerstin Konrad Eileen Oberwelland Weiss Geraldo F Busatto Mario R Louza Sarah Durston Pieter J Hoekstra Jaap Oosterlaan Michael C Stevens J Antoni Ramos-Quiroga Oscar Vilarroya Damien A Fair Joel T Nigg Paul M Thompson Jan K Buitelaar Stephen V Faraone Philip Shaw Henning Tiemeier Janita Bralten Barbara Franke

Am J Psychiatry 2019 07 24;176(7):531-542. Epub 2019 Apr 24.

The Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands (Hoogman, Guimaraes, Shumskaya, Wolfers, Bralten, Franke); the Donders Institute for Brain, Cognition, and Behavior, Radboud University, Nijmegen, the Netherlands (Hoogman, Shumskaya, Mennes, Wolfers, Buitelaar, Bralten, Franke); the Department of Child and Adolescent Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands (Muetzel, El Marroun, White, Tiemeier); the Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands (Muetzel); the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands (Guimaraes, Zwiers, Buitelaar); the Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Marina del Rey, Calif. (Jahanshad, Thompson); National Human Genome Research Institute, Bethesda, Md. (Sudre, Shaw); the Department of Behavioral Neuroscience, Oregon Health and Science University, Portland (Earl, Fair, Nigg); the Department of Psychiatry and Forensic Medicine, Autonomous University of Barcelona, Cerdanyola del Vallès, Spain (Soliva Vila, Ramos-Quiroga, Vilarroya); Instituto ITACA, Polytechnic University of Valencia, Valencia, Spain (Vives-Gilabert); the Olin Neuropsychiatry Research Center, Hartford Hospital, Hartford, Conn. (Khadka, Novotny, Stevens); University of Groningen, University Medical Center Groningen (UMCG), Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation (ICPE), Groningen, the Netherlands (Hartman, Schweren); Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam (Heslenfeld); the Department of Child and Adolescent Psychiatry, University of Groningen, University Medical Center Groningen, the Netherlands (Hoekstra); NICHE Lab, Department of Psychiatry, UMC Utrecht Brain Center, Utrecht, the Netherlands (Ambrosino, Oranje, de Zeeuw, Durston); Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil (Chaim-Avancini, Rosa, Zanetti, Busatto); the Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil (Chaim-Avancini, Rosa, Zanetti, Busatto); the Developmental Imaging Group, Murdoch Children's Research Institute, Melbourne, Australia (Malpas); the Clinical Outcomes Research Unit (CORe), Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia (Malpas); the Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia (Malpas); the Child Neuropsychology Section, University Hospital RWTH Aachen, Aachen, Germany (Kohls, Konrad; Child and Adolescent Psychiatry, University Hospital RWTH Aachen, Aachen, Germany (Polier, Seitz); Institute of Neuroscience and Medicine-Brain and Behavior (INM-7), Research Center Jülich, Jülich, Germany (Polier); the Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Department of Psychiatry, Massachusetts General Hospital, Boston (Biederman); the Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston (Biederman, Doyle); the Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (Doyle); the Departments of Neurosciences, Radiology, and Psychiatry and the Center for Multimodal Imaging and Genetics, University of California San Diego (Dale); the Clinical and Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine (van Erp); the Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati (Epstein, Tamm); the Center for Human Development, University of California San Diego, San Diego (Jernigan); the Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany (Ziegler, Lesch); the Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam (Schrantee, Reneman); the Department of Clinical Medicine, University of Bergen, Bergen, Norway (Høvik); the Division of Psychiatry, Haukeland University Hospital, Bergen, Norway (Høvik, Haavik); the Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway (Lundervold); the K.G. Jebsen Center for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway (Lundervold, Haavik); the School of Psychology and the Department of Psychiatry, School of Medicine, and the Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland (Kelly); the Department of Child and Adolescent Psychiatry, NYU Langone Medical Center, New York (Kelly, Castellanos, Yoncheva); the Department of Psychiatry, Trinity College Dublin, Ireland (McCarthy, Skokauskas, Frodl); the Centre for Advanced Medical Imaging, St. James's Hospital, Dublin, Ireland (McCarthy); the Center for Child and Adolescent Mental Health, NTNU, Norway, Norwegian University of Science and Technology, Norway (Skokauskas); the Center for MR Research, University Children's Hospital, and the Zurich Center for Integrative Human Physiology, Zurich (O'Gorman Tuura); Magnetic Resonance Image Core Facility, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain (Calvo, Lazaro); the Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic, Barcelona, Spain (Lera-Miguel, Nicolau, Lazaro); the Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Chantiluke, Christakou, Cubillo, Rubia); the School of Psychology and Clinical Language Sciences, Centre for Integrative Neuroscience and Neurodynamics, University of Reading, Reading, U.K. (Christakou); the Department of Paediatrics, University of Melbourne, Australia (Vance, Coghill, Silk); the Department of Neuroscience, Brighton and Sussex Medical School, Falmer, Brighton, U.K. (Cercignani, Gabel, Harrison); the Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Asherson, Kuntsi); the Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany (Baumeister, Brandeis, Hohmann, Banaschewski); the Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Zurich (Brandeis, Brem, Walitza); the Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich (Brandeis, Brem, Walitza); the D'Or Institute for Research and Education, Rio de Janeiro (Bramati, Tovar-Moll, Mattos); the Morphological Sciences Program, Federal University of Rio de Janeiro, Rio de Janeiro (Tovar-Moll); the Department of Psychiatry and Psychotherapy, University Hospital of Tübingen, Tübingen, Germany (Fallgatter, Schwarz, Ethofer); LEAD Graduate School, University of Tübingen, Germany (Fallgatter); the Department of Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany (Kardatzki, Ethofer); the National Medical Research Center for Children's Health, Department of Magnetic Resonance Imaging and Densitometry, Moscow (Anikin); the National Medical Research Center for Children's Health, Moscow (Baranov, Solovieva); Russian National Research Medical University, Ministry of Health and Social Development of the Russian Federation, Central Clinical Hospital MSHE, Moscow (Namazova-Baranova); the National Medical Research Center for Children's Health, Laboratory of Neurology and Cognitive Health, Moscow (Gogberashvili, Karkashadze); the National Medical Research Center for Children's Health, Department of Information Technologies, Moscow (Kapilushniy); the Department of Pediatrics, Erasmus MC-Sophia, Rotterdam, the Netherlands (El Marroun); the Department of Psychology, Education, and Child Studies, Erasmus University Rotterdam, Rotterdam, the Netherlands (El Marroun); the Department of Radiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands (White); Federal University of Rio de Janeiro, Rio de Janeiro (Mattos); the Department of Psychiatry, University of Melbourne, Melbourne, Australia (Coghill); the Murdoch Children's Research Institute, Melbourne, Australia (Coghill, Silk); the Division of Neuroscience, University of Dundee, Dundee, U.K. (Coghill); the Child and Adolescent Mental Health Center, Capital Region Copenhagen (Plessen); the Division of Child and Adolescent Psychiatry, Department of Psychiatry, University Hospital Lausanne, Switzerland (Plessen); the Department of Neuroimaging, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Mehta, Paloyelis); Sussex Partnership NHS Foundation Trust, Swandean, East Sussex, U.K. (Harrison); the Monash Institute for Cognitive and Clinical Neurosciences (MICCN) and the School of Psychological Sciences, Monash University, Melbourne, Australia (Bellgrove); Deakin University, School of Psychology, Geelong, Australia (Silk); the Department of Medicine, University of Barcelona, Barcelona, Spain (Lazaro); the Department of Psychiatry and Psychotherapy, Otto von Guericke University Magdeburg, Germany (Frodl); the German Center for Neurodegenerative Diseases (DZNE), Germany (Frodl); Bezirksklinikum Regensburg, Germany (Zentis); the Nathan Kline Institute for Psychiatric Research, Orangeburg, N.Y. (Castellanos); the Brain Imaging Center, Amsterdam University Medical Centers, Amsterdam (Reneman); the Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Tübingen, Germany (Conzelmann); the Department of Psychology, Biological Psychology, Clinical Psychology, and Psychotherapy, University of Würzburg, Würzburg, Germany (Conzelmann, Pauli, Baur-Streubel, Zierhut); the Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow (Lesch); the Department of Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, the Netherlands (Lesch); the Department of Psychiatry, Psychosomatic Medicine, and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany (Reif); JARA Institute Molecular Neuroscience and Neuroimaging (INM-11), Institute for Neuroscience and Medicine, Research Center Jülich, Germany (Konrad); Translational Neuroscience, Child and Adolescent Psychiatry, University Hospital RWTH Aachen, Aachen, Germany (Oberwelland Weiss); Cognitive Neuroscience (INM-3), Institute for Neuroscience and Medicine, Research Center Jülich, Germany (Oberwelland Weiss); the Department of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil (Busatto, Louza); the Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam (Oosterlaan); Emma Children's Hospital Amsterdam Medical Center, Amsterdam (Oosterlaan); the Department of Pediatrics, VU Medical Center, Amsterdam (Oosterlaan); the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (Stevens); the Department of Psychiatry, Vall d'Hebron University Hospital, Barcelona, Spain (Ramos-Quiroga); Biomedical Network Research Center on Mental Health (CIBERSAM), Barcelona, Spain (Lazaro, Ramos-Quiroga); Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain (Vilarroya); the Department of Psychiatry, Oregon Health and Science University, Portland (Fair, Nigg); Karakter Child and Adolescent Psychiatry University Center, Nijmegen, the Netherlands (Buitelaar); Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York (Faraone); NIHM, Bethesda, Md. (Shaw); the Department of Social and Behavioral Science, Harvard T.H. Chan School of Public Health, Boston (Tiemeier).

Objective: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies.

Methods: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707).

Results: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample.

Conclusions: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.
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http://dx.doi.org/10.1176/appi.ajp.2019.18091033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879185PMC
July 2019

Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis.

J Neurol Neurosurg Psychiatry 2019 06 25;90(6):642-651. Epub 2019 Jan 25.

Translational Neuromodeling Unit (TNU), Institute for Biomedical Engineering, University of Zurich and ETH Zurich, Zurich, Switzerland.

Fatigue is one of the most common symptoms in multiple sclerosis (MS), with a major impact on patients' quality of life. Currently, treatment proceeds by trial and error with limited success, probably due to the presence of multiple different underlying mechanisms. Recent neuroscientific advances offer the potential to develop tools for differentiating these mechanisms in individual patients and ultimately provide a principled basis for treatment selection. However, development of these tools for differential diagnosis will require guidance by pathophysiological and cognitive theories that propose mechanisms which can be assessed in individual patients. This article provides an overview of contemporary pathophysiological theories of fatigue in MS and discusses how the mechanisms they propose may become measurable with emerging technologies and thus lay a foundation for future personalised treatments.
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http://dx.doi.org/10.1136/jnnp-2018-320050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581095PMC
June 2019

What's in a name? How about being listed in the "Psychiatry" category in Clarivate's Journal Citation Index!

Brain Behav Immun 2019 05 16;78:3-4. Epub 2019 Jan 16.

Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.

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http://dx.doi.org/10.1016/j.bbi.2019.01.005DOI Listing
May 2019

Face perception enhances insula and motor network reactivity in Tourette syndrome.

Brain 2018 11;141(11):3249-3261

Sackler Centre for Consciousness Science, University of Sussex, UK.

Tourette syndrome is a neurodevelopmental disorder, characterized by motor and phonic tics. Tics are typically experienced as avolitional, compulsive, and associated with premonitory urges. They are exacerbated by stress and can be triggered by external stimuli, including social cues like the actions and facial expressions of others. Importantly, emotional social stimuli, with angry facial stimuli potentially the most potent social threat cue, also trigger behavioural reactions in healthy individuals, suggesting that such mechanisms may be particularly sensitive in people with Tourette syndrome. Twenty-one participants with Tourette syndrome and 21 healthy controls underwent functional MRI while viewing faces wearing either neutral or angry expressions to quantify group differences in neural activity associated with processing social information. Simultaneous video recordings of participants during neuroimaging enabled us to model confounding effects of tics on task-related responses to the processing of faces. In both Tourette syndrome and control participants, face stimuli evoked enhanced activation within canonical face perception regions, including the occipital face area and fusiform face area. However, the Tourette syndrome group showed additional responses within the anterior insula to both neutral and angry faces. Functional connectivity during face viewing was then examined in a series of psychophysiological interactions. In participants with Tourette syndrome, the insula showed functional connectivity with a set of cortical regions previously implicated in tic generation: the presupplementary motor area, premotor cortex, primary motor cortex, and the putamen. Furthermore, insula functional connectivity with the globus pallidus and thalamus varied in proportion to tic severity, while supplementary motor area connectivity varied in proportion to premonitory sensations, with insula connectivity to these regions increasing to a greater extent in patients with worse symptom severity. In addition, the occipital face area showed increased functional connectivity in Tourette syndrome participants with posterior cortical regions, including primary somatosensory cortex, and occipital face area connectivity with primary somatosensory and primary motor cortices varied in proportion to tic severity. There were no significant psychophysiological interactions in controls. These findings highlight a potential mechanism in Tourette syndrome through which heightened representation within insular cortex of embodied affective social information may impact the reactivity of subcortical motor pathways, supporting programmed motor actions that are causally implicated in tic generation. Medicinal and psychological therapies that focus on reducing insular hyper-reactivity to social stimuli may have potential benefit for tic reduction in people with Tourette syndrome.
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http://dx.doi.org/10.1093/brain/awy254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202569PMC
November 2018

DMARDs for mental health symptoms in RA.

Nat Rev Rheumatol 2018 09;14(9):507-508

Department of Medicine, Brighton and Sussex Medical School, University of Sussex, Brighton, UK.

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http://dx.doi.org/10.1038/s41584-018-0063-zDOI Listing
September 2018

Interoception and Inflammation in Psychiatric Disorders.

Biol Psychiatry Cogn Neurosci Neuroimaging 2018 06 9;3(6):514-524. Epub 2018 Jan 9.

Clinical Imaging Sciences Centre, Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom; Sackler Centre for Consciousness Science, University of Sussex, Brighton, United Kingdom; Sussex Partnership NHS Foundation Trust, Brighton, United Kingdom. Electronic address:

Despite a historical focus on neurally mediated interoceptive signaling mechanisms, humoral (and even cellular) signals also play an important role in communicating bodily physiological state to the brain. These signaling pathways can perturb neuronal structure, chemistry, and function, leading to discrete changes in behavior. They are also increasingly implicated in the pathophysiology of psychiatric disorders. The importance of these humoral signaling pathways is perhaps most powerfully illustrated in the context of infection and inflammation. Here we provide an overview of how interaction of immune activation of neural and humoral interoceptive mechanisms mediates discrete changes in brain and behavior and highlight how activation of these pathways at specific points in neural development may predispose to psychiatric disorder. As our mechanistic understanding of these interoceptive pathways continues to emerge, it is revealing novel therapeutic targets, potentially heralding an exciting new era of immunotherapies in psychiatry.
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http://dx.doi.org/10.1016/j.bpsc.2017.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995132PMC
June 2018

Treatment-resistant depression and peripheral C-reactive protein.

Br J Psychiatry 2019 01 16;214(1):11-19. Epub 2018 May 16.

Immuno-Psychiatry, Immuno-Inflammation Therapeutic Area Unit,GlaxoSmithKline R&D,Stevenage,UK,Cambridgeshire and Peterborough NHS Foundation Trust,Cambridge,UKandDepartment of Psychiatry,University of Cambridge,UK.

Background: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations.

Method: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes.

Results: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood.

Conclusions: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.
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http://dx.doi.org/10.1192/bjp.2018.66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124647PMC
January 2019

A neurocomputational account of reward and novelty processing and effects of psychostimulants in attention deficit hyperactivity disorder.

Brain 2018 05;141(5):1545-1557

Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, UK.

Computational models of reinforcement learning have helped dissect discrete components of reward-related function and characterize neurocognitive deficits in psychiatric illnesses. Stimulus novelty biases decision-making, even when unrelated to choice outcome, acting as if possessing intrinsic reward value to guide decisions toward uncertain options. Heightened novelty seeking is characteristic of attention deficit hyperactivity disorder, yet how this influences reward-related decision-making is computationally encoded, or is altered by stimulant medication, is currently uncertain. Here we used an established reinforcement-learning task to model effects of novelty on reward-related behaviour during functional MRI in 30 adults with attention deficit hyperactivity disorder and 30 age-, sex- and IQ-matched control subjects. Each participant was tested on two separate occasions, once ON and once OFF stimulant medication. OFF medication, patients with attention deficit hyperactivity disorder showed significantly impaired task performance (P = 0.027), and greater selection of novel options (P = 0.004). Moreover, persistence in selecting novel options predicted impaired task performance (P = 0.025). These behavioural deficits were accompanied by a significantly lower learning rate (P = 0.011) and heightened novelty signalling within the substantia nigra/ventral tegmental area (family-wise error corrected P < 0.05). Compared to effects in controls, stimulant medication improved attention deficit hyperactivity disorder participants' overall task performance (P = 0.011), increased reward-learning rates (P = 0.046) and enhanced their ability to differentiate optimal from non-optimal novel choices (P = 0.032). It also reduced substantia nigra/ventral tegmental area responses to novelty. Preliminary cross-sectional evidence additionally suggested an association between long-term stimulant treatment and a reduction in the rewarding value of novelty. These data suggest that aberrant substantia nigra/ventral tegmental area novelty processing plays an important role in the suboptimal reward-related decision-making characteristic of attention deficit hyperactivity disorder. Compared to effects in controls, abnormalities in novelty processing and reward-related learning were improved by stimulant medication, suggesting that they may be disorder-specific targets for the pharmacological management of attention deficit hyperactivity disorder symptoms.
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http://dx.doi.org/10.1093/brain/awy048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917772PMC
May 2018

Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages.

J Leukoc Biol 2018 04 26;103(4):681-692. Epub 2018 Jan 26.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh, Scotland, UK.

Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti-TNFα therapies elicit positive mood. This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti-inflammatory drugs (indomethacin, prednisolone, and anti-TNFα antibody) on the response of human monocyte-derived macrophages (MDMs) from 6 individuals to LPS or IFN-α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P < 0.001) following LPS challenge, whereas a more limited subset of genes (499) responded to IFNα. Contrary to published reports, administered at nontoxic doses, neither monoaminergic antidepressant significantly modulated the transcriptional response to either inflammatory challenge. Each anti-inflammatory drug had a distinct impact on the expression of inflammatory cytokines and on the profile of inducible gene expression-notably on the regulation of enzymes involved in metabolism of tryptophan. Inter alia, the effect of anti-TNFα antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analyzed by targeted metabolomic studies on cellular supernatants. We suggest that inflammatory processes in the brain or periphery could impact on depression by altering the availability of tryptophan for serotonin synthesis and/or by increasing production of neurotoxic kynurenine.
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http://dx.doi.org/10.1002/JLB.3A0617-261RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918594PMC
April 2018

Psychogenic amnesia: syndromes, outcome, and patterns of retrograde amnesia.

Brain 2017 Sep;140(9):2498-2510

King's College London, Academic Neuropsychiatry, Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, London, SE1 7EH UK.

There are very few case series of patients with acute psychogenic memory loss (also known as dissociative/functional amnesia), and still fewer studies of outcome, or comparisons with neurological memory-disordered patients. Consequently, the literature on psychogenic amnesia is somewhat fragmented and offers little prognostic value for individual patients. In the present study, we reviewed the case records and neuropsychological findings in 53 psychogenic amnesia cases (ratio of 3:1, males:females), in comparison with 21 consecutively recruited neurological memory-disordered patients and 14 healthy control subjects. In particular, we examined the pattern of retrograde amnesia on an assessment of autobiographical memory (the Autobiographical Memory Interview). We found that our patients with psychogenic memory loss fell into four distinct groups, which we categorized as: (i) fugue state; (ii) fugue-to-focal retrograde amnesia; (iii) psychogenic focal retrograde amnesia following a minor neurological episode; and (iv) patients with gaps in their memories. While neurological cases were characterized by relevant neurological symptoms, a history of a past head injury was actually more common in our psychogenic cases (P = 0.012), perhaps reflecting a 'learning episode' predisposing to later psychological amnesia. As anticipated, loss of the sense of personal identity was confined to the psychogenic group. However, clinical depression, family/relationship problems, financial/employment problems, and failure to recognize the family were also statistically more common in that group. The pattern of autobiographical memory loss differed between the psychogenic groups: fugue cases showed a severe and uniform loss of memories for both facts and events across all time periods, whereas the two focal retrograde amnesia groups showed a 'reversed' temporal gradient with relative sparing of recent memories. After 3-6 months, the fugue patients had improved to normal scores for facts and near-normal scores for events. By contrast, the two focal retrograde amnesia groups showed less improvement and continued to show a reversed temporal gradient. In conclusion, the outcome in psychogenic amnesia, particularly those characterized by fugue, is better than generally supposed. Findings are interpreted in terms of Markowitsch's and Kopelman's models of psychogenic amnesia, and with respect to Anderson's neuroimaging findings in memory inhibition.
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http://dx.doi.org/10.1093/brain/awx186DOI Listing
September 2017

Interferon-Alpha Reduces Human Hippocampal Neurogenesis and Increases Apoptosis via Activation of Distinct STAT1-Dependent Mechanisms.

Int J Neuropsychopharmacol 2018 02;21(2):187-200

Section of Stress, Psychiatry and Immunology and Perinatal Psychiatry, King's College London, London, United Kingdom.

Background: In humans, interferon-α treatment for chronic viral hepatitis is a well-recognized clinical model for inflammation-induced depression, but the molecular mechanisms underlying these effects are not clear. Following peripheral administration in rodents, interferon-α induces signal transducer and activator of transcription-1 (STAT1) within the hippocampus and disrupts hippocampal neurogenesis.

Methods: We used the human hippocampal progenitor cell line HPC0A07/03C to evaluate the effects of 2 concentrations of interferon-α, similar to those observed in human serum during its therapeutic use (500 pg/mL and 5000 pg/mL), on neurogenesis and apoptosis.

Results: Both concentrations of interferon-α decreased hippocampal neurogenesis, with the high concentration also increasing apoptosis. Moreover, interferon-α increased the expression of interferon-stimulated gene 15 (ISG15), ubiquitin-specific peptidase 18 (USP18), and interleukin-6 (IL-6) via activation of STAT1. Like interferon-α, co-treatment with a combination of ISG15, USP18, and IL-6 was able to reduce neurogenesis and enhance apoptosis via further downstream activation of STAT1. Further experiments showed that ISG15 and USP18 mediated the interferon-α-induced reduction in neurogenesis (potentially through upregulation of the ISGylation-related proteins UBA7, UBE2L6, and HERC5), while IL-6 mediated the interferon-α-induced increase in apoptosis (potentially through downregulation of aquaporin 4). Using transcriptomic analyses, we showed that interferon-α regulated pathways involved in oxidative stress and immune response (e.g., Nuclear Factor (erythroid-derived 2)-like 2 [Nrf2] and interferon regulatory factor [IRF] signaling pathway), neuronal formation (e.g., CAMP response element-binding protein [CREB] signaling), and cell death regulation (e.g., tumor protein(p)53 signaling).

Conclusions: We identify novel molecular mechanisms mediating the effects of interferon-α on the human hippocampus potentially involved in inflammation-induced neuropsychiatric symptoms.
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http://dx.doi.org/10.1093/ijnp/pyx083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793815PMC
February 2018

Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder.

Biol Psychiatry 2018 Jan 6;83(1):70-80. Epub 2017 Jul 6.

Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Cambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge, United Kingdom; ImmunoPsychiatry, GlaxoSmithKline Research & Development, Stevenage, United Kingdom. Electronic address:

Background: Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation.

Methods: We used microarray data on whole blood from two independent case-control studies of MDD: the GlaxoSmithKline-High-Throughput Disease-specific target Identification Program [GSK-HiTDiP] study (113 patients and 57 healthy control subjects) and the Janssen-Brain Resource Company study (94 patients and 100 control subjects). Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold (q = .025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance.

Results: A total of 165 genes were differentially expressed in both studies with concordant direction of fold change. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. In contrast, the 75 genes underexpressed (or DOWN genes) in MDD were associated with the adaptive immune response and included clusters of genes with correlated expression in T cells, natural killer cells, and erythroblasts. Consistently, the MDD patients with overexpression of UP genes also had underexpression of DOWN genes (correlation > .70 in both studies).

Conclusions: MDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression.
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http://dx.doi.org/10.1016/j.biopsych.2017.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720346PMC
January 2018

Magnetization transfer imaging identifies basal ganglia abnormalities in adult ADHD that are invisible to conventional T1 weighted voxel-based morphometry.

Neuroimage Clin 2017 30;15:8-14. Epub 2017 Mar 30.

Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, University of Sussex, Brighton, UK.

In childhood, Attention Deficit Hyperactivity Disorder (ADHD) is reliably associated with reduced volume of the striatum. In contrast, striatal abnormalities are infrequently detected in voxel-based morphometry (VBM) neuroimaging studies of adults with ADHD. This discrepancy has been suggested to reflect normalisation of striatal morphology with age and prolonged treatment of symptoms. If so, this would indicate that while striatal abnormalities are linked to symptom expression in childhood, they cannot explain the persistence of these symptoms in adulthood. However, this may not be case. Instead, we hypothesized that the lack of evidence for striatal abnormalities in adult ADHD may reflect poor sensitivity of typical (T1-weighted) neuroimaging to detect subcortical differences. To address this, we acquired both magnetisation transfer (MT) saturation maps optimised for subcortical contrast, and conventional T1-weighted images in 30 adults with ADHD and 30 age, IQ, gender and handedness-matched controls. Using VBM of both datasets, we demonstrate volumetric reductions within the left ventral striatum on MT that are not observed on identically pre-processed T1-weighted images from the same participants. Nevertheless, both techniques reported similar sensitivity to cortical abnormalities in the right inferior parietal lobe. Additionally, we show that differences in striatal iron may potentially explain this reduced sensitivity of T1-weighted images in adults. Together, these findings indicate that prior VBM studies reporting no abnormalities in striatal volume in adult ADHD might have been compromised by the methodological insensitivity of T1-weighted VBM to subcortical differences, and that structural abnormalities of the striatum in ADHD do indeed persist into adulthood.
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http://dx.doi.org/10.1016/j.nicl.2017.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397127PMC
March 2018