Bernardo Dell'Osso1, Claudia Cinnante2, Annabella Di Giorgio3, Laura Cremaschi4, M Carlotta Palazzo4, Marta Cristoffanini2, Leonardo Fazio5, Cristina Dobrea4, Sabrina Avignone2, Fabio Triulzi2, Alessandro Bertolino6, A Carlo Altamura4. 1. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Dipartimento di Salute Mentale, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milano, Italy; Bipolar Disorders Clinic, Stanford Medical School, Stanford University, CA, United States. Electronic address: bernardo.dellosso@unimi.it. 2. U.O. Neuroradiologia, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milano, Italy. 3. Servizio di Consulenza Psichiatrica, IRCCS "Casa Sollievo della Sofferenza", Viale Cappuccini 1, 71013 San Giovanni Rotondo, Italy. 4. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Dipartimento di Salute Mentale, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milano, Italy. 5. Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, "Aldo Moro" University, Piazza Giulio Cesare 11, 70124 Bari, Italy. 6. Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, "Aldo Moro" University, Piazza Giulio Cesare 11, 70124 Bari, Italy; pRED, NORD DTA, F. Hoffman-La Roche Ltd., Basel, Switzerland.
Abstract
BACKGROUND: Working memory (WM) deficits are among the most frequently impaired cognitive domains in patients with Bipolar Disorder (BD), being considered promising cognitive endophenotype of the disorder. However, the related neurobiological correlates still deserve further investigation. The present study was aimed to explore whether dorsolateral prefrontal cortex (DLPFC) activity during WM processing was abnormal in euthymic bipolar patients and may represent a potential trait-related phenotype associated with the disorder. METHODS: Using 3 Tesla functional Magnetic Resonance Imaging (3T fMRI), we studied 28 euthymic bipolar patients (15 BDI and 13 BDII), and 27 healthy controls (HCs), matched for a series of socio-demographic variables, while performing the N-back task for WM assessment. RESULTS: We found that euthymic bipolar patients showed increased right middle frontal gyrus engagement compared with HCs (FWE-corrected p = 1 × 10(-3)), regardless of WM load, and in spite of similar WM behavioral performance between groups. In particular, BDI patients had greater BOLD signal change compared to HCs (post-hoc Tukey HSD, p = 1 × 10(-3)), while BDII patients expressed an intermediate pattern of activation between BDI patients and HCs. No other significant effects were detected in the corrected whole-brain analysis. LIMITATIONS: Sample size, cross-sectional assessment and potential influence of some clinical variables. CONCLUSIONS: Results provide direct evidence of a primary physiological abnormality in DLPFC function in BDI and II, even in the absence of behavioral differences with HCs. Such exaggerated fMRI response suggests inefficient WM processing in prefrontal circuitry, and further studies are warranted to investigate whether the dysfunction is related to the genetic risk for the disorder.
BACKGROUND:Working memory (WM) deficits are among the most frequently impaired cognitive domains in patients with Bipolar Disorder (BD), being considered promising cognitive endophenotype of the disorder. However, the related neurobiological correlates still deserve further investigation. The present study was aimed to explore whether dorsolateral prefrontal cortex (DLPFC) activity during WM processing was abnormal in euthymic bipolarpatients and may represent a potential trait-related phenotype associated with the disorder. METHODS: Using 3 Tesla functional Magnetic Resonance Imaging (3T fMRI), we studied 28 euthymic bipolarpatients (15 BDI and 13 BDII), and 27 healthy controls (HCs), matched for a series of socio-demographic variables, while performing the N-back task for WM assessment. RESULTS: We found that euthymic bipolarpatients showed increased right middle frontal gyrus engagement compared with HCs (FWE-corrected p = 1 × 10(-3)), regardless of WM load, and in spite of similar WM behavioral performance between groups. In particular, BDI patients had greater BOLD signal change compared to HCs (post-hoc Tukey HSD, p = 1 × 10(-3)), while BDII patients expressed an intermediate pattern of activation between BDI patients and HCs. No other significant effects were detected in the corrected whole-brain analysis. LIMITATIONS: Sample size, cross-sectional assessment and potential influence of some clinical variables. CONCLUSIONS: Results provide direct evidence of a primary physiological abnormality in DLPFC function in BDI and II, even in the absence of behavioral differences with HCs. Such exaggerated fMRI response suggests inefficient WM processing in prefrontal circuitry, and further studies are warranted to investigate whether the dysfunction is related to the genetic risk for the disorder.
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