title: Successful antidepressant chronotherapeutics enhance fronto-limbic neural responses and connectivity in bipolar depression.
abstract: The identification of antidepressant response predictors in bipolar disorder (BD) may provide new potential enhancements in treatment selection. Repeated total sleep deprivation combined with light therapy (TSD+LT) can acutely reverse depressive symptoms and has been proposed as a model antidepressant treatment. This study aims at investigating the effect of TSD+LT on effective connectivity and neural response in cortico-limbic circuitries during implicit processing of fearful and angry faces in patients with BD. fMRI and Dynamic Causal Modeling (DCM) were combined to study the effect of chronotherapeutics on neural responses in healthy controls (HC, n = 35) and BD patients either responder (RBD, n = 26) or non responder (nRBD, n = 11) to 3 consecutive TSD+LT sessions. Twenty-four DCMs exploring connectivity between anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), Amygdala (Amy), fusiform gyrus and visual cortex were constructed. After treatment, patients significantly increased their neural responses in DLPFC, ACC and insula. nRBD showed lower baseline and endpoint neural responses than RBD. The increased activity in ACC and in medial prefrontal cortex, associated with antidepressant treatment, was positively associated with the improvement of depressive symptomatology. Only RBD patients increased intrinsic connectivity from DLPFC to ACC and reduced the modulatory effect of the task on Amy-DLPFC connection. A successful antidepressant treatment was associated with an increased functional activity and connectivity within cortico-limbic networks, suggesting the possible role of these measures in providing possible biomarkers for treatment efficacy.
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), Università Vita-Salute San Raffaele, Italy; Department of Human Studies, Libera Università Maria Ss. Assunta, Roma, Italy. Electronic address: b.vai@hotmail.it.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Vai
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), Università Vita-Salute San Raffaele, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Poletti
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), Università Vita-Salute San Raffaele, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Radaelli
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), Università Vita-Salute San Raffaele, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Dallaspezia
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bulgarelli
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), Università Vita-Salute San Raffaele, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Locatelli
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), Università Vita-Salute San Raffaele, Italy; PhD in Philosophy and Sciences of Mind, Università Vita-Saluta San Raffaele, Milan, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Bollettini
authors.affiliation: Department of Neuroradiology, Scientific Institute Ospedale San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), Università Vita-Salute San Raffaele, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Falini
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), Università Vita-Salute San Raffaele, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Colombo
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), Università Vita-Salute San Raffaele, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Smeraldi
authors.affiliation: Department of Clinical Neurosciences, Scientific Institute Ospedale San Raffaele, Milan, Italy; C.E.R.M.A.C. (Centro di Eccellenza Risonanza Magnetica ad Alto Campo), Università Vita-Salute San Raffaele, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Benedetti
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D003131:Combined Modality Therapy; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D055870:Drug Chronotherapy; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008032:Limbic System / Q000187:drug effects*; D016651:Lithium Carbonate / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000187:drug effects*; D010789:Phototherapy; D017397:Prefrontal Cortex / Q000187:drug effects*; D012892:Sleep Deprivation
chemical_list: D016651:Lithium Carbonate
keywords: BOLD fMRI; Bipolar disorder; Chronotherapeutics; Deprivation; Dynamic Causal Modeling; Emotion; Light therapy; Sleep