title: Improving response inhibition systems in frontotemporal dementia with citalopram.
abstract: Disinhibition is a cardinal feature of the behavioural variant of frontotemporal dementia, presenting as impulsive and impetuous behaviours that are often difficult to manage. The options for symptomatic treatments are limited, but a potential target for therapy is the restoration of serotonergic function, which is both deficient in behavioural variant frontotemporal dementia and closely associated with inhibitory control. Based on preclinical studies and psychopharmacological interventions in other disorders, we predicted that inhibition would be associated with the right inferior frontal gyrus and dependent on serotonin. Using magnetoencephalography and electroencephalography of a Go-NoGo paradigm, we investigated the neural basis of behavioural disinhibition in behavioural variant frontotemporal dementia and the effect of selective serotonin reuptake inhibition on the neural systems for response inhibition. In a randomized double-blinded placebo-controlled crossover design study, 12 patients received either a single 30 mg dose of citalopram or placebo. Twenty age-matched healthy controls underwent the same magnetoencephalography/electroencephalography protocol on one session without citalopram, providing normative data for this task. In the control group, successful NoGo trials evoked two established indices of successful response inhibition: the NoGo-N2 and NoGo-P3. Both of these components were significantly attenuated by behavioural variant frontotemporal dementia. Cortical sources associated with successful inhibition in control subjects were identified in the right inferior frontal gyrus and anterior temporal lobe, which have been strongly associated with behavioural inhibition in imaging and lesion studies. These sources were impaired by behavioural variant frontotemporal dementia. Critically, citalopram enhanced the NoGo-P3 signal in patients, relative to placebo treatment, and increased the evoked response in the right inferior frontal gyrus. Voxel-based morphometry confirmed significant atrophy of inferior frontal gyrus, alongside insular, orbitofrontal and temporal cortex in our patient cohort. Together, these data suggest that the dysfunctional prefrontal cortical systems underlying response inhibition deficits in behavioural variant frontotemporal dementia can be partially restored by increasing serotonergic neurotransmission. The results support a translational neuroscience approach to impulsive neurological disorders and indicate the potential for symptomatic treatment of behavioural variant frontotemporal dementia including serotonergic strategies to improve disinhibition.media-1vid110.1093/brain/awv133_video_abstractawv133_video_abstract.
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, UK 2 Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK laura.hughes@mrc-cbu.cam.ac.uk.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hughes
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Rittman
authors.affiliation: 3 Division of Clinical Pharmacology, Department of Pharmacology and Toxicology, University of Leipzig, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Regenthal
authors.affiliation: 4 Department of Psychology, University of Cambridge, Cambridge, UK 5 Behavioural and Clinical Neuroscience Institute, Cambridge, UK.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
authors.affiliation: 1 Department of Clinical Neurosciences, University of Cambridge, UK 2 Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK 5 Behavioural and Clinical Neuroscience Institute, Cambridge, UK.
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
mesh_terms: D000368:Aged; D015283:Citalopram / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004569:Electroencephalography; D005260:Female; D057180:Frontotemporal Dementia / Q000188:drug therapy* / Q000523:psychology*; D006801:Humans; D007266:Inhibition, Psychological; D008279:Magnetic Resonance Imaging; D015225:Magnetoencephalography; D008297:Male; D008875:Middle Aged; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
chemical_list: D015283:Citalopram; D017367:Selective Serotonin Reuptake Inhibitors
keywords: citalopram; frontotemporal dementia; magnetoencephalography; response inhibition; voxel-based morphometry