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.

Keywords: citalopram; frontotemporal dementia; magnetoencephalography; response inhibition; voxel-based morphometry.

Disinhibition is a cardinal feature of behavioural variant frontotemporal dementia, arising from both frontal atrophy and serotonin depletion. Hughes et al. show that neurophysiological signatures of inhibition are reduced in frontotemporal dementia, and that citalopram rescues prefrontal neurophysiological deficits relative to placebo. Boosting serotoninergic transmission may facilitate management of disinhibition.

Figure 1

The regions of grey matter loss in patients with bvFTD compared to the control group. Atrophy is evident in inferior and middle temporal gyrus, inferior and superior frontal gyrus, bilateral temporal poles and orbitofrontal gyrus. Images are thresholded with a cluster-based family-wise error correction P < 0.05 (after P < 0.001 voxel-wise uncorrected threshold).

Figure 2

Neurophysiological responses by task and drug conditions. (A) ERPs from three midline electrodes, Fz, Cz and Pz for successful Go and NoGo trials. Time point 0 denotes the stimulus onset and for convention, negativity is plotted upwards. For NoGo trials, the bvFTD placebo group (n = 10) show significant reductions in peak amplitudes of all three components of interest: the P2 at Fz, N2 at Cz and P3 at Pz compared to controls. Citalopram enhanced the P3 at Pz in bvFTD (n = 9), restoring the amplitude towards normal levels compared to placebo. The black and grey horizontal lines indicate significant differences in onset latencies between controls and bvFTD on placebo, and citalopram versus placebo, respectively. (B) Topographies of the peak response for the P2, N2 and P3 components during the NoGo trials, with the Go trials presented at the same latency for comparison.

Figure 3

sLORETA contrast images for successful NoGo trials, for controls and bvFTD patients on placebo. Controls show sustained frontal and temporal source responses across the first two time windows (100–200 and 250–350 ms), which are greater for NoGo than Go trials (P < 0.05 FWE). For the bvFTD placebo group, compared to controls, right frontal and temporal sources are significantly reduced for NoGo trials from 100–200 ms (P < 0.05 FWE corrected within region of interest), and a trend for a reduced right inferior frontal gyrus response after 250 ms (P = 0.08 FWE corrected within region of interest). Data plots show peak differences in NoGo source responses between the control and placebo groups. The regions of interest of right inferior frontal gyrus and right temporal lobe are outlined in black.

Figure 4

sLORETA contrast of citalopram versus placebo for successful NoGo trials in patients with bvFTD, during the 250–350 ms time window. Citalopram enhanced activation (mean current source density) in the right inferior frontal gyrus (P < 0.05 FWE corrected within region of interest). Data plot shows peak difference between citalopram and placebo within the right inferior frontal gyrus region of interest, for NoGo trials.