Study suggests new treatment for impulsivity in some dementia patients.
Restoring the low levels of the chemical serotonin may help improve brain function and reduce impulsivity in some dementia patients, according to Cambridge researchers. A study published in the July edition of the journal Brain suggests a potential new treatment for people affected by frontotemporal dementia.
Around 16,000 people in the UK are estimated to be affected by frontotemporal dementia (also known as Pick’s disease). Patients are often affected at a young age, 50-65 years old. The disease affects the frontal and temporal lobes of the brain, at the front with both shrinkage and loss of important brain chemicals like serotonin. As a result, symptoms of frontotemporal dementia include changes in personality and behaviour, and difficulties with language.
One of the key symptoms is disinhibition – impulsivity and impetuous behaviour. This is partly a result of a deficiency in serotonin, an important chemical within the brain which is responsible for maintaining normal behaviour as well as mood.
A team led by Dr James Rowe from the University of Cambridge and the Medical Research Council (MRC) Cognition and Brain Sciences Unit at Cambridge looked at whether citalopram, a commonly-prescribed antidepressant, might restore the brain function – and potentially alleviate the symptoms of disinhibition. Citalopram is known to restore levels of serotonin, even in patients who do not have depression; this increase in serotonin helps the brain activity needed make decisions about what to do, and what not to do.
The researchers examined the brain activity associated with disinhibition in patients and healthy volunteers. The patients received either a dose of citalopram or a placebo, in a double-blinded placebo-controlled trial. Participants took part in a ‘Go-NoGo’ task whilst their brain activity was monitored using a combination of magnetoencephalography (MEG) and electroencephalography (EEG). In the task, the volunteers needed to intermittently hold back from a habitual action, choosing to press or not to press buttons.
As expected, patients with frontotemporal dementia made many errors on the task, with difficulty holding back from actions. The performance on the task was closely related to their everyday impulsive and disinhibited behaviours. Compared to the placebo, citalopram boosted activity in the dementia patients in their right inferior frontal gyrus, a critical region of the brain for controlling our behaviour, even though this part of the brain was shrunken by the disease.
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.
Dr Laura Hughes from the University of Cambridge and the MRC Cognition and Brain Sciences Unit, first author on the study, says: “This is a very promising result, which builds on a lot of basic laboratory science here in Cambridge. It suggests that it may be possible to treat patients safely and effectively for high risk and challenging impulsive behaviours, although more work is needed to identify those who are most likely to benefit from this type of drug.”
About this neuroscience research
Funding: The research was primarily funded by the Wellcome Trust with additional support from the Medical Research Council and the NIHR Cambridge Biomedical Research Centre.
Source: Craig Brierley – University of Cambridge Image Credit: Image adapted from the video Video Source: The video is available at the Brain: A Journal of Neurology YouTube page Original Research: Full open access research for “Improving response inhibition systems in frontotemporal dementia with citalopram” by Laura E. Hughes, Timothy Rittman, Ralf Regenthal, Trevor W. Robbins, and James B. Rowe in Brain. Published online May 22 2015 doi:10.1093/brain/awv133
Improving response inhibition systems in frontotemporal dementia with citalopram
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.
“Improving response inhibition systems in frontotemporal dementia with citalopram” by Laura E. Hughes, Timothy Rittman, Ralf Regenthal, Trevor W. Robbins, and James B. Rowe in Brain. Published online May 22 2015 doi:10.1093/brain/awv133