Abstract
Post-traumatic stress disorder (PTSD) leads to impairments in both cognitive and affective functioning. Animal work suggests that chronic stress reduces dopamine tone, and both animal and human studies argue that changes in dopamine tone influence working memory, a core executive function. These findings give rise to the hypothesis that increasing cortical dopamine tone in individuals with greater PTSD symptomatology should improve working memory performance. In this pharmacological functional magnetic resonance imaging (fMRI) study, 30 US military veterans exhibiting a range of PTSD severity completed an emotional working memory task. Each subject received both placebo and the catechol-O-methyl transferase inhibitor tolcapone, which increases cortical dopamine tone, in randomized, double-blind, counterbalanced fashion. Mnemonic discriminability (calculated with d′, an index of the detectability of working memory signals) and response bias were evaluated in the context of task-related brain activations. Subjects with more severe PTSD showed both greater tolcapone-mediated improvements in d′ and larger tolcapone-mediated reductions in liberally-biased responding for fearful stimuli. FMRI revealed that tolcapone augmented activity within bilateral frontoparietal control regions during the decision phase of the task. Specifically, tolcapone increased cortical responses to fearful relative to neutral stimuli in higher severity PTSD subjects, and reduced cortical responses to fearful stimuli for lower severity PTSD subjects. Moreover, tolcapone modulated prefrontal connectivity with areas overlapping the default mode network. These findings suggest that enhancing cortical dopamine tone may represent an approach to remediating cognitive and affective dysfunction in individuals with more severe PTSD symptoms.
Highlights
Post-traumatic stress disorder (PTSD) is a potentially debilitating mental disorder that affects up to 22.1% of US military veterans [1]
Behavioral analysis To evaluate the effects of PTSD severity and the influence of tolcapone on working memory, an affective working memory task was used to assess military veterans with a range of PTSD symptomatology
To directly assess these cognitive deficits, this study evaluated the ability of a novel dopaminergic intervention to improve working memory and affective functioning in military veterans with a range of PTSD severity
Summary
Post-traumatic stress disorder (PTSD) is a potentially debilitating mental disorder that affects up to 22.1% of US military veterans [1]. Given the central role of dopamine within prefrontal cortex (PFC) for working memory in both animals and humans [3, 4], it has been argued that this PTSD-related impairment may be linked to dysfunctional dopaminergic neurotransmission in PFC [5]. In support of this idea, chronic stress in rodents results in tonically low levels of prefrontal dopamine and corresponding deficits in spatial working memory that can be reversed by the administration of a D1 dopamine agonist [6]. D1 receptor activation has been shown to be important for emotion regulation, as D1-deficient mice exhibit normal acquisition but impaired extinction of fear memories, and infusions of a D1 agonist into the rodent PFC block emotional memory recall [8]
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