Altered reward processing in the nucleus accumbens and mesial prefrontal cortex of patients with posttraumatic stress disorder
Introduction
Posttraumatic stress disorder (PTSD) is an anxiety disorder which develops after experiencing or witnessing traumatic, often life-threatening events. It is characterised by intrusive memories, emotional numbing, intense physiological and psychological distress when exposed to reminders of the trauma, and avoidance of such reminders (DSM-IV; American Psychiatric Association, 1994). Individuals with PTSD often also exhibit deficits in concentration and working memory (Vasterling, Brailey, Constans, & Sutker, 1998; Vasterling et al., 2002) which are assumed to be functions of the prefrontal cortex (PFC). The role of the medial PFC in PTSD has become clear in a number of neuroimaging studies. The medial PFC includes the anterior cingulate cortex (ACC), subcallosal cortex and medial frontal gyrus. It is closely connected to the “fear system”, particularly the amygdala (Barbas, 1995; Carmichael & Price, 1995). Via downward projections, the medial PFC can inhibit activation of the amygdala (Delgado, Olsson, & Phelps, 2006; Rosenkranz & Grace, 2002). Such an inhibiting effect is also supported by findings demonstrating that experimental lesions in the medial PFC of rodents block the extinction of conditioned fear (Milad & Quirk, 2002), and that an insufficient level of potentiation in the medial PFC during the extinction of learned fear leads to persistent fear responses (Herry & Garcia, 2002). Acute stress may lead to the depression of synaptic excitability in the medial PFC which could cause long-lasting affective changes in vulnerable individuals (Herry & Garcia, 2002, Yehuda, McFarlane, & Shalev, 1998). Failure of medial prefrontal networks to regulate amygdala activity may thus result in hyper-reactivity to threatening stimuli (Bremner, 1999; Grossman, Buchsbaum, & Yehuda, 2002; McNally, 2006; Nutt & Malizia, 2004), or a more general inability to dealing with emotional conflict (Etkin, Egner, Peraza, Kandel, & Hirsch, 2006).
This pathophysiologic model of PTSD is supported by reports of abnormalities in the medial PFC and the amygdala in patients with PTSD. Structurally, PTSD patients have smaller ACC volumes than trauma-exposed individuals without PTSD (Araki et al., 2005, Rauch et al., 2003, Woodward et al., 2006, Yamasue et al., 2003). It even seems that the smaller the ACC volume, the worse is the severity of PTSD symptoms (Rauch et al., 2003, Woodward et al., 2006, Yamasue et al., 2003). Functionally, ACC activation in PTSD patients was found to be reduced not only under exposure to trauma-related stimuli (Bremner et al., 1999, Lanius et al., 2001, Shin et al., 2001, Shin et al., 2004; Yang, Wu, Hsu, & Ker, 2004) but also under neutral (rest) conditions (Semple et al., 2000). On the other hand, extinction of PTSD symptoms following pharmacologic treatment led to increased blood flow in the medial PFC (Fernandez et al., 2001).
This hypoactivity of the medial PFC is in some studies coupled to a hyperactive amygdala. For example, reduced ACC activation to pictures of fearful versus happy faces was associated with an increased activation of the amygdala (Shin et al., 2005). Similarly, a reduced medial PFC and enhanced amygdala response occurred to targets in a non-emotional auditory oddball task (Bryant et al., 2005). These results suggest that the medial prefrontal-amygdala dysregulation in PTSD is not specific to emotional or trauma-related stimuli, but generalises to other categories of salient stimuli.
In concordance with this assumption, PTSD patients are impaired in a range of non-trauma related executive tasks relying on prefrontal functioning (Sutker, Vasterling, Brailey, & Allain, 1995; Uddo, Vasterling, Brailey, & Sutker, 1993; Vasterling et al., 2002) such as tasks involving sustained attention, working memory, and initial learning of verbal information (Vasterling et al., 2002). Large-scale epidemiological studies have also revealed impaired problem-solving in PTSD when it was associated with other psychiatric diagnoses (Barrett, Green, Morris, Giles, & Croft, 1996; Horner & Hamner, 2002). It has also been suggested that error monitoring and the sensitivity to errors or other signals of nonreward are altered in individuals with PTSD (Casada & Roache, 2005) as well as in anxious individuals without PTSD (Compton et al., 2007; Paulus, Feinstein, Simmons, & Stein, 2004). All these abilities are crucial for optimal decision-making. Thus, there is reason to assume that decision-making is impaired in PTSD.
One critical structure for decision-making is the medial PFC (for a review, see Krawczyk, 2002), a structure known to be affected in PTSD. For example, the ACC is activated during error detection (Carter et al., 1998), hypothesis testing (Elliott & Dolan, 1998) and conflict monitoring (Botvinick, Nystrom, Fissell, Carter, & Cohen, 1999). In this context, ACC activation was related to internal cognitive representations guiding a choice, or to the evaluation of emotion-related aspects of the choice (Krawczyk, 2002; Gehring & Willoughby, 2002).
Thus, both the cognitive impairments of PTSD patients and the altered brain activation in decision-relevant areas hint at decision-making processes being altered in these patients. To investigate this question, we adapted an existing EEG task from the literature that has previously been shown to engage the ACC (Gehring & Willoughby, 2002; Nieuwenhuis, Yeung, Holroyd, Schurger, & Cohen, 2004). In this task, subjects chose between two values. The chosen value was then either added to or subtracted from a total depending on whether it was deemed a gain or loss. Just after subjects learned of a negative outcome, a negative event-related potential (ERP) was found which originated from the ACC, providing support for a rapid response signalling an outcome. In contrast to the original task in which the outcomes were random, the outcomes in our version of this task were determined according to a certain pattern. By learning this pattern, the subjects could maximise their total profit.
We hypothesised decreased activation in the medial PFC, in particular the ACC, during the processing of negative feedback in patients with PTSD relative to controls. Such decreased activation could lead to an impairment in the processing or evaluation of negative feedback, or in the adjustment of behaviour based on negative feedback information. Consequently, we expected that PTSD patients would (1) learn the correct response pattern more slowly than controls, while (2) showing reduced activation in the ACC in response to loss feedback compared to controls. We further explored whether the brain activation following gains versus losses differed in other reward-related regions such as the striatum and the orbitofrontal cortex.
Section snippets
Subjects
After a first screening of 27 trauma-exposed women who were interested in taking part in the study, 14 of them were found to meet the criteria for participation: they were diagnosed with PTSD according to DSM-IV, as assessed by a structured clinical interview (SKID, Wittchen & Unland, 1991), were right-handed, as assessed with the Edinburgh Handedness Inventory (Oldfield, 1971), and were free from neurological illnesses, personality disorders, previous head injury or current substance abuse.
Cognitive testing
PTSD patients did not differ from controls with regard to attention and concentration as measured by the COG or in their nonverbal learning and memory abilities as measured by the NVLT. Patients scored, however, significantly lower in the subtest task-oriented effort of the OLMT (F = 9.33, p < .01). This subtest measures the motivation to put effort into the task assigned. This task requires to press one of two buttons in rapid succession to cover as many fields as possible in a set course on the
Discussion
The present study investigated the neural response to feedback of gains and losses in a decision-making task. By deriving a particular response pattern, healthy subjects and patients with PTSD could learn to make correct responses only. However, losses were unavoidable even when all the responses were correct. This allowed us to examine the reaction to gains and losses both during an early and a late stage of learning.
Behaviourally, both groups increased their performance and decreased their
Acknowledgements
This study was funded by a fellowship of the Deutsche Forschungsgemeinschaft (DFG) to U.S. and grant no. 11437 from the Austrian National Bank (OENB). We thank the Schuhfried GmbH for providing the test material and S. Nieuwenhuis for making available the instruction of his experiment.
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