Original articleAn fMRI study of anterior cingulate function in posttraumatic stress disorder
Introduction
Posttraumatic stress disorder (PTSD) is marked by nightmares, flashbacks, and intrusive recollections of traumatic events (American Psychiatric Association 1994). In individuals with PTSD, exposure to reminders of the trauma is associated with self-reported distress, peripheral psychophysiologic arousal Orr et al 1998, Pitman et al 1987, Pitman et al 1990, and regional cerebral blood flow (rCBF) increases in amygdala, orbitofrontal cortex, anterior temporal poles, insular cortex, and posterior cingulate cortex Bremner et al 1999a, Bremner et al 1999b, Liberzon et al 1999, Rauch et al 1996, Semple et al 2000, Shin et al 1997, Shin et al 1999.
Several neuroimaging studies have reported no significant activation or decreased activation in anterior cingulate cortex (ACC) in PTSD Bremner et al 1999a, Bremner et al 1999b, Semple et al 2000, Shin et al 1999. For example, Shin et al (1999) found that the trauma-exposed control group, but not the PTSD group, exhibited significant rCBF increases in rostral ACC during the recollection and imagery of personal traumatic events. Bremner and colleagues (1999a) reported no significant activation in rostral ACC, as well as decreased activation in ventral portions of ACC (subcallosal gyrus; Brodmann area 25) in PTSD. Semple et al (2000) found that patients with PTSD exhibited lower rCBF in rostral ACC during both rest and an auditory continuous performance task than did healthy comparison subjects. Missing from the current literature are neuroimaging studies that implement cognitive tasks specifically designed to further examine the functional integrity of ACC in PTSD.
One type of paradigm that appears to reliably activate ACC in healthy individuals is the Stroop task in which subjects are shown a series of words and are asked to name the color in which each word is printed (e.g., Bench et al 1993, Bush et al 1998, Carter et al 1995, Derbyshire et al 1998, George et al 1994, George et al 1997, Leung et al 2000, Pardo et al 1990, Peterson et al 1999; for a review, see Bush et al 2000). Researchers interested in studying the processing of emotional information in psychiatric patients have used disorder-relevant words as stimuli and have measured response times of subjects performing the color-naming task. This research has demonstrated that individuals with PTSD exhibit longer response times while naming the color of trauma-related words (e.g., “bodybags” and “firefight” for combat-related PTSD) than neutral, positive, or generally negative words (e.g., Bryant and Harvey 1995, Cassiday et al 1992, Dubner and Motta 1999, Foa et al 1991, Kaspi et al 1995, Litz et al 1996, McNally et al 1990, McNally et al 1993, McNally et al 1996, Moradi et al 1999, Thrasher et al 1994, Vrana et al 1995).
Initial studies of brain activation during the performance of emotional variants of the Stroop task in healthy individuals have yielded some consistent findings. In a positron emission tomography (PET) study, George et al (1994) reported activation in ACC during the performance of an emotional Stroop task involving sadness-related words. Activation in ACC was also reported by Whalen et al (1998) in a functional magnetic resonance imaging (fMRI) study using the Emotional Counting Stroop. During each trial, subjects saw emotionally negative or neutral words on a screen, counted the number of words, and pressed a button indicating their response. Although response times did not differ between conditions, the Negative versus Neutral comparison revealed fMRI blood oxygenation level–dependent (BOLD) signal increases in a rostral portion of ACC.
Anatomic studies suggest that rostral ACC has extensive connectivity with other limbic regions Amaral et al 1992, Pandya et al 1981, Vogt et al 1992, and it may be useful to consider rostral ACC as an affective subdivision of anterior cingulate cortex (see Bush et al 1998, Devinsky et al 1995, Vogt et al 1992, Vogt et al 1995, Whalen 1998 see also Bush et al 2000 for a review). Consistent with this notion, activation in the vicinity of rostral ACC has been associated with emotional state induction in healthy individuals Dougherty et al 1999, George et al 1995, George et al 1996, Kimbrell et al 1999, Lane et al 1998, Rauch et al 1999, Shin et al 2000, aversive gustatory stimulation (Zald et al 1998), procaine-induced fear Ketter et al 1996, Servan-Schreiber et al 1998, and the prediction of treatment response in depression (Mayberg et al 1997). Whalen et al (1998) reported that in healthy individuals, rostral ACC activation can occur in the absence of behavioral interference (i.e., response time increases) in an emotional Stroop task and thus proposed that activation in rostral ACC might reflect a regulatory response; that is, the successful processing of emotional stimuli in the service of facilitating task performance. Because rostral ACC may be considered a regulatory area that is activated during normal processing of emotional stimuli (Mayberg 1997), one might predict that patients with anxiety disorders would fail to show significant activation in this region during the presentation of disorder-relevant words in an emotional Stroop task.
In our study, we implemented the Emotional Counting Stroop (ecStroop; Whalen et al 1998) and fMRI to study the functional integrity of rostral ACC in eight Vietnam combat veterans with PTSD (PTSD group) and eight Vietnam combat veterans without PTSD (non-PTSD group). We selected the ecStroop because it has been shown to reliably recruit rostral ACC in healthy individuals and because previous offline behavioral studies of PTSD have used similar modified Stroop tasks containing emotional words (e.g., Bryant and Harvey 1995, Cassiday et al 1992, Dubner and Motta 1999, Foa et al 1991, Kaspi et al 1995, Litz et al 1996, McNally et al 1990, McNally et al 1993, McNally et al 1996, Moradi et al 1999, Thrasher et al 1994, Vrana et al 1995). In the current experiment, subjects received blocked presentations of combat-related (Combat), generally negative (General Negative), and neutral (Neutral) words. During each trial, subjects were required to count the number of words on the screen and to press a button corresponding to the correct number. We compared fMRI BOLD signal in the Combat versus control (General Negative or Neutral) conditions. We were particularly interested in the Combat versus General Negative comparison because its results might best isolate the processing of trauma-related information per se.
Given the results of Whalen et al (1998), we predicted that the non-PTSD group would exhibit significant fMRI BOLD signal increases in rostral ACC in the Combat versus General Negative comparison; however, given the results of recent symptom provocation neuroimaging studies of PTSD and the theoretical view of rostral ACC as performing a regulatory role in the processing of emotional stimuli, we predicted that the PTSD group would not show significant BOLD signal increases in rostral ACC and would have longer response times in the Combat versus General Negative condition than the non-PTSD group. In addition, we expected that a direct between-group comparison would confirm these predicted findings by showing greater BOLD signal (in the Combat condition) in rostral ACC in the non-PTSD group than in the PTSD group. Finally, in the Combat versus General Negative comparison, we predicted that the PTSD group would exhibit significant fMRI BOLD signal increases in amygdala and insular cortex, two regions that have been activated in recent symptom provocation neuroimaging studies of PTSD.
Section snippets
Subjects
Subjects were 16 right-handed (Oldfield 1971) male Vietnam combat veterans; eight met diagnostic criteria for PTSD (PTSD group), and eight were free of current PTSD (non-PTSD group). (One non-PTSD subject had met criteria for PTSD in the past.) We established PTSD diagnoses using the Clinician-Administered PTSD Scale (CAPS; Blake et al 1995). The PTSD and non-PTSD subjects were enrolled into the study in parallel. The groups did not significantly differ in age (50.6 years ± 4.6 [PTSD] and 54.1
Behavioral data
Response time and error rate data (see Table 1) were submitted to separate 2 (Group) × 3 (Word Type) analyses of variance (ANOVAs). A main effect of Group revealed that the PTSD group had longer response times than the non-PTSD group across all conditions [F(1,12) = 26.4; p = .0002]. The main effect of Word Type and the Word Type × Group interaction were not significant (ps > .22).
In the ANOVA for error rates, a main effect of Group showed that the PTSD group had higher error rates than the
Discussion
In the comparison of Combat versus General Negative word conditions, the non-PTSD group exhibited significant activation in rostral ACC, but the PTSD group did not. These findings are interesting in light of previously reported abnormalities in ACC in PTSD Bremner et al 1999a, Bremner et al 1999b, De Bellis 2000, Semple et al 2000, Shin et al 1999.
The results of both the present and previous studies are consistent with a neuroanatomic model of PTSD that posits a failure of medial prefrontal
Acknowledgements
Drs. Shin, Whalen, and Bush are supported in part by the National Alliance for Research on Schizophrenia and Depression (NARSAD). Drs. Whalen, Bush, and Rauch are supported by National Institute of Mental Health Grants Nos. K01 MH-01866, K01 MH-01611, and MH-60219, respectively. Drs. Pitman and Orr are supported by Veterans Affairs Medical Research Service Merit Review grants. We would like to thank Patrick and Gianna Shin for their comments on the manuscript and Mary Foley and Terry Campbell
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