Diminished medial prefrontal cortex activation during the recollection of stressful events is an acquired characteristic of PTSD.

BACKGROUND: Previous research has shown relatively diminished medial prefrontal cortex activation and heightened psychophysiological responses during the recollection of personal events in post-traumatic stress disorder (PTSD), but the origin of these abnormalities is unknown. Twin studies provide the opportunity to determine whether such abnormalities reflect familial vulnerabilities, result from trauma exposure, or are acquired characteristics of PTSD. METHODS: In this case-control twin study, 26 male identical twin pairs (12 PTSD; 14 non-PTSD) discordant for PTSD and combat exposure recalled and imagined trauma-unrelated stressful and neutral life events using a standard script-driven imagery paradigm during functional magnetic resonance imaging and concurrent skin conductance measurement. RESULTS: Diminished activation in the medial prefrontal cortex during Stressful v. Neutral script-driven imagery was observed in the individuals with PTSD, relative to other groups. CONCLUSIONS: Diminished medial prefrontal cortex activation during Stressful v. Neutral script-driven imagery may be an acquired characteristic of PTSD. If replicated, this finding could be used prospectively to inform diagnosis and the assessment of treatment response.

Decreased regional cerebral blood flow in medial prefrontal cortex during trauma-unrelated stressful imagery in Vietnam veterans with post-traumatic stress disorder.

BACKGROUND: Neuroimaging research has demonstrated medial prefrontal cortex (mPFC) hyporesponsivity and amygdala hyperresponsivity to trauma-related or emotional stimuli in post-traumatic stress disorder (PTSD). Relatively few studies have examined brain responses to the recollection of stressful, but trauma-unrelated, personal events in PTSD. In the current study, we sought to determine whether regional cerebral blood flow (rCBF) abnormalities in mPFC and amygdala in PTSD could be observed during the recollection of trauma-unrelated stressful personal events. METHOD: Participants were 35 right-handed male combat veterans (MCVs) and female nurse veterans (FNVs) who served in Vietnam: 17 (seven male, 10 female) with current military-related PTSD and 18 (nine male, nine female) with no current or lifetime PTSD. We used positron emission tomography (PET) and script-driven imagery to study rCBF during the recollection of trauma-unrelated stressful versus neutral and traumatic events. RESULTS: Voxelwise tests revealed significant between-group differences for the trauma-unrelated stressful versus neutral comparison in mPFC, specifically in the anterior cingulate cortex (ACC). Functional region of interest (ROI) analyses demonstrated that this interaction in mPFC represented greater rCBF decreases in the PTSD group during trauma-unrelated stressful imagery relative to neutral imagery compared to the non-PTSD group. No differential amygdala activation was observed between groups or in either group separately. CONCLUSIONS: Veterans with PTSD, compared to those without PTSD, exhibited decreased rCBF in mPFC during mental imagery of trauma-unrelated stressful personal experiences. Functional neuroanatomical models of PTSD must account for diminished mPFC responses that extend to emotional stimuli, including stressful personal experiences that are not directly related to PTSD.

The Multi-Source Interference Task: validation study with fMRI in individual subjects.

Dorsal anterior cingulate cortex (dACC) plays critical roles in cognitive processing, but group-averaging techniques have generally been required to obtain significant dACC activation in functional neuroimaging studies. Development of a task that reliably and robustly activates dACC within individuals is needed to improve imaging studies of neuropsychiatric disorders and localization of dACC in normal volunteers. By combining sources of cognitive interference (Stroop, Eriksen and Simon) with factors known to increase dACC activity, the Multi-Source Interference Task (MSIT) maximally taxes dACC, making it possible to reliably activate dACC within individuals using functional magnetic resonance imaging (fMRI). In this study, eight normal adult volunteers performed the MSIT during fMRI. We compared fMRI responses and performance data between interference and control trials. Significant dACC activation (P < 1.7 x 10(-4)) was observed in all eight individuals and in the group-averaged fMRI data. In addition to dACC activation, group data also showed activation of presumably networked regions including dorsolateral prefrontal, premotor, and parietal cortices. The MSIT's reaction time interference effect (overall mean 312 +/- 61 ms) was up to 10 times greater than that of its component predecessors and temporally stable over hundreds of trials. The robustness, reliability and stability of the neuroimaging and performance data should make the MSIT a useful task with which to study normal human cognition and psychiatric pathophysiology.

An fMRI study of anterior cingulate function in posttraumatic stress disorder.

BACKGROUND: Several recent neuroimaging studies have provided data consistent with functional abnormalities in anterior cingulate cortex in posttraumatic stress disorder (PTSD). In our study, we implemented a cognitive activation paradigm to test the functional integrity of anterior cingulate cortex in PTSD. METHODS: Eight Vietnam combat veterans with PTSD (PTSD Group) and eight Vietnam combat veterans without PTSD (non-PTSD Group) underwent functional magnetic resonance imaging (fMRI) while performing the Emotional Counting Stroop. In separate conditions, subjects counted the number of combat-related (Combat), generally negative (General Negative), and neutral (Neutral) words presented on a screen and pressed a button indicating their response. RESULTS: In the Combat versus General Negative comparison, the non-PTSD group exhibited significant fMRI blood oxygenation level-dependent signal increases in rostral anterior cingulate cortex, but the PTSD group did not. CONCLUSIONS: These findings suggest a diminished response in rostral anterior cingulate cortex in the presence of emotionally relevant stimuli in PTSD. We speculate that diminished recruitment of this region in PTSD may, in part, mediate symptoms such as distress and arousal upon exposure to reminders of trauma.

Probing striato-thalamic function in obsessive-compulsive disorder and Tourette syndrome using neuroimaging methods.

In summary, contemporary pathophysiological models of OCD and related disorders implicate CSTC circuitry. In this chapter, we have reviewed relevant concepts related to implicit learning and more specifically, the use of an implicit sequence learning paradigm as a probe of striato-thalamic function. An initial PET investigation of patients with OCD confirmed a priori hypotheses of failure to recruit right striatum, despite the absence of a performance deficit (22). A modified version of the SRT was studied in conjunction with fMRI and yielded reliable right-lateralized striatal activation in a cohort of 10 male subjects, with clear spatial dissociation of caudate and putamen activation foci (119). Subsequent studies in our laboratory suggest that this paradigm also yields a reliable temporal window of thalamic deactivation, and hence a means for assessing thalamic gating in human subjects (120). Finally, as presented in this chapter, preliminary data from the fMRI-SRT in patients with OCD and TS as well as normal control subjects appear to replicate and extend the findings from our original PET-SRT study in OCD. Future investigations in our laboratory will seek to elaborate upon these preliminary results. In particular, we intend to study psychiatric comparison groups to establish the generalizability and/or specificity of these findings across disorders. Within OCD, we hope to explore the relationship between abnormal brain-activation patterns and symptom dimensions (34). Further, by studying subjects with remitted OCD who have been successfully treated, we hope to determine whether the observed brain-activation abnormalities represent state or trait markers. Finally, we have already begun to test a hypothesis of parallel processing deficiency in OCD by using a dual-task version of the SRT that makes simultaneous demands on implicit and explicit information processing systems (128). It is our hope that this program of research will yield new insights about OCD and related disorders, including TS. Most importantly, as other teams of investigators pursue complementary lines of inquiry, it is our wish that collective efforts in this field will lead to improved diagnosis and treatment, if not cure or prevention, for those who are afflicted with these illnesses.

Investigating the pathogenesis of posttraumatic stress disorder with neuroimaging.

Rapidly evolving brain neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) are proving fruitful in exploring the pathogenesis and pathophysiology of posttraumatic stress disorder (PTSD). Structural abnormalities in PTSD found with MRI include nonspecific white matter lesions and decreased hippocampal volume. These abnormalities may reflect pretrauma vulnerability to develop PTSD, or they may be a consequence of traumatic exposure, PTSD, and/or PTSD sequelae. Functional neuroimaging symptom provocation and cognitive activation paradigms using PET measurement of regional cerebral blood flow have revealed greater activation of the amygdala and anterior paralimbic structures (which are known to be involved in processing negative emotions such as fear), greater deactivation of Broca's region (motor speech) and other nonlimbic cortical regions, and failure of activation of the cingulate cortex (which possibly plays an inhibitory role) in response to trauma-related stimuli in individuals with PTSD. Functional MRI research has shown the amygdala to be hyperresponsive to fear-related stimuli in this disorder. Research with PET suggests that cortical, notably hippocampal, metabolism is suppressed to a greater extent by pharmacologic stimulation of the noradrenergic system in persons with PTSD. The growth of knowledge concerning the anatomical and neurochemical basis of this important mental disorder will hopefully eventually lead to rational psychological and pharmacologic treatments.

Differential prefrontal cortex and amygdala habituation to repeatedly presented emotional stimuli.

Repeated presentations of emotional facial expressions were used to assess habituation in the human brain using fMRI. Significant fMRI signal decrement was present in the left dorsolateral prefrontal and premotor cortex, and right amygdala. Within the left prefrontal cortex greater habituation to happy vs fearful stimuli was evident, suggesting devotion of sustained neural resources for processing of threat vs safety signals. In the amygdala, significantly greater habituation was observed on the right compared to the left. In contrast, the left amygdala was significantly more activated than the right to the contrast of fear vs happy. We speculate that the right amygdala is part of a dynamic emotional stimulus detection system, while the left is specialized for sustained stimulus evaluations.

A functional MRI study of human amygdala responses to facial expressions of fear versus anger.

Functional magnetic resonance imaging (fMRI) of the human brain was used to compare changes in amygdala activity associated with viewing facial expressions of fear and anger. Pictures of human faces bearing expressions of fear or anger, as well as faces with neutral expressions, were presented to 8 healthy participants. The blood oxygen-level dependent (BOLD) fMRI signal within the dorsal amygdala was significantly greater to Fear versus Anger, in a direct contrast. Significant BOLD signal changes in the ventral amygdala were observed in contrasts of Fear versus Neutral expressions and, in a more spatially circumscribed region, to Anger versus Neutral expressions. Thus, activity in the amygdala is greater to fearful facial expressions when contrasted with either neutral or angry faces. Furthermore, directly contrasting fear with angry faces highlighted involvement of the dorsal amygdaloid region.

Differential response in the human amygdala to racial outgroup vs ingroup face stimuli.

Here we describe response in the human amygdala to the presentation of racial outgroup vs ingroup faces. Functional magnetic resonance imaging (fMRI) measures of brain activity were acquired while subjects who identified themselves as White or Black viewed photographs of both White and Black faces. Across all subjects, we observed significantly greater blood oxygen-level-dependent (BOLD) signal in the amygdala to outgroup vs ingroup faces, but only during later stimulus presentations. A region of interest (ROI)-based analysis of these voxels revealed a significant interaction between amygdala response to outgroup and ingroup faces over time. Specifically, the greater amygdala activation to outgroup faces during later stimulus presentations was the result of amygdala response habituation to repeated presentations of ingroup faces with sustained responses to outgroup faces. The present results suggest that amygdala responses to human face stimuli are affected by the relationship between the perceived race of the stimulus face and that of the subject. Results are discussed as consistent with a role for the amygdala in encoding socially and/or biologically relevant information. We conclude that researchers seeking to study brain responses to face stimuli in human subjects should consider the relationship between the race of subjects and stimuli as a significant potential source of variance. Moreover, these data provide a foundation for future related studies in the neuroscience of social cognition and race.

Activation of anterior paralimbic structures during guilt-related script-driven imagery.

BACKGROUND: Several recent neuroimaging studies have examined the neuroanatomical correlates of normal emotional states, such as happiness, sadness, fear, anger, anxiety, and disgust; however, no previous study has examined the emotional state of guilt. METHODS: In the current study, we used positron emission tomography and the script-driven imagery paradigm to study regional cerebral blood flow (rCBF) during the transient emotional experience of guilt in eight healthy male participants. In the Guilt condition, participants recalled and imagined participating in a personal event involving the most guilt they had ever experienced. In the Neutral condition, participants recalled and imagined participating in an emotionally neutral personal event. RESULTS: In the Guilt versus Neutral comparison, rCBF increases occurred in anterior paralimbic regions of the brain: bilateral anterior temporal poles, anterior cingulate gyrus, and left anterior insular cortex/inferior frontal gyrus. CONCLUSIONS: These results, along with those of previous studies, are consistent with the notion that anterior paralimbic regions of the brain mediate negative emotional states in healthy individuals.

Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study.

BACKGROUND: Converging lines of evidence have implicated the amygdala in the pathophysiology of posttraumatic stress disorder (PTSD). We previously developed a method for measuring automatic amygdala responses to general threat-related stimuli; in conjunction with functional magnetic resonance imaging, we used a passive viewing task involving masked presentations of human facial stimuli. METHODS: We applied this method to study veterans with PTSD and a comparison cohort of combat-exposed veterans without PTSD. RESULTS: The findings indicate that patients with PTSD exhibit exaggerated amygdala responses to masked-fearful versus masked-happy faces. CONCLUSIONS: Although some previous neuroimaging studies of PTSD have demonstrated amygdala recruitment in response to reminders of traumatic events, this represents the first evidence for exaggerated amygdala responses to general negative stimuli in PTSD. Furthermore, by using a probe that emphasizes automaticity, we provide initial evidence of amygdala hyperresponsivity dissociated from the "top-down" influences of medial frontal cortex.

Neural activation during sexual and competitive arousal in healthy men.

To investigate the mediating neuroanatomy of positively valenced arousal, we used script-driven imagery in conjunction with positron emission tomography to measure relative regional cerebral blood flow (rCBF) during sexual and competitive arousal, as well as neutral comparison states. Subjects were eight healthy right-handed men. Psychophysiologic responses and subjective ratings confirmed that the desired state manipulations were achieved. Statistical parametric mapping revealed similar patterns of rCBF changes for both positively valenced arousal conditions: increases were found within anterior cingulate and anterior temporal cortex as well as the ventral globus pallidus; decreases were found within widespread heteromodal association areas. These results complement findings from studies of other normal and pathological emotional states, and provide new insights regarding the neural substrates of pleasurable arousal in healthy men.

Anger in healthy men: a PET study using script-driven imagery.

BACKGROUND: An understanding of the neurobiological basis of normal emotional processing is useful in formulating hypotheses regarding the pathophysiology of psychiatric illnesses. METHODS: This study examined the mediating functional neuroanatomy of anger in eight healthy men. Narrative scripts were developed from autobiographical information to induce anger and neutral states. The subjects imagined the content of the narrative scripts to induce anger during positron emission tomography to measure normalized regional cerebral blood flow (rCBF). Psychophysiologic responses and subjective ratings of emotional state were measured for each condition. Statistical parametric maps were constructed to reflect the Anger versus Neutral state contrast. RESULTS: Anger was associated with activation of the left orbitofrontal cortex, right anterior cingulate cortex affective division, and bilateral anterior temporal poles. CONCLUSIONS: These results suggest that the subjective experience of anger is associated with rCBF increases in anterior paralimbic regions of the brain.

Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: A PET investigation.

OBJECTIVE: The purpose of this study was to determine whether anterior limbic and paralimbic regions of the brain are differentially activated during the recollection and imagery of traumatic events in trauma-exposed individuals with and without posttraumatic stress disorder (PTSD). METHOD: Positron emission tomography (PET) was used to measure normalized regional cerebral blood flow (CBF) in 16 women with histories of childhood sexual abuse: eight with current PTSD and eight without current PTSD. In separate script-driven imagery conditions, participants recalled and imagined traumatic and neutral autobiographical events. Psychophysiologic responses and subjective ratings of emotional state were measured for each condition. RESULTS: In the traumatic condition versus the neutral control conditions, both groups exhibited regional CBF increases in orbitofrontal cortex and anterior temporal poles; however, these increases were greater in the PTSD group than in the comparison group. The comparison group exhibited regional CBF increases in insular cortex and anterior cingulate gyrus; increases in anterior cingulate gyrus were greater in the comparison group than in the PTSD group. Regional CBF decreases in bilateral anterior frontal regions were greater in the PTSD group than in the comparison group, and only the PTSD group exhibited regional CBF decreases in left inferior frontal gyrus. CONCLUSIONS: The recollection and imagery of traumatic events versus neutral events was accompanied by regional CBF increases in anterior paralimbic regions of the brain in trauma-exposed individuals with and without PTSD. However, the PTSD group had greater increases in orbitofrontal cortex and anterior temporal pole, whereas the comparison group had greater increases in anterior cingulate gyrus.

The judgement of absence in neglect.

The usual way of looking at neglect is by investigating how neglect patients fail to detect that something is there. In this study, we look at how neglect patients correctly detect that something is not there. Patients with parietal lesions (11 with and 16 without neglect) and 23 control subjects indicated whether a dot target was or was not present in a geometrical display. While control subjects were consistently (and unexpectedly) faster in the no-dot than in the dot condition, the distinguishing response time pattern of right parietal patients with neglect was not--as one might expect--a relatively longer response time to left vs right targets, but a longer response time to target absence vs presence. This may be due to a serial search or, alternatively, it might result from double-checking for target absence, produced by lowered perceptual confidence. Since this "wariness" about stimulus absence seems to operate in parallel with neglect patients' denial of the deficit, we conclude that the response time pattern observed in this study could be used as a measure of subjective (un)awareness of neglect.

Visual imagery and perception in posttraumatic stress disorder. A positron emission tomographic investigation.

BACKGROUND: Relative regional cerebral blood flow (rCBF) changes were measured in Vietnam combat veterans with and without posttraumatic stress disorder (PTSD) during exposure to combat-related stimuli. METHODS: Positron emission tomography was used to measure rCBF in 7 combat veterans with PTSD (PTSD group) and 7 healthy combat veterans (control group) who viewed and generated visual mental images of neutral, negative, and combat-related pictures. RESULTS: Unlike control subjects, subjects with PTSD had increased rCBF in ventral anterior cingulate gyrus and right amygdala when generating mental images of combat-related pictures; when viewing combat pictures, subjects with PTSD showed decreased rCBF in Broca's area. CONCLUSIONS: Results suggest that ventral anterior cingulate gyrus and right amygdala play a role in the response of combat veterans with PTSD to mental images of combat-related scenes. Reexperiencing phenomena of PTSD, which often involve emotional visual mental imagery, may be likewise associated with increased rCBF in these regions.

Neural effects of visualizing and perceiving aversive stimuli: a PET investigation.

Cerebral blood flow was recorded (using positron emission tomography) while middle-aged subjects viewed or visualized pictures of neutral or aversive stimuli, and then determined whether auditorily presented statements correctly described the stimuli. Visualizing aversive stimuli enhanced cerebral blood flow, relative to visualizing neutral stimuli, in areas 17 (right) and 18 (bilateral), as well as the anterior insula (bilateral) and middle frontal cortex (left). Areas 17 and 18 have been identified as supporting the representations that underlie the experience of imagery, and the anterior insula is a major cortical recipient of input from the autonomic nervous system. Perceiving aversive stimuli enhanced cerebral blood flow, relative to neutral stimuli, in area 46, the angular gyrus and area 19, area 47, and the middle temporal gyrus (all in the left hemisphere). All of these areas have previously been implicated in visual object identification. It is striking that negative emotion did not modulate activation in any areas in the same way during imagery and perception.

Association of intelligence with severity of posttraumatic stress disorder symptoms in Vietnam Combat veterans.

OBJECTIVE: The purpose of this study was to determine whether intelligence predicts variance in posttraumatic stress disorder (PTSD) symptoms beyond that predicted by extent of combat exposure. METHOD: The subjects were 105 male Vietnam combat veterans. They completed the Mississippi Scale for Combat-Related Posttraumatic Stress Disorder, the Combat Exposure Scale, and the Shipley Institute for Living Scale, a measure of general intelligence. Number of years of education was recorded for each subject. RESULTS: Multiple regression analyses revealed that estimated full-scale IQ significantly predicted variance in PTSD symptoms beyond that predicted by extent of combat exposure. The lower a subject's intelligence, the more severe were his PTSD symptoms. CONCLUSIONS: Cognitive variables may affect the ability to cope with trauma, thereby affecting whether a person develops chronic PTSD.