**2. A single disorder with many different facets**

In life-threatening situations, mammals tend to react in two ways: "fight or flight" or "freezing". In light of adaptive evolutionary theory, both types of responses lead to adaptive gains for survivors. The defensive cascade animal model shows that several animals flee from or confront other predators, whereas others "pretend" to be dead when captured (Broman-Fulks et al., 2006). More than 100 studies have pointed to a distinction between simple and complex PTSD; therefore, some researchers have sought to include the dissociative subtype in the DSM-V (van der Kolk, 2006). Although based on recent literature, "freeze, flight, fight, fright, faint" provides a more comprehensive description of the human acute stress response sequence than current descriptions (Bracha et al., 2004). Two main behavioral systems are involved in PTSD: (1) hyperstimulation of sympathetic reactivity with expressive activity of the adrenergic system typically involved in fight or flight responses, and (2) dissociation with parasympathetic reactivity involved in freeze responses (Bremner et al., 2003). Supporting these two PTSD subtypes is a model of risk factors for PTSD developed after a study with a group of acutely burned people. Two pathways to PTSD were discerned: 1) from the size of the burn and level of pain following the acute anxiety, and then to PTSD; and 2) from the size of the burn to the level of acute dissociation following the burn, and then to PTSD. Together these pathways accounted for almost 60% of variance in PTSD symptoms and constituted a model with excellent fit indices. These findings support a model of complex etiology for childhood PTSD in which two independent pathways may be mediated by different biobehavioral systems (Saxe et al., 2005). Similar results were found in a different sample of sexually abused children. Independent pathways—anxiety/arousal and dissociation—through which sexually abused children are likely to develop later PTSD symptoms, accounted for about 57% of variance in PTSD symptoms (Kaplow et al., 2005). The finding that high levels of dissociative symptoms may be related to suppression of autonomic physiological responses to stress supports Bremner's conceptualization of dissociative symptoms as comprising one of two subtypes of the acute stress response, differing physiologically as well as subjectively from a predominantly hyperarousal or intrusive symptom response (Creamer et al., 2005). The dissociative subtype may be seen in adults with a history of sexual abuse during childhood who present a consistent picture of dissociative amnesia, which occurs more often in victims of interpersonal violence during childhood than in combat soldiers and accident victims (who do not present hyperarousal symptoms).

#### **2.1 Subtype I**

396 Neuroimaging for Clinicians – Combining Research and Practice

2009). How people process stressors may be critical in determining whether or not trauma will be experienced, as well as the different constellation of symptoms if traumatization is

A single traumatic event can be processed in very different ways by individuals who experienced the same traumatic episode (Peres et al., 2005; 2011). The psychopathological signs of trauma are not static over time, nor is the form of the expression of traumatic memories. This fluidity is a consequence of the sensitization that is driven by reminders of the traumatic event and the vulnerability of memory to being modified with repeated recall (Peres et al., 2008; 2011). The sensitization of neural pathways involved in this reactivity is central to understanding the neurobiology of PTSD. The purpose of this chapter is to attempt to integrate both neuroimaging and psychotherapeutic findings in relation to PTSD, so that integration might bring greater efficacy to the treatment of psychologically

In life-threatening situations, mammals tend to react in two ways: "fight or flight" or "freezing". In light of adaptive evolutionary theory, both types of responses lead to adaptive gains for survivors. The defensive cascade animal model shows that several animals flee from or confront other predators, whereas others "pretend" to be dead when captured (Broman-Fulks et al., 2006). More than 100 studies have pointed to a distinction between simple and complex PTSD; therefore, some researchers have sought to include the dissociative subtype in the DSM-V (van der Kolk, 2006). Although based on recent literature, "freeze, flight, fight, fright, faint" provides a more comprehensive description of the human acute stress response sequence than current descriptions (Bracha et al., 2004). Two main behavioral systems are involved in PTSD: (1) hyperstimulation of sympathetic reactivity with expressive activity of the adrenergic system typically involved in fight or flight responses, and (2) dissociation with parasympathetic reactivity involved in freeze responses (Bremner et al., 2003). Supporting these two PTSD subtypes is a model of risk factors for PTSD developed after a study with a group of acutely burned people. Two pathways to PTSD were discerned: 1) from the size of the burn and level of pain following the acute anxiety, and then to PTSD; and 2) from the size of the burn to the level of acute dissociation following the burn, and then to PTSD. Together these pathways accounted for almost 60% of variance in PTSD symptoms and constituted a model with excellent fit indices. These findings support a model of complex etiology for childhood PTSD in which two independent pathways may be mediated by different biobehavioral systems (Saxe et al., 2005). Similar results were found in a different sample of sexually abused children. Independent pathways—anxiety/arousal and dissociation—through which sexually abused children are likely to develop later PTSD symptoms, accounted for about 57% of variance in PTSD symptoms (Kaplow et al., 2005). The finding that high levels of dissociative symptoms may be related to suppression of autonomic physiological responses to stress supports Bremner's conceptualization of dissociative symptoms as comprising one of two subtypes of the acute stress response, differing physiologically as well as subjectively from a predominantly hyperarousal or intrusive symptom response (Creamer et al., 2005). The dissociative subtype may be seen in adults with a history of sexual abuse during childhood who present a consistent picture of dissociative amnesia, which occurs more often in victims

characterized.

traumatized patients.

**2. A single disorder with many different facets** 

In a situation of unknown risk, heart and visceral alterations point to autonomous nervous system hyperactivity, whereas a subjective state of arousal potentiates an immediate search for syntheses and parameters for generating behavior. Peripheral and metabolic alterations (eg, tachycardia, mydriasis) reflect hyperactivity of the sympathetic nervous system and the hypothalamus-hypophysis-adrenal (HPA) axis leading to an immediate self-preservation response (Peres et al., 2007). Neurofunctional studies with hyperarousal PTSD patients using symptom provocation paradigms (in most cases, the retrieval of traumatic memories) suggest that the difficulty of synthesizing, classifying, and integrating a traumatic memory in narrative form may be related to the decreased activity of the prefrontal cortex involved in reducing negative feedback from the activity of the amygdala (Shin et al., 2004). Studies have implicated the HPA and the sympathetic-adrenal-medullar stress axes as key components of this pathogenic process (Boscarino et al., 2006). The relationship between anxiety level and performance is no longer advantageous after a certain point. Selfgenerated information flooding into sensory pathways affects the perceptual processing of data from surroundings, thus hampering the ability to formulate new hypotheses and syntheses.

Trauma-related studies involving epinephrine (E), norepinephrine (NE), and serotonin (5- HT) suggested that alterations in NE, E, and 5-HT may have relevance for symptoms commonly seen in survivors with PTSD, including hypervigilance, exaggerated startle, irritability, impulsivity, aggression, and intrusive memories (Southwick et al., 1999). Studies related to the role of NE in arousal, orienting to novel stimuli, selective attention, and vigilance demonstrated heightened noradrenergic neuronal reactivity, increased -2 receptor sensitivity and exaggerated arousal in organisms that have been exposed to chronic uncontrollable stress. The way an individual cognitively processes a traumatic event may trigger an anxious/arousal or a dissociative reaction.

#### **2.2 Subtype II**

Tonic immobility (TI) is a possible component of the fear response characterized by freezing or immobility in situations involving extreme fear coupled with physical restraint, and is observed in 30% to 40% of rape victims (Kaplow et al., 2005). A study of TI in victims of childhood sexual abuse (CSA)—female undergraduates (*n* = 39) and female psychiatric inpatients (*n* = 41)—showed that more than 52% of all participants reported TI in response to CSA. TI reports were associated with greater current psychological impairment (Heidt et al., 2005) and may be typical not only of rape and sexual abuse victims, but other kinds of directly experienced traumas as well (Bados et al., 2008).

Emotional factors play a role in many reflex TI manifestations referred to as *feigning death*. Whether orienting and defense responses provide a valid model in humans has yet to be proven, but the dissociative response in certain trauma cases resembles animal TI. Bovin and colleagues (2008) asked whether TI mediates relations between perceived inescapability, peritraumatic fear, and PTSD symptom severity among sexual assault survivors. Their findings indicated that TI fully mediated relations between perceived inescapability and overall PTSD symptom severity, as well as re-experiencing and

PTSD, Neuroimaging and Psychotherapy: A Fruitful Encounter 399

increased perfusion in limbic and paralimbic structures of the right hemisphere, including the orbit frontal cortex, insular cortex, anterior temporal pole, and middle temporal cortex. Broca's area in the left inferior frontal cortex showed significantly decreased blood flow during provocation of traumatic memories, though not all studies have replicated this

There is consensus that limbic and paralimbic regions are involved in the expression of emotional memories (Grillon et al., 1996; Shalev et al., 2000; Shalev, 2002; Moscovitch et al., 2005). More specifically, activation of the amygdala and anterior paralimbic structures is implicated in the processing of negative emotions such as fear. Studies of war veterans with PTSD, during visualisation of combat images showed increased activation of the anterior ventral cingulate gyrus and right amygdala, and reduced activity in Broca's area (Shin et al., 1999; Pissiota et al., 2002) A SPECT study by Liberzon and colleagues (1999) using combat veterans with and without PTSD and healthy controls, found left amygdala activation in response to combat sounds in PTSD patients only, but no amygdala activity in response to neutral sounds. Similarly, Rauch and colleagues (2000) found that people with PTSD showed greater activation of the right amygdala when shown frightening faces, compared

PET has been used to study veterans to measure patterns of neural activity associated with traumatic images and sounds. Decrease in activity of the left prefrontal cortex (PFC) and anterior cingulate cortex of those individuals has also been demonstrated (Bremner et al., 1999). In another study with war veterans, fMRI was used to measure changes in activation of the left anterior cingulate cortex in response to a cognitive activation model – counting stroop for combat-related, negative, and neutral words (Shin et al., 2001). Individuals with PTSD showed decreased activity in the left PFC and AC when compared to the control group. In contrast, other SPECT studies of war veterans, did not find differential activity in these regions in response to trauma-related stimuli in PTSD, but found increased activity in the middle prefrontal cortex that was not correlated with symptoms (Shin et al., 1999; Zubieta et al., 1999). Two PET studies of women victims of childhood sexual abuse utilized directed scripts of neutral images and events related to the trauma (Bremner et al., 2002; Bremner et al., 1999). The scripts evoked memories of abuse experiences in all women, and resulted in increased bilateral activation of the posterior cingulate and motor cortex, but there was no differential activity in the middle prefrontal cortex or AC in women with PTSD relative to controls. Liberzon and colleagues (1999) and Zubieta and colleagues (1999) conducted a SPECT using similar methodology, involving war veterans with PTSD, publishing findings on PFC activity, which appeared to modulate the response to fear. In contrast to the typical findings, a regional increase in blood flow (not decrease) was found in PFC in individuals with PTSD. This discrepancy may that relate to the selection of this region in a region-of-interest analysis, which was derived from a separate control group or a confounding variable of a dissociative subtype of PTSD. Lanius and colleagues (2004), using a script-driven symptom provocation paradigm, have observed greater activity in the right posterior cingulate, right parietal lobe, and right occipital lobe, in PTSD and less activity in the left hemisphere. These findings support the suggestion of the inherently nonverbal nature of traumatic memory recall in PTSD subjects, compared to a more verbal pattern of

Despite some inconsistencies, there are reproducible neuroimaging findings in studies of traumatic memories. Functional neuroimaging has revealed greater activation of the right

finding (McFarlane et al., 1997; Peres et al., 2007).

traumatic memory recall in subjects without PTSD.

to the controls.

avoidance/numbing symptom clusters. Beyond the hyperarousal PTSD model, TI may be a pathway through which trauma survivors develop severe PTSD symptoms. Supporting this hypothesis, psychophysiological changes associated with peritraumatic dissociation in female recent-rape victims were studied, as well as the relation between these changes and PTSD symptoms. Individuals in the high peritraumatic dissociation group showed a significantly different pattern of physiological responses from those in the low dissociation group. There was suppression of autonomic physiological responses in the former group, which also showed a discrepancy between self-reports of distress and objective physiological indicators in the laboratory setting (low heart rate and skin conductance), whereas high measures of subjective suffering were observed while volunteers talked about rape. On the other hand, the low dissociation group showed increased sympathetic system response (heart rate and skin conductance) during the same task. These findings support the hypothesis that in addition to the anxiety/arousal subtype, there is a dissociative subtype of persons with PTSD symptoms who exhibit diminished physiological reactivity (Griffing et al., 2006). Another study found that female rape victims with acute PTSD who scored high on the Peritraumatic Dissociative Experiences Questionnaire exhibited suppression of physiological responses during exposure to trauma-related stimuli (Kaufman et al., 2002).

Routes to traumatic amnesia from dissociative detachment (loss of emotional content leading to loss of factual content) and from dissociative compartmentalization (failure in integration) are frequent in PTSD subtype II patients. Women with high disability pain were more likely to have experienced child abuse, adult sexual assault, more severe spousal abuse, lifetime abuse-related injuries, and PTSD symptoms.

Neuroimaging studies found distinct neural reciprocities for the two types of responses. The first pattern of sympathetic excitability involved attenuation of medial-prefrontal cortex activity and heightened amygdala activity leading to continuous autonomic arousal and state of alert. The second pattern (dissociative) showed heightened activity of the medialprefrontal cortex resulting in inhibition of amygdala activity, blunting the sympathetic response and leading to emotional numbing (Peres et al., 2011).
