3

Neurobiology

This chapter describes the neurobiology of posttraumatic stress disorder (PTSD) and provides a setting for discussing the optimal treatment for PTSD (see Chapter 7). It begins with a discussion of adaptive versus maladaptive stress responses and describes fear conditioning and fear extinction. Models for the development of PTSD are then presented with an overview of the modulators that affect PTSD expression. In particular, in response to the committee’s statement of task, physiological markers for PTSD are described (see section on biomarkers) as are brain imaging studies (see section on studies using human subjects) and studies correlating brain region physiology and the diagnosis of PTSD (see section on implications for PTSD prevention, diagnosis, and treatment). The chapter concludes with a discussion of the implications of the neurobiology of PTSD for its prevention, diagnosis, and treatment.

Although some research on the neurobiology of PTSD is funded by the National Institutes of Health, other research on this topic is also sponsored by the Department of Defense (DoD) and the Department of Veterans Affairs (VA) (see Chapter 4). For example, the DoD is funding a study on multimodal neurodiagnostic imaging of traumatic brain imaging (TBI) and PTSD and a study on the neurobiology of tinnitus with PTSD as a secondary outcome, but these studies are ongoing and results are not available. The VA is also funding studies on the neurobiology of PTSD, including examinations of memory and the hippocampus in twins, brain imaging of psychotherapy for PTSD, and neural correlates of cognitive rehabilitation in PTSD.

The etiology of PTSD is linked to a known incident or repeated incidences



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3 Neurobiology T his chapter describes the neurobiology of posttraumatic stress dis- order (PTSD) and provides a setting for discussing the optimal treatment for PTSD (see Chapter 7). It begins with a discussion of adaptive versus maladaptive stress responses and describes fear condition- ing and fear extinction. Models for the development of PTSD are then presented with an overview of the modulators that affect PTSD expression. In particular, in response to the committee’s statement of task, physiological markers for PTSD are described (see section on biomarkers) as are brain imaging studies (see section on studies using human subjects) and studies correlating brain region physiology and the diagnosis of PTSD (see section on implications for PTSD prevention, diagnosis, and treatment). The chap- ter concludes with a discussion of the implications of the neurobiology of PTSD for its prevention, diagnosis, and treatment. Although some research on the neurobiology of PTSD is funded by the National Institutes of Health, other research on this topic is also sponsored by the Department of Defense (DoD) and the Department of Veterans Af- fairs (VA) (see Chapter 4). For example, the DoD is funding a study on multimodal neurodiagnostic imaging of traumatic brain imaging (TBI) and PTSD and a study on the neurobiology of tinnitus with PTSD as a second- ary outcome, but these studies are ongoing and results are not available. The VA is also funding studies on the neurobiology of PTSD, including examinations of memory and the hippocampus in twins, brain imaging of psychotherapy for PTSD, and neural correlates of cognitive rehabilitation in PTSD. The etiology of PTSD is linked to a known incident or repeated inci- 59

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60 PTSD IN MILITARY AND VETERAN POPULATIONS dences in which an individual is exposed to a life-threatening event that causes the development of PTSD symptoms. Stimuli present at the time of trauma exposure often become associated with the traumatic event such that subsequent exposure to one or more of those stimuli triggers fear and anxiety. PTSD patients often develop strategies to avoid trauma-associated contexts or cues and develop multiple symptoms, including cognitive and memory impairments and sleep disturbances. The advent of neuroimaging tools during the past two decades along with the advancement of preclinical research has provided a platform upon which to begin to examine the neurobiology of PTSD, from predisposing factors leading to its development to developing novel strategies to treat the disorder. This chapter reviews some of the models and experimental approaches used in this domain. The committee must emphasize that a comprehensive review of the literature in this area of research is beyond the scope of this report. Moreover, the committee emphasizes there is not a single experimental model that can or will be able to capture every aspect of this complex disorder, and every experimental model (clinical or preclinical) has its advantages and disadvantages (see review by Brewin and Holmes, 2003). With this perspective in mind, the committee uses many references that rely on one or more experimental models or approaches to examine the neurobiology of PTSD, with an objective to build a wealth of information from different approaches that may lead to a comprehensive understanding of the disorder. ADAPTIVE AND MALADAPTIVE STRESS RESPONSES The diagnosis of PTSD requires that a person have “experienced, wit- nessed, or [been] confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others” and that “the person’s response involved fear, helplessness or horror” (APA, 2000); see Chapter 2 for the complete diagnostic criteria for PTSD. Research suggests that the term stress in relation to disease should be “restricted to conditions where an environmental demand exceeds the natu- ral regulatory capacity of an organism, in particular situations that include unpredictability and uncontrollability” (Koolhaas et al., 2011). Examples of unpredictable and uncontrollable situations include rape, childhood abuse, and military combat (Breslau et al., 1991, 1998; Kessler et al., 1995). Research on PTSD has concentrated on two systems, the sympathetic ner- vous system and the hypothalamic-pituitary-adrenal (HPA) axis, but there are other neurobiologic systems such as the serotonin system, the opiate system, and sex steroidal systems that have been implicated in pathologic and protective responses to stress (IOM, 2008). The HPA axis is a neuroendocrine system from which there is succes-

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61 NEUROBIOLOGY sive release of several hormones that leads to the release of cortisol from the adrenal glands. Cortisol circulates to other tissues where it causes an elevation in circulating glucose and, if appropriate, activates immune-cell migration to injured or infected areas of the body. There is some evidence that chronically elevated cortisol concentrations may impair many forms of memory (memory that is dependent on the hippocampus or prefrontal cortex), but such elevated concentrations favor memories that trigger fear (memory that is dependent on the amygdala) (see reviews by McEwen, 2005, 2006; Vanitallie, 2002). This is an important distinction because fear memories depend on the amygdala and extinction memories depend on the hippocampus and prefrontal cortex. Events that are perceived as uncontrollable and threatening cause a series of reactions via the HPA axis, the locus coeruleus, and the nor- adrenergic system (Koenen et al., 2009a). These systems have recipro- cal connections with limbic structures that mediate fear conditioning and memory consolidation (the amygdala and hippocampus) and prefrontal brain structures that mediate the extinction of fear memories. Structures in the brain initially respond to stress caused by an acute threat through adaptive mechanisms such as energy mobilization, increased vigilance and focus, and the facilitation of memory formation (Charney, 2004). When the body determines there is no longer an acute threat, it attempts to return to homeostasis through an elaborate negative feedback system. Figure 3-1 shows the major pathways that are triggered during a response to stress. There are some cases where the adaptive response described above becomes persistent and pathologic (Koenen et al., 2009a). When a person is exposed to a traumatic event, sensory stimuli present at the time of ex- posure become associated with it. Later exposure to one or more of the now-conditioned sensory cues can lead to reactivation of the traumatic memories. The initial re-exposure to the conditioned cues leads to the expression of intense fear and anxiety in most people. Repeated exposure to those cues in the absence of additional negative reinforcement (that is, without additional traumatic events) will lead to the gradual reduction of emotion associated with the traumatic event (that is, extinction). As stated by Mao et al. (2006), “much evidence indicates that extinction training does not erase memory traces but instead forms inhibitory learning that prevents the expression of the original memory” (see also Quirk, 2002). Reinstatement, renewal, and spontaneous recovery are phenomena that provide direct evi- dence that fear extinction is new inhibitory learning rather than erasure or forgetting (Archbold et al., 2010; Bouton, 2004; Myers and Davis, 2007). Reinstatement is a phenomenon in which a person or animal undergoes extinction training and is then exposed to an unsignaled unconditioned stimulus (see Box 3-1 for definition), resulting in the reappearance of an ex-

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62 Fear Processing Fear Response §Skeletal motor activation (that is, the “fight or flight” response) Cortex §Facial expressions of fear §Hyperventilation Thalamus Amygdala Locus Coeruleus §Parasympathetic and sympathetic nervous system activation Fearful Sensory Pontine Reticular Hippocampus Stria Terminalis RAS Activated Input Formation §Neuroendocrine and neuropeptide release (that is, the “hormonal stress response”) Hypothalamus- Epinephrine, Hypothalamus Pituitary-Adrenal Cortisol Axis FIGURE 3-1 Depiction of the major pathways triggered during a response to stress. During a normal stress response, the sympathetic nervous system and the reticular activating system (RAS) are activated. The sympathetic nervous system controls the response of internal organs (for example, increasing the heart rate, decreasing digestion activities, and mobilizing energy stores from the liver). The RAS, which is required for a stress response, activates the pontine reticular formation (which induces the startle response), activates the thalamus to stimulate the cortex, and communicates with forebrain structures to activate the hypothalamus, which triggers the HPA axis and the release of epinephrine (IOM, 2008). Figure 3-2 new

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63 NEUROBIOLOGY tinguished fear response. Renewal occurs when an extinguished conditioned response (see Box 3-1 for definition) reappears in a person or animal in a context that is different from the context in which the extinction training took place. Spontaneous recovery is the term used when the extinguished conditioned response reappears after nothing but the passage of time fol- lowing extinction training. It has been hypothesized that PTSD may result from a failure to recover from a traumatic experience, which leads to an inability to extinguish the fear and anxiety associated with conditioned sensory cues. For example, a service member might witness a friend being killed while a helicopter is hov- BOX 3-1 Definitions of Selected Terms Associated with Fear Conditioning and Fear Extinction Classical conditioning—A process by which previously neutral stimuli acquire meaning to the organism Unconditioned stimulus (US)—A trigger that produces an automatic, unlearned response Unconditioned response (UR)—A naturally occurring reaction to a US Conditioned stimulus (CS)—A neutral trigger that, through classical condition- ing, is able to produce a conditioned response Conditioned response (CR)—The learned reaction and instrumentational ac- tions to a CS Acquisition—The initial stage of learning, where a neutral stimulus (CS) is asso- ciated with a meaningful stimulus (US) and obtains the capacity to elicit a similar response (CR) Short-term memory—Memory that is held for a short period of time Long-term memory—Memory that lasts over a long period of time Consolidation—The process by which short-term memory is converted into long-term memory Retrieval—Reactivation of the memory trace or expression of a fear memory Reconsolidation—A process by which a previously consolidated memory, which has been retrieved and becomes labile, undergoes another consolidation Extinction—The process by which a CS loses the ability to elicit a CR SOURCE: Adapted from Garakani et al., 2006; reproduced with permission of John Wiley & Sons, Inc.

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64 PTSD IN MILITARY AND VETERAN POPULATIONS ering overhead. The service member associates the sounds of the helicopter with the friend’s death. Later, when the service member hears a helicopter, he or she may experience the same fear and anxiety that were experienced during the traumatic event. This is a prototypic example of Pavlovian con- ditioning whereby sounds of the helicopter trigger the service member to prepare for an attack. This reaction would be adaptive in a combat situa- tion but is maladaptive outside of it. Conditioned fear may also lead to instrumental behaviors that contrib- ute to the development and maintenance of PTSD. Instrumental behaviors often take the form of active and passive avoidance. Such behaviors are exhibited when the organism has control over threats and can minimize exposure to threats and traumas (conditioned and unconditioned stimuli) by virtue of how it responds. For example, a person diagnosed with PTSD may actively avoid reminders of the traumatic event, such as avoiding members of his or her unit because they are reminders of the traumatic ex- perience of combat. A person diagnosed with PTSD may also passively (or involuntarily) avoid reminders of a traumatic situation, such as becoming disengaged. Fear extinction is therefore about learning that the conditioned stimulus no longer predicts the unconditioned stimulus, thus eliminating the need for all defensive responding (such as fear reactions and instrumental responses). Both active and passive avoidance strategies prevent fear reac- tions and subjective feelings of fear, and they can be adaptive provided they do not interfere with normal activities. Active avoidance mechanisms may even have relevance to active coping strategies that effectively deal with traumatic fear (Cain and LeDoux, 2007). Fear and anxiety are a normal response to trauma. For the majority of exposed individuals, this fear and anxiety extinguish over time. For a significant minority, they do not. Therefore, it has been hypothesized that PTSD is a disorder of fear extinction (Cohen and Richter-Levin, 2009; Herry et al., 2010; Lang et al., 2000; Rasmusson and Charney, 1997; Rothbaum and Davis, 2003; Siegmund and Wotjak, 2006). The commit- tee recognizes that other models have been proposed, including models for learning and for processing stress, information, memory, and emotion (see reviews by Brewin and Holmes, 2003; Cahill and Foa, 2007; and Ursano et al., 2008). However, it is difficult for one model to capture all aspects of PTSD phenomenology, especially associated symptoms such as shame and guilt, the latter two symptoms are not included in the Diagnostic and Statistical Maual of Mental Disorders, Fourth Edition (DSM-IV) list of symptoms for the diagnosis of PTSD (APA, 2000). Box 3-1 defines some terms commonly used in association with fear conditioning and fear extinction. The fear-conditioning model was first described by Pavlov (1927) in a study with dogs. As described by Pitman and Delahanty (2005), a “traumatic event (unconditioned stimulus) over-

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65 NEUROBIOLOGY stimulates endogenous stress hormones (unconditioned response); these mediate an overconsolidation of the event’s memory trace; recall of the event in response to reminders (conditioned stimulus) releases further stress hormones (conditioned response); these cause further overconsolidation; and the overconsolidated memory generates PTSD symptoms. Noradren- ergic hyperactivity in the basolateral amygdala is hypothesized to mediate this cycle.” The three main clusters of PTSD symptoms that result from a persistent pathologic response to uncontrollable stress are re-experiencing or reliving the traumatic event, avoiding reminders of the traumatic event (which prevents extinction of the fear memory) and emotional numbing, and generalized state of hyperarousal or hypervigilance (Koenen et al., 2009a). In the model of fear extinction, the animal is able to adapt to its envi- ronment by dissociating the acquired conditioned fear response from the conditioned stimulus (Cohen and Richter-Levin, 2009). The inability to extinguish a conditioned fear response may play a role in the persistence of PTSD symptoms (Pitman, 1988; Rauch et al., 1998). Of particular in- terest is whether fear extinction is the result of learning a new response when presented with a conditioned stimulus, unlearning the original fear response when presented with a conditioned stimulus, habituation of the fear response, or a combination of these. As discussed earlier in this section, several reviews point toward the concept that fear extinction is a process more of relearning rather than of removal of a previous memory (Bouton et al., 2011; Cohen and Richter-Levin, 2009; Herry et al., 2010; Maren, 2011; Milad and Quirk, 2012). Animal studies have shown that the recollection of previously consoli- dated conditioned fear memories can bring them into a labile state, and these memories then need to go through another phase of reconsolidation. Interrupting this second wave of reconsolidation by using, for example, protein synthesis inhibitors such as anisomycin, has the potential to prevent the restorage of memory (Nader et al., 2000). Reconsolidation blockade has also been shown in humans, and it has been suggested that extinction training may substitute the use of pharmacologic agents to block memory reconsolidation (Schiller et al., 2010). There is, however, some controversy surrounding the relationship between fear extinction and its relationship to fear reconsolidation (that is, memories that have been consolidated have the ability to be altered through retrieval or reactivation) (Myers and Davis, 2007). Differences may be caused by the methods used during studies where deficits were observed in reconsolidation or extinction. These factors may include the amount of time between re-exposure and the previously con- ditioned cue, protein synthesis in the amygdala and the medial prefrontal cortex, the strength of the conditioned fear memory, and the possibility that

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66 PTSD IN MILITARY AND VETERAN POPULATIONS the “extinction memory, once firmly established, itself undergoes reconsoli- dation” (Myers and Davis, 2007). Neurobiology that supports the animal model of fear conditioning has been much studied. The process is thought to rely heavily on neuro- nal circuits in the amygdala, prefrontal cortex, hippocampus, and brain stem (Herry et al., 2010; Milad and Quirk, 2012; Ressler, 2010). The neurobiologic processes underlying fear conditioning in animal models and human correlation studies of PTSD are well characterized, and the fear-conditioning model is a guide for the study of the neurobiology of PTSD (Amstadter et al., 2009a; Jovanovic and Ressler, 2010; Lonsdorf and Kalisch, 2011). However, it is important to note that the fear-conditioning model does not capture all features associated with PTSD and is sometimes criticized as too simplistic to explain its pathophysiology. A number of other experimental approaches have been used in both rodents and humans, including symptom-provocation studies, testing of brain responses to the explicit and implicit presentation of fear stimuli in humans, and prolonged- stress exposure models in rodents. MODELS FOR THE DEVELOPMENT OF PTSD Numerous experiments have been undertaken in animals and humans to gain a better understanding of the pathophysiology underlying PTSD. The experimental models have benefits and limitations, as will be discussed in the following sections. Animal Models Animal models of fear conditioning and extinction have been critical in improving understanding of the neurobiology of PTSD. They are useful because they allow the researcher to manipulate stressors and to control for other variable factors in an experiment. Such models start with a stressor, and the intensity of the stressor (and other determinants) predicts the PTSD. The usual stressors in animals include such conditions as restraint stress, exposure to predators, and underwater foot or tail shocks. Because human PTSD occurs chiefly in the context of life-threatening stressors, the intensity of the stressors used to develop valid animal models need especially careful consideration. In animal PTSD models, there are complex outcomes that are akin to the variety and severity of PTSD symptoms observed in humans (Kehne and Cain, 2010; Ursano et al., 2009). Animal outcomes include stress, the complementary outcome of fear, and anxiety. Those are sometimes dissocia- ble and indistinct, but all have been characterized in animals (Graham and Milad, 2011; Ressler, 2010; Shin and Liberzon, 2010). Both unconditioned- fear models (for example, experimental models that include an ethologically

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67 NEUROBIOLOGY relevant fear stimulus, elevated plus maze, light–dark test, social interac- tion, light-enhanced startle, or distress vocalizations) and conditioned-fear models (for example, experimental models that include a conditioned-fear paradigm, conditioned freezing, or fear-potentiated startle) have been de- veloped in animals. Through the extensive study of animal models of emotional learn- ing and memory (LeDoux, 2000; Maren, 2001), brain regions of interest for PTSD pathology have been described, fear circuits have been defined, and specific molecular outcomes of emotional learning and memory have been identified (Sotres-Bayon et al., 2009). These types of animal models, although they may be incomplete with respect to a full PTSD phenotype, suggest a process for the acquisition and storage of memories, plasticity processes (that is, the ability of pathways in the brain to reorganize struc- turally and functionally), and molecular markers that might be exploited during the investigation of PTSD resilience, diagnosis, and treatment. It is important to keep in mind the limitations when evaluating an animal model and its implications for humans. For example, diagnosis of PTSD in humans usually requires a person communicate his or her experi- ences, thoughts, dreams, and emotions, whereas animal models rely on the observation of behavior. Some of the PTSD phenotypes observed in humans may not be present in animals. Also, the traumatic event that triggers PTSD symptoms in humans may be perceived as life threatening; this perception may cause a type or severity of stress response different from the stress response in an animal after it is restrained or receives a foot shock (Cohen and Richter-Levin, 2009). There are also differences in timing that limit the translation of animal models to human applications. For example, service members may have much longer exposures to traumatic events than ani- mals, and because the average life span of animal models is relatively short, there may not be enough time for PTSD symptoms to develop. Although no single animal model can capture the complex clinical features of PTSD, a number of models have provided a wealth of in- formation regarding the neural circuits of emotional learning and mem- ory. Examples of animal models for the study of PTSD and PTSD-related phenomena include fear conditioning and extinction models (Cohen and Richter-Levin, 2009), stress-based models (Cohen and Richter-Levin, 2009; Khan and Liberzon, 2004; Yamamoto et al., 2009), fear-potentiated startle models (Davis, 1986; Lang et al., 2000), and learned-helplessness models (Rasmusson and Charney, 1997). Homologous Brain Structures Several brain structures and circuits relevant to the fear-learning and fear-extinction processes have been identified in animal models that are homologous to neurologic structures and circuits in humans. For example,

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68 PTSD IN MILITARY AND VETERAN POPULATIONS the rodent prelimbic cortex increases fear expression and opposes extinc- tion (Vidal-Gonzalez et al., 2006). The human homologue of the rodent prelimbic cortex is the dorsal anterior cingulate cortex (Etkin et al., 2011; Graham and Milad, 2011). The dorsal anterior cingulate cortex has been described as the center for processing cognitive stimuli, error processing and detection, and fear expression (Etkin et al., 2011; Vogt, 2005). The rodent infralimbic subregion plays a key role in inhibiting fear expression and promoting extinction (Milad and Quirk, 2002, 2012; Quirk and Mueller, 2008). The human homologue of the infralimbic subregion appears to be the ventromedial prefrontal cortex, and recent studies show that its struc- ture (Hartley et al., 2011; Milad et al., 2005) and function (Kalisch et al., 2006; Milad et al., 2007; Phelps et al., 2004) correlate with the magnitude of fear extinction. Evidence of the role of the ventromedial prefrontal cor- tex in the pathophysiology of PTSD comes from a number of recent condi- tioning and extinction studies in humans (Bremner et al., 2005; Linnman et al., 2012; Milad et al., 2009a). Studies Using Human Subjects In humans, the key region involved in fear learning and extinction is the amygdala, which is in the medial temporal lobe (Lang et al., 2000; Rauch et al., 2006). Some evidence suggests that regions of the lateral prefrontal cortex involved in the regulation of cognitive emotion may influence the amygdala (Delgado et al., 2008; Phan et al., 2005; Somerville et al., 2012). Of the 13 amygdala nuclei, 3 (the basal amygdala, lateral amygdala, and central nuclei) are implicated in the brain’s response to fear (Amorapanth et al., 2000; Cain and LeDoux, 2008; Garakani et al., 2006; Sah et al., 2003). Functional magnetic resonance imaging (MRI) has limited spatial resolu- tion, and human studies have not yet confirmed the importance of these specific anygdala subnuclei. Other neurologic areas of particular interest include subregions of the medial prefrontal cortex, hippocampus, and the insula. The involvement of these regions has been reported on the basis of resting activity studies that use positron emission tomography, functional MRI studies of patients who were performing a variety of emotional tasks or viewing emotional stimuli, and several structural MRI studies. Some of those findings are reviewed below. Neuroimaging Studies Using Symptom Provocation The initial neuroimaging studies of PTSD focused on a paradigm known as symptom provocation. In this paradigm, patients are reminded of their traumatic events while their brains are being scanned. The brain scans are then analyzed for increases and decreases in blood flow in particular

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69 NEUROBIOLOGY regions of the brain. For example, one study reported decreases in medial frontal gyrus blood flow in PTSD participants exposed to reminders of traumatic events compared with trauma-exposed controls who did not have PTSD, and medial frontal gyrus blood flow was inversely correlated with changes in amygdala blood flow (Bremner et al., 1999; Shin et al., 2004). Shin et al. (2004) also reported a positive correlation between changes in amygdala blood flow and symptom severity and a negative correlation between changes in medial frontal gyrus blood flow and symptom severity. Heightened amygdala activity (Rauch et al., 2000; Shin et al., 2004) and diminished ventromedial prefrontal cortex activity (Shin et al., 2005) have also been reported in PTSD subjects who viewed fearful faces during func- tional MRI compared to trauma-exposed controls who did not have PTSD. The results of those studies reveal critical areas of the brain that play a role in the pathophysiology of PTSD. Recent studies have also shown that the function of the ventromedial prefrontal cortex and amygdala in patients with PTSD appears to be im- paired even in response to the presentation of nontrauma-related stressful cues (Gold et al., 2011; Phan et al., 2006). In addition, functional abnor- malities (both resting state and functional reactivation) in the rostral and more dorsal areas of the anterior cingulate cortex have been reported when PTSD patients undergo cognitive tasks (Shin et al., 2009, 2011). Another area that plays a key role in the pathophysiology of PTSD include the insu- lar cortex. This brain region is involved in interoception and the monitoring of internal states and appears to also predict autonomic responses during fear learning (Linnman et al., 2012). People diagnosed with PTSD exhibit exaggerated insula activation in a number of different paradigms, such as during the responses to the presentation of fearful faces, painful stimuli, and traumatic memories (Simmons et al., 2008; Strigo et al., 2010). Neural Connectivity Studies More recent studies have used imaging techniques to measure the strength of connectivity between the ventromedial prefrontal cortex and the amygdala and to correlate it with traits that indicate anxiety. For example, when diffusion tensor imaging was used, the strength of the connections between the amygdala and the prefrontal cortex predicted the intensity of a person’s anxiety; the weaker the pathway, the greater the intensity of the traits associated with anxiety (Kim and Whalen, 2009). Another study re- ported that the resting state activity of the amygdala was positively coupled to ventromedial prefrontal cortex activity in subjects who had low levels of anxiety and negatively coupled to ventromedial prefrontal cortex activity in subjects who had high levels of anxiety (Kim et al., 2011a). Together, these studies suggest that a dysfunction in the connection between the ventrome-

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