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3 Neurobiology
Pages 59-110

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From page 59...
... . It begins with a discussion of adaptive versus maladaptive stress responses and describes fear conditioning and fear extinction.
From page 60...
... ADAPTIVE AND MALADAPTIVE STRESS RESPONSES The diagnosis of PTSD requires that a person have "experienced, witnessed, 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)
From page 61...
... . This is an important distinction because fear memories depend on the amygdala and extinction memories depend on the hippocampus and prefrontal cortex.
From page 62...
... . The RAS, which is required for a stress response, activates the pontine reticular formation (which induces the startle response)
From page 63...
... 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)
From page 64...
... . Box 3-1 defines some terms commonly used in association with fear conditioning and fear extinction.
From page 65...
... . In the model of fear extinction, the animal is able to adapt to its environment by dissociating the acquired conditioned fear response from the conditioned stimulus (Cohen and Richter-Levin, 2009)
From page 66...
... . 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)
From page 67...
... For example, service members may have much longer exposures to traumatic events than animals, 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 information regarding the neural circuits of emotional learning and memory.
From page 68...
... . The human homologue of the infralimbic subregion appears to be the ventromedial prefrontal cortex, and recent studies show that its structure (Hartley et al., 2011; Milad et al., 2005)
From page 69...
... . Another study reported 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)
From page 70...
... . In another, enhanced fear conditioning combined with impairments in fear extinction were reported in PTSD subjects compared with trauma-exposed controls who did not have PTSD, and there was a positive correlation between symptom severity and both the enhanced conditioning and the impairment in extinction (Norrholm et al., 2011)
From page 71...
... . Decreases in anterior cingulate cortex blood flow and increases in ventromedial prefrontal cortex blood flow have been reported after CBT for panic disorders (Sakai et al., 2006)
From page 72...
... and damage to the human ventromedial prefrontal cortex, which is critically involved in fear extinction, differentially affects men and women. Specifically, a unilateral ventromedial prefrontal cortex lesion in the right hemisphere produces severe emotional defects in men, but lesions in the left hemisphere of the same brain region produce no effect (Tranel et al., 2005)
From page 73...
... For example, viewing emotionally salient stimuli has been shown to activate the amygdala, the ventromedial prefrontal cortex, and other brain regions involved in the stress-response circuitry differently when a subject is in a high-estrogen state compared to when that subject in a low-estrogen state (Goldstein et al., 2010)
From page 74...
... . Fear extinction in the adult rat activates the ventromedial prefrontal cortex to inhibit the amygdala, whereas extinction training in early age appears to erase the conditioned fear associations in the amygdala (Gogolla et al., 2009; Kim and Richardson, 2008)
From page 75...
... argued that the comparable effectiveness of cognitive and exposure therapy for the treatment of fear disorders supports the importance of higher-level cognitive processes in extinction. One hypothesis is that persons with greater cognitive ability are more effective and efficient in engaging in such higher-level cognitive processing and thus more effective in extinguishing fear memories.
From page 76...
... For example, several candidate-gene studies found significant effects of specific genetic variants only under conditions of extreme traumatic stress (Binder et al., 2008; Kilpatrick et al., 2007)
From page 77...
... that are associated with immune system reactivity in participants who have PTSD. Another study showed that SLC6A4 methylation modified the effect that traumatic events had on the development of PTSD when the SLC6A4 genotype was controlled for (Koenen et al., 2011)
From page 78...
... SLC6A4 (HTT, 5HTT, Serotonin transporter 17q11 13 10 3 SERT, 5-HTTLPR) (Grabe et al., 2009; (Mellman et al., 2009; Kilpatrick et al., 2007; Sayin et al., 2010; Koenen et al., 2009c; Valente et al., 2011)
From page 79...
... BDNF Brain-derived 11p13 3 0 3 neurotrophic factor (Lee et al., 2006; Mustapic et al., 2007; Valente et al., 2011) NPY Neuropeptide Y 7p15.1 1 0 1 (Lappalainen et al., 2002)
From page 80...
... Although a systematic literature review was conducted, this list is not exhaustive and includes only human studies published in English.
From page 81...
... Restoring healthy sleep patterns may also preserve REM sleep that contributes to the consolidation of memories associated with fear conditioning and fear extinction. Mohammed et al.
From page 82...
... The implication of these results is that adequate sleep could potentially allow generalization of the beneficial effects of therapy to a number of fear-inducing stimuli in PTSD patients. Chronic Stressors Chronic stressors can play a role in the development of PTSD by altering brain hormones and receptors that are responsible for fear learning, fear extinction, decision and risk assessment, and mood, thereby increasing vulnerability to fear conditioning.
From page 83...
... Exposure to corticosterone over a long period of time, as might be experienced by service members, can lead to a decrease in endogenous corticosterone response to the re-exposure of the fearful context, impair extinction of fear learning, and decrease sucrose preference that is associated with emotional numbing. Chronic corticosterone exposure also decreases the quantity of receptors in the cortex, changing the functioning of the ventromedial prefrontal cortex responsible for processing fear, decision making, and risk taking.
From page 84...
... These studies are informative, but a better understanding of the neural circuits underlying fear inhibition and extinction is necessary to elucidate the role of resilience in preventing the onset or severity of PTSD symptoms. Potential Targets for Pharmacologic Treatment of PTSD Numerous neurotransmitter and neurohormonal systems are involved in the regulation of stress and the dysregulation that characterizes PTSD.
From page 85...
... investigated yohimbine in rats in the context of six different experiments and found that it reduced short-term and long-term freezing caused by the extinguished conditioned stimulus. In contrast, although yohimbine may decrease freezing in rats, there is evidence that it does not strengthen the retention of fear extinction.
From page 86...
... Most of the results have been negative (Hoge et al., 2012; Pitman et al., 2002; Stein et al., 2007) , but there is some evidence that treatment with propranolol may block memory reconsolidation through fear extinction (Schiller et al., 2010)
From page 87...
... A meta-analysis of English-language journal articles from 1998 to 2007 led to the conclusion that DCS has the ability to enhance fear extinction and exposure therapy if administered immediately before or after extinction training in animals or exposure therapy in humans (Norberg et al., 2008)
From page 88...
... . The authors also observed that prolonged exposure to glucocorticoids due to chronic stress may reduce BDNF concentrations and may result in retraction, restructuring, and disconnection of dendrites in the hippocampus and ventromedial prefrontal cortex.
From page 89...
... . The authors found that BDNF messenger RNA expression was significantly upregulated in the frontal cortex after chronic dosing with tranylcypromine and that BDNF and trkB messenger RNA expression was significantly upregulated in the hippocampus after chronic dosing with all of the antidepressants.
From page 90...
... Several preliminary studies in rats have shown increases in the expression of FGF2 mRNA in the hippocampus and medial prefrontal cortex after exposure to stress that was uncontrollable (inescapable tail shock) and behaviorally controllable (escapable tail shock)
From page 91...
... Some that have recently been studied include the difference in activity between certain areas of the brain, such as the dorsolateral prefrontal cortex (Shin et al., 2004, 2006; Pissiota et al., 2002) , amygdala (Pissiota et al., 2002; Shin et al., 2004, 2006; Vermetten and Bremner, 2002)
From page 92...
... 2009b. Variant in RGS2 moderates posttraumatic stress symptoms follow ing potentially traumatic event exposure.
From page 93...
... 2007. Fear conditioning in posttraumatic stress disorder: Evidence for delayed extinction of autonomic, experiential, and behavioural responses.
From page 94...
... 2003. Gender differences in the relationship between acute stress disorder and posttraumatic stress disorder following motor vehicle accidents.
From page 95...
... gene and susceptibility to posttraumatic stress disorder: A study and replication. Biological Psychiatry 40:368-372.
From page 96...
... ‘A' system alleles, or DRD2 haplo types, and posttraumatic stress disorder. Biological Psychiatry 45:620-625.
From page 97...
... 2011. De creased regional cerebral blood flow in medial prefrontal cortex during trauma-unrelated stressful imagery in Vietnam veterans with post-traumatic stress disorder.
From page 98...
... 2009. Posttraumatic stress disorder may be associated with impaired fear inhibition: Relation to symptom severity.
From page 99...
... 2011. Slc6a4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder.
From page 100...
... 2005. Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder.
From page 101...
... 2007. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocam pus in concert.
From page 102...
... 2011. Fear extinction in traumatized civilians with posttraumatic stress disorder: Relation to symptom severity.
From page 103...
... 2006. Corticolimbic blood flow during nontraumatic emotional processing in posttraumatic stress disorder.
From page 104...
... 2005. Stress-induced enhancement of fear learn ing: An animal model of posttraumatic stress disorder.
From page 105...
... 2005. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder.
From page 106...
... 2009. Dissociable roles for the ventromedial prefrontal cortex and amygdala in fear extinction: NR2B contribution.
From page 107...
... 2011. Candidate-gene approach in posttraumatic stress disorder after urban violence: Association analysis of the genes encoding serotonin transporter, dopa mine transporter, and BDNF.
From page 108...
... 2009. Single prolonged stress: Toward an animal model of posttraumatic stress disorder.
From page 109...
... 2011. Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats.


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