Table of Contents

Cover

Title Page

List of contributors

Introduction

Reference

Section I: Preclinical sciences of stress

Chapter 1: Posttraumatic stress disorder: from neurobiology to clinical presentation
1. 1.1 PTSD: prevalence, risk factors, and etiology
2. 1.2 Neurobiology of PTSD
3. 1.3 Synthesis of findings: from neurobiology to treatment of PTSD
4. References
Chapter 2: The epidemiology of posttraumatic stress disorder in children and adolescents: a critical review
1. 2.1 Introduction
2. 2.2 Studies involving general population surveys
3. 2.3 Prevalence of exposure to traumatic events in youth populations
4. 2.4 Community surveys assessing child-adolescent PTSD prevalence
5. 2.5 Childhood/adolescent PTSD rates according to type of trauma
6. 2.6 Child-adolescent PTSD and comorbid disorders
7. 2.7 Risk factors associated with child-adolescent PTSD
8. 2.8 Summary
9. 2.9 Acknowledgement
10. References
Chapter 3: Early life stress and development: preclinical science
1. 3.1 Overview
2. 3.2 Early life stress and the hypothalamic–pituitary–adrenal (HPA) axis
3. 3.3 Rodent models of early life stress/trauma
4. 3.4 Non-human primate models of early life stress/trauma
5. 3.5 Impact of early life stress on prefrontal-limbic brain circuits across species: biological and evolutionary mechanisms
6. 3.6 Conclusions
7. 3.7 Acknowledgements
8. References
Chapter 4: Amygdala contributions to fear and safety conditioning: insights into PTSD from an animal model across development
1. 4.1 Introduction
2. 4.2 Stress and defensive responding
3. 4.3 Fear conditioning
4. 4.4 Safety conditioning
5. 4.5 Ontogeny of fear and safety conditioning
6. 4.6 Implications for PTSD
7. 4.7 Conclusion
8. 4.8 Acknowledgement
9. References
Chapter 5: Preclinical evidence for benzodiazepine receptor involvement in the pathophysiology of PTSD, comorbid substance abuse, and alcoholism
1. 5.1 Introduction
2. 5.2 Stress and the Benzodiazepine Receptor
3. 5.3 Interaction of Stress, Alcohol Intake and the Benzodiazepine Rector
4. 5.4 Stress, Drug Abuse and the Benzodiazepine Receptor
5. 5.5 Translation from Neurobiology to PTSD
6. 5.6 Conclusions
7. References
Chapter 6: Psychosocial predator stress model of PTSD based on clinically relevant risk factors for trauma-induced psychopathology
1. 6.1 Introduction
2. 6.2 General characteristics of PTSD
3. 6.3 Preclinical models of PTSD
4. 6.4 Psychosocial predator stress model of PTSD
5. 6.5 Summary: the challenge of modeling PTSD in animals
6. 6.6 Acknowledgements
7. References
Chapter 7: Coping with stress in wild birds – the evolutionary foundations of stress responses
1. 7.1 Introduction
2. 7.2 Physiological changes associated with chronic stress in wild birds
3. 7.3 Lessons from wild birds
4. 7.4 Conclusions
5. 7.5 Acknowledgements
6. References
Chapter 8: Stress, fear, and memory in healthy individuals
1. 8.1 Introduction
2. 8.2 Time-dependent effects of stress on episodic memory in healthy humans
3. 8.3 Stress and fear conditioning in humans
4. 8.4 Stress-induced modulation of multiple memory systems
5. 8.5 Stress and memory in healthy subjects: implications for PTSD
6. References

Section II: Neurobiology of PTSD

Chapter 9: Neurotransmitter, neurohormonal, and neuropeptidal function in stress and PTSD
1. 9.1 Introduction
2. 9.2 Noradrenergic system
3. 9.3 HPA axis
4. 9.4 PTSD and inflammation
5. 9.5 Acetylcholine and vagal nerve function
6. 9.6 Dopaminergic system
7. 9.7 NMDA
8. 9.8 Serotonin
9. 9.9 GABA/benzodiazepine system
10. 9.10 Opioid peptides
11. 9.11 Neurotensin
12. 9.12 Somatostatin
13. 9.13 Cholecystokinin
14. 9.14 Neuropeptide Y
15. 9.15 Galanin
16. 9.16 Ghrelin
17. 9.17 Substance P
18. 9.18 Vasoactive intestinal peptide
19. 9.19 Vasopressin and oxytocin
20. 9.20 Neurosteroids and neurohormones
21. 9.21 Conclusions
22. References
Chapter 10: Genomics of PTSD
1. 10.1 Introduction
2. 10.2 Genetic studies in PTSD
3. 10.3 Gene–environment interaction studies in PTSD
4. 10.4 Epigenetic and gene expression studies in PTSD
5. 10.5 Conclusions
6. References
Chapter 11: Cortisol and the Hypothalamic–Pituitary–Adrenal Axis in PTSD
1. 11.1 Introduction
2. 11.2 HPA axis and the stress response
3. 11.3 HPA axis alterations in PTSD
4. 11.4 HPA feedback functioning and GR sensitivity
5. 11.5 Gender, PTSD, and HPA axis activity
6. 11.6 HPA alterations as a risk factor for PTSD
7. 11.7 Genetic and epigenetic influences on GR sensitivity
8. 11.8 Modifying glucocorticoid responsiveness: implications for prevention and treatment
9. 11.9 Conclusion
10. References
Chapter 12: Neuroimaging of PTSD
1. 12.1 History and background
2. 12.2 Neural circuits of PTSD
3. 12.3 Changes in brain structure and cognitive functioning in PTSD
4. 12.4 Neurohormonal responses to PTSD
5. 12.5 Functional neuroimaging studies in PTSD
6. 12.6 Neuroreceptor Studies in PTSD
7. 12.7 Conclusions
8. References

Section III: PTSD and co-occuring conditions

Chapter 13: PTSD and mild traumatic brain injury
1. 13.1 Introduction
2. 13.2 Mild TBI
3. 13.3 Posttraumatic stress disorder
4. 13.4 Overlap between mTBI and PTSD
5. 13.5 Summary and conclusions
6. References
Chapter 14: Stress-related psychopathology and pain
1. 14.1 Introduction
2. 14.2 Depression
3. 14.3 Schizophrenia
4. 14.4 Anorexia nervosa
5. 14.5 Borderline personality disorder
6. 14.6 Post-traumatic stress disorder
7. 14.7 Conclusion
8. References
Chapter 15: Stress and health
1. 15.1 Introduction
2. 15.2 Stress and cardiovascular disease
3. 15.3 Depression and cardiovascular disease
4. 15.4 PTSD and cardiovascular disease
5. 15.5 Potential mechanisms linking stress to cardiovascular disease
6. 15.6 Mechanisms through which depression and PTSD may increase CVD risk
7. 15.7 Stress, PTSD and functional pain disorders
8. 15.8 Conclusions
9. References

Section IV: PTSD: from neurobiology to treatment

Chapter 16: Pharmacotherapy for PTSD: effects on PTSD symptoms and the brain
1. 16.1 Introduction
2. 16.2 Agents acting on the GABA–benzodiazepine receptor complex
3. 16.3 Agents acting on norepinephrine and serotonin receptors
4. 16.4 Tricyclic and monoamine oxidase inhibitor antidepressants
5. 16.5 Medications with other mechanisms of action
6. 16.6 Selective norepinephrine reuptake inhibitors
7. 16.7 Selective serotonin reuptake inhibitors
8. 16.8 Antidepressants with actions on norepinephrine and epinephrine reuptake
9. 16.9 Mood stabilizers
10. 16.10 Antipsychotic medications
11. 16.11 Glutamatergic agents
12. 16.12 MDMA
13. 16.13 Effect of pharmacotherapy on the brain and neurobiology in PTSD
14. 16.14 Conclusions
15. References
Chapter 17: Effects of psychotherapy for psychological trauma on PTSD symptoms and the brain
1. 17.1 Psychotherapy for psychological trauma
2. 17.2 The neuroscience of early interventions for trauma
3. 17.3 Psychological therapy for psychological trauma
4. 17.4 Effects of psychotherapy on the brain
5. 17.5 Brain imaging of psychotherapy in PTSD
6. 17.6 Conclusions
7. References
Copyright

End User License Agreement

List of Illustrations

Chapter 4: Amygdala contributions to fear and safety conditioning: insights into PTSD from an animal model across development

Figure 4.1 Threats trigger survival circuit activation and initiate defensive responding. Defensive responses are organized hierarchically, and greater threats lead to greater survival circuit activation and more intense, reflexive responses. Responses at the high end of the spectrum model human fear (e.g., freezing), whereas those at the low end of the spectrum model anxiety (e.g., risk assessment behaviors).
Figure 4.2 Pavlovian fear conditioning. Conditioned stimulus (CS) presentations (e.g., tones) usually precede aversive unconditioned stimulus (US) presentations (e.g., shocks) by seconds or minutes and the stimuli coterminate. Unlike instrumental conditioning, subjects have no control over the delivery of stimuli with a Pavlovian procedure.
Figure 4.3 Fear conditioning is believed to form a link between conditioned stimulus (CS) and unconditioned stimulus (US) representations in the brain (rather than a direct link between the CS and individual defensive responses). This allows the animal to anticipate the US and emit defensive responses appropriate to the situation. Conditioned responses are typically weaker than unconditioned responses because the CS activates the US representation less intensely than the US itself.
Figure 4.4 Hebbian fear conditioning plasticity in the lateral amygdala (LA). Prior to conditioning, conditioned stimulus (CS) presentations result in weak depolarization of LA neurons and little to no activation of downstream brain areas mediating conditioned fear responses. However, with CS – unconditioned stimulus (US) pairings, neurons are strongly depolarized resulting in initiation of an LTP-like process that strengthens the synapses between CS afferents and LA neurons. Following conditioning, CS presentations strongly depolarize LA neurons, triggering action potentials and neurotransmitter release to activate downstream targets. epsp, excitatory postsynaptic potential.
Figure 4.5 Amygdala FC circuitry. After conditioning, conditioned stimulus (CS) presentations activate lateral amygdala (LA) neurons, which project to basal amygdala (BA) “fear cells,” intercalated cells (itc), and lateral/capsular division (CeL) of the central amygdala (CeA). CS processing in these regions leads to simultaneous stimulation and disinhibition of the medial division of the CeA (CeM). The CeM projects to downstream effector regions (e.g., periacqueductal gray) that mediate specific fear reactions (e.g., freezing). Prelimbic-prefrontal cortex (pl-PFC) neurons help sustain conditioned responding over longer intervals via projections to the BA. Pathways contributing to expression of conditioned fear responses are highlighted in red. il-PFC, infralimbic-PFC.
Figure 4.6 Relapse-prone vs. relapse-resistant fear extinction. After acquisition, conditioned stimulus (CS)-alone presentations lead to a gradual and progressive weakening of fear conditioned responses (CRs) (extinction). In adults, extinction creates a new inhibitory memory that suppresses, but does not erase, the fear conditioning (FC) memory. This allows the subject to flexibly respond to threats depending on the context. However, fear relapse is common after adult extinction; fear returns with the passage of time (spontaneous recovery), with context changes (renewal) and with stress (reinstatement). Early in development, fear extinction is relapse-resistant and probably results from erasure or weakening of the original FC memory. Ctxt, context.
Figure 4.7 Amygdala fear extinction circuitry (adult). Extinction learning counteracts fear responding in a number of ways: (i) by strengthening feed-forward inhibition in the lateral amygdala (LA); (ii) through infralimbic-prefontal cortex (il-PFC) activation of intercalated cells (itc) that inhibit medial division of the central amygdala (CeM); (iii) through a subset of basal amygdala (BA) “extinction cells” that project to GABAergic neurons, possibly itc neurons, which inhibit CeM output; (iv) through synaptic depression of projections from PFC to BA “fear cells” (FC); and (v) through increased inhibition of fear conditioning cells in the BA by local interneurons. The hippocampus plays a critical role in gating extinction according to context via connections to the il-PFC and BA. Pathways contributing to expression of fear extinction are highlighted in blue.
Figure 4.8 Ontogeny of fear conditioning. During the sensitive period, odor-shock conditioning produces an odor preference through an amygdala-independent mechanism. This odor conditioned stimulus (CS) can also support attachment interactions with the mother. As pups age and exit the stress hyporesponsive period, conditioning elicits a greater cortisol/corticosterone (CORT) response, which engages amygdala processes that produce fear/avoidance of the odor CS. Abusive rearing conditions can lead to abnormally high CORT responses in the late sensitive period and precocious fear/avoidance learning. Maternal presence during the transitional period weakens the CORT response and enables preference learning. After postnatal day 16 (PN16), conditioning produces fear/avoidance and CORT only modulates the degree of learning.

Chapter 5: Preclinical evidence for benzodiazepine receptor involvement in the pathophysiology of PTSD, comorbid substance abuse, and alcoholism

Figure 5.1 Mean (+ SEM) latency to onset of myoclonus and clonus following an intraperitoneal injection of bicuculline (4, 6, or 8 mg/kg) 2 hours after 80 escapable shocks, inescapable shocks, restraint, or no treatment (naïve). Vertical bars represent standard errors. * denotes that all subjects went to the cut-off without a seizure.
Figure 5.2 The effects of inescapable shock on muscimol-stimulated ³⁶Cl^– uptake. (a) Muscimol-stimulated ³⁶Cl^– uptake is decreased in cerebral cortical synaptoneurosomes from rats that fail to learn the shuttlebox escape task on day 2 of the learned helplessness paradigm when compared with naïve controls. Each bar represents the mean + SEM of ³⁶Cl^– uptake measured in six individual subjects following the shuttle escape task. Muscimol-stimulated ³⁶Cl^– uptake was decreased 29% from 30.4 ± 2.2 in naïve controls to 21.6 ± 1.0 nmol/mg protein in subjects that “fail”. Subjects from each experimental group were assayed simultaneously. (b) Inescapable footshock alone (comparable to the “fail” condition in a) did not alter muscimol-stimulated ³⁶Cl^– uptake. Each bar represents the mean + SEM of ³⁶Cl^– uptake measured in quadruplicate in six individual subjects. Control: 34.16 ± 3.6 vs. footshock: 36.66 ± 3.1 nmol/mg protein. *P < 0.05, by Newman–Keuls post hoc comparison with naïve controls after ANOVA.
Figure 5.3 In vivo [3H]Ro15-1788 binding is decreased in cortex and hippocampus (hippo) of rats that fail to learn the shuttlebox escape task on day 2 of the learned helplessness paradigm. [3H]Ro15-1788 in vivo binding is decreased in hypothalamus (hypo), midbrain and cerebellum of both subjects that “learn” and subjects that “fail” the shuttlebox escape task 24 hours after exposure to inescapable shock. Each bar represents the mean + SEM of specific binding in eight to 15 subjects. There was no change in non-specific binding in either “learn” or “fail” subjects compared with controls. *P <0.05, **P < 0.01, by Newman–Keuls post hoc comparison to naïve control values after ANOVA.
Figure 5.4 Mean percentage of naïve control ethanol-induced sleep time for rats given escapable shock (open bars) or yoked-inescapable shock (hatched bars). The left panel represents the response when the injection was given in a dose of 3 g/kg either immediately or 2 hours after stress, and the right panel represents the response when the drug was given in a dose of 4 g/kg either immediately or 2 hours after stress (n = 8–16 rats per group. Vertical bars represent SEM. * indicates significantly different from naïve control (P < 0.05) by Newman–Keuls post hoc comparison after ANOVA.
Figure 5.5 Mean time spent on the rotarod for rats 2 hours following exposure to escapable shock, yoked-inescapable shock, or no shock (naïve) and injected with 0.6, 0.8, or 1.0 g/kg of ethanol 5 minutes prior to rotarod testing. Vertical bars represent + SEM (8–10 subjects/group). * (at the 0.6 g/kg dose) indicates a significant difference from the naïve group (P < 0.05); + indicates a significant difference from the escape group (P < 0.01). For the 0.8 g/kg group, ++ indicates significantly different from both yoked and naïve groups (P < 0.01) by Newman–Keuls post hoc comparisons after ANOVA.
Figure 5.6 Mean time spent on the rotarod 2 hours post-stress for rats exposed to escapable shock, yoked-inescapable shock or no shock (naïve), and injected with 0.6 g/kg ethanol 12 minutes prior to rotarod testing. Vertical bars represent mean ± SEM (10–12 rats per group). * indicates a significant difference from both escapable shock and naïve groups by Newman–Keuls post hoc comparisons after ANOVA.
Figure 5.7 Mean (± SEM) time spent on the rotarod 2 or 24 hours after stress exposure. Rotarod performance was assessed 12 minutes after an ataxic dose of ethanol hydroxide. Inescapable shock significantly reduced time on the rotarod compared with all other groups at both 2 and 24 hours post-stress by Newman–Keuls post hoc comparisons after ANOVA.
Figure 5.8 Mean time spent on rotarod 2 hours following stress for rats receiving escapable shock, yoked-inescapable shock, or no shock (naïve). Rats were injected with 0.5, 1.0 or 2.0 mg/kg midazolam (intraperitoneally) 10 minutes before the rotarod test. Vertical bars represent mean ± SEM (8–10 rats per group). * indicates a significant difference from the naïve group (P < 0.01); + indicates a significant difference from the escapable shock group (P < 0.05) by Newman–Keuls post hoc comparisons after ANOVA.
Figure 5.9 Mean time spent on the rotarod for subjects 24 hours after an injection of either FG7142 or equivolume vehicle solution, and subsequent placement in a restraining tube of a Plexiglas home cage. Ten minutes prior to the rotarod test all subjects received an intraperitoneal injection of ethanol (0.6 g/kg). The histograms indicate means (n = 8–10 per group), and vertical bars represent SEMs. * indicates significantly different from vehicle-home cage controls as determined by Newman–Keuls post hoc comparisons (P < 0.05) after ANOVA.
Figure 5.10 Mean time spent on the rotarod for subjects 24 hours following an injection of either FG 7142 or vehicle, and subsequent placement in either restraint tubes or a Plexiglas home cage. Ten minutes prior to the rotarod test, all subjects were injected (intraperitoneally) with 0.5 mg/kg midazolam. Histograms represent means (n = 12–14 per group), and vertical bars indicate SEMs.

Chapter 6: Psychosocial predator stress model of PTSD based on clinically relevant risk factors for trauma-induced psychopathology

Figure 6.1 General description of the timeline of events in the psychosocial predator stress model of posttraumatic stress disorder (PTSD). Rats were exposed to a fear-conditioning chamber and tone followed by immobilization and cat exposure on days 1 and 11; unstable housing occurring daily from the first day of cat exposure through day 31. Beginning on day 32, fear conditioning memory testing, as well as all behavioral and physiological assessments took place.
Figure 6.2 Rats exhibited strong fear memory for the context and cue associated with cat exposure. On days 1 and 11, rats were exposed to the fear conditioning chamber for 3 minutes, which terminated with a 20-second tone, followed by immobilization of the rats, followed by cat exposure, which took place in another room. On day 32, rats were re-exposed to the original chamber (context memory) and tone (cue memory) in a different chamber, with an assessment of their conditioning fear (freezing). The group exposed to the chamber/tone followed by cat exhibited significantly greater freezing in response to re-exposure to the context (top) and cue (bottom) compared with the control group, which had not been exposed to the cat. (Data adapted from Zoladz et al., 2008, 2012.)

Chapter 7: Coping with stress in wild birds – the evolutionary foundations of stress responses

Figure 7.1 Daytime measurements of baseline heart rate (HR) (a) and HR variability (HRV) (b) before (pre-chronic stress [CS]; white bars), during (days 1–16; gray bars), and after (after day 22; black bars) chronic stress treatment. Because measurements were taken every other day, with half of the birds measured on one day and the other half measured the next, means are grouped in 2-day increments. Sample sizes are indicated within bars. Asterisks indicate significant differences from pre-CS values. Spaces (labeled “nm” for “not measured”) were added in (b) so that the graphs line up. (From Cyr et al., 2009; reprinted with permission.)
Figure 7.2 Mean heart rate (HR) taken before and 15 minutes during an acute stressor (restraint) on the first day (open circles) and the last day (filled circles) of the chronic stress (CS) period, as well as days 34–35 (dashed line, black squares; i.e., 18–19 days after the completion of the CS period). The arrow denotes the initiation of restraint. Note the increased baseline HR at the end of chronic stress that is repeated from Figure 7.1, but the relative lack of response to restraint. bpm, beats/minute. (From Cyr et al., 2009; reprinted with permission.)
Figure 7.3 Heart rate responses to a startle stressor. Startle response for wild-caught, newly captive starlings (new) and long-term captivity controls (controls) at 36 hours (a), 88 hours (b), or 228 hours (c) after surgery, which occurred < 6 hours after initial trapping. The arrow indicates the time period at which the startle was given. (From Dickens & Romero, 2009; reprinted with permission.)
Figure 7.4 Baseline corticosterone concentrations during and after the chronic stress period. Because measurements were taken every other day, with half of the birds measured on one day and the other half measured the next, means are grouped in 2-day increments. Asterisks represent significant difference from controls. (From Rich & Romero, 2005; reprinted with permission.)
Figure 7.5 Corticosterone (CORT) responses following translocation stress. Birds recaptured after the translocation procedure were compared with control individuals that were not exposed to human interference prior to sampling. (a) Baseline plasma concentrations (mean ± SE). (b) Total CORT released after 15 minutes of restraint stress as mean ± SE of individual integrated stress-induced CORT concentrations. (c) Total CORT decrease 30 minutes after dexamethasone (DEX) suppression test as mean ± SE of individual integrated DEX-suppressed CORT concentrations. Asterisk indicates significance at P < 0.05. (Adapted from Dickens et al., 2009; reprinted with permission.)

Chapter 8: Stress, fear, and memory in healthy individuals

Figure 8.1 Circuits activated by stress. If a situation is perceived as a threat for the physiological or psychological integrity of the organism, the brain activates two lines of defense mechanisms that serve to adapt to the demand and to restore balance: the rapidly acting autonomic nervous system (ANS) and the slower hypothalamic–pituitary–adrenal (HPA) axis. The first line of defense sets in immediately after the stressor occurs when the amygdala activates the hypothalamus. Activation of the hypothalamus in turn stimulates the sympathetic arm of the ANS, which secretes norepinephrine at its postganglionic nerve endings. Among the effector organs of the ANS is the adrenal medulla, which releases epinephrine and norepinephrine. Autonomic activation can indirectly (via the vagal nerve, solitary tract nucleus, and locus coeruleus) lead to the release of norepinephrine in the brain. The second line of defense is initiated by the secretion of corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus. CRH causes the secretion of β-endorphin and adrenocorticotropic hormone (ACTH) from the anterior pituitary, which is transported in the bloodstream to the cortex of the adrenal glands, inducing the secretion of glucocorticoids. Glucocorticoids exert negative feedback via receptors at the pituitary and hypothalamus, thereby reducing the enhanced activity of the HPA axis. (Reproduced from Schwabe et al., 2010b.)
Figure 8.2 Time-dependent effects of stress on hippocampus-dependent episodic memory. Stress before learning may enhance memory when it occurs within the context of a learning experience (e.g., shortly before or during learning), whereas stress out of the learning context (e.g., relatively long before learning) impairs memory. Stress shortly after learning strengthens subsequent memory, particularly for emotionally arousing information. Conversely, stress before retention testing typically reduces retrieval performance, again particularly for emotionally arousing information. In addition, stress may also interfere with the re-stabilization (“reconsolidation”) of memories after retrieval. (Reproduced from Schwabe & Wolf, 2013.)

Chapter 9: Neurotransmitter, neurohormonal, and neuropeptidal function in stress and PTSD

Figure 9.1 Neurotransmitters in posttraumatic stress disorder (PTSD). Neurotransmitters involved in the stress response and PTSD symptoms include norepinephrine (NE), with cell bodies in the locus coeruleus and projections to the amygdala, hippocampus, prefrontal cortex, and hypothalamus, and the hypothalamic–pituitary–adrenal (HPA) axis, with corticotropin-releasing factor (CRF) release from the hypothalamus, which stimulates adrenocorticotropic hormone (ACTH) release from the pituitary, and cortisol from the adrenal.
Figure 9.2 Afferents from the vagal nerve to central areas of the brain. AMB = nucleus ambiguous; DMX = dorsal motor nucleus of the vagus, IML = intermediolateral column of spinal cord (symp pregang); VLM = ventrolateral medulla; Amyg = amygdala; INS = insular cortex; ILC - infralimbic cortex; PBN = parabrachial nucleus; DR = dorsal Raphe; LC = locus coeruleus; Thal = thalamus; Hypothal = hypothalamus. (Used with permission from Thomas Cunningham PhD, University of North Texas Health Sciences Center.)

Chapter 10: Genomics of PTSD

Figure 10.1 Simplified heuristic representation of the mechanisms leading to the development of posttraumatic stress disorder (PTSD) and posttraumatic growth (PTG). A complex interplay among potentially traumatizing events, multiple gene variants, and epigenetic mechanisms results in changes in the expression of genes that are involved in the regulation of neurotransmission, hypothalamic–pituitary–adrenal (HPA) axis activity, emotion and cognition. This shapes endophenotypes and, ultimately, vulnerability or resilience phenotypes. DNDEs, DNA demthylating enzymes; DNMTs, DNA methyltransferases; HMEs, histone-modifying enzymes.

Chapter 11: Cortisol and the Hypothalamic–Pituitary–Adrenal Axis in PTSD

Figure 11.1 Normal functioning of the hypothalamic–pituitary–adrenal axis. The normal reaction to acute or brief stress or threat involves increases in cortisol and corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). CRH stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary, which in turn stimulates the production of cortisol in the adrenal cortex. Cortisol provides negative feedback and inhibits the further release of CRH, AVP and ACTH, leading to the containment of the stress response and return to homeostasis.
Figure 11.2 Conceptual model of hypothalamic–pituitary–adrenal axis regulation by glucocorticoid receptor (GR) and FK506 binding protein 5 (FKBP5). Early life experience (e.g., adversity) and later life stressors (e.g., trauma) may influence GR and FKBP5 methylation; these influences may interact with genotype to increase risk. Higher GR responsiveness and lower cortisol in PTSD may result from lower GR methylation and expression. Low cortisol levels probably contribute to higher FKBP5 methylation and lower FKBP5 gene expression, corresponding to lower FKBP5 protein expression, and ultimately more GR responsiveness (glucocorticoid negative feedback) at the hypothalamus and pituitary. Green arrows indicate a positive influence (+) and red arrows a negative influence (−). Blue arrows depict a relationship. GR encoded by the NR3C1 gene, FKBP5 FK506 binding protein 5 encoded by the FKBP5 gene. CRH, corticotropin-releasing hormone; AVP, arginine vasopressin; ACTH, adrenocorticotropic hormone.

Chapter 12: Neuroimaging of PTSD

Figure 12.1 Brain regions involved stress and emotion. The medial prefrontal cortex includes parts of the prefrontal cortex, including mesofrontal cortex (Brodmann's area (BA 9), anterior cingulate (AC, BA 32), subcallosal gyrus (BA 25), and orbitofrontal cortex. Other areas shown include the motor cortex, posterior cingulate (BA 31), and hippocampus.
Figure 12.2 Hippocampal volume on magnetic resonance imaging in posttraumatic stress disorder (PTSD). There is smaller hippocampal volume in this patient with PTSD compared with a control (from Bremner, 2005).
Figure 12.3 Medial prefrontal cortex (PFC) dysfunction in PTSD. There was a failure of medial prefrontal activation in a group of combat veterans with PTSD compared with combat veterans without PTSD during exposure to traumatic combat-related slides and sounds. The light areas represent decreased function in the medial PFC, which includes both Brodmann's rea (BA) 25 and anterior cingulate (AC) BA 32. Each image represents an adjacent slice of the brain, with the light areas representing a composite of areas of relative decrease in blood flow in PTSD patients compared with controls (from Bremner, 2005).

List of Tables

Chapter 2: The epidemiology of posttraumatic stress disorder in children and adolescents: a critical review

Table 2.1 Community surveys assessing child-adolescent posttraumatic stress disorder (PTSD) prevalence
Table 2.2 Studies of child-adolescent posttraumatic stress disorder (PTSD) in war settings
Table 2.3 Studies of child-adolescent posttraumatic stress disorder (PTSD) following criminal victimization
Table 2.4 Child-adolescent posttraumatic stress disorder (PTSD) research following natural disasters/accidents
Table 2.5 Child-adolescent posttraumatic stress disorder (PTSD) and comorbid disorders

Chapter 9: Neurotransmitter, neurohormonal, and neuropeptidal function in stress and PTSD

Table 9.1 Evidence for altered catecholaminergic function in PTSD
Table 9.2 Evidence for alterations in other neurotransmitter systems in PTSD

Chapter 10: Genomics of PTSD

Table 10.1 Gene–environment interaction studies in posttraumatic stress disorder (PTSD)
Table 10.2 Gene expression studies in posttraumatic stress disorder (PTSD)

Chapter 13: PTSD and mild traumatic brain injury

Table 13.1 Symptom overlap of posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI)
Table 13.2 Changes in brain function in posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI)

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

Posttraumatic stress disorder : from neurobiology to treatment / [edited by] J. Douglas Bremner.

List of contributors

Karl-Juergen Bär, M.D
Department of Psychiatry and Psychotherapy, University Hospital, Jena, Germany

Elisabeth Binder, Ph.D
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

J. Douglas Bremner, M.D
Departments of Psychiatry & Behavioral Sciences and Radiology, Emory University School of Medicine, and the Atlanta VA Medical Center, Atlanta, GA, USA

Christopher Cain, Ph.D
Department of Child and Adolescent Psychiatry, New York University School of Medicine, New York, NY, and The Emotional Brain Institute, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA

Carolina Campanella, Ph.D
Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA, USA

Nicolaos Daskalakis, Ph.D
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Lori Davis, M.D
Department of Psychiatry, University of Alabama-Birmingham and the Tuscaloosa VA Medical Center, Tuscaloosa, AL, USA

David Diamond, Ph.D
Departments of Psychology and Molecular Pharmacology & Physiology, University of South Florida, Tampa, FL, USA

Molly J. Dickens, Ph.D
Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, USA

Robert Drugan, Ph.D
Department of Psychology, University of New Hampshire, Durham, NH, USA

Bernet M. Elzinga, Ph.D
Institute for Psychological Research, Section Clinical Psychology, Leiden University, The Netherlands

Dora B. Guzman, M.S
Department of Psychiatry & Behavioral Science, School of Medicine, and Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA

Mark Hamner, M.D
Department of Psychiatry, Medical University of South Carolina, and The Charleston VA Medical Center, Charleston, SC, USA

Brittany Howell, Ph.D
Institute of Child Development, University of Minnesota, Minneapolis, MN, USA

Amy Lehrner, Ph.D
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Emeran Mayer, M.D
UCLA School of Medicine, Los Angeles, CA, USA

Leah A. McGuire, Ph.D
Center for Attention and Learning, Department of Psychiatry, Lenox Hill Hospital, North Shore LIJ Health System, New York, NY, USA

Divya Mehta, Ph.D
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

Christian J. Merz, Ph.D
Institute of Cognitive Neuroscience, Cognitive Psychology, Ruhr-University, Bochum, Germany

Brad Pearce, Ph.D
Department of Epidemiology, Rollins School of Public Health, Atlanta, GA, USA

Sarah C. Reitz, M.D
Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

Michael Romero, Ph.D
Department of Biology, Tufts University, Medford, MA, USA

Mar Sanchez, Ph.D
Department of Psychiatry & Behavioral Science, School of Medicine, and Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA

Christian Schmahl, M.D
Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

Lars Schwabe, Ph.D
Institute for Psychology, Department of Cognitive Psychology, University of Hamburg, Hamburg, Germany

Arieh Y. Shalev, Ph.D
Department of Psychiatry, New York University School of Medicine, Langone Medical Center, New York, NY, USA

Nathaniel P. Stafford, B.S
Department of Psychology, University of New Hampshire, Durham, NH, USA

Regina Sullivan, Ph.D
Department of Child and Adolescent Psychiatry, New York University School of Medicine, New York, NY, and The Emotional Brain Institute, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA

Viola Vaccarino, M.D, Ph.D
Department of Epidemiology, Emory University Rollins School of Public Health, and Department of Internal Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA, USA

Timothy A. Warner, B.A
Department of Psychology, University of New Hampshire, Durham, NH, USA

Rachel Yehuda, Ph.D
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Anthony S. Zannas, Ph.D
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

Phillip R. Zoladz, Ph.D
Department of Psychology, Sociology, & Criminal Justice, Ohio Northern University, Ada, OH, USA

Introduction

J. Douglas Bremner

Since the establishment of posttraumatic stress disorder (PTSD) as a psychiatric diagnosis for the first time in 1980 by the American Psychiatric Association's (APA) manual for psychiatric disorders, the Diagnostic and Statistical Manual III (Saigh & Bremner, 1999), there has been an expansion of research on the effects of traumatic stress on the individual. Basic science research on the effects of stress on brain circuits and systems has complemented clinical research. Together, this increased understanding of stress has been beneficial for the treatment of PTSD. This volume brings together some of the most authoritative researchers and authors on the topic of traumatic stress in both the basic science and clinical dimensions, and relates this to a better understanding of treatment approaches for PTSD.

The diagnosis of PTSD requires exposure to an event which involves a threat to one's life or self-integrity. In addition, the diagnosis requires the presence of symptoms in three clusters, including intrusions, avoidance and hyperarousal, and the presence of clinically significant distress or impairment. The diagnosis requires at least one symptom in the intrusion category, three in the avoidance category, and two in the hyperarousal category. Intrusive symptoms include recurrent intrusive memories, nightmares, feeling as if the event were recurring, and feeling a lot worse with reminders of the event, and having increased physiological reactivity with the event. Avoidant symptoms include avoidance of reminders of the event, avoidance of thoughts and feelings related to the event, trouble remembering an important aspect of the trauma, decreased interest in things, feeling detached or cut off from others, emotional numbing, and a sense of a foreshortened future. Hyperarousal symptoms include a difficulty falling or staying asleep, irritability or outbursts of anger, difficulty concentrating, hypervigilance, and exaggerated startle response.

Symptoms of PTSD are a behavioral manifestation of stress-induced changes in brain structure and function. Stress causes acute and chronic changes in neurochemical systems and specific brain regions, which result in long-term changes in brain “circuits” involved in the stress response.

The premise of our understanding of the effects of stress on neurobiology is based on animal models. The chapters in this volume outline how stress affects important stress-sensitive circuits, including norepinephrine, the cortisol/hypothalamic–pituitary–adrenal (HPA) axis, dopamine, serotonin, neuropeptides, the glutamatergic/excitatory amino acids systems, and the gamma-aminobutyric acid (GABA)/benzodiazepine systems, as well as numerous other neuropeptidal and neurohormonal systems.

A critical field of study that has important public health implications is the interaction between early life stress and brain development. Two key chapters address this, and outline brain areas involved in the stress response, including the hippocampus, amygdala, and medial prefrontal cortex. Other chapters review the effects of stress on memory, including both animal models of showing the effects of stress on the hippocampus, which plays an important role in short-term memory, and mechanisms of new learning, including long-term potentiation, as well as studies in PTSD of neuropsychological testing of memory and brain imaging of the hippocampus. Finally, later chapters review brain imaging studies in PTSD, and the effects of both pharmacotherapy and psychotherapy on brain function in PTSD. Later chapters also review the important topics of the effects of stress and PTSD on cardiovascular health and other physical parameters, and the role of genetic factors in the development of PTSD.

Posttraumatic stress disorder is a common condition that can be associated with considerable morbidity and mortality and is often only partially treated with current therapies. The chapters in this volume outline how PTSD is associated with long-term changes in the brain and stress-responsive systems. Changes in brain areas including the amygdala, hippocampus, and frontal cortex, can lead to memory problems, maintenance of abnormal fear responses and other symptoms of PTSD. A better understanding of neurobiological changes in PTSD will inform the development of new treatments for this disabling disorder. Integrating basic science and clinical approaches to stress and PTSD, as is done in this volume, has the greatest potential impact for patients with PTSD.

Reference

Saigh PA, Bremner JD (1999). The history of posttraumatic stress disorder. In: Saigh PA, Bremner JD, eds. Posttraumatic Stress Disorder: A Comprehensive Text. Needham Heights, MA: Allyn & Bacon, pp. 1–17.