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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
POSTTRAUMATIC STRESS DISORDER Posttraumatic Stress Disorder: From Neurobiology to Treatment presents a comprehensive look at this key neuropsychiatric disorder. The text examines the neurobiological basis of posttraumatic stress and how our understanding of the basic elements of the disease has informed and been translated into new and existing treatment options. The book begins with a section on animal models in posttraumatic stress disorder research, which have served as the basis of much of our neurobiological information. Chapters then delve into applications of the clinical neuroscience of posttraumatic stress disorder. The final part of the book explores treatments and the way in which our basic and clinical research is now being converted into treatment methods. Taking a unique basic science to translational intervention approach, Posttraumatic Stress Disorder: From Neurobiology to Treatment is an invaluable resource for researchers, students, and clinicians dealing with this complex disorder. * Comprehensive coverage of this key neuropsychiatric disorder * Chapters written by a global team of experts on basic and clinical aspects of posttraumatic stress disorder * Takes a translational approach, moving from basic research to clinical interventions
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Veröffentlichungsjahr: 2016
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Table of Contents
Cover
Title Page
Copyright
List of contributors
Introduction
Reference
Section I: Preclinical sciences of stress
Chapter 1: Posttraumatic stress disorder: from neurobiology to clinical presentation
1.1 PTSD: prevalence, risk factors, and etiology
1.2 Neurobiology of PTSD
1.3 Synthesis of findings: from neurobiology to treatment of PTSD
References
Chapter 2: The epidemiology of posttraumatic stress disorder in children and adolescents: a critical review
2.1 Introduction
2.2 Studies involving general population surveys
2.3 Prevalence of exposure to traumatic events in youth populations
2.4 Community surveys assessing child-adolescent PTSD prevalence
2.5 Childhood/adolescent PTSD rates according to type of trauma
2.6 Child-adolescent PTSD and comorbid disorders
2.7 Risk factors associated with child-adolescent PTSD
2.8 Summary
2.9 Acknowledgement
References
Chapter 3: Early life stress and development: preclinical science
3.1 Overview
3.2 Early life stress and the hypothalamic–pituitary–adrenal (HPA) axis
3.3 Rodent models of early life stress/trauma
3.4 Non-human primate models of early life stress/trauma
3.5 Impact of early life stress on prefrontal-limbic brain circuits across species: biological and evolutionary mechanisms
3.6 Conclusions
3.7 Acknowledgements
References
Chapter 4: Amygdala contributions to fear and safety conditioning: insights into PTSD from an animal model across development
4.1 Introduction
4.2 Stress and defensive responding
4.3 Fear conditioning
4.4 Safety conditioning
4.5 Ontogeny of fear and safety conditioning
4.6 Implications for PTSD
4.7 Conclusion
4.8 Acknowledgement
References
Chapter 5: Preclinical evidence for benzodiazepine receptor involvement in the pathophysiology of PTSD, comorbid substance abuse, and alcoholism
5.1 Introduction
5.2 Stress and the Benzodiazepine Receptor
5.3 Interaction of Stress, Alcohol Intake and the Benzodiazepine Rector
5.4 Stress, Drug Abuse and the Benzodiazepine Receptor
5.5 Translation from Neurobiology to PTSD
5.6 Conclusions
References
Chapter 6: Psychosocial predator stress model of PTSD based on clinically relevant risk factors for trauma-induced psychopathology
6.1 Introduction
6.2 General characteristics of PTSD
6.3 Preclinical models of PTSD
6.4 Psychosocial predator stress model of PTSD
6.5 Summary: the challenge of modeling PTSD in animals
6.6 Acknowledgements
References
Chapter 7: Coping with stress in wild birds – the evolutionary foundations of stress responses
7.1 Introduction
7.2 Physiological changes associated with chronic stress in wild birds
7.3 Lessons from wild birds
7.4 Conclusions
7.5 Acknowledgements
References
Chapter 8: Stress, fear, and memory in healthy individuals
8.1 Introduction
8.2 Time-dependent effects of stress on episodic memory in healthy humans
8.3 Stress and fear conditioning in humans
8.4 Stress-induced modulation of multiple memory systems
8.5 Stress and memory in healthy subjects: implications for PTSD
References
Section II: Neurobiology of PTSD
Chapter 9: Neurotransmitter, neurohormonal, and neuropeptidal function in stress and PTSD
9.1 Introduction
9.2 Noradrenergic system
9.3 HPA axis
9.4 PTSD and inflammation
9.5 Acetylcholine and vagal nerve function
9.6 Dopaminergic system
9.7 NMDA
9.8 Serotonin
9.9 GABA/benzodiazepine system
9.10 Opioid peptides
9.11 Neurotensin
9.12 Somatostatin
9.13 Cholecystokinin
9.14 Neuropeptide Y
9.15 Galanin
9.16 Ghrelin
9.17 Substance P
9.18 Vasoactive intestinal peptide
9.19 Vasopressin and oxytocin
9.20 Neurosteroids and neurohormones
9.21 Conclusions
References
Chapter 10: Genomics of PTSD
10.1 Introduction
10.2 Genetic studies in PTSD
10.3 Gene–environment interaction studies in PTSD
10.4 Epigenetic and gene expression studies in PTSD
10.5 Conclusions
References
Chapter 11: Cortisol and the Hypothalamic–Pituitary–Adrenal Axis in PTSD
11.1 Introduction
11.2 HPA axis and the stress response
11.3 HPA axis alterations in PTSD
11.4 HPA feedback functioning and GR sensitivity
11.5 Gender, PTSD, and HPA axis activity
11.6 HPA alterations as a risk factor for PTSD
11.7 Genetic and epigenetic influences on GR sensitivity
11.8 Modifying glucocorticoid responsiveness: implications for prevention and treatment
11.9 Conclusion
References
Chapter 12: Neuroimaging of PTSD
12.1 History and background
12.2 Neural circuits of PTSD
12.3 Changes in brain structure and cognitive functioning in PTSD
12.4 Neurohormonal responses to PTSD
12.5 Functional neuroimaging studies in PTSD
12.6 Neuroreceptor Studies in PTSD
12.7 Conclusions
References
Section III: PTSD and co-occuring conditions
Chapter 13: PTSD and mild traumatic brain injury
13.1 Introduction
13.2 Mild TBI
13.3 Posttraumatic stress disorder
13.4 Overlap between mTBI and PTSD
13.5 Summary and conclusions
References
Chapter 14: Stress-related psychopathology and pain
14.1 Introduction
14.2 Depression
14.3 Schizophrenia
14.4 Anorexia nervosa
14.5 Borderline personality disorder
14.6 Post-traumatic stress disorder
14.7 Conclusion
References
Chapter 15: Stress and health
15.1 Introduction
15.2 Stress and cardiovascular disease
15.3 Depression and cardiovascular disease
15.4 PTSD and cardiovascular disease
15.5 Potential mechanisms linking stress to cardiovascular disease
15.6 Mechanisms through which depression and PTSD may increase CVD risk
15.7 Stress, PTSD and functional pain disorders
15.8 Conclusions
References
Section IV: PTSD: from neurobiology to treatment
Chapter 16: Pharmacotherapy for PTSD: effects on PTSD symptoms and the brain
16.1 Introduction
16.2 Agents acting on the GABA–benzodiazepine receptor complex
16.3 Agents acting on norepinephrine and serotonin receptors
16.4 Tricyclic and monoamine oxidase inhibitor antidepressants
16.5 Medications with other mechanisms of action
16.6 Selective norepinephrine reuptake inhibitors
16.7 Selective serotonin reuptake inhibitors
16.8 Antidepressants with actions on norepinephrine and epinephrine reuptake
16.9 Mood stabilizers
16.10 Antipsychotic medications
16.11 Glutamatergic agents
16.12 MDMA
16.13 Effect of pharmacotherapy on the brain and neurobiology in PTSD
16.14 Conclusions
References
Chapter 17: Effects of psychotherapy for psychological trauma on PTSD symptoms and the brain
17.1 Psychotherapy for psychological trauma
17.2 The neuroscience of early interventions for trauma
17.3 Psychological therapy for psychological trauma
17.4 Effects of psychotherapy on the brain
17.5 Brain imaging of psychotherapy in PTSD
17.6 Conclusions
References
Copyright
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Guide
Cover
Table of Contents
Introduction
Section I: Preclinical sciences of stress
Begin Reading
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
36
Cl
–
uptake. (a) Muscimol-stimulated
36
Cl
–
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
36
Cl
–
uptake measured in six individual subjects following the shuttle escape task. Muscimol-stimulated
36
Cl
–
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
36
Cl
–
uptake. Each bar represents the mean + SEM of
36
Cl
–
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)
Posttraumatic Stress Disorder
From Neurobiology to Treatment
EDITED BY
J. Douglas Bremner
Departments of Psychiatry & Behavioral Sciences and Radiology,Emory University School of Medicine, and the Atlanta VA Medical Center,Atlanta, GA, USA
Copyright © 2016 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, New Jersey
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Library of Congress Cataloging-in-Publication Data:
Posttraumatic stress disorder (Bremner)
Posttraumatic stress disorder : from neurobiology to treatment / [edited by] J. Douglas Bremner.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-118-35611-1 (hardback)
I. Bremner, J. Douglas, 1961- , editor. II. Title.
[DNLM: 1. Stress Disorders, Post-Traumatic. 2. Stress, Psychological. WM 172.5]
RC552.P67
616.85′21–dc23
2015036889
Cover image: © Katie Nesling/Getty
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.
Section I
Preclinical sciences of stress
Chapter 1Posttraumatic stress disorder: from neurobiology to clinical presentation
Arieh Y. Shalev1 & J. Douglas Bremner2
1Department of Psychiatry, New York University School of Medicine, Langone Medical Center, New York,, NY,, USA
2Departments of Psychiatry & Behavioral Sciences and Radiology, Emory University School of Medicine, and the Atlanta VA Medical Center, Atlanta,, GA,, USA
1.1 PTSD: prevalence, risk factors, and etiology
Posttraumatic stress disorder (PTSD) is a chronic, disabling, and prevalent anxiety disorder. It is triggered by exposure to a psychologically traumatic event, yet only a minority of those exposed actually develop the disorder. Trauma characteristics, as well as genetic, biological, and psychosocial risk factors, contribute to the occurrence of PTSD among survivors of traumatic events. PTSD, therefore is a prime example of gene-environment and psycho-biological interaction. There is a large amount of research in animals on the effects of stress on neurobiology. This has been translated into clinical neuroscience research in PTSD patients. The overarching goal is for our understanding of the neurobiology of the stress response and the long-term effects of stress on stress-responsive systems to inform treatment approaches to PTSD patients. The chapters in this volume, from researchers in all areas of the stress field, including basic scientists as well as research and clinical psychologists and psychiatrists, illustrate the advances in the field that have continued to move from neurobiology to treatment of PTSD. This chapter serves as an introduction to the volume and gives a broad overview of the field.
Posttraumatic stress disorder was first recognized as a distinct psychiatric disorder in the third edition of the American Psychiatric Association's (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM-III; APA, 1981). Subsequent studies have established – and slightly modified – the disorder's symptom structure, evaluated its natural course, and assessed the disorder's biological features. The DSM-IV-TR has been in use for many years, and PTSD symptoms based on that are shown in Box 1.1; however, recently the DSM-5 was released (APA, 2014), and the changes from DSM-IV-TR are described later in this chapter.
Box 1.1 Diagnostic and statistical manual of mental disorders-IV-TR criteria for posttraumatic stress disorder
A. The person has been exposed to a traumatic event in which both of the following were present:
1.
The person experienced, witnessed, or was confronted with an event that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others.
2.
The person's response involved intense fear, helplessness, or horror. Note: In children this may be expressed, instead, by disorganized or agitated behavior.
B. The traumatic event is persistently re-experienced in one (or more) of the following ways:
1.
Recurrent and intrusive distressing recollections of the event, including images, thoughts, or perceptions. Note: In young children, repetitive play may occur in which themes or aspects of the trauma are expressed.
2.
Recurrent distressing dreams of the event. Note: In children, there may be frightening dreams without recognizable content.
3.
Acting or feeling as if the traumatic event were recurring (includes a sense of reliving the experience, illusions, hallucinations, and dissociative flashback episodes, including those that occur on awakening or when intoxicated). Note: In young children, trauma-specific re-enactment may occur.
4.
Intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event.
5.
Physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event.
C. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma), as indicated by three (or more) of the following:
1.
Efforts to avoid thoughts, feelings, or conversations associated with the trauma.
2.
Efforts to avoid activities, places, or people that arouse recollections of the trauma.
3.
Inability to recall an important aspect of the trauma.
4.
Markedly diminished interest or participation in significant activities.
5.
Feeling of detachment or estrangement from others.
6.
Restricted range of affect (e.g., unable to have loving feelings).
7.
Sense of a foreshortened future (e.g., does not expect to have a career, marriage, children, or a normal life span).
D. Persistent symptoms of increased arousal (not present before the trauma), as indicated by two (or more) of the following:
1.
Difficulty falling or staying asleep.
2.
Irritability or outbursts of anger.
3.
Difficulty concentrating.
4.
Hypervigilance.
5.
Exaggerated startle response.
E. Duration of the disturbance (symptoms in criteria B, C, and D) is more than 1 month
F. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning
Specify if:
Acute – if duration of symptoms is less than 3 months.
Chronic – if duration of symptoms is 3 months or more.
With delayed onset – if onset of symptoms is at least 6 months after the stressor.
Posttraumatic stress disorder frequently follows a chronic course and can be associated with recurrences related to exposure to multiple traumas. In addition, PTSD is frequently comorbid with other psychiatric conditions, such as anxiety disorders, depression and substance abuse (Kessler et al., 1995).
Posttraumatic stress disorder is hypothesized to involve the brain's emotional-learning circuitry, and the various brain structures (e.g., prefrontal lobes) and neuroendocrine systems (e.g., the hypothalamic–pituitary–adrenal [HPA] axis) that modulate the acquisition, retention, and eventual extinction of fear conditioning (Bremner & Charney, 2010).
The purpose of this chapter is to bridge the gap between neurobiology and treatment of PTSD that is covered in more detail in the many chapters in this volume related to these topics. This chapter will address issues concerning the acquisition and course of PTSD, including physiological and neuroendocrine factors; recognition and impairment; recent studies of psychotherapy and pharmacotherapy and their effects on neurobiology as well as symptom response; and suggest some directions for research.
1.1.1 The syndrome
Formally, PTSD is defined by the co-occurrence of three clusters of symptoms (re-experiencing, avoidance, and hyperarousal) in an individual who had undergone a traumatic event (Box 1.1).
Symptoms of re-experiencing consist of intrusive, uncontrollable and involuntary instances of re-living the traumatic event, with feelings of fear and panic, and with corresponding physiological responses such as palpitation, sweating or muscular tension. Such “intrusive” experiences often occur upon exposure to cues that remind the person of the traumatic event, but they also occur spontaneously, such as during nightmares or periods of relaxed attention.
Avoidancein PTSD includes phobic avoidance (i.e., of cues and situations that resemble the traumatic event) along with extended avoidance and numbing, expressed as restricted range of affects, diminished interest in previously significant activities, feelings of detachment and estrangement from others and a sense of foreshortened future. The latter clearly resemble symptoms of depression, and may explain the frequent overlap between PTSD and depression.
Symptoms of PTSD hyperarousal include insomnia, anger, difficulties concentrating, hypervigilance and exaggerated startle. Importantly, these symptoms are unrelated to specific reminders of the traumatic event, and constitute an unrelenting and pervasive background of tension and irritability, affecting the patient's entire life.
In the recently released DSM-5, symptoms of PTSD have remained mostly the same, but the trauma definition no longer requires feelings of fear, helplessness, or horror in conjunction with the trauma (APA, 2014). In addition, new qualifying symptoms were added. As can be seen from Box 1.1, symptoms must be present for at least 1 month for a formal diagnosis of PTSD to be made. If symptoms are present for less than 3 months, the disorder is termed “acute,” while symptoms enduring beyond 3 months are considered “chronic” PTSD.
The symptom criteria of PTSD have been rather consistent across successive revisions of the DSM. The few changes that were made concerned manifestations of guilt, which figured in DSM-III, and were omitted from subsequent editions, and the presence of bodily responses upon exposure to reminders of the traumatic event, a diagnostic criterion which has been moved from the “hyperarousal” cluster into the “re-experiencing” cluster. More recently, DSM-5 added a new criterion of negative alterations in cognition and mood, which comprises symptoms such as a persistent and distorted blame of self or others, and a persistent negative emotional state. A new symptom of reckless or destructive behavior was also added as part of the hyperarousal symptom cluster.
In contrast, the appraisal of the traumatic event has changed considerably. The original description of PTSD, in DSM-III, was clearly influenced by the consequences of the Vietnam war, and therefore defined the traumatic event as being out of the range of normal human experiences and capable of provoking distress among most subjects exposed. This perception has been eroded by studies that showed that PTSD could develop in the aftermath of frequently occurring traumata, such as road traffic accidents or physical assault (Shalev et al., 1988). Consequently, the current definition of a traumatic event is very permissive indeed and applies to a large array of situations and events. DSM-IV-TR required both exposure to a threatening event and intense response in the form of fear, horror, or helplessness in order for an event to formally qualify as “traumatic.” The requirement of the latter was dropped in the most recent version, DSM-5. Overall the DSM-5 has loosened the criteria for PTSD, so that a much larger proportion of the population is expected to meet criteria for PTSD under the new definition (APA, 2014).
The risk of developing PTSD varies according to the type of trauma. The disorder's lifetime prevalence rates among civilians has been estimated at (Davidson et al., 1991; Kessler et al., 1995). A higher lifetime PTSD prevalence of around has been reported for Vietnam veterans and female victims of rape in retrospective epidemiological studies (Kulka et al., 1990; Resnick et al., 1993). In common with many other psychiatric disorders, a higher prevalence of PTSD occurs in women than in men (Kessler et al., 1995).
1.1.2 Natural course, vulnerability and risk factors
Many trauma survivors develop transient and self-remitting forms of PTSD. Prospective studies have shown recovery from fully expressed PTSD among survivors of motor vehicle accidents (Kessler et al., 1995), and recovery within 1 year of a traumatic event of 236 survivors of miscellaneous civilian events who had PTSD 1 month after the traumatic event (Shalev et al., 1993b). However, the recovery curve of PTSD reaches a plateau after 72 months (Solomon et al., 1989), with most cases of recovery occurring during the first year that follows the traumatic event. Recovery from chronic PTSD is often incomplete (Pelcovitz et al., 1994; Shalev et al., 1993b), and those who recover remain vulnerable to subsequent stress.
Prospective studies have also shown that the symptoms of early and “recoverable” PTSD resemble those seen months and years later in people who remain ill (van der Kolk et al., 1996). Moreover, subjects who continue to suffer from PTSD seem to express the same intensity of symptoms that they have expressed shortly after the traumatic event. The phenotype, therefore, appears to remain over time, whereas the nature of the underlying mechanisms might change. This is in line with a general model of learning (Andreski et al., 1998), according to which neuronal mechanisms that mediate the acquisition of new behavior are not the same as those involved in its subsequent practice. Reversibility during the latter phase is obviously more difficult than during acquisition, and this may explain the prolonged and treatment-resistant nature of chronic PTSD.
In its chronic form, PTSD is often complicated by co-occurring depression. The nature of the association between PTSD and depression is unclear, with some studies suggesting that depression develops as a secondary consequence of PTSD (Solomon et al., 1989; Turnbull, 1998) and others suggesting that the two may be independent consequences of traumatic events, and develop simultaneously (Pelcovitz et al., 1997). In addition to depression, substance abuse is commonly reported in survivors of traumatic events with PTSD, physical health often declines, and social relationships can be adversely affected (Bremner et al., 1996c). Thus, chronic PTSD is very disabling, with symptoms affecting patients' well-being, interpersonal relationships and vocational capacity. PTSD is associated with a significant loss of role functioning, as expressed by absence from work or unemployment (Shalev et al., 1996).
1.1.3 Understanding the occurrence of PTSD
There are two competing models for understanding the occurrence and the persistence of PTSD among some survivors. The first model assumes that PTSD is triggered by an abnormal initial response to traumatic stress, affecting memory consolidation and aversive learning (Chilcoat & Breslau, 1998; Fesler, 1991). This view is supported by findings of intense autonomic response during the traumatic event (Shalev et al., 1988, 1998). These initial “unconditioned” responses were thought to reinforce aversive learning via excessive adrenergic drive and through a failure to mount sufficient amounts of the protective stress hormone cortisol (Yehuda & Antelman, 1993). The model points to the need to address the very early bodily and emotional responses to a traumatic event in order to prevent PTSD.
The alternative model postulates that PTSD is significantly affected by factors that follow the traumatic event and is, therefore, a “disorder of recovery.” In a recent meta-analysis of risk factors for PTSD, for example, deficient recovery environment and adversity following trauma were found to be the major risk factors for subsequent PTSD (Brewin et al., 2000). A prospective study has also shown that abnormal startle response – a typical symptom of PTSD – develops within the first few months after the traumatic event in individuals who continue to express PTSD symptoms (Shalev et al., 2000). These findings are in line with the progressive sensitization model of PTSD, according to which the occurrence and persistence of PTSD symptoms progressively alter the central nervous system (CNS). It suggests that preventive interventions be conducted during the acquisition phase of the disorder (i.e., the first few months following exposure).
Finally, the likelihood of developing PTSD is significantly affected by factors that precede the traumatic event. For example, a twin study of Vietnam veterans (Goldberg et al., 1990; True et al., 1993) showed a significant contribution of inherited vulnerability PTSD symptoms following combat. Inherited factors also affect the likelihood of being exposed to combat (Goldberg et al., 1990; True et al., 1993). Other vulnerability factors include lifetime occurrence of psychiatric disorders, cumulated exposure to traumatic events and adversities during childhood, lower education levels and adverse family environments.
Thus, PTSD should be seen as the compounded result of several risk factors, in the presence of which a traumatic event triggers a cascade of biological, mental and interpersonal processes leading to chronic PTSD.
Recent studies of the extinction of fear responses raise the previously discussed possibility that PTSD might be the result of a failure to extinguish an initial fear response (Bremner & Charney, 2010). Functional brain imaging studies, reviewed later in this chapter, have explored the role of medial prefrontal structures in PTSD.
1.1.4 Delayed and chronic forms of PTSD
The onset of PTSD can be delayed for years. In a large study by Solomon et al. (1989) looking at individuals who presented for treatment within 6 years of the Lebanon war, were considered delayed onset, were delayed help-seeking, were exacerbation of subclinical PTSD, were reactivation of recovered PTSD, and the remaining had other psychiatric disorders. This is confirmed in the study by Shalev et al. (1996), in which of patients were truly delayed-onset PTSD and the rest were mainly PTSD patients who recovered and were then reactivated by another event.
Most cases of PTSD recover within 1 year, and after 6 years recovery without treatment is unlikely (Kessler et al., 1995). However, up to of patients with acute PTSD end by having a chronic condition. Chronic PTSD is prolonged and may be unremitting, and subject to reactivation upon exposure to stressors. In addition, it can be disabling and associated with substantial comorbidity. The risk of developing secondary comorbid disorders is related to a number of factors, including the severity of the trauma, gender, family history, past history and the complexity of the PTSD reaction. Chronic PTSD is linked with abuse of alcohol, drugs and prescription medications (Kulka et al., 1990). It is also associated with an increase in suicidal behavior, although studies have not documented an increase in completed suicide (Krysinska & Lester, 2010). The percentages of individuals with PTSD who have at least one other lifetime disorder is for men and for women. The major comorbid disorder seen with PTSD is depression, occurring in of men and of women. Other comorbid disorders include dysthymia, simple phobia and generalized anxiety disorder.
1.1.5 Disability associated with PTSD
The chronic form of PTSD is often debilitating. The disability associated with PTSD includes work impairment, change in life trajectories, impaired social relations, marital instability and perpetuation of violence. This represents a burden not only to the individual but also to society.
