As was mentioned earlier, what lies at the root of brain alterations in PTSD are alterations in neurochemicals such as neurotransmitters, hormones, and neuro-peptides. These alterations ultimately lead to changes at the synaptic level, which lead to changes in circuitry and connectivity and the way different brain areas interact with and influence each other. These neural changes occur within the larger behavioral and neurobiological context of the stress response and the fear response and its various brains structures and systems outlined in the preceding section. In the stress response, there is a release of stress hormones and activation of stress-related neurotransmitters systems. Figure 6.4 outlines the brain regions involved in this process.
Hippothalamus Adrenal Medulla
Glucocorticoids Norepinephrine and Epinephrine
Notes: The amygdala is activated, which activates the hypothalamus, which releases CRF (or CRH). The anterior pituitary releases adrenocorticotropic hormone (ACTH). The adrenal cortex releases glucocorticoids (e.g., cortisol), which effect glucose metabolism by helping break down proteins and converting them to glucose, making fat available for energy, increasing blood flow, and stimulating responsive behavior. The sympathetic nervous system activates the adrenal medulla, which releases norepinephrine and epinephrine. Epinephrine activates glucose metabolism, which provides the brain and body energy to respond to the threat and serves to increase blood flow to muscles by increasing heart output. Norepinephrine is both a stress hormone and a neurotransmitter and is involved in the stimulation of heart activity, dilation of blood vessels, and increase in respiration.
Research has shown that PTSD involves the activity of the following neuro-chemicals:
Catecholamines (norepinephrine and dopamine)
Hormones and peptides (glucocorticoids (e.g., cortisol) and corticotropin-releasing factor)
The benzodiazepine system and GABA
Catecholamine levels in the brain are responsive to stress. They are among the critical neurochemicals involved in stress and fear responding. When there are exaggerated catecholamine levels there are increases in physiological and behavioral reactivity (Southwick, Krystal, Johnson, & Charney, 1995; Zigmond, Fin-lay, & Sved, 1995). Southwick, Rasmusson, Barron, and Arnsten (2005) refer to this as stress sensitization. As catecholamines become subsequently activated either by repeated stress or very intense stimuli, their sensitization results in a heightened state of reactivity. This reactivity is reflected in the arousal symptoms and vigilance of PTSD.
Catecholamines are also involved in the regulation of the amygdala. An increase in catecholamines increases amygdala functioning, promoting fear conditioning and the formation, or stamping in, of emotionally important memories. Again, catecholamine function is implicated in the hyperarousal of PTSD.
In turn, the amygdala influences catecholamine release in the prefrontal cortex. Increases in catecholamines (and glucocorticoids) suppress cognitive functioning in the PFC, such as planned and organized behavior. The amygdala stimulates the release of catecholamines and cortisol for better functioning, but this process suppresses the prefrontal cortex. This leads to an inability of the PFC to appropriately inhibit the amygdala, and thus the amygdala operates unchecked. As the amygdala goes unchecked, it is more reactive, again a process reflected in the hyperarousal of PTSD.
The catecholamines are also implicated in memory functioning. Generally, the catecholamines have an inverted U relationship with memory formation. They are involved in memory consolidation and have been shown to amplify explicit memory during emotional arousal. However, at very low levels or at very high levels of catecholamines, memory consolidation is impaired. PTSD sufferers have fragmented memories for the traumatic events specifically and also have generally impaired memory functioning.
So individuals with PTSD should show elevations in catecholamines, right? Elevated levels of norepinephrine in 24-hour blood plasma measures have been found in combat veterans with PTSD when compared to combat veterans without
PTSD; civilians living next to Three Mile Island following the nuclear-meltdown scare; and women with histories of child abuse (Davidson & Baum, 1986; Limieux & Coe, 1995; Yehuda, 1998a, 1998b). Other studies, using sophisticated biochemical manipulations to produce functional increases in norepinephrine, have shown that such experimental manipulation of norepinephrine can cause panic attacks and increases in specific PTSD symptoms such as hypervigilance, intrusive memories, and full-blown flashbacks in subjects diagnosed with PTSD (Southwich et al., 1993).
Norepinephrine is a specific catecholamine that has been implicated in PTSD pathology. It is a critical neurotransmitter in the amygdala fear circuit. Brain regions that have high concentrations of norepinephrine have been implicated in behaviors that orient an organism to its environment. Activation of nor-epinephrine stimulates alertness and vigilance. Attention resources are also activated, and responses to novel stimuli are increased. Finally, norepinephrine is involved in mobilizing the body for action and responding to danger.
The LC contains the vast majority of norepinephrine-producing cell bodies. It is involved in processing relevant sensory information and facilitates fear-related physiological, motor, cognitive, and neuroendocrine responses. Experimental stimulation of the LC produces fear-related behavior and increases release of norepinephrine in numerous brain areas, including the amygdala, hippocampus, hypothalamus, and the PFC (Southwick et al., 2005). Research has shown that animals that are intensely or repeatedly stressed will respond with exaggerated norepinephrine responsivity and reflect stress sensitization effects. Southwick and colleagues (2005) cite that this increased sensitivity is more typical in episodes of uncontrollable stress as opposed to controllable stress. This is certainly consistent with the types of traumatic stressors associated with PTSD.
Stimulation of the ventral tegmentum by the amygdala after a fear stimulus has been perceived results in the activation of dopamine stimulation. This leads to activation of the nucleus accumbens and subsequent activation and invigora-tion because dopamine facilitates synaptic transmission in the pathway from the nucleus accumbens and the pallidum, which is ultimately involved in the control of movement and motor responses.
It has long been thought that dopamine is involved in the reward system of the brain (i.e., learning from reinforcement). Stimulation of a particular region of the hypothalamus as fibers to the brainstem are activated results in stimulation of targeted neurons that make dopamine in the ventral tegmentum. They then project to the forebrain, releasing dopamine widely throughout the brain.
Research has shown that emotional numbing, anhedonia, and social disconnection are associated with dopamine dysfunction in the mesocortical and mesolimbic systems (Bremner, Southwick, & Chamey, 1999). Also, dopamine is implicated in anticipatory behavior and may be implicated in the hypervigilance of PTSD because dopamine projections to the amygdala facilitate fear conditioning, leading to possible overreactivity of the amygdala subsequent to dopamine dysfunction.
Posttraumatic Stress Disorder symptoms have been associated with alterations in serotonin levels in the brain. Serotonin is an important neurotransmitter in multiple brain systems including the amygdala, the orbitofrontal cortex, the LC, the hippocampus, and the nucleus accumbens. Although the amygdala sits at the center of the fear circuit and receives and projects to many brain regions, it is thought to typically ignore most information coming to it. It has a reaction point or set point, and it is not simply reactive. Its reaction point is controlled or determined by many processes (see the discussion of the medial pre-frontal cortex), but it also has an internal control mechanism mediated by its internal neurochemical makeup. Danger signaling stimuli overcome the amygdala's typical set point. The neurochemical set point of the amygdala can be significantly altered in two ways: by inputs having been altered upstream in the circuits sending input projections to it and if its own internal properties are altered. Serotonin levels have been implicated in altering the set point. When serotonin levels are sufficient, the set point functions adequately, but significant drops in functional serotonin levels result in less inhibition of the amygdala, lowering its trigger point and resulting in more reactivity. The stress hormone cortisol has been found to interfere with serotonin's ability to inhibit the amygdala as well.
Serotonin in the orbitofrontal cortex is involved in filtering and processing social and emotional information. Dysfunction here can result in poor decision making, poor recognition of emotion of others (resulting in attribution errors), and even aggression. The orbitofrontal cortex is sensitive to serotonin effects with depletions in serotonin causing dysfunction. Finally, reductions in serotonin levels have been shown to increase the firing rate of norepinephrine neurons in the LC.
Under stress, the medial prefrontal cortex increases serotonin metabolism, but with chronic stress, there can be decreases or reductions in functional serotonin levels. Low serotonin can be related to difficulties in modulating arousal, as is seen in exaggerated startle responding. Serotonin checks norepinephrine's responsiveness and norepinephrine-related arousal as well. There can also be higher levels of hostility, aggressiveness, impulsivity, and depression. All of these are common comorbid conditions with PTSD. van der Kolk (1996) proposes that serotonin plays a role in an organism's ability to monitor the environment and react flexibly to stimulation with situation-appropriate responses instead of reacting to internal stimuli that may be unrelated to current demands.
The Hypothalamic-Pituitary-Adrenal Axis, Neuropeptides, and Neurohormones
As previously outlined, three brain areas-the hypothalamus, the pituitary, and the adrenal cortex-have been specifically implicated in the biology of PTSD because of their role in neuropeptide and neurohormone activity. These brain areas are part of what is called the hypothalamic-pituitary-adrenal axis (HPA axis). When the amygdala is activated, it in turn activates or stimulates the hypothalamus. The hypothalamus is stimulated to release the neuropeptide: corticotropin-releasing factor (CRF). Release of CRF leads to the release of adrenocorticotropin-releasing factor by the pituitary, which leads to the release of the glucocorticoids, specifically cortisol, from the adrenal cortex.
Corticotropin-Releasing Factor (CRF)
As was previously mentioned, CRF is a critical component in the stress response. In addition to its role in the eventual release of cortisol, CRF itself has been implicated in PTSD pathophysiology. Corticotropin-releasing factor is distributed in numerous brain areas that are involved in stress responding, such as the amygdala, hippocampus, PFC, and LC. Stress increases levels of CRF in the hypothalamus. Bonne et al. (2004) report that exposure to stress early in life can produce long-term elevations in CRF and sensitization of CRF neurons with future stress. Brunson, Avishai-Eliner, Hatalski, and Baram (2001) have implicated CRF elevations in hippocampal damage. Further, research has shown that patients with PTSD have elevations of CRF in their cerebral spinal fluid (Baker et al., 1999).
During the stress response, the adrenal cortex secretes cortisol. It is considered a glucocorticoid because it has an impact on glucose metabolism by helping to break down proteins and converting them to glucose, making fats available for energy, increasing blood flow, and providing needed energy for danger responding. Cortisol's other roles in the stress response include inhibition of growth and sexual reproductive systems and modulation of inflammatory responses of the immune system. Cortisol is essential to the activation of the relevant systems of fight or flight and eventual survival.
Cortisol also modulates the effects of serotonin on GABA in the amygdala, which can result in altering the sensitivity of the amygdala. Cortisol's relation to fear responding is somewhat complex. In addition to its modulation of GABA in the amygdala, its release eventually can also lead back to the amygdala for increased function. This same process, however, suppresses PFC function. As was already discussed, PFC dysfunction is implicated in PTSD with dysfunction in working memory and ultimately in amygdala dysregulation.
Secretion of stress hormones can affect how memories are laid down and established. For instance, traumatic memories are more easily accessed and recalled under states of high arousal, even generic arousal. Conversely, oxytocin and endorphins have been found to interfere with memory for traumatic events.
Part of the stress response is the mobilization of resources to cope with or ignore pain. Stress-induced analgesia is caused by endogenous opiates. In addition, endogenous opiates are involved in modulating the stress responses of CRF and norepinephrine. Although endogenous opiates serve positive and adaptive functions under stress, they may have negative effects related to PTSD symptoms. It is thought they may be responsible for emotional blunting or flattening. This may also be related to dissociation as memory formation has been found to be affected by these substances as well.
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