Over the years, one thing that I have realized in both my clinical practice and in my academic work is that in order to understand pathological functioning, it is critical to have a firm grasp on what constitutes normal functioning. In the case of PTSD, understanding abnormal or pathological reactions to traumatic stressors involves understanding the typical processes by which the human mind and body respond to fear. For instance, McEwan (1998) proposes that PTSD pathology is the consequence of the normal systems of allostatic maintenance failing to shut off once the load of an actual stressor is gone. Posttraumatic Stress Disorder, then, might be understood as a consequence of the organism's inability to shut off its fear-response mechanisms.
Joseph LeDoux identifies the amygdala as the brain structure at the center of our defense or danger responding system. It lies at the center of fear. The amygdala is critical to emotional processing in general and is crucial to fear-conditioning, involved in associating stimuli that elicit fear with stimuli that do not normally elicit fear. This fear-learning process involves the development of a conditioned emotional response or a classically conditioned fear response. As LeDoux states, "amygdala activation, in other words, turns a plain perceptual experience into a fearful one" (2002, p. 225). When this occurs, our consciousness is adaptively and understandably dominated by amygdala activation for the purpose of orienting us for appropriate action. LeDoux identifies what he calls the motive circuit in which emotional arousal plays a central role in shaping our motivated and intentional acts. Emotional arousal gives rise to a motivational state, leading to coordinated brain activity in the service of the motivation and arousal and guidance of behavior toward positive goals and away from aversive stimuli. With fear conditioning, our motive circuit is motivated toward survival.
When the amygdala is active, we are in defense or danger mode. Overstimulation of the amygdala has been shown to potentiate an animal's startle response. They are more reactive. Stimulation of the amygdala in general has been shown to lead to hyperarousal and hyperreactivity, increased heart rate, increased blood pressure, increased muscle tension, activation of the stress response system, and subjective experiences of fear and anxiety.
The brain systems that send input to the amygdala and the systems to which the amygdala sends output are all critical. The amygdala receives input from the sensory cortex, the medial temporal lobe memory system (the hippocampus), and the frontal lobe (specifically, the medial prefrontal cortex and the orbitofrontal cortex), which is shown in Figure 6.2.
Media Temporal Frontal Cortex
Lobe Memory System
FIGURE 6.2 Inputs to Amygdala.
FIGURE 6.3 Amygdala Outputs.
Other Memory Systems
Stress Response System
FIGURE 6.3 Amygdala Outputs.
Other Memory Systems
The amygdala then sends output to the stress response system, the hippocampus, various other memory systems, and the frontal cortex, which is shown in Figure 6.3.
Fear Learning, the Amygdala, and the Hippocampus
As one can see, the hippocampus both sends information to and receives information from the amygdala. The hippocampus helps shape or determine what the amygdala responds to. It provides contextual information about stimuli, such as location in space and time (i.e., the sites, sounds, and time frames within which a fear-conditioned event occurred). It provides memory-based information about fear-inducing situations.
The amygdala has been implicated in the assigning of emotional valence or qualitative importance to explicit memories. The central nucleus of the amygdala triggers the release of adrenal hormones, which ultimately provide feedback to the brain. The amygdala's connections to the hippocampus (and other memory systems) can strengthen memory consolidation in the hippocampus, subsequently rendering these memories more vivid and more easily retrieved (LeDoux, 2002). However, in states of high arousal, our memory systems are impaired.
Other processes and connections of the hippocampus are critical to understanding fear-learning in their own right. For example, by virtue of its connections to the frontal cortex, the hippocampus provides contextual information to our working memory system as it processes current and active threat. Of critical importance to fear learning is memory. Without memory, there is no learning.
Therefore, we cannot understand PTSD without knowing about memory. After all, memory is central to PTSD, either failing to forget danger or being reminded of danger on a relentless and persistent basis. Posttraumatic Stress Disorder is about fear and the memories of fear-inducing stimuli and the psycho-biological underpinnings of fear and memory.
From a neurobiological perspective, many theorists and researchers view memory as essentially synonymous with a process called long-term potentiation (LTP). Long-term potentiation is a process in which relatively permanent changes occur at the synapse level of neurons in response to stimulation. After a neuron is stimulated, it will return to its prefiring baseline activation point. But LTP shows us that as a neuron is repeatedly stimulated by a particular stimulus, the neurophysiology of that neuron is altered, resulting in the firing of that neuron now being differentially or characteristically associated with a particular stimulus. It remains poised and ready for activation, potentiated to respond to a particular stimulus. This process is thought to be the neural basis of memory reflecting relatively permanent changes in our neurons from repeated stimulation from a specific input. As long as a neuron remains potentiated, a memory remains.
Let's return now to the hippocampus. Long-term potentiation has been demonstrated repeatedly in the hippocampus. In addition to the hippocampus, explicit memory processes (e.g., events, distinct episodes, and conscious memory processes) have been associated with the rhinal cortex, the amygdala, and the prefrontal cortex. Each of these areas has extensive neural connections with the thalamus, the forebrain, and the sensory areas of the neocortex. Hence, it is not surprising that the hippocampus, with its demonstrated LTP, is a critical brain structure in PTSD.
The hippocampus is important in the formation of explicit memories; short-term memory; temporal aspects of experience; assessing reward, punishment, and novelty; and learning from experience. Research has shown that when an animal is subject to fear conditioning to a particular stimulus, it will respond to cues in the environment with the same response. That is, the stimulus has been contextualized, and the hippocampus is crucial to this process. Lesions in the hippocampus result in canceling or eliminating the role of these contextual cues. The hippocampus anchors the fear response in time and space; without this, we see free-floating and decontextualized fear responses as we see in PTSD. The subjective experience is one of being overreactive and, always and in all places, in fear. Nowhere is safe because fear is not anchored to a time or place. As van der Kolk (1996) mentioned, this accounts for the heightened state of arousal to a broad range of essentially unrelated stimuli.
Intense amygdala activity can suppress hippocampus functioning, and stress-induced corticosterone suppresses hippocampus activity. Increases in glucocorticoids for prolonged periods can lead to cell death. Numerous studies have substantiated reductions in hippocampus volume in those with PTSD and other subjects who have experienced either very intense acute stressors and went on to develop PTSD or individuals who have been exposed to prolonged periods of intense stress, such as victims of child physical abuse or domestic violence. Some studies have found that the hippocampus may, in fact, be able to regenerate cells after damage. However, high stress levels have been found to inhibit this process. At least theoretically, a reduction in hippocampus volume results in a limited ability of the hippocampus to consolidate memories and a reduction in its ability to provide useful or even accurate information to the amygdala.
Branching out from the hippocampus for just a minute, research with epilepsy patients has found that stimulation of the temporal lobe (where the hippocampus is located) can result in symptoms and experiences similar to flashbacks in PTSD. These include complex visual hallucinations or illusions, déjà vu, and emotional distress.
In turn, the amygdala is partially controlled or regulated by its connections to the medial prefrontal cortex. This is another reciprocal relationship in which when one is active, the other is inhibited, and so on. The prefrontal cortex (PFC) is part of the ever so important executive control systems of the frontal lobe. It is a critical structure in the planning and organization of behavior. The PFC serves as a check or monitor of amygdala reactivity, when it is not functioning properly, the amygdala is more reactive and less inhibited by the reality of current input from working memory and from the controlling features of rationality and appropriate planning. In turn, the amygdala can interrupt the selective attention and working memory processes of the frontal cortex in order to alert the organism to a threat.
The orbitofrontal cortex, a section of the PFC, has been implicated in the failure of extinction in fear learning. Lesion research with the orbitofrontal cortex has also shown symptoms of intense fear and even visual hallucinations akin to the flashbacks of PTSD. When the orbitofrontal cortex is damaged, animals have been found to have poor extinction and, therefore, are perpetually responsive to old stimuli to which they should have habituated.
The locus coeruleus (LC) has long been understood to play a role in stress responding. Norepinephrine is prominent in the LC (see norepinephrine section below). The LC is connected to multiple brain regions also involved in stress and fear responding, such as the amygdala and the hippocampus. The LC is regulated by both neurotransmitters and neuropeptides (hormones). Corti-cotrophin releasing factor (CRF) and glutamate stimulate the LC, while nor-epinephrine, epinephrine, the endogenous opiates, gamma-aminobutyric acid (GABA), and serotonin have been found to inhibit its function. Bremner (1999) identifies the LC as a central relay station that receives information from multiple inputs and responds with norepinephrine release. Novel stimuli can stimulate the LC, and subsequent sympathetic nervous system activation occurs. Fear and stress response behaviors occur with LC activation. Research has shown that animals that have a prior exposure to chronic stress have an exaggerated nor-epinephrine response under current threat conditions (Bremner, 1999). Researchers have also found that chronic stress results in more active LC firing. Ultimately, Bremner, Southwick, Johnson, Yehuda, et al. (1993) conclude that increased LC firing and responsiveness and subsequent norepinephrine release may represent the neural substrate of stress sensitization and hyperreactivity in PTSD.
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