what happens to the Brain in PTSD?

“In 1937, James Papez proposed in his now-classic article, based on his anatomical research, “emotions have an anatomical mechanism and location in the brain” (“A Proposed Mechanism of Emotion.” Arch. Neurol. Psychiatry (1937): 38).

Dr. MacLean, the leading authority in limbic neurology, in general championed Papez`s findings. He insisted that in the process of evolution from reptiles to mammals, the mammalian sub-cortex evolved in complexity, developing an anatomical cyto-architecture identical to that of neocortex.

For those students who have a special interest, I refer you to “The Limbic Brain” by Andrew Lautin, M.D (Kluwer Academic/Plenum Publishers, 2001).

Fear conditioning causes an array of stress induced behaviors such as “freezing” and “acoustic startle,” even in rodents (LeDoux, J. “Fear and the Brain.” Biological Psychiatry, 1998).

But integrating intelligence into limbic functions allowed stimulus response reactions to support more complex responses to threat, including hesitation and response selection (Maclean. “Culminating Developments in the Evolution of the Limbic System.” Raven Press, 1986).

MacLean’s findings led to the additional proposal that the cingulate subdivision of the limbic system was also involved in early bonding behaviors such as playfulness and sound communications, allowing for a more complex set of survival skills that characterize the evolutionary transition from reptiles to mammals.

Once the limbic brain acquired advanced neocortex, mechanisms of survival evolved beyond visceral and simple reflective behaviors, such as “freezing,” towards more complex behaviors that serve communal attachment and parental bonding.

The hippocampus therefore plays a role in providing memory with context and emotional relevance and restrains the amygdala from activating fear responses.

It is also responsible for notifying the prefrontal brain for response choices which are both diverse and receptive to change (when comparing humans with other primates).

The evolution of neocortex into the limbic brain allows primates to acquire the “instrumental coping skills” that allow for more evolved response choices (Maclean).

This allows for a wide variety of defensive instrumental behaviors, including reflection, planning, and response selection.

Fifteen years after the inception of PTSD, neuroscientists remained limited in their understanding of its biological mechanisms (Yehuda and McFarlane. “Conflict Between the Knowledge of PTSD and its Conceptual Basis.” Am J Psychiatry, Dec. 1995).

The neuroscience community remained baffled by the contradictory findings reported by different investigators.

At this point, we had begun to search for markers showing activation of “limbic” circuitry in the brains of trauma survivors.

Since the limbic brain regulates emotions, and knowing that PTSD causes “hyper-arousal,” common sense predicted that probes measuring activation of the fear-circuitry would be helpful in diagnosing PTSD.

Activated stress circuits in all vertebrates express themselves through the autonomic (sympathetic) nervous system (via brainstem nerve outlets) and via the Hypothalamic-Pituitary-Adrenal Axis, where activation leads to a hormonal stress cascade.

Physiologically, the part of the brain that functions as the “fear center” is the amygdala (Davis. J. Neuropsychiatry Clin. Neurosc., 1997).

It is a relatively small body of neurons deeply embedded in close proximity to the emotional circuits, as well as the “Master Endocrine Glands” known as the hypothalamus and pituitary.

In contrast, the hippocampus functions as a switch and “control center” (Jacobson and Sapolsky. Endocrinology Review, 1991).

In primates (including human beings), the hippocampus is the most complex and delicate part of the brain.

The function of the hippocampus is to contextualize an event, tag it to an emotion, transform it into a language transcript, and finally download a coded file into the temporal lobe of the brain.

It appears as if in the brains of patients with PTSD, the hippocampus continues to remain on “high alert” to retrieve previous recollections when reminded of a similar threat. For adaptive purposes, memories associated with strong emotional content are more consolidated than nonthreatening cues (McNally and colleagues. “Selective Processing of Threat Cues in PTSD.” J Abnorm Psychol, 1990).

The hippocampus and amygdala also function as endocrine brain structures. They produce proteins and other neurotransmitters which then flow downstream to activate hormonal glands (such as the adrenals) and neural networks throughout the body.

Targets affected by the HPA dysregulation include the cardiovascular system, coagulation, the gastrointestinal system, immune responsiveness, and many other somatic systems known to be affected by stress.

Cortisol released by the adrenal glands returns to the hippocampus.

When the hippocampus is flooded by stress induced neuro-excitatory amino acids or peptides such as glutamate, Glucocorticoid, or its precursor Glucocorticoid Releasing Factor (GRF), it shuts down its governance and restraint of the amygdala.

While the ensuing somatic and behavioral responses may have evolved as an adaptation against predators, if the overproduction of cortisol continues (in conjunction with other neuro-excitatory transmitters such as glutamate), hippocampal cells degenerate and eventually die (apoptosis) (Bremner. “Alterations in Brain Structure and Function Associated with PTSD.” Seminars in Clinical Neuropsychiatry, 1999).

This has been demonstrated by Functional MRI studies showing hippocampal changes in the immediate aftermath of physical or sexual assault (Bremner and colleagues. “MRI Measurement of Hippocampal Volume in PTSD Related to Childhood Physical and Sexual Abuse.” Bio Psychiatry (1997): 41).

When rodents have their adrenal glands removed and are then subjected to stress, their hippocampus remains normal (Moghaddam. Brain Research, 1994).

This means that the presence of cortisol at the hippocampal receptor is critical to the cascade leading to neuronal cell death (Mathew, Sanjay and colleagues. CNS Spectrums 6.7, Jul. 2001).

Once the hippocampal restraint over the limbic brain is removed, emotional dysregulation occurs.

In acute trauma, when the trauma overwhelms coping defenses, this translates into activation of the fear cascade.

The resulting effect of the dual over-activation of the amygdala and paralysis of the hippocampus provides the neurobiological substrate for most of the observed symptoms in PTSD.

The lateral hypothalamus mediates activation of the sympathetic nervous system via the Locus Cereleous, which is closely located in the brain stem and responsible for the manufacture of nor-adrenaline.

The adrenal glands, situated above and behind the kidneys, are also recruited via spinal outlets to produce adrenaline. Thus the adrenaline cascade breaks out of the confines of the central nervous system with the adrenal glands pumping adrenaline directly into the bloodstream.

The final step in the stress cascade occurs with the production of the hormone responsible for the psychological sense of dread.

In contrast to the lateral hypothalamus (which governs the autonomic nervous system), the medial hypothalamus is responsible for the production of Glucocorticoid Releasing Factor (GRF).

This travels a short distance to the pituitary gland, where it stimulates the production of ACTH (Adrenocorticoid-Trophic Hormone), which then enters the bloodstream and activates the adrenal gland to produce cortisol.

Adrenaline, as well as cortisol, is involved in mediating stress responses, explaining the wide array of “downstream” physiological symptoms accompanying extreme autonomic arousal.

Hypothalamic-Pituitary-Adrenal Axis dysregulation is the final common biological signature of all stress.

While trauma undoubtedly activates the Hypothalamic-Pituitary-Adrenal Axis, this was contradicted by the unexpected findings of normal-to-low levels of cortisol in the body fluids of traumatized populations.

In the early 1990’s, probes were still measuring stress hormones such as cortisol in the urine, saliva, serum, and spinal fluid.

Rachel Yehuda and colleagues published several articles reporting low urinary excretion of cortisol in patients with PTSD (J Nerv Ment Dis (1990): 178; Am J Psychiatry (1995): 152).

This finding initially caught the scientific world by surprise because some stressed and traumatized individuals were showing lower levels of cortisol in their blood and saliva.

At first the findings of lower than expected cortisol in abuse victims was extremely counterintuitive.

Despite strong circumstantial evidence that implicated functional impairment in key limbic brain structures, traditional CT scans and MRI’s also failed to show consistent anatomical changes in the hippocampus or amygdala.

Only with the advent of functional imagery studies such as PET scans, Functional MRI, and Magnetic Spectroscopy did patients with PTSD show significant functional impairment (Schuff and colleagues. “Decreased Hippocampal N-Acetyl-Aspartate in the Absence of Atrophy in PTSD.” Biological Psychiatry, 2001).

It became clear that earlier probes were only capable of showing anatomical shrinkage.

Fewer probes were showing that neocortical cells were in distress long before they atrophied.

Functional imaging not only revealed drastic shifts in metabolic activity in the hippocampus, and amygdala of victims with PTSD, but also confirmed the validity of MacLean’s construct, including pre-frontal cortex in the Hippocampal Dentate Nucleus and in the cingulate subdivision of the limbic brain of primates.

In this case, if you have PTSD, your traumatic injury has activated a sustained fear response.

Messenger RNA in the hypothalamus (as a protective device), is informed by the Glucocorticoid receptor to produce less CRF (Corticotropin Releasing Factor) receptors.

Several studies have indeed shown that stressed individuals down-regulate their pituitary CRF receptors. They therefore respond sluggishly in their production of ACTH when given CRF. The downstream effect is to discourage the adrenal glands from releasing cortisol.

The second explanation has to do with your pituitary gland and its “negative feedback” mechanism mediated by cortisol autoreceptors. Since your body “knows” that your prolonged exposure to high cortisol is “bad,” your cortisol (Glucocorticoid) receptors have become “up-regulated.” This is because these receptors function as “negative feedback loops.”

Their function is to “switch–down” the production of ACTH from an overstimulated pituitary. The Glucocorticoid receptor functions as a messenger, warning the cell to prevent the production of ACTH. Your body is trying to prevent the inevitable cascade which would lead to the excess production of cortisol.

Therefore, if you have PTSD, the pituitary gland is receiving two conflicting messages:

CRF from the amygdala and hypothalamus is demanding the production of ACTH, but the up-regulated Glucocorticoid receptor tries to prevent this from happening, via a negative feedback loop, to reduce the production of ACTH.  The usual winner in this “tug-of-war” is the negative counter responses. The net result of this tug-of-war may even lead to a decreased production of ACTH and cortisol.

This finding initially caught the scientific world by surprise because some stressed and traumatized individuals were showing lower levels of cortisol in their blood and saliva.

Some investigators quickly went to test this negative feedback hypothesis.

Metyrapone is a substance that blocks cortisol synthesis. Administering Metyrapone will therefore eliminate any negative feedback effect of cortisol on the pituitary gland.

When given Metyrapone, victims of combat and rape showed much more elevation of ACTH and cortisol than control subjects (Yehuda. “Pychoneuroedocrinology,” 1996).

In other words, once the negative feedback loop of cortisol has been removed, CRF becomes free to stimulate the pituitary unimpeded by cortisol’s opposing (negative feedback) effect at the upregulated Glucocorticoid receptor site.

This study was replicated sufficiently to convince investigators that cortisol levels, per se, are a poor marker for the diagnosis of PTSD.

Another test works in the opposite direction: Stressed victims show blunted responses of ACTH when given dexamethasone, a potent Glucocorticoid.

In other words, if you have PTSD, you will produce less ACTH when given a potent Glucocorticoid because of up-regulation of the cortisol mediated brakes applied to your ACTH producing cells.

Naïve control subjects don’t have up-regulated negative feedback loop receptors. When healthy volunteers receive dexamethasone, there is a measured suppression by the pituitary of ACTH.

But once trauma has up-regulated the negative feedback loops, dexamethasone causes an exaggerated suppression of cortisol production (Goenjian. Am J Psychiatry, 1995).

The amygdala, which is at the center of the brain’s fear circuitry, will continue to produce large amounts of CRF in PTSD victims (Baker and colleagues. “Serial CRF Levels in the CSF and Adrenal Activity in Combat Veterans with PTSD.” Am J Psychiatry (1999): 156).

However, the pituitary gland attempts to “protect itself” from the toxic assault posed by stress generated hormones by dynamically shifting into a defensive mode. Certain neuronal receptors are called into play in order to apply “brake systems.”

Brake systems express themselves in the brain by down-regulating receptors that activate systems, and up-regulating receptors that inhibit stress systems.

The sustained fear response in patients with PTSD is, to some extent, a result of a breakdown of these negative feedback mechanisms.

Negative feedback Glucocorticoid auto-receptors relay to the Messenger RNA, via second messengers in the hypothalamus, as a protective device during conditions of sustained stress to produce less CRF.

Several studies have indeed shown that stressed individuals do down-regulate. The hypothalamus will respond sluggishly in the production of ACTH when given CRF. The downstream effect is to discourage the adrenal glands from releasing cortisol.

Similarly, the pituitary gland has its “negative feedback” mechanism mediated by cortisol autoreceptors. Since the body “knows” that prolonged exposure to high cortisol is “bad,” Glucocorticoid receptors also function as “negative feedback loops.”

Their function is to “switch down” the production of ACTH from an overstimulated pituitary.

Hence, the Glucocorticoid receptor can also function as a messenger, warning the cells to prevent neuropeptides such as CRF in the hypothalamus, ACTH in the pituitary, and the hormonal cascade which would lead to the excess production of cortisol.

The ultimate effect of the brake system is to protect the CNS from the degenerative effects of the stress hormones and their downstream wear and tear on the body.

In patients with PTSD, the pituitary gland is therefore receiving two conflicting messages:

1.The CRF from the amygdala and hypothalamus is requesting the production of ACTH.

2.The Glucocorticoid negative auto-receptor is trying to prevent the production of ACT via a negative feedback loop.

The usual winner in this “tug-of-war” is the negative counter responses.

The net result of this tug-of-war may even lead to a decreased production of ACTH and cortisol.

Some investigators quickly went to test this negative feedback hypothesis.

Metyrapone is a substance that blocks cortisol synthesis.

One would therefore expect Metyrapone (by blocking the synthesis of cortisol) to eliminate the negative feedback effect of cortisol on the pituitary gland.

When given Metyrapone, victims of combat and rape (when compared with control subjects), did, as predicted, show much more elevation of ACTH and cortisol (Yehuda and colleagues. “Pychoneuroedocrinology,” 1996).

In other words, once the negative feedback loop of cortisol has been removed, CRF becomes free to stimulate the pituitary unimpeded by cortisol’s opposing (negative feedback) effect at the upregulated Glucocorticoid receptor site.

This study was replicated sufficiently to convince investigators that cortisol levels, per se, are a poor marker for the diagnosis of PTSD.

The “Dexamethasone Suppression Test” works in the opposite direction: Chronically stressed victims gradually up-regulate those receptors that are responsible for negative feedback loops.

When administered Dexamethasone (a potent Glucocorticoid), PTSD patients show a more dramatic decrease in ACTH production than controls.

In other words, PTSD patients produce less ACTH when given a potent Glucocorticoid agent such as Dexamethasone because they have activated negative feedback loops.

Goenjian and colleagues elegantly demonstrated this by measuring cortisol levels among adolescent survivors of the 1988 earthquake in Armenia before and after receiving Dexamethasone (Am J Psychiatry (1995): 153).

In PTSD victims, these Glucocorticoid receptors become up-regulated, function as a “brake-system,” and are dedicated to “containing” the stress cascade.

Naïve control subjects don’t have upregulated negative feedback loop receptors.

Therefore, when healthy volunteers receive Dexamethasone, the reduced production by the pituitary of ACTH is much less significant.

As long as PTSD remains untreated, a problem remains in that the Hypothalamic-Pituitary-Adrenal axis is being simultaneously stimulated (by increased CRF) and restrained (by hypersensitivity to normal or even low cortisol in the blood).

In an automobile, this would be like pushing the gas pedal and the brakes at the same time!

The continued state of this dynamic conflict has an obvious “wear and tear” effect on the entire aforementioned neuroendocrine system when PTSD is not treated.

In PTSD, this system remains “turned on” well after the immediate stress has subsided. It is easily reactivated to specific trauma triggers, a phenomenon referred to scientifically as “Long Term Potentiation.”

Initially, this facilitates the hippocampus to “over-memorize” traumatic events (Roozdaal and colleagues. “Amygdala Noradrenergic Influence Enables Enhancement of Memory Consolidation by Hippocampal Glucocorticoid Receptor Activation.” Proc Natl Sci USA, 1999).

This also expresses itself in the body via somatic and other stress related symptoms such as fatigue, various chronic pain syndromes, and increased stress on the immune and cardiovascular systems.

This is described in further detail by B. Rothschild in “The Psychophysiology of Trauma and Trauma Treatment” (New York: W.W. Norton, 2000).”

 

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