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The Neurobiology of Post-traumatic Stress Disorder

Authored by Henry Strick van Linschoten

In DSM-5 (2013) Post-traumatic Stress Disorder (PTSD) was taken out of the chapter on anxiety disorders and placed in a new chapter, ‘Trauma and stressor-related disorders’. Stress and trauma are understood to be similar in their impact on biological systems in the human body, although they are distinct in that trauma is always negative and overwhelming.

The general stress response – a summary

Selye (1956) developed the idea that when human beings, as well as most mammals, are exposed to a significant stressor, they typically respond with a ‘general adaptation syndrome’ – a system of reactions which can be described in three phases:

  • Phase 1: the immediate shock response – also described as the ‘fight or flight’ response, the acute stress response or hyper-arousal. This was first described by Cannon (e.g. 1932/1939), dominated by the locus coeruleus-noradrenergic system
  • Phase 2: resistance and adaptation – in which the hypothalamic-pituitary-adrenal axis (HPA axis) predominates
  • Phase 3: either exhaustion (including possibly lasting damage, dysregulation or resetting of certain biological systems), or recovery.

Out of the complexity of these multiple and interlocking responses, this part of the module highlights the noradrenergic system response and the HPA axis, examining how they differ in cases of PTSD from a normal or even severe stress response.

Stress, trauma and vulnerability to trauma

When the systematic study of PTSD began in the 1970s it was thought that PTSD was a response to trauma on a continuum with the normal stress response to a stressor. It has become clear that this is not the case. Even though the same biological systems are affected, the key characteristic of PTSD is that it represents a chronic, lasting dysregulation of the stress response systems which does not readjust itself to normal functioning automatically, and needs special intervention. Much research has been devoted to establishing exactly what these abnormalities in the different systems consist of, in the hope of providing guidance to more successful treatment (Sherin & Nemeroff, 2011).

Further research has been linked to our knowledge that when people are exposed to trauma, only some go on to develop lasting PTSD. From this, a question arose: is this due to something that happened during the exposure to trauma? In the period immediately after? Or might it be caused by a vulnerability to trauma that some people have more than others?

Sherin & Nemeroff (2011) propose that factors contributing to vulnerability for developing PTSD include “genetic susceptibility factors, female gender, prior trauma, early developmental stage at the time of traumatic exposure, and physical injury (including traumatic brain injury) at the time of psychological trauma.”

The locus coeruleus-noradrenergic system

The noradrenergic system regulates the first response to a shock caused by a stressor, initiating a major stress response in which separate systems inside and outside of the brain increase the availability of noradrenaline.

Noradrenaline (norepinephrine, according to the internationally preferred medical standard) is a monoamine – more specifically, a catecholamine – functioning as a hormone as well as a neurotransmitter. It cannot cross the blood-brain barrier. It is manufactured in the adrenal medulla (the central part of the adrenal glands lying on top of the kidneys). The cells manufacturing noradrenaline are under the direct control of the sympathetic branch of the autonomic nervous system. Inside the brain, noradrenaline is manufactured in the locus coeruleus: a small spot high up in the brain stem directly linked with a number of other major brain areas, including the amygdala.

As a neurotransmitter and a stress hormone, noradrenaline plays the main role in the process of mobilising the sympathetic nervous system in the ‘fight or flight’ response to stress, attack, medical insult or trauma. Via the blood circulation, it immediately raises the heart rate, increases blood pressure, causes the release of glucose reserves and increases blood flow to the muscles. In the brain it affects the amygdala, the hippocampus and numerous other parts.

In PTSD the noradrenergic system is deregulated. Base levels of noradrenaline tend to be in the normal range, but there is a chronic hyper-reactivity to stress, especially stress similar to the originating trauma of the PTSD (Southwick et al., 2005, 2011).

A thorough review of research into the noradrenergic systems is Berridge & Waterhouse (2003), whose summary of clinical implications for PTSD treatment (Berridge & Waterhouse, 2003: 67-68) is particularly interesting. It suggests that the noradrenergic system’s role in PTSD is less specific than was previously believed. Their conclusion is that the noradrenergic system may have more to do with handling the salience of stimuli than only with fear or threat detection.

The hypothalamic-pituitary-adrenal axis 

The hypothalamic-pituitary-adrenal axis (HPA axis) is the term for a system of organs and interactions which, together, form one of the main stress response systems of the body. It describes the connections between the hypothalamus (part of the brain), the anterior pituitary gland (lying just below the brain), and the cortical part of the adrenal glands (lying on top of the kidneys). The HPA axis is described in more detail in neuroscience and endocrinology textbooks: one description can be found in Southwick et al. (2005). The system regulates the presence of cortisol in the body and brain. Cortisol is a steroid hormone – more specifically, a corticosteroid and glucocorticoid – circulating in the blood and having a range of impacts. The hypothalamus is the part of the brain that links the nervous system to the endocrine system, and the HPA axis is one part of this influencing process.

Cortisol increases blood sugar levels, suppresses the immune system and modulates a number of metabolic systems. It can cross the blood-brain barrier and do damage to organs and parts of the brain, especially if it is present for a long time at elevated levels.

Because of its centrality in the stress response, there have been many studies of the HPA axis and how it is affected by PTSD. It is clear that there is an impact, but after the many studies done the effects of this impact remain unclear. There are PTSD populations in which basal cortisol levels are abnormally high, and ones where it is abnormally low. There is a range of speculative ideas about how this could be explained without a clear and universally accepted conclusion. One tentative conclusion from a major review by Yehuda (2005) is that perhaps the alterations to the HPA axis of people with PTSD do not go beyond a fairly normal range, and are not pathologically dysregulated.

A detailed survey article of the HPA axis is Tsigos & Chrousos (2002).

Other impacts of PTSD on neuro-anatomy – brief summary 

There are many other bodily systems affected by stress and PTSD with considerable complexity, especially as many of the substances and systems interact with each other and there are a number of identified negative feedback loops designed to preserve homeostasis.

Other substances which have been investigated in research studies of groups of people diagnosed with PTSD are as follows:

  • monoamine neurotransmitters dopamine and serotonin (with its receptor systems) (Southwick et al., 2010)
  • neurotransmitters ?-aminobutyric acid (GABA) and glutamate
  • neuropeptides corticotropin-releasing hormone (CRH), neuropeptide Y, endorphins and enkephalins

Attempts have been made to find drugs that impact on PTSD by adjusting the disturbances in these systems. As is known from subsequent randomised control trials to confirm effectiveness, these attempts have not had any significant success, demonstrating that it is much easier to identify neurobiological changes than to turn the findings into effective treatment options. A number of these studies can be found in Sherin & Nemeroff (2011).

Apart from investigating the impact of PTSD on specific biochemical systems, there has been research into the impact of PTSD on specific brain parts or locations, with the most interesting areas being the amygdala, hippocampus and (medial) prefrontal cortex. One main conclusion is that the amygdala – known to play a central role in regulating emotions, in particular, fear and threat assessment – is involved in the expression of PTSD symptoms. It appears that for many people with PTSD, the hippocampus volume is reduced. However, it remains uncertain whether this is a consequence of the trauma and its sequels, or whether the hippocampus was smaller already before the trauma and constituted a key vulnerability, making it more likely that this particular person would develop PTSD after the trauma. These problems are described in Skelton et al. (2012) and in Shin et al. (2005).

The interaction between amygdala and parts of the medial prefrontal cortex are probably important in stress response as well as in the development of PTSD. Further information on this line of enquiry can be found in Shin et al. (2005).

One interesting example of investigation becoming more precise and specific is Porges’ attempt to differentiate between the functions of parts of the autonomic nervous system. Porges believes that two branches of the vagal nerve, part of the autonomic nervous system, need far more attention, and are crucial in a more complete understanding of stress responses as well as the role of social interaction (Porges, 2011; the book summarises decades of research available in the form of articles).

Some of the tentative evidence regarding genetic abnormalities or specific epigenetic developments leading to a heightened vulnerability for the development of PTSD are summarised in Skelton et al. (2012), which also mentions that no hypothesis-neutral genome-wide association studies have been conducted for PTSD.

The linkage with traumatic brain injury 

It was conjectured by C.S. Myers (1916, 1940), and even before him, that the development of PTSD might not be a uniquely psychological phenomenon; rather, in many cases it could be reinforced by and connected with symptoms caused by brain injury as a result of physical shock, especially in cases of military ‘shell shock’ (an early designation of PTSD), earthquakes, car accidents, etc. Sherin & Nemeroff (2011) give special attention to the connections between research into PTSD and research into traumatic brain injury. A good source of information about traumatic brain injury is an introduction by Hurley (n.d.)available on the website of the National Center for PTSD.

The psychotherapeutic utility of neurobiological findings 

Neurobiological findings do not yet point to specific recommendations for treatment of PTSD in that no specific psychotherapeutic actions are proven to directly affect – for example – the noradrenaline level in the brain or the activation of the amygdala. “The best science can offer is a conceptual framework, supported but not yet proven by research.” (Siegel, 2010). However, the repetition of environmental stimuli is shown (in non-therapeutic studies) to have a lasting impact on people’s physiology, in structure, metabolism, and the setting of homeostasis points. There is a rapidly developing field of interpersonal neurobiology but this has not as yet resulted in findings that relate directly to the treatment of PTSD.

Van der Kolk (2006) suggests that if there is activity in particular brain areas then therapeutic action that affects other psychological functions involving those brain areas is likely to have an impact on the PTSD.

Allan Schore (2012: Ch. 2, 3, 8) reformulates complex PTSD as relational or attachment trauma, and his ideas are considered very helpful by certain practitioners. He expands on the differences between left and right brain, and on the importance of attachment theory and affect regulation.

Yehuda (2002) and Brewin (2005) give cautious examples of drawing clinical conclusions from neurobiological findings.

Fuchs (2004) provides a wide-ranging survey article of neurobiology and psychotherapy. This work makes links with the practice of psychotherapy, including attachment-based ways of working. It also mentions mirror neurons. However, it does not deal specifically with PTSD or trauma. Irle et al (2010) summarise the relationships between social phobia and the size of amygdala and hippocampus, summarising earlier research. This work is discussed in the context of psychotherapy.

As a separate but related issue, there is believed to be a role for psychoeducation in explaining the neurobiological symptoms of PTSD to psychotherapy clients/patients. (Taylor, (2006 – Ch. 4). It is suggested that this type of explanation may make psychotherapy more effective and reduce the drop-out rate for all forms of treatment of PTSD.

Material for further review 

Neurobiology is a separate professional specialty with a lot of medical detail and inevitably, the above descriptions were summarised. To get a deeper insight and to compare different ideas on applying neurobiological findings to the understanding of trauma and PTSD, the following sources are offered by recognised authorities in the field of neurobiology.

Bibliography 

Berridge, C.W. & Waterhouse, B.D. (2003). The locus coeruleus-noradrenergic system: Modulation of behavioral state and state-dependent cognitive processes. Brain Research Reviews, 42: 33-84.

Brewin, C.R. (2005). Implications for psychological intervention. In J.J. Vasterling & C.R. Brewin (Eds.), Neuropsychology of PTSD: Biological, Cognitive, and Clinical Perspectives. New York: Guilford Press.

Cannon, W.B. (1932/1939). The Wisdom of the Body. New York: W.W. Norton & Company, Inc.

Deak, T. & Panksepp, J. (2004). Stress, sleep and sexuality in psychiatric disorders. In J. Panksepp (Ed.), Textbook of Biological Psychiatry. Hoboken, NJ: Wiley-Liss.

Friedman, M.J., Keane, T.M. & Resick, P.A. (Eds.) (2010). Handbook of PTSD: Science and Practice. New York: Guilford Press.

Neurobiology and psychotherapy: an emerging dialogue. Current Opinion in Psychiatry 17: 479-485)

Fuchs, T. (2004). Neurobiology and psychotherapy: an emerging dialogue. Current Opinion in Psychiatry17: 479-485.

Hurley, R.A. (n.d.). Windows to the Brain: Neuropsychiatry of TBI, video/slide presentation for the National Center for PTSD, US Department of Veterans Affairs. Available at: www.ptsd.va.gov (accessed 28 May 2013).

Irle, E., Ruhleder, M., Lange, C., Seidler-Brandler, U., Salzer, S., Dechent, P., Weniger, G., Leibing, E. & Leichsenring, F. (2010). Reduced amygdalar and hippocampal size in adults with generalized social phobia. Journal of Psychiatry and Neuroscience 35(2): 126-131

Krystal, J.H. (2011). Stress, resiliency and PTSD: From neurobiology to treatment, video. Available at: www.youtube.com (accessed 28 May 2013).

Myers, C.S. (1916). Contributions to the study of shell shock. The Lancet, 187(4829): 608-613.

Myers, C.S. (1940). Shell Shock in France. 1914-1918: Based on a War Diary. Cambridge: Cambridge University Press.

Paquette, V., Levesque, J., Mensour, B., Leroux, J.M., Beaudoin, G., Bourgouin, P. & Beauregard, M. (2003). “Change the mind and you change the brain”: effects of cognitive-behavioral therapy on the neural correlates of spider phobia. Neuroimage 18(2): 401-409.

Porges, S.W. (2011). The Polyvagal Theory: Neurophysiological Foundations of Emotions, Attachment, Communication, Self-Regulation. New York: W.W. Norton & Company.

Schore, A.N. (2012). The Science of the Art of Psychotherapy. New York: W W Norton & Company.

Siegel, D.J. (2010). Mindsight: The New Science of Personal Transformation. New York: Bantam Books.

Selye, H. (1956). The Stress of Life. New York: McGraw-Hill.

Sharpley, C.F. (2010). A review of the neurobiological effects of psychotherapy for depression. Psychotherapy Theory, Research, Practice, Training. 47(4): 603-615.

Sherin, J.E. & Nemeroff, C.B. (2011). Post-traumatic stress disorder: The neurobiological impact of psychological trauma. Dialogues in Clinical Neuroscience 13(3): 263-278.

Shin, L.M., Rauch, S.L. & Pitman, R.K. (2005). Structural and functional anatomy of PTSD: Findings from neuroimaging research. In J.J. Vasterling & C.R. Brewin (Eds.), Neuropsychology of PTSD: Biological, Cognitive, and Clinical Perspectives. New York: Guilford Press.

Skelton, K., Ressler, K.J., Norrholm, S.D., Jovanovic, Y. & Bradley-Davino, B. (2012). PTSD and gene variants: New pathways and new thinking. Neuropharmacology 62(2): 628-637.

Southwick, S.M., Rasmussen, A., Barron, J. & Arnsten, A. (2005). Neurobiological and neurocognitive alterations in PTSD: A focus on norepinephrine, serotonin, and the hypothalamic-pituitary-adrenal axis. In J.J. Vasterling & C.R. Brewin (Eds.), Neuropsychology of PTSD: Biological, Cognitive, and Clinical Perspectives. New York: Guilford Press.

Southwick, S.M., Davis, L.L., Aikins, D.E., Rasmusson, A., Barron, J. & Morgan, C.A. (2010). Neurobiological alterations associated with PTSD. In M.J. Friedman, T.M. Keane & P.A. Resick (Eds.), Handbook of PTSD: Science and Practice. New York: Guilford Press.

Taylor, S. (2006). Clinician’s Guide to PTSD: A Cognitive-behavioral Approach. New York: Guilford Press.

Tsigos, C. & Chrousos, G.P. (2002). Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. Journal of Psychosomatic Research 53: 865-871.

Van der Kolk, B.A. (2006). Clinical implications of neuroscience research in PTSD. Annals of the New York Academy of Sciences 1071: 277-293.

Yehuda, R. (2002). Clinical relevance of biologic findings in PTSD. Psychiatric Quarterly 73(2): 123-133.

Yehuda, R. (2005). Neuroendocrine aspects of PTSD. In T. Steckler, N.H. Kalin & J.M.H.M. Reul (Eds.), Handbook of Stress and the Brain: Part 2: Stress: Integrative and Clinical Aspects. Amsterdam: Elsevier.

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