Post-Traumatic Stress Disorder &

Acute Stress DisorderA Neurobiological Perspective

John C. CaccavielloBoston University School of Medicine

Outline

• Relevant Neuroanatomy• Definitions: Acute Stress Disorder (ASD) and Post Traumatic Stress Disorder (PTSD)

• Effects of Stress on Cognitive Functioning• Hypothalamic-Pituitary-Adrenal Axis (HPA Axis)• Gross Anatomical Comparison• Current Treatment Options• The Future: Treatment Options being Explored• References

Brain Lobes and Orientation

http://static.memrise.com/uploads/mems/output/6698623-141104191214.pnghttps://classconnection.s3.amazonaws.com/845/flashcards/3675845/png/blah-1410DC391CF2B96591B.pnghttps://commons.wikimedia.org/wiki/File:Blausen_0111_BrainLobes.png

What were the three brain regions that you learned about?

Name 1 function of each.

Amygdala Group of nuclei within the

temporal lobe that are involved in memory, decision making, emotions, and other limbic system functions. Limbic – emotion,

motivation, behavior

Coronal MRI section of right amygdala.

Shin, L. M., et al. (2006). "Amygdala, medial prefrontal cortex, and hippocampal function in PTSD." Ann N Y Acad Sci 1071: 67-79.https://commons.wikimedia.org/wiki/File:MRI_Location_Amygdala_up.png

Hippocampus Part of limbic system. Involved in the consolidation of short-term memory to long-term memory.

Located in medial temporal lobe.

Shin, L. M., et al. (2006). "Amygdala, medial prefrontal cortex, and hippocampal function in PTSD." Ann N Y Acad Sci 1071: 67-79https://commons.wikimedia.org/w/index.php?curid=9451294https://commons.wikimedia.org/wiki/File:Gray739-emphasizing-hippocampus.png

Medial Prefrontal Cortex

Cortex towards the anterior of the frontal lobe.

Planning of complex behavior, personality, decision making, social behavior, executive function, formation of thoughts, internal goals/motivation, and specific forms of learning.

https://commons.wikimedia.org/wiki/File:Prefrontal_cortex_(left)_-_medial_view.png

Definitions: Acute Stress Disorder

• Psychiatric disorder following traumatic experience.• Acute symptoms occur between 3 days and 1 month (DSM V).

• Altered “fear-processing” pathway mediated by Amygdala and prefrontal cortex hyperactivity. Discovered through face-matching fMRI task.

Shin, L. M., et al. (2006). "Amygdala, medial prefrontal cortex, and hippocampal function in PTSD." Ann N Y Acad Sci 1071: 67-79.

Reynaud, E., Guedj, E., Trousselard, M., El Khoury-Malhame, M., Zendjidjian, X., Fakra, E., . . . Khalfa, S. (2015). Acute stress disorder modifies cerebral activity of amygdala and prefrontal cortex. Cogn Neurosci, 6(1), 39-43. doi:10.1080/17588928.2014.996212

Face Matching Task

• Face matching – comparing faces or selecting one face, in a different orientation, that matches.

http://sitn.hms.harvard.edu/flash/2015/the-human-microbiome-and-media-confusion/

Definitions: PTSD• Symptoms persistent after a month following traumatic event that is diagnosed at least 1 month after traumatic event (DSM V). Acute PTSD– 1-3 months Chronic PTSD– 3 months or more

• At the time of the trauma, the Hippocampus is suppressed by over-reactive adrenaline response. Prevents proper “recording” of the memory. Re-experiencing stimuli similar to trauma may induce a flashback.

Medina, J. (2008). "Neurobiology of PTSD." MOLECULES OF THE MIND: 29-33.

Definitions: PTSD

• Research in PTSD on specific populations. Veterans/Traumatic Brain Injury (TBI) Often comorbidity

• Currently, research on the neurobiology of PTSD returns mixed results. Sometimes, but not always, there is:

A heightened cortisol level Atrophy Hyper/Hypoactivation

Medina, J. (2008). "Neurobiology of PTSD." MOLECULES OF THE MIND: 29-33.

Effects of Stress on Cognitive Functioning

• Cortisol – Steroid hormone released by the adrenal gland. Released as a response to stress and low blood sugar.

• High Affinity Receptors – Easily binds molecules (low concentrations of molecules).

• Low Affinity Receptors – More difficult to bind molecules (increased concentration).

Medina, J. (2008). "Neurobiology of PTSD." MOLECULES OF THE MIND: 29-33.

Effects of Stress on Cognitive Functioning

• Moderate stress -> Cortisol binds to high affinity receptors -> Hippocampus activated and subjects performed better on tasks.

• Severe/Chronic Stress -> Cortisol binds to both low and high affinity receptors -> Hippocampus inhibited; subjects perform worse on tasks. (Since only high levels of cortisol can significantly activate low affinity receptors).

Medina, J. (2008). "Neurobiology of PTSD." MOLECULES OF THE MIND: 29-33.

Hypothalamic-Pituitary-Adrenal Axis (HPA Axis)

• Hypothalamus – Synthesis and secretion of hormones which stimulate/inhibit pituitary from secreting hormones. • Pituitary gland – Regulation of stress via hormone secretion.• Adrenal cortex – Production of glucocorticoids (steroid hormone) such as cortisol. Glands located above kidneys

Hypothalamic-Pituitary-Adrenal Axis

1. Chronic stress. 2. Increases in glucocorticoids. 3. Cellular changes in the hippocampus. 4. Decreased regulation of cortisol.

http://www.biology.ucr.edu/people/faculty/Garland/HPA_axis.jpgPariante, C. M. and S. L. Lightman (2008). "The HPA axis in major depression: classical theories and new developments." Trends Neurosci 31(9): 464-468.

What brain region, given your pre-class readings and lecture material, do you think is most

significantly affected in PTSD/chronic stress?

Does this region decrease or increase in size?

Hippocampus• Vietnam combat

veterans. • Brain Imaging (MRI)• Combat Veterans

found to have 8% reduction in right hippocampal volume.

• No significant differences in any other region.

• Measurable loss of neurons due to neurotoxicity (cortisol)

J. Douglas Bremner, M. D. (2000). "The Invisible Epidemic: Post-Traumatic Stress Disorder, Memory and the Brain."

Current Treatment Options

• Critical Incident Stress Management (CISM) (First Responders)

• Cognitive Behavioral Therapy Psychosocial intervention that teaches improved coping strategies and removing unwanted behaviors and emotions.

• Interpersonal psychotherapy Support groups with other persons with PTSD or Acute Stress Disorder.

Burkle, F. M., Jr. (1996). "Acute-phase mental health consequences of disasters: implications for triage and emergency medical services." Ann Emerg Med 28(2): 119-128.Wee, D. F., et al. (1999). "The effects of critical incident stress debriefing (CISD) on emergency medical services personnel following the Los Angeles Civil Disturbance." Int J Emerg Ment Health 1(1): 33-37.

Current Treatment Options

• Most accepted method is behavioral + psychotherapeutics

• Psychotherapeutics SSRIs – Antidepressant

Serotonin – Neurotransmitter associated with feeling of well-being Comorbidity with Depression. Promotes neurogenesis (growth of neurons) in hippocampus.

Benzodiazepines – Anxiolytics (anxiety reducing) Cannabinoids – Research pending

Burkle, F. M., Jr. (1996). "Acute-phase mental health consequences of disasters: implications for triage and emergency medical services." Ann Emerg Med 28(2): 119-128.Wee, D. F., et al. (1999). "The effects of critical incident stress debriefing (CISD) on emergency medical services personnel following the Los Angeles Civil Disturbance." Int J Emerg Ment Health 1(1): 33-37.Bremner, J. D. (2006). "Traumatic stress: effects on the brain." Dialogues Clin Neurosci 8(4): 445-461.

The Future

• Oculus Rift• Immersive Cognitive

Behavioral Therapy • Potential involvement

of Virtual Reality Re-exposure to the incident May allow for

psychological debriefing and reprocessing of the event within the hippocampus.

Boggio, P. S., et al. (2010). "Noninvasive brain stimulation with high-frequency and low-intensity repetitive transcranial magnetic stimulation treatment for posttraumatic stress disorder." J Clin Psychiatry 71(8): 992-999.http://www.kotaku.com.au/2016/10/how-to-play-virtual-reality-games-on-a-budget/

The Future: Treatment Options being Explored

• Fear Response Extinction Learning with MDMA MDMA (ecstasy) - Entering Phase III clinical trials in April 2017.

Cognitive Behavioral Therapy in conjunction with MDMA may allow patients to reprocess the event without becoming emotionally overwhelmed. MDMA has been shown to decrease fear response (biochemical process).

Philipps, D. (2016). "F.D.A. Agrees to New Trials for Ecstasy as Relief for PTSD Patients." New York Times.Boggio, P. S., et al. (2010). "Noninvasive brain stimulation with high-frequency and low-intensity repetitive transcranial magnetic stimulation treatment for posttraumatic stress disorder." J Clin Psychiatry 71(8): 992-999.

The Future: Treatment Options being Explored

• Research on psychoactive compounds to decrease hyperactivity in the Amygdala and prefrontal cortex.

• Noninvasive Brain Stimulation with High and Low-Frequency Intensity Repetitive Transcranial Magnetic Stimulation Treatment. Double blind experiment; placebo-controlled phase II trial. Wechsler Memory Scale Led to a significant decrease in manifestation of symptoms as shown by the PTSD Checklist and Treatment Outcome PTSD Scale and significant improvement in mood/anxiety.

Results long lasting; results significant at 3-month follow up.Gilbert, D. L. (2007). "Low and high-frequency repetitive transcranial magnetic stimulation for the treatment of spasticity." Dev Med Child Neurol 49(7): 486.

Transcranial Magnetic Stimulation (TMS)• High (10-20 Hz) and

low (1-5 Hz) frequency repetive TMS

• Frequency dependent opposite effect

• If one frequency inhibits, the other promotes

• Used mostly in depression

• Faraday’s law• Magnetic field

interacts with an electric force

https://c.o0bg.com/rf/image_960w/Boston/2011-2020/2016/03/15/BostonGlobe.com/Lifestyle/Images/160314_KDB_TMS_THERAPY_006.jpg

References:• Berlim, M. T., Van den Eynde, F., & Jeff Daskalakis, Z. (2013). Clinically meaningful efficacy and acceptability of low-frequency

repetitive transcranial magnetic stimulation (rTMS) for treating primary major depression: a meta-analysis of randomized, double-blind and sham-controlled trials. Neuropsychopharmacology, 38(4), 543-551. doi:10.1038/npp.2012.237

• Boggio, P. S., Rocha, M., Oliveira, M. O., Fecteau, S., Cohen, R. B., Campanha, C., . . . Fregni, F. (2010). Noninvasive brain stimulation with high-frequency and low-intensity repetitive transcranial magnetic stimulation treatment for posttraumatic stress disorder. J Clin Psychiatry, 71(8), 992-999. doi:10.4088/JCP.08m04638blu

• Bremner, J. D. (2006). "Traumatic stress: effects on the brain." Dialogues Clin Neurosci 8(4): 445-461.

• Bremner, J. D., et al. (1995). "MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder." Am J Psychiatry 152(7): 973-981.

• Burkle, F. M., Jr. (1996). Acute-phase mental health consequences of disasters: implications for triage and emergency medical services. Ann Emerg Med, 28(2), 119-128.

• Classen, C., Koopman, C., Hales, R., & Spiegel, D. (1998). Acute stress disorder as a predictor of posttraumatic stress symptoms. Am J Psychiatry, 155(5), 620-624. doi:10.1176/ajp.155.5.620

• Eche, J., Mondino, M., Haesebaert, F., Saoud, M., Poulet, E., & Brunelin, J. (2012). Low- vs High-Frequency Repetitive Transcranial Magnetic Stimulation as an Add-On Treatment for Refractory Depression. Front Psychiatry, 3, 13. doi:10.3389/fpsyt.2012.00013

• Gilbert, D. L. (2007). "Low and high-frequency repetitive transcranial magnetic stimulation for the treatment of spasticity." Dev Med Child Neurol 49(7): 486.

• J. Douglas Bremner, M. D. (2000). The Invisible Epidemic: Post-Traumatic Stress Disorder, Memory and the Brain. • Jakupcak, M., Roberts, L. J., Martell, C., Mulick, P., Michael, S., Reed, R., . . . McFall, M. (2006). A pilot study of behavioral activation for

veterans with posttraumatic stress disorder. J Trauma Stress, 19(3), 387-391. doi:10.1002/jts.20125• Kraft, D. (2012). Panic Disorder Without Agoraphobia. A Multi-Modal Approach: Solution-Focused Therapy, Hypnosis and

Psychodynamic Psychotherapy. Journal of Integrative Research, Counselling and Psychotherapy, 1(1), 4-15. • Medina, J. (2008). Neurobiology of PTSD. MOLECULES OF THE MIND, 29-33. • Mol, S. S., Arntz, A., Metsemakers, J. F., Dinant, G. J., Vilters-van Montfort, P. A., & Knottnerus, J. A. (2005). Symptoms of post-traumatic

stress disorder after non-traumatic events: evidence from an open population study. Br J Psychiatry, 186, 494-499. doi:10.1192/bjp.186.6.494

References:• Pariante, C. M., & Lightman, S. L. (2008). The HPA axis in major depression: classical theories and new

developments. Trends Neurosci, 31(9), 464-468. doi:10.1016/j.tins.2008.06.006• Philipps, D. (2016). F.D.A. Agrees to New Trials for Ecstasy as Relief for PTSD Patients. New York Times. • Reynaud, E., Guedj, E., Trousselard, M., El Khoury-Malhame, M., Zendjidjian, X., Fakra, E., . . . Khalfa, S. (2015).

Acute stress disorder modifies cerebral activity of amygdala and prefrontal cortex. Cogn Neurosci, 6(1), 39-43. doi:10.1080/17588928.2014.996212

• Shin, L. M., Rauch, S. L., & Pitman, R. K. (2006). Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann N Y Acad Sci, 1071, 67-79. doi:10.1196/annals.1364.007

• Speer, A. M., Kimbrell, T. A., Wassermann, E. M., J, D. R., Willis, M. W., Herscovitch, P., & Post, R. M. (2000). Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients. Biol Psychiatry, 48(12), 1133-1141.

• Valle, A. C., Dionisio, K., Pitskel, N. B., Pascual-Leone, A., Orsati, F., Ferreira, M. J., . . . Fregni, F. (2007). Low and high frequency repetitive transcranial magnetic stimulation for the treatment of spasticity. Dev Med Child Neurol, 49(7), 534-538. doi:10.1111/j.1469-8749.2007.00534.x

• Wee, D. F., Mills, D. M., & Koehler, G. (1999). The effects of critical incident stress debriefing (CISD) on emergency medical services personnel following the Los Angeles Civil Disturbance. Int J Emerg Ment Health, 1(1), 33-37.

Contact Information and Acknowledgements

• John Caccaviello• Jcaccavi@bu.edu

• I would like to acknowledge and thank: Nina Shaafi Kabiri for letting me present in her course and for her

mentorship The Vesalius committee for their support and assistance. Dr. Kevin Thomas and those in the laboratory for human neurobiology

for providing feedback at my practice sessions.