1. Post-Traumatic Stress Disorder
&
Acute Stress Disorder
A Neurobiological Perspective
John C. Caccaviello
Boston University School of Medicine

2. 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

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

4. What were the three brain regions that you
learned about?

5. Name 1 function of each.

6. 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_Am
ygdala_up.png

7. 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: 67-79
https://commons.wikimedia.org/w/index.php?curid=9451294
https://commons.wikimedia.org/wiki/File:Gray739-emphasizing-hippocampus.png

8. 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

9. 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

10. 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/

11. 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.

12. 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.

13. 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.

14. 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.

15. Hypothalamic-Pituitary-Adrenal Axis
(HPAAxis)
• 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

16. 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.jpg
Pariante, C. M. and S. L. Lightman (2008). "The HPA axis in
major depression: classical theories and new developments."
Trends Neurosci 31(9): 464-468.

17. What brain region, given your
pre-class readings and lecture
material, do you think is most
significantly affected in
PTSD/chronic stress?

18. Does this region decrease or
increase in size?

19. 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."

20. 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.

21. 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.

22. 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/

23. 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.

24. 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.

25. 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_KD
B_TMS_THERAPY_006.jpg

26. 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

27. 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.

28. 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.