Biological correlates of complex posttraumatic stress disorder—state of research and future directions

Figures & data

Table 1 Symptom domains related to PTSD and complex PTSD according to the proposed ICD-11 diagnostic criteria

PTSD	Complex PTSD
Re-experiencing a traumatic event	Re-experiencing a traumatic event
Avoiding reminders of the event	Avoiding reminders of the event
Hyperarousal	Hyperarousal
	Affect dysregulation
	Negative self-concept
	Problems in interpersonal relationships

Table 2 Studies on biological correlates of complex PTSD

Authors	Sample	Diagnostic tool	Method	Key findings
Thomaes et al., 2009	Child abuse-related complex PTSD	CAPS SIDES	fMRI	- ↑ activation in the left hippocampus and parahippocampal gyrus during preferential recall of negative words
Thomaes et al., 2010	Child abuse-related complex PTSD	CAPS SIDES	Structural MRI	- ↓ hippocampal volume - ↓ ACC volume - ↓ right orbitofrontal cortex volume
Thomaes et al., 2012	Child abuse-related complex PTSD	CAPS SIDES	fMRI	- trend for ↑ left anterior insula and dorsal ACC activation in the classic Stroop task - after therapy ↓ dorsal ACC and left anterior insula activation
Thomaes et al., 2013	Child abuse-related complex PTSD	CAPS SIDES	fMRI	(during encoding of negative words) - ↑ response in the left ventral ACC and dorsal ACC extending to the dorsomedial prefrontal cortex - trend for ↑ left hippocampus activation

fMRI=functional magnetic resonance imaging; complex PTSD=complex posttraumatic stress disorder; ACC=anterior cingulate cortex.

Table 3 Neurobiological correlates associated with PTSD and complex PTSD

	PTSD	Complex PTSD (pilot data in need of replication)
Structural imaging studies	- ↓ hippocampal volume - ↓ ACC volume	- ↓ hippocampal volume - ↓ ACC volume - ↓ right OFC volume
Functional imaging studies (implicated areas)	- hippocampus and parahippocampal gyrus - amygdala - prefrontal cortex - mid- and dorsal ACC - amygdala - ventromedial prefrontal cortex - inferior frontal gyrus	- hippocampus and parahippocampal gyrus - ventral and dorsal ACC - dorsomedial prefrontal cortex - ventrolateral prefrontal cortex - orbitofrontal cortex
Autonomic and Neurochemical measures	- heart rate - blood pressure - skin conductance - norepinephrine - serotonin - γ-aminobutyric acid (GABA) - glutamate - neuropeptide Y - endogenous opioid peptides - cortisol
Genetic predisposition	- polymorphisms in: - dopaminergic, serotonergic and norepinephrinergic genes - genes related to the HPA axis - neurotrophic factors - the retinoid-related orphan receptor alpha gene
Epigenetic factors	- DNA methylation of genes associated with immune functions - DNA methylation of repetitive elements

Studies assessing complex PTSD reviewed in the table included individuals with PTSD symptoms and complex PTSD symptoms consistent with the DESNOS conceptualization.

Table 4 Studies on biological correlates of PTSD related to childhood sexual abuse

Authors	Sample	Key findings
Schaefer et al., 2014	CSA-related PTSD	- ↑ serum levels of the fatty acid ethanolamide oleoylethanolamide
2007b	CSA-related PTSD	- resting afternoon hypocortisolemia with ↑ cortisol pulsatility
2005	CSA-related PTSD	- ↑ left amygdala activation with fear acquisition, and ↓ anterior cingulate function with fear extinction
2005	CSA-related PTSD	- ↑ in total T3 levels, total T3/free thyroxine ratio, free T3/total T3 ratio, and small ↓ in TSH
2004	CSA-related PTSD	- no significant differences in cardiovascular or hormonal response to standardized stress tests
2004	CSA-related PTSD	- indications for a dysfunction of a network of brain regions including the visual and parietal cortex and the anterior cingulate
2003b	CSA-related PTSD	- indications for a dysfunction of a network of brain regions including the medial prefrontal cortex, hippocampus and cingulate in a study of emotionally valenced declarative memory
2003a	CSA-related PTSD	- ↓ hippocampal volume and failure of hippocampal activation during verbal declarative memory tasks
1999	CSA-related PTSD	- ↑ index of lymphocyte activation (CD45RO/CD45RA)
1999	CSA-related PTSD	- ↑ orbitofrontal cortex and anterior temporal pole and ↓ increases in anterior cingulate gyrus blood flow compared to non-PTSD traumatized group
1999	CSA-related PTSD	- dysfunction of the medial prefrontal cortex, visual association cortex and hippocampus in pathological memories of childhood abuse - ↑ activation in motor cortex and posterior cingulate
1998	CSA-related PTSD	- larger physiologic responses during abuse-related scripts
1997	CSA-related PTSD	- ↑ suppression of plasma cortisol in response to dexamethasone
1995	CSA-related PTSD	- sympathetic and adrenocortical activation

CSA=childhood sexual abuse; PTSD=posttraumatic stress disorder.

Thomaes K., Dorrepaal E., Draijer N. P. J., De Ruiter M. B., Elzinga B. M., Van Balkom A. J., etal. Increased activation of the left hippocampus region in Complex PTSD during encoding and recognition of emotional words: A pilot study. Psychiatry Research. 2009; 171(1): 44–53.

 Google Scholar

Thomaes K., Dorrepaal E., Draijer N., De Ruiter M. B., Van Balkom A. J., Smit J. H., etal. Reduced anterior cingulate and orbitofrontal volumes in child abuse-related complex PTSD. Journal of Clinical Psychiatry. 2010; 71(12): 1636–1644.

 Google Scholar

Thomaes K., Dorrepaal E., Draijer N., De Ruiter M. B., Elzinga B. M., Van Balkom A. J., etal. Treatment effects on insular and anterior cingulate cortex activation during classic and emotional Stroop interference in child abuse-related complex post-traumatic stress disorder. Psychological Medicine. 2012; 42(11): 2337–2349.

 Google Scholar

Thomaes K., Dorrepaal E., Draijer N., De Ruiter M. B., Elzinga B. M., Sjoerds Z., etal. Increased anterior cingulate cortex and hippocampus activation in Complex PTSD during encoding of negative words. Social Cognitive and Affective Neuroscience. 2013; 8(2): 190–200.

 Google Scholar

Schaefer C., Enning F., Mueller J. K., Bumb J. M., Rohleder C., Odorfer T. M., etal. Fatty acid ethanolamide levels are altered in borderline personality and complex posttraumatic stress disorders. European Archives of Psychiatry and Clinical Neuroscience. 2014; 264(5): 459–463.

 Google Scholar

Binder E. B., Bradley R. G., Liu W., Epstein M. P., Deveau T. C., Mercer K. B., etal. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. The Journal of the American Medical Association. 2008; 299(11): 1291–1305.

 PubMed Web of Science ®Google Scholar

Bremner J. D., Randall P., Scott T. M., Bronen R. A., Seibyl J. P., Southwick S. M., etal. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. The American Journal of Psychiatry. 1995; 152(7): 973–981.

 Web of Science ®Google Scholar

Elklit A., Hyland P., Shevlin M. Evidence of symptom profiles consistent with posttraumatic stress disorder and complex posttraumatic stress disorder in different trauma samples. European Journal of Psychotraumatology. 2014; 5 24221, doi: http://dx.doi.org/10.3402/ejpt.v5.24221.

 Google Scholar

Klengel T., Mehta D., Anacker C., Rex-Haffner M., Pruessner J. C., Pariante C. M., etal. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neuroscience. 2013; 16(1): 33–41.

 Google Scholar

Bremner J. D., Vermetten E., Schmahl C., Vaccarino V., Vythilingam M., Afzal N., etal. Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychological Medicine. 2005; 35(6): 791–806.

 Google Scholar

Bremner J. D., Vythilingam M., Vermetten E., Southwick S. M., McGlashan T., Nazeer A., etal. MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. The American Journal of Psychiatry. 2003a; 160(5): 924–932.

 Web of Science ®Google Scholar

Bremner J. D., Vermetten E., Vythilingam M., Afzal N., Schmahl C., Elzinga B., etal. Neural correlates of the classic color and emotional stroop in women with abuse-related posttraumatic stress disorder. Biological Psychiatry. 2004; 55(6): 612–620.

 Google Scholar

Wilson S. N., Van der Kolk B., Burbridge J., Fisler R., Kradin R. Phenotype of blood lymphocytes in PTSD suggests chronic immune activation. Psychosomatics. 1999; 40(3): 222–225.

 Google Scholar

Shin L. M., McNally R. J., Kosslyn S. M., Thompson W. L., Rauch S. L., Alpert N. M., etal. Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: A PET investigation. The American Journal of Psychiatry. 1999; 156(4): 575–584. [PubMed Abstract].

 Google Scholar

Bremner J. D. Neuroimaging in posttraumatic stress disorder and other stress-related disorders. Neuroimaging Clinics of North America. 2007a; 17(4): 523–538.

 PubMed Web of Science ®Google Scholar

Orr S. P., Lasko N. B., Metzger L. J., Berry N. J., Ahern C. E., Pitman R. K. Psychophysiologic assessment of women with posttraumatic stress disorder resulting from childhood sexual abuse. Journal of Consulting and Clinical Psychology. 1998; 66(6): 906–913.

 Web of Science ®Google Scholar

Stein M. B., Yehuda R., Koverola C., Hanna C. Enhanced dexamethasone suppression of plasma cortisol in adult women traumatized by childhood sexual abuse. Biological Psychiatry. 1997; 42(8): 680–686.

 Google Scholar

Lanius R. A., Brand B., Vermetten E., Frewen P. A., Spiegel D. The dissociative subtype of posttraumatic stress disorder: Rationale, clinical and neurobiological evidence, and implications. Depression and Anxiety. 2012; 29(8): 701–708.

 Google Scholar