© 2013 Boyajyan et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

## **Alterations in the Immune Response, Apoptosis and Synaptic Plasticity in Posttraumatic Stress Disorder: Molecular Indicators and Relation to Clinical Symptoms**

Anna Boyajyan, Gohar Mkrtchyan, Lilit Hovhannisyan and Diana Avetyan

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52693

## **1. Introduction**

[147] Brush FR, Isaacson MD, Pellegrino LJ, Rykaszewski IM, Shain CN. Characteristics of the pituitary-adrenal system in the Syracuse high- and low-avoidance strains of rats

[148] Gupta P, Brush FR. Differential behavioral and endocrinological effects of corticotro‐ pin-releasing hormone (CRH) in the Syracuse high- and low-avoidance rats. Horm

[149] Del Paine SN, Brush FR. Adrenal morphometry in unilateral and sham adrenalec‐ tomized Syracuse high and low avoidance rats. Physiol Behav. 1990;48(2):299-306.

[150] Trullas R, Skolnick P. Differences in fear motivated behaviors among inbred mouse

[151] Gunay H, Tutuncu R, Aydin S, Dag E, Abasli D. Decreased plasma nesfatin-1 levels in patients with generalized anxiety disorder. Psychoneuroendocrinology 2012 Epub

[152] Pitsavos C, Panagiotakos DB, Papageorgiou C, Tsetsekou E, Soldatos C, Stefanadis C. Anxiety in relation to inflammation and coagulation markers, among healthy adults:

[153] MacLeod C, Mathews A. Cognitive bias modification approaches to anxiety. Annu

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strains. Psychopharmacology 1993;111(3):323-31.

the ATTICA study. Atherosclerosis 2006;185(2):320-6.

tivity to stress. Biol Psychiatry 2010;67(4):371-7.

Rev Clin Psychol. 2012;8:189-217.

Behav. 1998;34(3):262-7.

104 New Insights into Anxiety Disorders

ahead of print.

Posttraumatic stress disorder (PTSD) (ICD-10 codes: F43.1, F62.0; DSM-IV-TR code: 309.81) [1, 2] is a complex severe and chronic psychiatric illness influenced by environmental and genetic factors [3-10]. PTSD is an anxiety disorder developed in a person experiencing, wit‐ nessing, or learning about an extreme physically or psychologically distressing event, asso‐ ciated with unprecedented violence [11, 12].  Individuals who experience a trauma of this nature may develop symptoms that fall into three distinct clusters: re-experiencing phenomenon; avoidance and numbing; and autonomic hyperarousal. Symptoms usually be‐ gin within the first 3 months after the traumatic event and last for many years, although there may be a delay of months, or even years, before symptoms appear. PTSD patients are characterized by severe emotional state, sharp reduction in adaptive and information receiv‐ ing abilities. They usually remain out of society, become drug addicted, alcoholic and often commit suicide [21-24]. Degrees of risk to develop PTSD from different traumatic events are presented in table 1.

It was shown that 37% of Cambodian refugees, 86% of women refugees in Kabul and Paki‐ stan and 75% of Bosnian refugee women suffer from PTSD. In USA 60% of female rape sur‐

© 2013 Boyajyan et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

vivors and 35% of UK adult rape victims are affected by PTSD. Similar to adults, some children, who witness or experience traumatic events, develop PTSD.  In general, 10% of the world pop‐ ulation is suffering from PTSD, and 70% is under the risk of developing PTSD [26-28].

Alterations in the Immune Response, Apoptosis and Synaptic Plasticity in Posttraumatic Stress Disorder

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Patients with PTSD have a reduced quality of life, an increased number of suicides and hos‐ pitalizations, high frequency of depressions, alcohol and drug abuse; social, family life and

Molecular mechanisms of generation and development of PTSD and their relation to the clinical psychopathologic criteria of this disorder are not clear yet. The lack of knowledge in this field significantly limits the development of effective therapeutic approaches for treat‐

PTSD is characterized by the central and autonomic nervous systems hyperarousal that is caused by functional changes in the limbic system, which is located between the brainstem and the cerebral cortex and coordinates their activities.  It also plays a central role in memory processing. The hippocampus and amygdala, parts of the limbic system, regulate learning, memory, and emotion. The amygdala is important for the regulation of emotional memories, particularly for fear causing memories. It has been pro‐ ven that amygdala is activated in the extreme situations. The hippocampus, on the contrary, is suppressed in these conditions. It has been shown that PTSD is characterized by function‐

A number of data suggests that alterations in the hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal system (SAS) play a leading role in PTSD pathogenesis [13, 14, 44]. Thus, PTSD, as compared to norm, is characterized by low cortisol levels in plasma and sali‐ va [45], whereas elevated levels of dehydroepiandrosterone (DHEA) and DHEA-sulfate are detected in this disorder [44-46]. Moreover, increased levels of corticotrophin realizing hor‐ mone positively correlated with the high levels of cortisol in cerebrospinal fluid of PTSD pa‐ tients were observed [47]. Also, PTSD is characterized by increased glucocorticoid receptor sensitivity [48]. An increased levels of noradrenaline, neurotransmitter of central and pe‐ ripheral sympathetic (adrenergic) nervous system, were detected in the cerebrospinal fluid of PTSD patients [49]. Noradrenaline is considered as one of the important mediators of cen‐ tral and peripheral autonomic stress response and has an important role in the regulation process of emotional memory [50]. It was also shown that high levels of noradrenalinefof the PTSD of the PTSD in urine positively correlate with the symptoms of PTSD [51]. In addition, the increased levels of dopamine, another mediator of the sympathetic nervous system and precursor of noradrenaline, were found in the blood and body fluids of PTSD-affected sub‐

There are several data indicating assumption that functional abnormalities in neuroendo‐ crine system detected in PTSD patients are conditioned by hereditary factors [54]. Thus, as it

ment of PTSD-affected subjects and prevention of further complications.

al hyperactivity of the amygdala and hypoactivity of the hippocampus [41-43].

**2. Neuroendocrine alterations in PTSD**

work become impossible.

jects [51-53].

Equally as staggering are statistics, which monitor the incidence of PTSD among combat veterans. Here, 30% of the American Vietnam veterans and 56% of Australia's Vietnam War veterans, 10% of Desert Storm veterans, 31% of Australia's Gulf War veterans, 6-11% of Af‐ ghanistan veterans and 12-20% of Iraq veterans in the US suffer from PTSD [25-28].

Statistical data also demonstrates that women are more than twice as likely to develop PTSD as men. Available data suggests that about 8% of men and 20% of women go on to develop PTSD [26, 29-31]. Is was also shown that PTSD is most often developed in representatives of national minorities, people surviving stressful events at list once in their life, as well as in people with low level of education, mental problems, having mentally ill family member or experiencing lack of support from their family members or friends [26, 29-31]. Currently, for about 7-8% of the USA population, 2-3% of the UK population, 6.4% of Australians and 3% of Cambodians suffer from PTSD [26-28].

**Table 1.** Risk for developing PTSD depending on traumatic event [25-27]

In Armenia PTSD is quite common as well, and is basically found among the descendants of Armenian Genocide victims, including current generation, combatants, refugees and victims of earthquake [32-40]. Thus, according to Goenjian et al, 73% among 1988 Spitak Earthquake survivors developed PTSD 4.5 years after the disaster [36]. In general, 10% of the world pop‐ ulation is suffering from PTSD, and 70% is under the risk of developing PTSD [26-28].

Patients with PTSD have a reduced quality of life, an increased number of suicides and hos‐ pitalizations, high frequency of depressions, alcohol and drug abuse; social, family life and work become impossible.

Molecular mechanisms of generation and development of PTSD and their relation to the clinical psychopathologic criteria of this disorder are not clear yet. The lack of knowledge in this field significantly limits the development of effective therapeutic approaches for treat‐ ment of PTSD-affected subjects and prevention of further complications.

## **2. Neuroendocrine alterations in PTSD**

vivors and 35% of UK adult rape victims are affected by PTSD. Similar to adults, some children, who witness or experience traumatic events, develop PTSD. Thus, in the USA 90-100% of children, who witness a parental homicide or sexual assault, develop PTSD, and

Equally as staggering are statistics, which monitor the incidence of PTSD among combat veterans. Here, 30% of the American Vietnam veterans and 56% of Australia's Vietnam War veterans, 10% of Desert Storm veterans, 31% of Australia's Gulf War veterans, 6-11% of Af‐

Statistical data also demonstrates that women are more than twice as likely to develop PTSD as men. Available data suggests that about 8% of men and 20% of women go on to develop PTSD [26, 29-31]. Is was also shown that PTSD is most often developed in representatives of national minorities, people surviving stressful events at list once in their life, as well as in people with low level of education, mental problems, having mentally ill family member or experiencing lack of support from their family members or friends [26, 29-31]. Currently, for about 7-8% of the USA population, 2-3% of the UK population, 6.4% of Australians and 3%

> **Traumatic event Degree of risk, %** Rape 49.0

Other types of sexual violence 23.7 Physical violence, severe beating 31.9 Accident and/or serious injuries 16.8-20.0 Stabbing, shooting 15.4

Sudden death of a family member or friend 14.3

Natural disasters - hurricane - tsunami - earthquake (adults/youths)

**Table 1.** Risk for developing PTSD depending on traumatic event [25-27]

Child's life-threatening illness 10.4 Murder, death or serious injury witness 7.3

> Man-made disasters 29.0 Terrorist attacks 28.0

In Armenia PTSD is quite common as well, and is basically found among the descendants of Armenian Genocide victims, including current generation, combatants, refugees and victims of earthquake [32-40]. Thus, according to Goenjian et al, 73% among 1988 Spitak Earthquake

2.0-3.8 30.0-50.0 32.0-60.0 / 26.0-95.0

in the UK 50% of sexually abused children are affected by this disorder [25-27].

ghanistan veterans and 12-20% of Iraq veterans in the US suffer from PTSD [25-28].

of Cambodians suffer from PTSD [26-28].

106 New Insights into Anxiety Disorders

PTSD is characterized by the central and autonomic nervous systems hyperarousal that is caused by functional changes in the limbic system, which is located between the brainstem and the cerebral cortex and coordinates their activities.  It also plays a central role in memory processing. The hippocampus and amygdala, parts of the limbic system, regulate learning, memory, and emotion. The amygdala is important for the regulation of emotional memories, particularly for fear causing memories. It has been pro‐ ven that amygdala is activated in the extreme situations. The hippocampus, on the contrary, is suppressed in these conditions. It has been shown that PTSD is characterized by function‐ al hyperactivity of the amygdala and hypoactivity of the hippocampus [41-43].

A number of data suggests that alterations in the hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal system (SAS) play a leading role in PTSD pathogenesis [13, 14, 44]. Thus, PTSD, as compared to norm, is characterized by low cortisol levels in plasma and sali‐ va [45], whereas elevated levels of dehydroepiandrosterone (DHEA) and DHEA-sulfate are detected in this disorder [44-46]. Moreover, increased levels of corticotrophin realizing hor‐ mone positively correlated with the high levels of cortisol in cerebrospinal fluid of PTSD pa‐ tients were observed [47]. Also, PTSD is characterized by increased glucocorticoid receptor sensitivity [48]. An increased levels of noradrenaline, neurotransmitter of central and pe‐ ripheral sympathetic (adrenergic) nervous system, were detected in the cerebrospinal fluid of PTSD patients [49]. Noradrenaline is considered as one of the important mediators of cen‐ tral and peripheral autonomic stress response and has an important role in the regulation process of emotional memory [50]. It was also shown that high levels of noradrenalinefof the PTSD of the PTSD in urine positively correlate with the symptoms of PTSD [51]. In addition, the increased levels of dopamine, another mediator of the sympathetic nervous system and precursor of noradrenaline, were found in the blood and body fluids of PTSD-affected sub‐ jects [51-53].

There are several data indicating assumption that functional abnormalities in neuroendo‐ crine system detected in PTSD patients are conditioned by hereditary factors [54]. Thus, as it follows from table 2, PTSD is associated with the genetic mutations in a number of genes encoding neurotransmitters and hormones, their biosynthesis enzymes, receptors and trans‐ porters. Interestingly, 6 of the candidate genes for PTSD showed in the table 1 belong to the dopamine system. A positive association between the risk for development PTSD and TaqIA polymorphism of the dopamine D2 receptor gene was found [55]. Also, positive association was revealed between tandem repeat polymorphism of dopamine transporter gene and PTSD [56] as well as between dopamine D4 transporter gene long allele and severity of PTSD symptoms [57].

**3. Immune system alterations in PTSD**

total number or these cells, as well as a number of CD16+

ness, these alterations may be either under- or over-represented [97, 107].

T-killer cells (CD8+

**3.1. Cytokine network in PTSD**

actions in PTSD pathogenesis (table 3).

jects involved in our study.

Promising studies suggest the involvement of alterations in the immune status [48, 79-86], particularly low-grade inflammatory reactions, in the pathogenesis of PTSD [87-97]. Тhus, PTSD patients are characterized by hyperactivation of lymphocytes [80] and increased levels of lipopolysaccharide (LPS)-stimulated expression of interleukin (IL)-6, tumor necrosis fac‐ tor (TNF)-α, and interferon (IFN)-γ in immunocompetent cells [81, 82]. Segman et al detect‐ ed over-expression of immune response-related genes in monocytes of PTSD-affected subjects [85]. Also, in chronic PTSD patients, as compared to norm, a decreased number of

Alterations in the Immune Response, Apoptosis and Synaptic Plasticity in Posttraumatic Stress Disorder

) [98, 99] and an increase number of T-helper cells (CD4+

and CD56+

been shown, whereas in PTSD patients immediately after a traumatic event a decreased number of T-helper cells was detected [99]. A number of experimental data indicates that natural killer cells' cytotoxicity in PTSD is lower than in norm [97, 99, 101-104], while the

lation is higher than in norm [99, 104]. At the same time some studies show that natural kill‐ er cells' cytotoxicity in PTSD patients is higher than in healthy subjects [105, 106]. The analysis of the above mentioned data revealed altered cell-mediated immunity in PTSD pa‐ tients and demonstrates that depending on traumatic event, duration and stage of the ill‐

A number of studies have demonstrated changes in a functional state of cytokines and their receptors, important mediators and regulators of the immune response in PTSD-affected subjects. Here the increased blood levels of proinflammatory cytokines (e.g. IL-1β, IL-6, TNF-α, INF-γ) and decreased levels of anti-inflammatory cytokines (e.g. IL-4) are detected in chronic PTSD patients indicating the involvement of low-grade systemic inflammatory re‐

In our own study the levels of proinflammatory and chemotactic cytokines IL-1β, IL-6, TNFα, IL-8 and MCP-1 in the blood serum of chronic PTSD patients (combat veterans) and ageand sex-matched healthy subjects (HS; a control group) were determined using enzymelinked immunosorbent assay (ELISA). Assessment of possible correlation of the above mentioned parameters with each other and with the expression of PTSD clinical symptoms was also performed. The latest were evaluated using Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID PTSD module) [112] and Clinician-Administered PTSD Scale (CAPS) [113]. In particular, we assessed correlation between the levels of cytokines and the degree of expression of such PTSD clinical symptoms as persistent re-experiencing of the traumatic event (B cluster), persistent avoidance of stimuli associated with the trauma and emotional numbing (C cluster); persistent symptoms of increasing arousal (D cluster) [2]. In table 4 brief descriptions of the study groups is given. Table 5 demonstrates the indi‐ vidual symptom clusters (B, C, and D criteria), and total CAPS scores of PTSD-affected sub‐

) [98, 100] has

cells in their total popu‐

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109

The γ-3 subunit of γ-aminobutyric acid, another mediator of nervous system, has also been studied in PSTD patients. Patients heterozygous for this gene have a higher probability of developing somatic symptoms of PTSD, sleeping disturbances, fair and depression than ho‐ mozygous patients [58]. The studies of serotonin transporter gene showed that PTSD pa‐ tients carrying one or two short alleles of this gene have a higher level of depression and suicide compared to carriers of long allele, which has more transcriptional power [59, 60]. The association of the serotonin transporter repeat polymorphism with PTSD was also de‐ scribed [61-63]. Interestingly, recent study of 200 individuals from 12 multigenerational fam‐ ilies survived 1998 Spitak earthquake in Armenia demonstrated that PTSD is developing in those individuals, who carry mutations of tryptophan hydroxylase 1 and 2, the rate-limiting enzyme of serotonin biosynthesis [64].

**Table 2.** PTSD-related changes in the neuroendocrine system

## **3. Immune system alterations in PTSD**

follows from table 2, PTSD is associated with the genetic mutations in a number of genes encoding neurotransmitters and hormones, their biosynthesis enzymes, receptors and trans‐ porters. Interestingly, 6 of the candidate genes for PTSD showed in the table 1 belong to the dopamine system. A positive association between the risk for development PTSD and TaqIA polymorphism of the dopamine D2 receptor gene was found [55]. Also, positive association was revealed between tandem repeat polymorphism of dopamine transporter gene and PTSD [56] as well as between dopamine D4 transporter gene long allele and severity of

The γ-3 subunit of γ-aminobutyric acid, another mediator of nervous system, has also been studied in PSTD patients. Patients heterozygous for this gene have a higher probability of developing somatic symptoms of PTSD, sleeping disturbances, fair and depression than ho‐ mozygous patients [58]. The studies of serotonin transporter gene showed that PTSD pa‐ tients carrying one or two short alleles of this gene have a higher level of depression and suicide compared to carriers of long allele, which has more transcriptional power [59, 60]. The association of the serotonin transporter repeat polymorphism with PTSD was also de‐ scribed [61-63]. Interestingly, recent study of 200 individuals from 12 multigenerational fam‐ ilies survived 1998 Spitak earthquake in Armenia demonstrated that PTSD is developing in those individuals, who carry mutations of tryptophan hydroxylase 1 and 2, the rate-limiting

> **Candidate gene Chromosomal mapping Source** Dopamine D2 receptor 11q23 [22, 55, 65] Dopamine D4 receptor 11p15.5 [57] Dopamine transporter type 1 5p15.3 [56, 66]

Serotonin transporter 17q11 [10, 60, 63, 67- 71]

Serotonin type-2A receptor 13q14-q21 [68] Brain-derived neurotrophic factor 11p13 [72]

γ-aminobutyric acid receptor (subunit α-2) 4p12 [77]

Catechol-O-methyltransferase 22q11 [78]

11p15.3-p.14 12q21.1

[64]

Neuropeptide Y 7p15.1 [73] Glucocorticoid receptor 5q31.3 [74] Dopamine beta-hydroxylase 9q34 [75] Cannabinoid receptor 6q14-q15 [76]

PTSD symptoms [57].

108 New Insights into Anxiety Disorders

enzyme of serotonin biosynthesis [64].

Tryptophan hydroxylase 1 Tryptophan hydroxylase 2

**Table 2.** PTSD-related changes in the neuroendocrine system

Promising studies suggest the involvement of alterations in the immune status [48, 79-86], particularly low-grade inflammatory reactions, in the pathogenesis of PTSD [87-97]. Тhus, PTSD patients are characterized by hyperactivation of lymphocytes [80] and increased levels of lipopolysaccharide (LPS)-stimulated expression of interleukin (IL)-6, tumor necrosis fac‐ tor (TNF)-α, and interferon (IFN)-γ in immunocompetent cells [81, 82]. Segman et al detect‐ ed over-expression of immune response-related genes in monocytes of PTSD-affected subjects [85]. Also, in chronic PTSD patients, as compared to norm, a decreased number of T-killer cells (CD8+ ) [98, 99] and an increase number of T-helper cells (CD4+ ) [98, 100] has been shown, whereas in PTSD patients immediately after a traumatic event a decreased number of T-helper cells was detected [99]. A number of experimental data indicates that natural killer cells' cytotoxicity in PTSD is lower than in norm [97, 99, 101-104], while the total number or these cells, as well as a number of CD16+ and CD56+ cells in their total popu‐ lation is higher than in norm [99, 104]. At the same time some studies show that natural kill‐ er cells' cytotoxicity in PTSD patients is higher than in healthy subjects [105, 106]. The analysis of the above mentioned data revealed altered cell-mediated immunity in PTSD pa‐ tients and demonstrates that depending on traumatic event, duration and stage of the ill‐ ness, these alterations may be either under- or over-represented [97, 107].

#### **3.1. Cytokine network in PTSD**

A number of studies have demonstrated changes in a functional state of cytokines and their receptors, important mediators and regulators of the immune response in PTSD-affected subjects. Here the increased blood levels of proinflammatory cytokines (e.g. IL-1β, IL-6, TNF-α, INF-γ) and decreased levels of anti-inflammatory cytokines (e.g. IL-4) are detected in chronic PTSD patients indicating the involvement of low-grade systemic inflammatory re‐ actions in PTSD pathogenesis (table 3).

In our own study the levels of proinflammatory and chemotactic cytokines IL-1β, IL-6, TNFα, IL-8 and MCP-1 in the blood serum of chronic PTSD patients (combat veterans) and ageand sex-matched healthy subjects (HS; a control group) were determined using enzymelinked immunosorbent assay (ELISA). Assessment of possible correlation of the above mentioned parameters with each other and with the expression of PTSD clinical symptoms was also performed. The latest were evaluated using Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID PTSD module) [112] and Clinician-Administered PTSD Scale (CAPS) [113]. In particular, we assessed correlation between the levels of cytokines and the degree of expression of such PTSD clinical symptoms as persistent re-experiencing of the traumatic event (B cluster), persistent avoidance of stimuli associated with the trauma and emotional numbing (C cluster); persistent symptoms of increasing arousal (D cluster) [2]. In table 4 brief descriptions of the study groups is given. Table 5 demonstrates the indi‐ vidual symptom clusters (B, C, and D criteria), and total CAPS scores of PTSD-affected sub‐ jects involved in our study.

inflammatory disorders such as rheumatoid arthritis, psoriasis and inflammatory bowel dis‐ ease. Patients with PTSD are at a higher risk for diabetes mellitus and cardiovascular diseas‐ es (atherosclerosis, myocardial infarction) [116-123]. It is interesting that in peridontitis patients with PTSD higher expression of inflammatory processes was obtained than in those

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111

**Study group PTSD HS**

Mean age (M±SD) 42 ± 11.3 39 ± 9.1

[Cortisol]\* (M±SD), ng/ml 124 ± 47 145 ± 55 [DHEA]\* (M±SD), ng/ml 13 ± 7 10 ± 5

[DHEA-sulfate]\* (M±SD), μg/ml 1.8 ± 0.9 1.0 ± 0.5

**Symptom clusters Parameters PTSD patients scores** B cluster Frequency (0-20) 11.8±3.98

C cluster Frequency (0-28) 16.4±5.10

D cluster Frequency (0-20) 13.5±3.07

**B+C+D (Total)** Frequency (0-68) 41.7±9.85

**Table 5.** The individual symptom clusters (B, C, and D criteria), total and overall CAPS scores (M±SD) of PTSD-affected

Intensity (0-20) 11.6±3.46

Intensity (0-28) 14.8±4.96

Intensity (0-20) 12.2±2.52

Intensity (0-68) 38.6±9.18

Frequency + Intensity (0-40) 23.4±7.02

Frequency + Intensity (0-56) 31.2±9.85

Frequency + Intensity (0-40) 25.7±5.30

Frequency + Intensity (0-136) 80.3±18.50

Total number (male/female) 120 (116/4) 80 (76/4)

peridontitis patients, who were not affected by PTSD [88].

\* - measured in the blood serum

**Table 4.** Brief description of the study groups

subjects (Score ranges are indicated in parenthesis)

**Table 3.** Changes in the blood levels of some cytokines in chronic PTSD patients

Data statistics include nonparametric Mann-Whitney U-test and correlation analysis with calculation of Spearman's rank correlation coefficient (Rs). Parts of this study have been published [114, 115].

The results obtained indicated that PTSD, as compared to norm, is characterized by in‐ creased levels of the mentioned above cytokines (Table 6), which is consistent with reports by other research groups (Table 3) [46, 87, 89, 91, 93, 108, 110, 111].

A significant correlation between the levels of IL-1β and IL-6 (Rs=0.45; p<0.003), as well as between IL-1β and MCP-1 (Rs=0.3; p<0.03) in PTSD patients was revealed, whereas no sig‐ nificant correlation between the levels of cytokines was observed in control group. Also, a significant positive correlation of IL-1β and IL-6 blood levels with PTSD symptoms within B, C and D criteria (CAPS scores) was detected. Thus, levels of IL-1β positively correlated with B frequency (Rs=0.004, р=0.007), C frequency, intensity, and frequency + intensity (Rs=0.4, p=0.009; Rs=0.30, p=0.035, r=0.36, p<0.02, respectively), frequency of B, C and D (Rs =0.37, p<0.02), total intensity of B, C and D (Rs=0.3, p<0.048) and total frequency + intensity of B, C and D (Rs=0.3, p<0.03). Blood levels of IL-6 positively correlated with cluster B frequency (Rs=0.3, p=0.048).

Our data provides further evidence on the association of chronic inflammation with PTSD and clearly demonstrates the interrelation between the expression of PTSD symptoms and inflammatory reactions. Alterations in the immune response in PTSD accompanied by lowgrade systemic inflammation aggravate disease course and severity and contribute to devel‐ opment of complications. Thus, PTSD is often associated with autoimmune and inflammatory disorders such as rheumatoid arthritis, psoriasis and inflammatory bowel dis‐ ease. Patients with PTSD are at a higher risk for diabetes mellitus and cardiovascular diseas‐ es (atherosclerosis, myocardial infarction) [116-123]. It is interesting that in peridontitis patients with PTSD higher expression of inflammatory processes was obtained than in those peridontitis patients, who were not affected by PTSD [88].

**Table 4.** Brief description of the study groups

**Chronic PTSD patients: group description Changes in the blood levels of cytokines**

Individuals exposed to different traumatic events (n=60)

Individuals exposed to intimate partner violence (n=62)

**Table 3.** Changes in the blood levels of some cytokines in chronic PTSD patients

by other research groups (Table 3) [46, 87, 89, 91, 93, 108, 110, 111].

\* - ↑ - above the norm; ↓ - below the norm.

published [114, 115].

110 New Insights into Anxiety Disorders

(Rs=0.3, p=0.048).

Accidents survivors (n=13) ↑IL-1β, ↑IL-6, ↑TNF-α [89] Accident survivors (n=86) ↑IL-1β [46] Accidents survivors (n=14) ↑IL-1β, ↑TNF-α, ↓IL-4 [93] Bosnian refugees (n=12) ↑IL-6 [108] Combat veterans (n=19) ↑IL-1β, ↑IL-6, ↑TNF-α [87] Combat veterans (n=11) ↑IL-6, ↑TNF-α [91] Individuals abused in childhood (n=30) ↑INF-γ [109] Individuals abused in childhood (n=177) ↑TNF-α , ↓IL-4 [110]

Data statistics include nonparametric Mann-Whitney U-test and correlation analysis with calculation of Spearman's rank correlation coefficient (Rs). Parts of this study have been

The results obtained indicated that PTSD, as compared to norm, is characterized by in‐ creased levels of the mentioned above cytokines (Table 6), which is consistent with reports

A significant correlation between the levels of IL-1β and IL-6 (Rs=0.45; p<0.003), as well as between IL-1β and MCP-1 (Rs=0.3; p<0.03) in PTSD patients was revealed, whereas no sig‐ nificant correlation between the levels of cytokines was observed in control group. Also, a significant positive correlation of IL-1β and IL-6 blood levels with PTSD symptoms within B, C and D criteria (CAPS scores) was detected. Thus, levels of IL-1β positively correlated with B frequency (Rs=0.004, р=0.007), C frequency, intensity, and frequency + intensity (Rs=0.4, p=0.009; Rs=0.30, p=0.035, r=0.36, p<0.02, respectively), frequency of B, C and D (Rs =0.37, p<0.02), total intensity of B, C and D (Rs=0.3, p<0.048) and total frequency + intensity of B, C and D (Rs=0.3, p<0.03). Blood levels of IL-6 positively correlated with cluster B frequency

Our data provides further evidence on the association of chronic inflammation with PTSD and clearly demonstrates the interrelation between the expression of PTSD symptoms and inflammatory reactions. Alterations in the immune response in PTSD accompanied by lowgrade systemic inflammation aggravate disease course and severity and contribute to devel‐ opment of complications. Thus, PTSD is often associated with autoimmune and

**as compared to norm\***

↓IL-4 [97]

↑IL-6, ↑TNF-α, ↑INF-γ [111]

**Source**

**Table 5.** The individual symptom clusters (B, C, and D criteria), total and overall CAPS scores (M±SD) of PTSD-affected subjects (Score ranges are indicated in parenthesis)

[133-135]. Changes in the functional activity of the complement cascade contribute to the pathology of many human diseases [136-138], including mental disorders [139-144], and are also detected during physiological stress [145-146]. The alterations in the complement cas‐ cade have been considered as indicator of the implication of inflammatory component in

Alterations in the Immune Response, Apoptosis and Synaptic Plasticity in Posttraumatic Stress Disorder

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**Figure 1.** Complement activation pathways; C1Q, C1r, C1s – subunits of the complement C1 component; MBL - man‐ nan-binding lectin; MASP1 - MBL-associated serine peptidase 1; MASP2 - MBL-associated serine peptidase 2; FD - fac‐

The complement system with its central position in innate and adaptive immunity mediates a variety of effector functions. It consists of more than 30 circulating proteins, cell surface receptor and regulator proteins. It is a complex cascade involving proteolytic cleavage of se‐ rum glycoproteins often activated by cell receptors. This cascade ultimately results in induc‐ tion of the antibody responses, inflammation, phagocyte chemotaxis, and opsonization of apoptotic and necrotic cells, facilitating their recognition, clearance, and lysis. Complement exhibits three activation pathways - classical, alternative, and lectin, initiated via separate mechanisms, and a single terminal pathway that results in a formation of the membrane at‐ tack complex (Figure 1) and subsequent cell lysis [133-135]. During the past decades it has become evident that dysfunction of complement contributes to the pathology of many hu‐ man diseases [136-138], including mental disorders (schizophrenia, Alzheimer's disease, Huntington's and Pick's diseases) [139-142], and is also detected during physiological stress [145-146]. While, as it was already mentioned, PTSD-affected subjects showed a low-grade

disease etiology, pathogenesis and/or progression [136-138].

tor D; FB - factor B; MAC – membrane attack complex.

**Table 6.** Comparative analysis of the blood serum levels of proinflammatory and chemotactic cytokines in patients with PTSD and HS

The pathological mechanisms of the development of inflammatory reactions in PTSD are not clear. However, it is obvious that neuroendocrine and immune impairments in PTSD are in‐ terrelated. It is well-established fact that the immune system functional activity is regulated by neurotransmitters and hormones, particularly those related to HPA axis and SAS. On the other hand, immune system mediators and their receptors on the immunocompetent cells may regulate the neuroendocrine system. In normal physiological conditions the immune, endocrine and nervous systems maintain homeostasis by controlling each other, thus devel‐ oping adequate stress response [79, 124]. Changes in neuro-endocrine-immune interactions (influenced by either environmental or genetic factors) may result to abnormal response to stress and generation of PTSD. On the other hand, the action of cytokines, mediators of in‐ flammation, is tightly coupled with physiological and pathophysiological reactions of the organism, and their important role is to coordinate the efforts of the immune, endocrine and nervous systems during the stress response [125-128]. This may represent one of the possible mechanisms responsible for increased cytokines levels and development of chronic inflam‐ matory reactions in PTSD, the disease characterized by neuroimmune and endocrine altera‐ tions [82, 86, 129]. It connection with this it has to be also mentioned that a number of recent clinical and experimental data suggests the implication of low-grade systemic inflammatory reactions accompanied by increase in cytokines levels in pathogenesis of many psychiatric disorders [130-132].

#### **3.2. The complement system in PTSD**

The complement system is major effector of the immune response, which acts on the inter‐ face of innate and adaptive immunity, and is a key component and trigger of many immu‐ noregulatory mechanisms. Activation of the complement generates opsonins, anaphylatoxins, and chemotaxins, mediators of inflammation and apoptosis (Figure 1) [133-135]. Changes in the functional activity of the complement cascade contribute to the pathology of many human diseases [136-138], including mental disorders [139-144], and are also detected during physiological stress [145-146]. The alterations in the complement cas‐ cade have been considered as indicator of the implication of inflammatory component in disease etiology, pathogenesis and/or progression [136-138].

**Study group Cytokine Level ( M ± SD), pg/ml P =**

8.2 ± 1.0

19.0 ± 2.5

12.0 ± 1.6

11.5 ± 1.5

223.3 ± 30.6

0.002

0.025

0.049

0.022

0.030

IL-1β

IL-6

TNF-α

IL-8

MCP-1

HS 5.1 ± 0.7

HS 16.0 ± 2.3

HS 10.8 ± 1.4

HS 10.1 ± 1.3

HS 187.2 ± 25.5

**Table 6.** Comparative analysis of the blood serum levels of proinflammatory and chemotactic cytokines in patients

The pathological mechanisms of the development of inflammatory reactions in PTSD are not clear. However, it is obvious that neuroendocrine and immune impairments in PTSD are in‐ terrelated. It is well-established fact that the immune system functional activity is regulated by neurotransmitters and hormones, particularly those related to HPA axis and SAS. On the other hand, immune system mediators and their receptors on the immunocompetent cells may regulate the neuroendocrine system. In normal physiological conditions the immune, endocrine and nervous systems maintain homeostasis by controlling each other, thus devel‐ oping adequate stress response [79, 124]. Changes in neuro-endocrine-immune interactions (influenced by either environmental or genetic factors) may result to abnormal response to stress and generation of PTSD. On the other hand, the action of cytokines, mediators of in‐ flammation, is tightly coupled with physiological and pathophysiological reactions of the organism, and their important role is to coordinate the efforts of the immune, endocrine and nervous systems during the stress response [125-128]. This may represent one of the possible mechanisms responsible for increased cytokines levels and development of chronic inflam‐ matory reactions in PTSD, the disease characterized by neuroimmune and endocrine altera‐ tions [82, 86, 129]. It connection with this it has to be also mentioned that a number of recent clinical and experimental data suggests the implication of low-grade systemic inflammatory reactions accompanied by increase in cytokines levels in pathogenesis of many psychiatric

The complement system is major effector of the immune response, which acts on the inter‐ face of innate and adaptive immunity, and is a key component and trigger of many immu‐ noregulatory mechanisms. Activation of the complement generates opsonins, anaphylatoxins, and chemotaxins, mediators of inflammation and apoptosis (Figure 1)

PTSD

112 New Insights into Anxiety Disorders

PTSD

PTSD

PTSD

PTSD

with PTSD and HS

disorders [130-132].

**3.2. The complement system in PTSD**

**Figure 1.** Complement activation pathways; C1Q, C1r, C1s – subunits of the complement C1 component; MBL - man‐ nan-binding lectin; MASP1 - MBL-associated serine peptidase 1; MASP2 - MBL-associated serine peptidase 2; FD - fac‐ tor D; FB - factor B; MAC – membrane attack complex.

The complement system with its central position in innate and adaptive immunity mediates a variety of effector functions. It consists of more than 30 circulating proteins, cell surface receptor and regulator proteins. It is a complex cascade involving proteolytic cleavage of se‐ rum glycoproteins often activated by cell receptors. This cascade ultimately results in induc‐ tion of the antibody responses, inflammation, phagocyte chemotaxis, and opsonization of apoptotic and necrotic cells, facilitating their recognition, clearance, and lysis. Complement exhibits three activation pathways - classical, alternative, and lectin, initiated via separate mechanisms, and a single terminal pathway that results in a formation of the membrane at‐ tack complex (Figure 1) and subsequent cell lysis [133-135]. During the past decades it has become evident that dysfunction of complement contributes to the pathology of many hu‐ man diseases [136-138], including mental disorders (schizophrenia, Alzheimer's disease, Huntington's and Pick's diseases) [139-142], and is also detected during physiological stress [145-146]. While, as it was already mentioned, PTSD-affected subjects showed a low-grade systemic proinflammatory state, the complement system in PTSD has been never studied be‐ fore.

The results obtained in our study clearly demonstrated that pathogenesis of PTSD is charac‐ terized by complement dysfunction including hyperactivation state of the complement clas‐ sical pathway and hypoactivation state of the complement alternative pathway. The alternative pathway of complement is activated following spontaneous hydrolysis of the thioester bond of native C3, resulting into binding of factor B, which is cleaved by factor D, generating the efficient alternative pathway C3 convertase C3bBb. Multifunctional comple‐ ment protein C3 is the initial point of the alternative pathway, and, at the same time, a con‐ verge point of all three complement activation pathways, i.e. starting point for the terminal pathway [93, 135, 153]. Hypoactivation state of the alternative pathway together with de‐ creased activity of the complement C3 component, detected in PTSD affected subjects, prob‐ ably reflects depletion of the C3 component due to its overutilization through the terminal pathway. This suggestion is convenient with correlation data indicating positive correlation between CH50 and C3H50 and absence of any correlation between AH50 and fBH50, and AH50 and fDH50 in PTSD affected subjects. Thus, it is obvious that the alternative pathway in PTSD is suppressed on the initial stage of its activation, and that PTSD is also character‐ ized by overactivated terminal complement pathway. On the other hand, absence of correla‐ tion between AH50 and CH50 suggests that alterations in activities of the classical and the

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115

As it was mentioned above, alterations in the complement cascade have been considered as indicator of the implication of inflammatory component in disease etiology, pathogenesis and/or progression [136-138]. Our study demonstrates that PTSD is associated with dysfunc‐ tion of the complement system, and reveals the altered chains of the complement cascade. The results obtained provide further evidence on the involvement of the inflammatory com‐ ponent in pathogenesis of PTSD. Here we hypothesize that neuroendocrine mechanisms re‐ lated to PTSD modulating the immune function might affect the initial steps in the inflammatory cascade and thus influence alterations in the functional activity of the major mediator of the inflammatory response, the complement system. However, to address mo‐ lecular mechanisms responsible for the complement dysfunction in PTSD as well as their

Formation of immune complexes (IC) is a normal physiological reaction of organism to for‐ eign or autoantigen. IC may interact with both humoral and cellular components of the im‐ mune recognition system, activate the complement cascade, and thus affect the immune response on multiple levels [154-156]. In healthy conditions IC are easily eliminating from circulation through complement deposition, followed by their opsonization, phagocytosis, and further processing by proteases [154, 156-158]. In pathologic conditions inappropriate clearance or deposition of IC result in increased levels of IC in circulation. Circulating IC may deposit in endothelial or vascular structures provoking prolonged inflammatory re‐ sponse by permanent activation of the complement cascade through the classical pathway, generation of cytotoxic agents and tissue damage [159-163]. Deposition of IC is a prominent feature of many diseases [162-164] including those characterized by low-grade systemic in‐

alternative complement pathways in PTSD are not interdependent.

role in PTSD pathogenesis further studies are needed.

**3.3. Immune complexes in PTSD**

In our study we assessed the functional activity of the complement cascade in PTSD by de‐ termining total hemolytic activities of its classical and alternative pathways, and hemolytic activities of its individual components, C1, C2, C3, C4, factor B and factor D, in the blood serum of chronic PTSD patients (combat veterans) and HS (tables 4, 5). C1, C2 and C4 are main components of the classical pathway, factor B and factor D are essential components of the alternative pathway, and C3 is the initial point for the alternative pathway and a con‐ verge point of all three complement activation pathways, starting up for the terminal path‐ way (Figure 1) [133-135]. In addition, correlation study between all measured parameters was also performed. Hemolytic activities of the complement classical and alternative path‐ ways (CH50 and AH50, respectively) and of the complement components C1 (C1H50), C2 (C2H50), C3 (C3H50), C4 (C4H50), factor B (fBH50), and factor D (fDH50) in the blood se‐ rum of PTSD-affected and healthy subjects were measured by application of the earlier de‐ veloped methods [147, 148]. Data was analyzed by Student's unpaired two-tailed t-test and Pearson's correlation analysis including calculation of relevant correlation coefficient (r). Parts of this study have been published [149-152].

The results obtained are presented in table 7. According to the results obtained, mean values of serum CH50, C1H50, C2H50 and C4H50 in PTSD patients were significantly 2.1, 1.34, 1.2 and 1.6 times significantly higher than in case of HS (p<0.05). On the contrary, mean values of serum C3H50, AH50, fBH50, and fDH50 in PTSD patients were 1.5, 1.7, 1.6, and 2.3 times significantly lower as compared to HS (p<0.05). Correlation analysis also demonstrated that in PTSD affected subjects C1H50 is significantly correlated with C2H50 (r=-0.375, p<0.04), C3H50 is significantly correlated with C1H50, C2H50 and C4H50 and AH50 (r=0.53, p<0.037; r=0.72, p=0.002; r=0.5, p=0.05; r=0.57, p=0.027, respectively). No significant correlation be‐ tween the above-mentioned parameters was detected in the HS group (p>0.05).

\* - one unit (U) of hemolytic activity is defined as an amount of serum that causes a 50% hemol‐ ysis of erythrocytes in a reaction mixture.

The results obtained in our study clearly demonstrated that pathogenesis of PTSD is charac‐ terized by complement dysfunction including hyperactivation state of the complement clas‐ sical pathway and hypoactivation state of the complement alternative pathway. The alternative pathway of complement is activated following spontaneous hydrolysis of the thioester bond of native C3, resulting into binding of factor B, which is cleaved by factor D, generating the efficient alternative pathway C3 convertase C3bBb. Multifunctional comple‐ ment protein C3 is the initial point of the alternative pathway, and, at the same time, a con‐ verge point of all three complement activation pathways, i.e. starting point for the terminal pathway [93, 135, 153]. Hypoactivation state of the alternative pathway together with de‐ creased activity of the complement C3 component, detected in PTSD affected subjects, prob‐ ably reflects depletion of the C3 component due to its overutilization through the terminal pathway. This suggestion is convenient with correlation data indicating positive correlation between CH50 and C3H50 and absence of any correlation between AH50 and fBH50, and AH50 and fDH50 in PTSD affected subjects. Thus, it is obvious that the alternative pathway in PTSD is suppressed on the initial stage of its activation, and that PTSD is also character‐ ized by overactivated terminal complement pathway. On the other hand, absence of correla‐ tion between AH50 and CH50 suggests that alterations in activities of the classical and the alternative complement pathways in PTSD are not interdependent.

As it was mentioned above, alterations in the complement cascade have been considered as indicator of the implication of inflammatory component in disease etiology, pathogenesis and/or progression [136-138]. Our study demonstrates that PTSD is associated with dysfunc‐ tion of the complement system, and reveals the altered chains of the complement cascade. The results obtained provide further evidence on the involvement of the inflammatory com‐ ponent in pathogenesis of PTSD. Here we hypothesize that neuroendocrine mechanisms re‐ lated to PTSD modulating the immune function might affect the initial steps in the inflammatory cascade and thus influence alterations in the functional activity of the major mediator of the inflammatory response, the complement system. However, to address mo‐ lecular mechanisms responsible for the complement dysfunction in PTSD as well as their role in PTSD pathogenesis further studies are needed.

#### **3.3. Immune complexes in PTSD**

systemic proinflammatory state, the complement system in PTSD has been never studied be‐

In our study we assessed the functional activity of the complement cascade in PTSD by de‐ termining total hemolytic activities of its classical and alternative pathways, and hemolytic activities of its individual components, C1, C2, C3, C4, factor B and factor D, in the blood serum of chronic PTSD patients (combat veterans) and HS (tables 4, 5). C1, C2 and C4 are main components of the classical pathway, factor B and factor D are essential components of the alternative pathway, and C3 is the initial point for the alternative pathway and a con‐ verge point of all three complement activation pathways, starting up for the terminal path‐ way (Figure 1) [133-135]. In addition, correlation study between all measured parameters was also performed. Hemolytic activities of the complement classical and alternative path‐ ways (CH50 and AH50, respectively) and of the complement components C1 (C1H50), C2 (C2H50), C3 (C3H50), C4 (C4H50), factor B (fBH50), and factor D (fDH50) in the blood se‐ rum of PTSD-affected and healthy subjects were measured by application of the earlier de‐ veloped methods [147, 148]. Data was analyzed by Student's unpaired two-tailed t-test and Pearson's correlation analysis including calculation of relevant correlation coefficient (r).

The results obtained are presented in table 7. According to the results obtained, mean values of serum CH50, C1H50, C2H50 and C4H50 in PTSD patients were significantly 2.1, 1.34, 1.2 and 1.6 times significantly higher than in case of HS (p<0.05). On the contrary, mean values of serum C3H50, AH50, fBH50, and fDH50 in PTSD patients were 1.5, 1.7, 1.6, and 2.3 times significantly lower as compared to HS (p<0.05). Correlation analysis also demonstrated that in PTSD affected subjects C1H50 is significantly correlated with C2H50 (r=-0.375, p<0.04), C3H50 is significantly correlated with C1H50, C2H50 and C4H50 and AH50 (r=0.53, p<0.037; r=0.72, p=0.002; r=0.5, p=0.05; r=0.57, p=0.027, respectively). No significant correlation be‐

tween the above-mentioned parameters was detected in the HS group (p>0.05).

**Hemolytic activity, U/ml\* PTSD (M ± SD) HS (M ± SD) P =**

\* - one unit (U) of hemolytic activity is defined as an amount of serum that causes a 50% hemol‐

CH50 375.00 ± 164.40 176.00 ± 88.50 0.0002 C1H50 92.21 ± 52.83 68.80 ± 37.39 0.0400 C2H50 67.60 ± 35.10 58.80 ± 8.80 0.0450 C3H50 37.57 ± 16.26 55.92 ± 28.60 0.0300 C4H50 60.10 ± 28.42 36.64 ± 20.31 0.0300 AH50 52.30 ± 18.17 87.60 ± 9.80 0.0001 fBH50 40.80 ± 14.30 65.2 ± 34.1 0.0200 fBH50 71.70 ± 15.98 163.70 ± 70.58 0.0010

Parts of this study have been published [149-152].

ysis of erythrocytes in a reaction mixture.

**Table 7.** Functional state of the complement system in PTSD patients and HS

fore.

114 New Insights into Anxiety Disorders

Formation of immune complexes (IC) is a normal physiological reaction of organism to for‐ eign or autoantigen. IC may interact with both humoral and cellular components of the im‐ mune recognition system, activate the complement cascade, and thus affect the immune response on multiple levels [154-156]. In healthy conditions IC are easily eliminating from circulation through complement deposition, followed by their opsonization, phagocytosis, and further processing by proteases [154, 156-158]. In pathologic conditions inappropriate clearance or deposition of IC result in increased levels of IC in circulation. Circulating IC may deposit in endothelial or vascular structures provoking prolonged inflammatory re‐ sponse by permanent activation of the complement cascade through the classical pathway, generation of cytotoxic agents and tissue damage [159-163]. Deposition of IC is a prominent feature of many diseases [162-164] including those characterized by low-grade systemic in‐ flammation, such as schizophrenia [144], diabetes mellitus [165, 166], ischemic and hemor‐ rhagic stroke [167-169].

terations in mechanisms responsible for their recognition and clearance by the above men‐ tioned cells. High levels of C3d-IC result in hyper-production of antibodies, because binding of C3d-IC to type-2 complement receptors (СR2) on the surface of B-lymphocytes induces the production of immunoglobulins by these cells [154, 156-158]. Therefore, our results indi‐ cate that PTSD is characterized by altered mechanisms of IC recognition and clearance, which may be responsible for the increased classical pathway functional activity, chronic ac‐

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117

**3.4. Interrelation between inflammatory response, apoptosis and synaptic plasticity in**

As it was already mentioned, the molecular pathomechanisms responsible for development of inflammatory reactions in PTSD are yet unclear, which limits the progress in develop‐ ment of the efficient measures of PTSD rehabilitation therapy and prevention of its compli‐ cations. On the other hand, it is known that apoptosis plays an important role in downregulation of the inflammatory response by reducing the lifespan of activated immunocompetent cells [171-173]. Therefore, we proposed that one of the factors contribu‐ ting to PTSD-associated inflammation may be apoptotic dysfunction as it was observed in case of other disorders like familial Mediterranean fever [174], inflammatory bowel disease [175], systemic inflammatory response syndrome [176], pulmonary hemorrhage or endotox‐

On the third though, apoptosis is considered as the important regulator of synaptic plastici‐ ty. Apoptotic alterations have a significant input in synaptic dysfunction and lead to changes in structural and functional integrity of neuronal circuits [178-180]. Therefore, apop‐ tosis may be also responsible for altered synaptic plasticity in PTSD [181] resulting in cogni‐ tive impairments and development of depressions in PTSD affected subjects [182-184].

To check our hypotheses, in the blood serum of patients with PTSD, in comparison to HS the levels of marker proteins for apoptosis and synaptic plasticity, annexin-А5 [185] and complexin-2 [186], respectively, and the inflammatory marker, TNF-α, were determined by ELISA. The analysis of correlation between these parameters was performed. Brief charac‐ teristic of study groups is given in tables 4, 5. Data statistics include nonparametric Mann-Whitney U-test and correlation analysis with calculation of Spearman's rank correlation

According to the results obtained, the levels of both annexin-А5 and complexin-2 in PTSD patients were significantly 2.34 (p=0.0001) and 1.21 (p=0.03) times, respectively, lower than in case of HS (table 9). In addition, a significant positive correlation between the levels of annexin-А5 and complexin-2 (Rs=0.38, p=0.045), on the one hand, and a significant negative correlation between the levels of annexin-А5 and the increased levels of TNF-α (Rs= -0.35,

No statistical significant correlation was observed between these parameters in case of HS.

coefficient (Rs). The results presented below have not been published yet.

р=0.047), on the other hand, were detected in PTSD.

tivation of the immune system and systemic inflammation.

**PTSD**

emia [177], etc.

In our own study we, for the first time, determined total levels of IC as well as the levels of IC containing activation products of the complement system, C1q- and C3d-IC, in the blood serum of chronic PTSD patients (combat veterans) and HS. Brief characteristic of study groups is given in tables 3, 4. Total levels of IC were measured by a previously published spectrophotometric method and expressed in absorbency units at 280 nm (A280) [167]; C1qand C3d-IC were measured by ELISA. Data was analyzed by Student's unpaired two-tailed t-test and Pearson's correlation analysis including calculation of relevant correlation coeffi‐ cient (r). Parts of this study have been published [149, 150, 170].

According to the results obtained, PTSD-patients comparing to HS are characterized by sig‐ nificantly increased serum levels of total IC as well as C1q- and C3d-IC. Thus, the mean lev‐ el of total IC in PTSD patients was 1.5 times higher than in HS (p=0.0055) and the levels of C1q-IC, and C3d-IC were 1.7 (p=0.024) and 1.6 times (p=0.0004), respectively, higher as com‐ pared to HS. The results obtained are summarized in table 8.

**Table 8.** Serum levels of the total IC, C1q-IC and C3d-IC in PTSD patients and HS

In addition, a significant positive correlation between the levels of C1q- and C3d-IC (r=0.32; p<0.03) was detected in PTSD patients affected subjects. Moreover, in patients with PTSD we also revealed a significant positive correlation between the total levels of IC and hemo‐ lytic activity of the classical complement pathway. This finding indicates that increased total levels of IC in circulation may be responsible for hyperactivation of the classical comple‐ ment cascade detected in PTSD [149-152, 170].

The increased blood levels of C1q-IC in PTSD provide further evidence for this suggestion. C1q-IC contain C1q subunit of the complement protein C1, and binding of IC to C1q ini‐ tiates activation of the classical complement cascade (Figure 1) [133-135].

C3d-IC contain activation cleavage products of the complement С3 protein, opsonins C3b, iC3b and C3dg. These entire products contain "d"-terminal fragment of the С3 polypeptide chain. In healthy conditions C3d-IC are eliminated from the blood through interaction with the complement receptors on monocytes, neutrophils and erythrocytes. Monocytes and neu‐ trophils subject C3d-IC to phagocytosis, and erythrocytes transfer them to liver and spleen for further phagocytosis by macrophages. Increased blood levels of C3d-IC suggest about al‐ terations in mechanisms responsible for their recognition and clearance by the above men‐ tioned cells. High levels of C3d-IC result in hyper-production of antibodies, because binding of C3d-IC to type-2 complement receptors (СR2) on the surface of B-lymphocytes induces the production of immunoglobulins by these cells [154, 156-158]. Therefore, our results indi‐ cate that PTSD is characterized by altered mechanisms of IC recognition and clearance, which may be responsible for the increased classical pathway functional activity, chronic ac‐ tivation of the immune system and systemic inflammation.

flammation, such as schizophrenia [144], diabetes mellitus [165, 166], ischemic and hemor‐

In our own study we, for the first time, determined total levels of IC as well as the levels of IC containing activation products of the complement system, C1q- and C3d-IC, in the blood serum of chronic PTSD patients (combat veterans) and HS. Brief characteristic of study groups is given in tables 3, 4. Total levels of IC were measured by a previously published spectrophotometric method and expressed in absorbency units at 280 nm (A280) [167]; C1qand C3d-IC were measured by ELISA. Data was analyzed by Student's unpaired two-tailed t-test and Pearson's correlation analysis including calculation of relevant correlation coeffi‐

According to the results obtained, PTSD-patients comparing to HS are characterized by sig‐ nificantly increased serum levels of total IC as well as C1q- and C3d-IC. Thus, the mean lev‐ el of total IC in PTSD patients was 1.5 times higher than in HS (p=0.0055) and the levels of C1q-IC, and C3d-IC were 1.7 (p=0.024) and 1.6 times (p=0.0004), respectively, higher as com‐

**[IC], (M±SD) Study group P =**

[Total IC], A280 0.18 ± 0.1 0.12 ± 0.03 0.0055

[C1q-IC], μg/ml (M±SD) 44.6 ± 37.67 26.28 ± 16.33 0.024

[C3d-IC], μg/ml (M±SD) 29.75 ± 21.91 18.67 ± 8.22 0.0004

In addition, a significant positive correlation between the levels of C1q- and C3d-IC (r=0.32; p<0.03) was detected in PTSD patients affected subjects. Moreover, in patients with PTSD we also revealed a significant positive correlation between the total levels of IC and hemo‐ lytic activity of the classical complement pathway. This finding indicates that increased total levels of IC in circulation may be responsible for hyperactivation of the classical comple‐

The increased blood levels of C1q-IC in PTSD provide further evidence for this suggestion. C1q-IC contain C1q subunit of the complement protein C1, and binding of IC to C1q ini‐

C3d-IC contain activation cleavage products of the complement С3 protein, opsonins C3b, iC3b and C3dg. These entire products contain "d"-terminal fragment of the С3 polypeptide chain. In healthy conditions C3d-IC are eliminated from the blood through interaction with the complement receptors on monocytes, neutrophils and erythrocytes. Monocytes and neu‐ trophils subject C3d-IC to phagocytosis, and erythrocytes transfer them to liver and spleen for further phagocytosis by macrophages. Increased blood levels of C3d-IC suggest about al‐

tiates activation of the classical complement cascade (Figure 1) [133-135].

**PTSD HS**

cient (r). Parts of this study have been published [149, 150, 170].

pared to HS. The results obtained are summarized in table 8.

**Table 8.** Serum levels of the total IC, C1q-IC and C3d-IC in PTSD patients and HS

ment cascade detected in PTSD [149-152, 170].

rhagic stroke [167-169].

116 New Insights into Anxiety Disorders

### **3.4. Interrelation between inflammatory response, apoptosis and synaptic plasticity in PTSD**

As it was already mentioned, the molecular pathomechanisms responsible for development of inflammatory reactions in PTSD are yet unclear, which limits the progress in develop‐ ment of the efficient measures of PTSD rehabilitation therapy and prevention of its compli‐ cations. On the other hand, it is known that apoptosis plays an important role in downregulation of the inflammatory response by reducing the lifespan of activated immunocompetent cells [171-173]. Therefore, we proposed that one of the factors contribu‐ ting to PTSD-associated inflammation may be apoptotic dysfunction as it was observed in case of other disorders like familial Mediterranean fever [174], inflammatory bowel disease [175], systemic inflammatory response syndrome [176], pulmonary hemorrhage or endotox‐ emia [177], etc.

On the third though, apoptosis is considered as the important regulator of synaptic plastici‐ ty. Apoptotic alterations have a significant input in synaptic dysfunction and lead to changes in structural and functional integrity of neuronal circuits [178-180]. Therefore, apop‐ tosis may be also responsible for altered synaptic plasticity in PTSD [181] resulting in cogni‐ tive impairments and development of depressions in PTSD affected subjects [182-184].

To check our hypotheses, in the blood serum of patients with PTSD, in comparison to HS the levels of marker proteins for apoptosis and synaptic plasticity, annexin-А5 [185] and complexin-2 [186], respectively, and the inflammatory marker, TNF-α, were determined by ELISA. The analysis of correlation between these parameters was performed. Brief charac‐ teristic of study groups is given in tables 4, 5. Data statistics include nonparametric Mann-Whitney U-test and correlation analysis with calculation of Spearman's rank correlation coefficient (Rs). The results presented below have not been published yet.

According to the results obtained, the levels of both annexin-А5 and complexin-2 in PTSD patients were significantly 2.34 (p=0.0001) and 1.21 (p=0.03) times, respectively, lower than in case of HS (table 9). In addition, a significant positive correlation between the levels of annexin-А5 and complexin-2 (Rs=0.38, p=0.045), on the one hand, and a significant negative correlation between the levels of annexin-А5 and the increased levels of TNF-α (Rs= -0.35, р=0.047), on the other hand, were detected in PTSD.

No statistical significant correlation was observed between these parameters in case of HS.

in synaptic plasticity, and that anomalous apoptosis may represent one of the factors re‐

Alterations in the Immune Response, Apoptosis and Synaptic Plasticity in Posttraumatic Stress Disorder

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119

Institute of Molecular Biology, National Academy of Sciences, Yerevan, Republic of Arme‐

[1] ICD-10. International statistical classification of diseases and related health problems

[2] DSM-IV-TR. Diagnostic and statistical manual of mental disorders by the American Psychiatric Association (edition 4, text revised). USA: Amer. Psych. Pub; 2000.

[3] Segman RH, Shalev AY. Genetics of posttraumatic stress disorder. CNS Spectr

[4] Eley TC, Sugden K, Corsico A, Gregory AM, Sham P. Gene-environment interaction analysis of serotonin system markers with adolescent depression. Mol Psychiatry

[5] Grabe HJ, Lange M, Wolff B, Völzke H, Lucht M. Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social

[6] Koenen KC. Genetics of posttraumatic stress disorder: review and recommendations

[7] Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Heim CM, Nemeroff CB, Schwartz AC, Cubells JF, Ressler KJ. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disor‐

[8] Amstadter AB, Nugent NR, Koenen KC. Genetics of PTSD: fear conditioning as a

[9] Koenen KC, Aiello AE, Bakshis E, Amstadter AB, Ruggiero KJ, Acierno R, Kilpatrick DG, Gelernter J, Galea S. Modification of the association between serotonin trans‐ porter genotype and risk of posttraumatic stress disorder in adults by county-level

stressors and chronic disease burden. Mol Psychiatry 2005;10(2): 220-224.

sponsible for development of PTSD-associated chronic inflammation.

Anna Boyajyan, Gohar Mkrtchyan, Lilit Hovhannisyan and Diana Avetyan

(Edition: 10). Geneva: World Health Organization; 1992.

for future studies. J Trauma Stress 2007;20: 737-750.

der symptoms in adults. JAMA 2008; 299(11) 1291-1305.

model for future research. Psych Ann 2009;39: 358-367.

social environment. Am J Epidemiol 2009;169: 704-711.

\*Address all correspondence to<EMAIL_ADDRESS>
**Author details**

nia

**References**

2003;8(9): 693-698.

2004;9(10): 908-915.

**Table 9.** The levels of annexin A5 and complexin-2 (M ± SD) in PTSD patients and HS

Our results demonstrated that PTSD is characterized by the decreased blood levels of the apoptotic marker circulating annexin A5 indicating association of apoptosis hypofunction with this disorder.

On the base of the results obtained we suggest that PTSD is characterized by low rate of apoptosis associated with the defects in synaptic plasticity and that anomalous apoptosis may also represent one of the factors responsible for development of PTSD-associated chronic inflammation. This suggestion is confirmed by recent findings indicating the in‐ creased levels of leukocytes in the blood of chronic PTSD patients [48, 93, 94].

## **4. Conclusion**

The results presented in this chapter provide evidence on implication of altered immune re‐ sponse, particularly low-grade systemic inflammation, in pathogenesis of PTSD.

In particular, we demonstrated that chronic PTSD is characterized by increased blood levels of proinflammatory and chemotactic cytokines, IL-1β, IL-6, TNF-α and MCP-1, IL-8, respec‐ tively. Here, the increased levels of IL-1β and IL-6 positively correlate with the degree of ex‐ pression of clinically significant symptoms of this disease, which indicate that these cytokines may be considered as new therapeutic targets for PTSD treatment. In addition, we demonstrated that chronic PTSD is characterized by altered mechanisms of IC recognition and clearance resulting in the increased levels of total IC, as well as C1q-IC and C3d-IC in circulation. Furthermore, our results showed that chronic PTSD is characterized by altera‐ tions in functional activity of the complement pathways including hyperactivation state of the classical and terminal pathways, hypoactivation state of the alternative pathway and de‐ ficiency of the C3 complement protein. Here, the data obtained suggests that hyperactiva‐ tion of the classical complement pathway is induced by the increased levels of IC, particularly C1q-IC, in circulation. Regarding the alternative pathway, our results clearly demonstrated that it is suppressed at the initial stage of activation and that decreased activi‐ ty of this pathway in PTSD is stipulated by decreased activities of its components, factor B and factor D, and deficiency of the protein C3, a key component of the complement cascade.

In summery, we concluded that changes in functional activities of the proinflammatory and chemotactic cytokines and complement cascade, as well as disturbances in the IC recogni‐ tion and clearance processes are implicated in pathogenesis of chronic PTSD.

Another important conclusion that can be drawn from the results of our study is that patho‐ genesis of chronic PTSD is characterized by low rate of apoptosis associated with the defects in synaptic plasticity, and that anomalous apoptosis may represent one of the factors re‐ sponsible for development of PTSD-associated chronic inflammation.

## **Author details**

**Study group [Annexin-A5], ng/ml P = [Complexin-2], pg/ml P =**

121.5 ± 41.20

0.03

0.0001

Our results demonstrated that PTSD is characterized by the decreased blood levels of the apoptotic marker circulating annexin A5 indicating association of apoptosis hypofunction

On the base of the results obtained we suggest that PTSD is characterized by low rate of apoptosis associated with the defects in synaptic plasticity and that anomalous apoptosis may also represent one of the factors responsible for development of PTSD-associated chronic inflammation. This suggestion is confirmed by recent findings indicating the in‐

The results presented in this chapter provide evidence on implication of altered immune re‐

In particular, we demonstrated that chronic PTSD is characterized by increased blood levels of proinflammatory and chemotactic cytokines, IL-1β, IL-6, TNF-α and MCP-1, IL-8, respec‐ tively. Here, the increased levels of IL-1β and IL-6 positively correlate with the degree of ex‐ pression of clinically significant symptoms of this disease, which indicate that these cytokines may be considered as new therapeutic targets for PTSD treatment. In addition, we demonstrated that chronic PTSD is characterized by altered mechanisms of IC recognition and clearance resulting in the increased levels of total IC, as well as C1q-IC and C3d-IC in circulation. Furthermore, our results showed that chronic PTSD is characterized by altera‐ tions in functional activity of the complement pathways including hyperactivation state of the classical and terminal pathways, hypoactivation state of the alternative pathway and de‐ ficiency of the C3 complement protein. Here, the data obtained suggests that hyperactiva‐ tion of the classical complement pathway is induced by the increased levels of IC, particularly C1q-IC, in circulation. Regarding the alternative pathway, our results clearly demonstrated that it is suppressed at the initial stage of activation and that decreased activi‐ ty of this pathway in PTSD is stipulated by decreased activities of its components, factor B and factor D, and deficiency of the protein C3, a key component of the complement cascade. In summery, we concluded that changes in functional activities of the proinflammatory and chemotactic cytokines and complement cascade, as well as disturbances in the IC recogni‐

HS 1.92 ± 1.05 146.9 ± 56.64

creased levels of leukocytes in the blood of chronic PTSD patients [48, 93, 94].

sponse, particularly low-grade systemic inflammation, in pathogenesis of PTSD.

tion and clearance processes are implicated in pathogenesis of chronic PTSD.

Another important conclusion that can be drawn from the results of our study is that patho‐ genesis of chronic PTSD is characterized by low rate of apoptosis associated with the defects

**Table 9.** The levels of annexin A5 and complexin-2 (M ± SD) in PTSD patients and HS

PTSD 0.82 ± 0.70

with this disorder.

118 New Insights into Anxiety Disorders

**4. Conclusion**

Anna Boyajyan, Gohar Mkrtchyan, Lilit Hovhannisyan and Diana Avetyan

\*Address all correspondence to<EMAIL_ADDRESS>
Institute of Molecular Biology, National Academy of Sciences, Yerevan, Republic of Arme‐ nia

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**Chapter 6**

**Understanding the Causes of Reduced Startle**

**Reactivity in Stress-Related Mental Disorders**

Many questions have plagued the study of the etiology and subsequent treatment of men‐ tal illness.  Moreover, clinical studies have produced many different results concerning potential biomarkers for conditions such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). In this chapter, we review how we approached modeling a specific behavioral condition, suppression of the startle re‐ flex, by examining whether one of two commonly associated peripheral biomarkers of anxi‐ ety and depression could potentially cause this rather specific symptom. The two peripheral systems under investigation were the hypothalamic-pituitary-adrenal (HPA) axis and the peripheral pro-inflammatory immune response, both of which have been implicated as a vulnerability factor, causal factor, or resultant (perpetuating) effect of PTSD and MDD.

Our general theory is that peripheral endocrine and immune signals, measured to be abnor‐ mal in patients with either PTSD or MDD (as well as other mental disorders), are actually perpetuating the behavioral features of these disorders. At the same time, if an individual has an immunosensitivity or has an overactive adrenal gland, s/he would be more likely to experience some of the symptoms associated with one of the particular mental illnesses. This may then lead the brain to compensate for those peripheral abnormalities, but, at the same time, cause other imbalances, which lead to the experience of a decline into mental illness. Thus, treating these peripheral markers as part of the "mental" disorder may be quite bene‐

and reproduction in any medium, provided the original work is properly cited.

© 2013 Beck and Catuzzi; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

ficial in normalizing certain aspects of the diagnosed abnormal behavior.

Kevin D. Beck and Jennifer E. Catuzzi

http://dx.doi.org/10.5772/53066

**1. Introduction**

Additional information is available at the end of the chapter

## **Understanding the Causes of Reduced Startle Reactivity in Stress-Related Mental Disorders**

Kevin D. Beck and Jennifer E. Catuzzi

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53066

## **1. Introduction**

Many questions have plagued the study of the etiology and subsequent treatment of men‐ tal illness.  Moreover, clinical studies have produced many different results concerning potential biomarkers for conditions such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). In this chapter, we review how we approached modeling a specific behavioral condition, suppression of the startle re‐ flex, by examining whether one of two commonly associated peripheral biomarkers of anxi‐ ety and depression could potentially cause this rather specific symptom. The two peripheral systems under investigation were the hypothalamic-pituitary-adrenal (HPA) axis and the peripheral pro-inflammatory immune response, both of which have been implicated as a vulnerability factor, causal factor, or resultant (perpetuating) effect of PTSD and MDD.

Our general theory is that peripheral endocrine and immune signals, measured to be abnor‐ mal in patients with either PTSD or MDD (as well as other mental disorders), are actually perpetuating the behavioral features of these disorders. At the same time, if an individual has an immunosensitivity or has an overactive adrenal gland, s/he would be more likely to experience some of the symptoms associated with one of the particular mental illnesses. This may then lead the brain to compensate for those peripheral abnormalities, but, at the same time, cause other imbalances, which lead to the experience of a decline into mental illness. Thus, treating these peripheral markers as part of the "mental" disorder may be quite bene‐ ficial in normalizing certain aspects of the diagnosed abnormal behavior.

© 2013 Beck and Catuzzi; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **2. The startle reflex and mental health**

### **2.1. The startle reflex as an assessment tool**

One of the major impediments to the mechanistic study of mental illness is establishing ana‐ logs of the abnormal behaviors expressed in humans in animal models, especially in sub-pri‐ mate species. This has led some to adopt reflex-based measures such that the face and construct validity of the behavior change can be readily translated between the model and patient populations. Consequently, a popular measures for the study of anxiety disorders has been the potentiation of the startle reflex; however, there is growing evidence that a dampening of the startle response may be indicative of changes in physiology that underlie different mental disorders.

The startle reflex comprises a 3-synaptic sensory-motor neuronal pathway that serves as a defensive behavioral response to abrupt, usually intense, stimuli. The acoustic startle re‐ sponse (ASR) is the most commonly used form for studying this reflex. As shown in Figure 1, the primary ASR circuit begins with neurons in the cochlear nerve, transmitting the repre‐ sentation of the acoustic stimulus from the cochlea of the inner ear to the cochlear nucleus (in the brainstem). Efferent pathways from the cochlear nucleus project to the nucleus reticu‐ laris pontis caudalis (PnC), in the pons, forming the second synapse in this reflex arc. The third synapse forms from the efferent projections from the PnC to various motor nuclei, through the recticulospinal spinal tracts to the muscles of the torso [1] and the muscles ener‐ vated by the facial nerve. These muscle enervations create a rapid cascade of near-immedi‐ ate behavioral responses to abrupt acoustic stimuli, ranging from less than 10 ms to approximately 50 ms.

**Figure 1.** There are several nuclei within the midbrain/brainstem area that can directly modulate the intrinsic ASR cir‐ cuit at the level of the nucleus reticularis pontis caudalis (PnC). Dashed red lines represent cholinergic inhibitory influ‐ ences from the laterodorsal tegmental nuclei (LDT) and pedunculopontine tegmentum (PPT). Dashed black lines represent inhibitory GABAergic projections from the substantial nigra pars reticulata (SNR). A solid line from the para‐

Understanding the Causes of Reduced Startle Reactivity in Stress-Related Mental Disorders

http://dx.doi.org/10.5772/53066

137

Over all other mental disorders, PTSD is associated with changes in the startle reflex. Com‐ monly associated with exaggerated startle responses [11-14], higher or exaggerated startle reflex responses are a criteria symptom for the diagnosis of PTSD [15]. However, recent evi‐ dence suggests that this may not always be the case. In fact, others have reviewed the litera‐ ture and found there are a significant number of reports where the startle responses in PTSD patients are not exaggerated [16]. More extreme, there are reports, albeit limited, where pa‐ tients diagnosed with PTSD appeared to have blunted motor reflex responses to an acoustic stimulus [17, 18]. These populations had distinctive qualities that were different than those studies that had found enhanced startle reactivity in their PTSD patients. First, the one study was exclusively female [18] and the other had a majority of female subjects [17], suggesting there may be a sex difference in the presentation of ASR in females as a result of experienc‐ ing trauma. However, others have reported enhanced startle responses in a different popu‐ lation of women diagnosed with PTSD following automobile accidents [19]. Thus, a second distinction between the two studies that observed suppressed startle reactions, which should be considered, is that the trauma was specifically associated with being the target of violence [17, 18].  Abnormalities in the expression of the startle reflex in mental disorders**

brachial nucleus (PBN) is an example of a direct excitatory input to the PnC.

The ASR is modulated by several afferent connections originating from higher brain areas (midbrain, limbic, and cortical nuclei). At the level of the PnC, there are several inputs that can either enhance or inhibit the magnitude of an elicited ASR. In the area of fear and anxi‐ ety, the central amygdala and bed nucleus of the stria terminalis (BNST) are considered the 2 major excitatory modulation structures on this reflex [2]. Some have proposed that the BNST is the origin of anxiety-like behaviors whereas the nuclei of the amygdala are the ori‐ gin of acute fear responses and explicit fear-learning [3, 4]. The amygdala is predominately associated with causing classically conditioned fear-potentiated ASRs [5], and, in fact, has been specifically shown not to have a role in startle inhibition, at least via a learned condi‐ tioned inhibitor [6]. On the other hand, the process known as pre-pulse inhibition of the startle reflex (PPI) has elucidated neural pathways that can inhibit the expression of the ASR. For instance, the substantial nigra pars retriculata (SNR), pedunculopontine tegmen‐ tum (PPT) and laterodorsal tegmental nuclei (LDT) have inhibitory influence upon the PnC, thus reducing the measured ASR [7-10]. These three mid-brain nuclei (inhibitory) receive projections from various forebrain areas, including the amygdala, BNST, and medial pre‐ frontal cortex (mPFC). Thus, limbic system modulation of the ASR can occur through direct enervation of the PnC (excitatory) or indirect enervation through mid-brain nuclei.

Understanding the Causes of Reduced Startle Reactivity in Stress-Related Mental Disorders http://dx.doi.org/10.5772/53066 137

**2.  This has led some to adopt reflex-based measures such that the face and construct validity of the behavior change can be readily translated between the model and patient populations. Consequently, a popular measures for the study of anxiety disorders has been the potentiation of the startle reflex; however, there is growing evidence that a dampening of the startle response may be indicative of changes in physiology that underlie

The startle reflex comprises a 3-synaptic sensory-motor neuronal pathway that serves as a defensive behavioral response to abrupt, usually intense, stimuli. The acoustic startle re‐ sponse (ASR) is the most commonly used form for studying this reflex. As shown in Figure 1, the primary ASR circuit begins with neurons in the cochlear nerve, transmitting the repre‐ sentation of the acoustic stimulus from the cochlea of the inner ear to the cochlear nucleus (in the brainstem). Efferent pathways from the cochlear nucleus project to the nucleus reticu‐ laris pontis caudalis (PnC), in the pons, forming the second synapse in this reflex arc. The third synapse forms from the efferent projections from the PnC to various motor nuclei, through the recticulospinal spinal tracts to the muscles of the torso [1] and the muscles ener‐ vated by the facial nerve. These muscle enervations create a rapid cascade of near-immedi‐ ate behavioral responses to abrupt acoustic stimuli, ranging from less than 10 ms to

The ASR is modulated by several afferent connections originating from higher brain areas (midbrain, limbic, and cortical nuclei). At the level of the PnC, there are several inputs that can either enhance or inhibit the magnitude of an elicited ASR. In the area of fear and anxi‐ ety, the central amygdala and bed nucleus of the stria terminalis (BNST) are considered the 2 major excitatory modulation structures on this reflex [2]. Some have proposed that the BNST is the origin of anxiety-like behaviors whereas the nuclei of the amygdala are the ori‐ gin of acute fear responses and explicit fear-learning [3, 4]. The amygdala is predominately associated with causing classically conditioned fear-potentiated ASRs [5], and, in fact, has been specifically shown not to have a role in startle inhibition, at least via a learned condi‐ tioned inhibitor [6]. On the other hand, the process known as pre-pulse inhibition of the startle reflex (PPI) has elucidated neural pathways that can inhibit the expression of the ASR. For instance, the substantial nigra pars retriculata (SNR), pedunculopontine tegmen‐ tum (PPT) and laterodorsal tegmental nuclei (LDT) have inhibitory influence upon the PnC, thus reducing the measured ASR [7-10]. These three mid-brain nuclei (inhibitory) receive projections from various forebrain areas, including the amygdala, BNST, and medial pre‐ frontal cortex (mPFC). Thus, limbic system modulation of the ASR can occur through direct

enervation of the PnC (excitatory) or indirect enervation through mid-brain nuclei.

**2.1. The startle reflex as an assessment tool**

different mental disorders.

136 New Insights into Anxiety Disorders

approximately 50 ms.

**Figure 1.** There are several nuclei within the midbrain/brainstem area that can directly modulate the intrinsic ASR cir‐ cuit at the level of the nucleus reticularis pontis caudalis (PnC). Dashed red lines represent cholinergic inhibitory influ‐ ences from the laterodorsal tegmental nuclei (LDT) and pedunculopontine tegmentum (PPT). Dashed black lines represent inhibitory GABAergic projections from the substantial nigra pars reticulata (SNR). A solid line from the para‐ brachial nucleus (PBN) is an example of a direct excitatory input to the PnC.

#### **2.2. Abnormalities in the expression of the startle reflex in mental disorders**

Over all other mental disorders, PTSD is associated with changes in the startle reflex. Com‐ monly associated with exaggerated startle responses [11-14], higher or exaggerated startle reflex responses are a criteria symptom for the diagnosis of PTSD [15]. However, recent evi‐ dence suggests that this may not always be the case. In fact, others have reviewed the litera‐ ture and found there are a significant number of reports where the startle responses in PTSD patients are not exaggerated [16]. More extreme, there are reports, albeit limited, where pa‐ tients diagnosed with PTSD appeared to have blunted motor reflex responses to an acoustic stimulus [17, 18]. These populations had distinctive qualities that were different than those studies that had found enhanced startle reactivity in their PTSD patients. First, the one study was exclusively female [18] and the other had a majority of female subjects [17], suggesting there may be a sex difference in the presentation of ASR in females as a result of experienc‐ ing trauma. However, others have reported enhanced startle responses in a different popu‐ lation of women diagnosed with PTSD following automobile accidents [19]. Thus, a second distinction between the two studies that observed suppressed startle reactions, which should be considered, is that the trauma was specifically associated with being the target of violence [17, 18].  A third quality of at least one of these two reports is that the subjects also exhibited symptoms associated with major depressive disorder [18]. This suggests stressful experiences may not cause a uniform change in sensory reactivity, and the expression of the coping response to the trauma may have psychophysiological ramifications that are quite different, both in terms of effects upon sensory-motor responding to acoustic stimuli as well as the full expression of symptoms.