**4. Clinical implications**

#### **4.1. Autonomic cardiac dysregulation in PTSD**

Unlike animals, which generally are able to restore their standard mode of functioning once a fear‐provoking stimulus is past, humans often are not, and they may find themselves stuck in the autonomic profile associated with response that was tied to the original danger or trauma. This is traumatization of the nervous system. When the nervous system is trauma‐ tized, current environmental stimuli, or associatively conditioned reminders of the original danger, repetitively trigger the behavioral response to past fearful events. A simple working definition of PTSD then, apart from the formal clinical diagnostic criteria, is that the ANS of the traumatized individual has become stuck in, or is easily shifted into, a state of ergotropic behavioral response to fear, dominated by sympathetic outflow and its accelerative effects on cardiac adjustment. As a result, PTSD influences on autonomic control of heart rate and HRV impact orienting and stimulus appraisal [9].

The effect of PTSD on HRV has been studied since the late 1990s. Our own meta‐analysis assessed all available studies of sympathetic and parasympathetic influences on HRV to determine effect sizes and the utility of HRV as a potential psychophysiological indicator of PTSD, summarized below [74]. Using keywords "PTSD" and ("heart rate or HRV or vagal or autonomic nervous system"), 453 potentially relevant studies were identified; after inclusion criteria were added, 39 studies were considered; exclusion criteria reduced the study sample to 19, all of which were then included in the meta‐analysis. The meta‐analysis was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) and Cochrane Handbook guidelines, using Comprehensive Meta‐analysis Software, ver. 2.0. We calculated the Hedges' g effect size with 95% confidence interval (CI), statistical significance (*p*), and heterogeneity for each effect size estimate. Several HRV variables were considered, and for each an individual, meta‐analysis was performed. Heart rate (HR) was significantly elevated in PTSD patients. The available scientific literature clearly showed that reductions in SDNN, RMSSD, and HF power, and increased LF/HF ratio, have utility as indicators of autonomic effects of PTSD, which can be associated with impaired vagal activity. The positive LF/HF effect size indicates increase in sympatho‐vagal function under PTSD as compared with controls, and also reflects, we believe, non‐linearity in co‐occurring shifts in LF and HF power with proportionately greater reduction in HF than LF [74].

HRV has been shown to be significantly correlated with eyeblink conditioning in normal adults [11, 69]; in combat veterans with and without PTSD (PTSD+ and PTSD‐, respectively), EB conditioning was associated with resting HRV. In the PTSD+ veterans, frequency and amplitude of eyeblinks, HRV, and immediate memory on a verbal learning test were all lower than in the control group [12]. Factor analysis revealed four separable factors corresponding to (1) eyeblink amplitude, (2) HRV, (3) immediate memory, and (4) self‐report of mood state (depression and anxiety), and eyeblink frequency was significantly predicted by HRV and immediate memory. Furthermore, and importantly, in this study reduced HRV was also shown to be associated with poorer performance on the immediate verbal memory test [12]. Further analysis revealed the effects of eyeblink conditioning on heart rate responding in the same study [10]. In this paradigm, which was discriminative conditioning, a light signal was presented for 5 s followed by a tone conditioning stimulus (CS) that was paired with either an eyepuff (CS+) or no eyepuff (CS‐). Thus, there was a 5‐s vigilance period before onset of the tone CS. A linear HR deceleration from baseline during the 5‐s vigilance period before onset of the tone CS was found in the PTSD‐ subgroup but was not present in the PTSD+ subgroup. This is strong evidence that PTSD disrupts bradycardia during vigilance.

#### **4.2. PTSD and attention bias**

eyeblink [69]. At the single neuron recording level, mPFC processing of stimulus information

Since the same set of stimulus contingencies will classically condition both autonomic function and somatomotor behavior, the existence of a process that integrates the two would be expected. The septo‐hippocampal system may be the brain circuit that performs this activity. Extinction of classically conditioned bradycardia is delayed by vasopressin, which increases peripheral vascular resistance and arterial blood pressure, a result that seemingly increases the autonomic conditioning cortico‐limbic circuit to include hypothalamus and pituitary [71]. Intraseptal injection of the antimuscarinic anticholinergic scopolamine in the concomitant autonomic and somatomotor conditioning paradigm enhanced cardiac deceleration and impaired eyeblink conditioning [72]. Thus, there may be a central border zone cardiac‐somatic linkage [39] that couples and uncouples cortico‐limbic (stimulus registration and appraisal) from neostriatal (response selection) activities [73]. More research is needed in this area to integrate these crucially important past and current constructs of arousal, attention, and

Unlike animals, which generally are able to restore their standard mode of functioning once a fear‐provoking stimulus is past, humans often are not, and they may find themselves stuck in the autonomic profile associated with response that was tied to the original danger or trauma. This is traumatization of the nervous system. When the nervous system is trauma‐ tized, current environmental stimuli, or associatively conditioned reminders of the original danger, repetitively trigger the behavioral response to past fearful events. A simple working definition of PTSD then, apart from the formal clinical diagnostic criteria, is that the ANS of the traumatized individual has become stuck in, or is easily shifted into, a state of ergotropic behavioral response to fear, dominated by sympathetic outflow and its accelerative effects on cardiac adjustment. As a result, PTSD influences on autonomic control of heart rate and

The effect of PTSD on HRV has been studied since the late 1990s. Our own meta‐analysis assessed all available studies of sympathetic and parasympathetic influences on HRV to determine effect sizes and the utility of HRV as a potential psychophysiological indicator of PTSD, summarized below [74]. Using keywords "PTSD" and ("heart rate or HRV or vagal or autonomic nervous system"), 453 potentially relevant studies were identified; after inclusion criteria were added, 39 studies were considered; exclusion criteria reduced the study sample to 19, all of which were then included in the meta‐analysis. The meta‐analysis was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) and Cochrane Handbook guidelines, using Comprehensive Meta‐analysis Software, ver. 2.0. We calculated the Hedges' g effect size with 95% confidence interval (CI), statistical significance (*p*), and heterogeneity for each effect size estimate. Several HRV variables were considered,

appears to be driving decelerative heart rate‐conditioned responding [70].

52 A Multidimensional Approach to Post-Traumatic Stress Disorder - from Theory to Practice

behavior.

**4. Clinical implications**

**4.1. Autonomic cardiac dysregulation in PTSD**

HRV impact orienting and stimulus appraisal [9].

Healthy adaptation requires people to allocate attention to genuine threats in the environ‐ ment while ignoring other similar stimuli. Traumatic events offset this delicate balance and induce cognitive biases that give rise to threat avoidance and threat‐related hypervigilance, among other clinical symptoms. Attentional problems are a common complaint of patients with a PTSD diagnosis, and clinical research data support this. Vietnam veterans with PTSD were found to be significantly worse on controls without PTSD on tasks measuring focused and sustained attention [75]. Using the attentional network test [43], PTSD participants were found to be impaired in inhibiting irrelevant information, a function of the executive atten‐ tional network [76].

PTSD may be associated with hypervigilance to salient and threat‐related stimuli, but results of attention bias studies in PTSD have found biases both toward and away from threat. Hypervigilance manifest as attention biased toward threat cues while avoidance of threat‐ related stimuli. Attention bias indexes the degree to which attention fluctuates between vigilance and avoidance and is based on reaction time data derived from variants of the classic dot‐probe task. In this task, pairs of threat and neutral (or positive) stimuli are simultaneously presented across repeated trials. Each stimulus pair is followed by a target probe appearing at the location of either the threat stimulus (congruent trials) or the neutral stimulus (incongruent trials). An attention bias score is calculated as the difference between the mean reaction times of these two types of trials.

Attentional bias toward threat in PTSD could reflect either difficulty disengaging from threat‐related stimuli or facilitated engagement of such stimuli, although there is some evi‐ dence that attentional bias toward threat in PTSD reflects difficulty disengaging as opposed to facilitated engagement [77]. Early dot probe studies in PTSD in adults and children re‐ ported mixed findings. Some studies found bias toward trauma or threat‐elated stimuli in PTSD [78–82], while others reported an association between PTSD and a bias away from trauma or threat [83, 84]. Still others have failed to find significant attentional bias differen‐ ces between PTSD and control groups, consisting of healthy individuals and a group of re‐ cent trauma survivors that included individuals both with and without acute stress disorder [85, 86]. Difficulty disengaging from threatening stimuli has been associated with the 5‐ HTTLPR serotonin transporter gene polymorphism [87], although the significance of this finding has not been explained.

Iacoviello [88] derived a measure of attention bias by grouping, or "binning," consecutive 20‐ trial sequences on the dot‐probe task and calculating a bias score for each bin. The standard deviation of the bias scores across bins was then divided by the participant's mean reaction time to generate the measure of attention bias for each subject throughout the session. Results of this study revealed greater attention bias in participants with PTSD than in trauma‐exposed participants without PTSD and nonexposed healthy participants. Attention bias was also positively correlated with PTSD symptom severity.

Different selective attentional orienting mechanisms underlying anxiety‐related attentional bias have been identified, such as engagement and disengagement of attention [89]. These mechanisms are thought to contribute to the onset and maintenance of general anxiety dis‐ orders and have relevance for the study of attention bias in PTSD. General anxiety seems to be associated with a preferential bias for negativity. The measure of attention bias has re‐ cently been refined by employing a moving average technique, rather than the previously employed binning method, to generate a more stable index that is influenced less by the number of trials in any particular study [90]. However, attention bias is still something of a novel measure, and we know of no reports of test‐retest reliability. Overall, attention bias may be best conceptualized as reflecting natural plasticity built into the threat‐monitoring system that is influenced by different contexts and situations, rather than indexing a stable trait.

Attentional training (sometimes called attention bias modification, ABM) is aimed at reduc‐ ing symptoms and behaviors associated with anxiety by systematically reducing negative attentional biases and training selective attention to orient away, or to disengage, from threat [91]. Attention control training, but not attention bias modification, was found to sig‐ nificantly reduce attention bias and reduce PTSD symptoms [92]. Thus, further study of treatment efficacy for attention bias, and its underlying neurocognitive mechanisms, seems warranted.
