POSTTRAUMATIС STRESS DISORDER – THE NEUROSCIENTIFIC BASIS OF EVIDENCE-BASED TREATMENTS*

Posttraumatic stress disorder (PTSD) is a relatively common anxiety spectrum syndrome, in which memory of a triggering trauma becomes aberrantly linked to autonomic and emotional arousal. The recurrent, internally generated stress response can produce enduring behavioral and brain changes. Mechanistically, this may involve both dysregulation of the hypothalamo-pituitaryadrenal axis as well as degradation of the capacity of supramodal cortical areas to process and manage trauma-related emotional content. The optimal balance of information processing and hence behavioral reactivity shifts from the refl ective prefrontal cortex in favor of the more emotionally reactive amygdala. Trauma-focused therapies exploit adaptive neuroplasticity to decouple the memory of the trauma from the aberrant emotional and behavioral responses, in effect reconfi guring brain networks. The effect-size of such psychological therapies is generally larger than that for pharmacological treatments which are currently limited to drugs repurposed for PTSD. Nonetheless, in a signifi cant number of patients, some symptoms can be at least partially attenuated by selective serotonin reuptake inhibitors. In addition, the frequency and intensity of trauma-related nightmares can usually be lowered by adrenergic alpha-1 receptor agonists. Even as novel modalities continue to be developed, the judicious implementation of currently available evidence-based treatments for PTSD can target the underlying neurobiology, provide symptomatic relief, and promote psychosocial recovery.

Since the majority of individuals exposed to signifi cant trauma do not develop PTSD, the disorder can be considered as a deviation from the normative course of recovery. The expected weakening of the association between the initial traumatic event(s) and the acute psychological and biological reactions does not occur. In addition, the autonomic and emotional concomitants become decoupled from the initial trauma and can subsequently be triggered either by external or internal stimuli. Mechanistically, this refl ects a maladaptive neuroplasticity of synaptic connections.
Repeated stimulation increases the effi ciency of synaptic transmission (Hebb, 1949). "Neurons wire together if they fi re together" (Lowel and Singer, 1992). While numerous brain circuits are potentially available for activation at any given moment, the precise activation pattern is dynamically determined 'on the fl y' by internally-and externally-driven demands (Cole et al., 2013). In the case of PTSD, the repeated activation of circuits linking the traumatic memory with emotional and behavioral responses, becomes excessively facilitated.
Under normal conditions, information about a given event enters the brain where it can be briefl y retained in short-term memory and then, depending on other factors, may be encoded, consolidated and stored in long-term memory until it is retrieved ( Figure 1) (Lewis, 1979).

Introduction
Posttraumatic Stress Disorder (PTSD) is an anxiety spectrum syndrome that was added to the International Classifi cation of Diseases and Related Health Problems version 9 (ICD-9) in 1978 and to the Diagnostic and Statistical Manual -III (DSM-III) in 1980 (American Psychiatric Association, 1980;World Health Organization, 1978). As is the case for other psychiatric disorders, the nosology of PTSD is currently based in phenomenology, that is in the emergence and course of nonspecific and often variable symptoms and not in reproducible neurobiological indices (Kendler, 2009;Stephan et al., 2016). While diagnostic elements have varied over time, criteria common to DSM-5 and ICD-10 include a) exposure to a signifi cant traumatic event, b) intrusive recollections, c) avoidant symptoms d) increased physiological arousal (in ICD-10, arousal may be replaced by element of amnesia for the traumatic event) (American Psychiatric Association, 2013; World Health Organization, 1993) ( Table 1). The trauma must be signifi cant, but can be experienced directly or indirectly (Table 2).
In the United States (US), the estimated lifetime prevalence of exposure to at least one qualifying trauma is 70-90%, with most people experiencing two or more traumatic events (Kilpatrick et al., 2013;Resnick et al., 1993). The estimated risk of developing PTSD after a single traumatic exposure is 10-30%, with a higher risk associated with violent (e.g. rape, combat) or repeated trauma (Breslau et al., 1998;Friedman et al., 2007a;Grinage, 2003;Kilpatrick et al., 2013). While the reported prevalence of PTSD varies with diagnostic criteria, the quality of data collection and particularly on the population sampled, PTSD is estimated to affect some 8-10% The full memory may integrate not just the facts about a given event (declarative memory -where and what happened) but also emotional value (pleasure, threat) and sensory concomitants (visual, olfactory, auditory, etc.). In PTSD, at least some of these elements become aberrantly linked to autonomic and other responses which initially cause and then are reinforced by chronic brain-based behavioral and cognitive changes ( Figure 2). The human brain can be broadly conceptualized as having three phylogenetically, anatomically and functionally different systems, namely primary, limbic and neocortex; these interact at multiple levels ( Figure 3). While all are neuroplastic, the complexity and responsiveness of their neuroplasticity to voluntary control increases from brainstem to neocortex. The neocortex is also distinguished by regional specialization for information processing (Benson, 1993). Executive function, that is the allocation of overall attention as well as integration of information from multiple brain levels, is mediated within the prefron-tal cortex (PFC). This phylogenetically unique region and particularly its layer III subserve enhanced information processing capabilities (Amatrudo et al., 2012) which constitute the most distinguishing functional feature of the human brain (Elston et al., 2006). Unfortunately, such specialization is accompanied by a heightened vulnerability to homeostatic imbalance.
Preclinical studies demonstrate that neurochemical changes induced by acute stress immediately degrade the ability of the PFC to provide executive function; repeated bouts of uncontrollable stress can lead to long-term structural changes such as impoverishment of the dendritic arbor and spines of PFC pyramidal cells, particularly those of layer III . Despite the variability between studies, the overall data implicate enduring dysregulation of the HPA axis in at least some patients with PTSD.

Treatment
Currently, no pharmacological treatments specifi cally target either symptoms of PTSD ( Encouraging case reports prompted a randomized, double-blind, placebo-controlled clinical trial. In a preliminary sample of male veterans with PTSD related to their service during the Vietnam war, both phenelzine and imipramine were found to be superior to placebo in relieving distress related to intrusive phenomena (nightmares, fl ashbacks, recollections) but not in addressing non-specifi c anxiety or avoidance . The results were confi rmed in the full patient sample with phenelzine showing a modest advantage over imipramine (Kosten et al., 1991). The potential side effects and dietary measures associated with MAOI use, however, limited the appeal of this drug class.
The emerging availability of serotonin reuptake inhibitors (SSRIs) with a more favorable side-effect profi le and better tolerability prompted their ad hoc use in small groups of patients. Subsequently, in a seminal, double-blind, placebo-controlled 12-week trial, sertraline proved superior to placebo in attenuating avoidance and numbing, but was less effective against hyperarousal (Brady et al., 2000). Additional fi ndings were that i) sertraline was generally well tolerated, ii) attendant symptomatic relief evolved slowly and iii) the placebo response (32%) was surprisingly large (Brady et al., 2000). Furthermore, while signifi cantly more patients in the sertraline group reached predetermined criteria for treatment response (53%), overall the effects were quite modest and many pa-tients showed incomplete symptom resolution (Brady et al., 2000). Pharmacological responsiveness of symptoms may provide clues about underlying neurobiology. The receptor profi les of SSRIs, SNRIs and prazosin have prompted investigations of the serotonergic and adrenergic systems. In comparison to controls, subsets of patients with PTSD were found to be more sensitive to the anxiogenic effects of an intravenously administered serotonin type 2C receptor (5HT 2C ) agonist or an adrenergic α 2 receptor antagonist . This raised the possibility that certain PTSD symptoms in patient subgroups were mediated by hypersensitive 5HT 2C receptors; downregulation of these receptors could potentially provide symptomatic relief . Analogously, since presynaptic α 2 receptors inhibit effl ux of noradrenaline, their dysregulation could contribute to excessive activation of postsynaptic α 1 receptors in other patient subsets (Kelmendi et al., 2016). This could explain the effi cacy of α 1 -adrenergic receptor antagonists against nightmares. Of course, many other potential contributors to sleep disturbances (e.g. poor sleep hygiene, gastroesophageal refl ux syndrome, restless leg syndrome, sleep apnea) should be identifi ed and treated as well ( Table 4). The quality of sleep in PTSD can also be improved through cognitive behavioral therapy (Ho et al., 2016).
Several psychotherapies have been developed based on an emerging understanding of how memories are formed and integrated with emotional and behavioral responses. The association between a stimulus and these responses usually weakens during the process of extinction (Pavlov, 1927). In PTSD, this extinction fails. It had long been known that memory consolidation, the process converting information from short term memory to long term memory (Figure 1) depends on protein synthesis (Flexner et al., 1962). It was also believed, however, that initially consolidated memories were relatively fi xed. Later preclinical studies demonstrated that with each retrieval of a stored memory, the relevant information had to be reconsolidated via a protein synthesis-dependent mechanism (Debiec et al., 2002;Duvarci et al., 2008;Nader et al., 2000). In other words, storage of a given memory is not necessarily a unique event but rather a process repeated after each retrieval of that memory. As a result, retrieval renders the associative links of a given memory temporarily available for modifi cation at the cellular and systems level (Nader, 2015). Memory itself can be designated as a treatment target.
An astute clinical psychologist observed that that recurring, distressing thoughts in PTSD could be permanently attenuated, if the subject's eyes were automatically moving in a multi-saccadic manner while the disturbing thought was being held in consciousness (Shapiro, 1989(Shapiro, , 1996. The declarative or explicit memory, that is the facts of the traumatic event, was not abolished, but its intrusive nature and attendant autonomic and emotional concomitants were removed. This catalyzed the development of Eye Movement Desensitization and Reprocessing therapy (EMDR) (Bisson et al., 2007; Jeffries and Davis, 2013). It is thought to exploit the limited capacity of the brain to process information at any given point in time. By deliberately focusing on a sensory stimulus during retrieval of the memory, the individual is less able to attend to its distressing associations. Repetition of this process presumably weakens the links between the declarative memory and its previously distressing autonomic and emotional concomitants. Although the declarative memory remains and can be retrieved at will, it becomes progressively less intrusive and no longer evokes distress.
Analogous neurobiological mechanisms are likely operative in other trauma focused cognitive behavioral therapies (TFCBTs) (Bisson et al., 2007). Stimulus generalization (Pavlov, 1927) for example, may allow irrelevant or neutral stimuli to involuntarily trigger circuits (fear, fi ght or fl ight) that generate a maladaptive response (Figure 3). Some psychotherapeutic approaches focus on encouraging patients to rationally examine their symptom   (Boukezzi et al., 2017). In other words, when successful, these psychotherapeutic approaches may partially reverse or otherwise mitigate PTSD-induced brain changes that mediate symptoms and disability.
Such analyses inform treatment in other ways. Increasing data support a bi-directional relationship between PTSD and sleep disturbances. Suboptimal quality and quantity of sleep is a non-specifi c brain stress; even a few days of sleep deprivation or circadian misalignment affect metabolism, appetite, autonomic tone and various infl ammatory biomarkers (McEwen and Karatsoreos, 2015). Sleep-disordered breathing is independently associated with changes in the functional connectivity of brain regions (Park et al., 2016) as well as with reductions in brain regional cortical volume (Shi et al., 2017). Such anti-trophic effects on the brain would be expected to augment or even synergize with the primary pathophysiology in PTSD. In turn, PTSD is itself associated with a markedly increased risk of sleep-disturbances (

Summary
The pathophysiology of PTSD is complex but involves genetic, neurohumoral and neurochemical mechanisms as well as neuroinfl ammatory processes that change the brain at the molecular, structural and functional levels.
As is the case for other psychiatric disorders, PTSD is mediated by brain networks rather than by any single neurotransmitter system (Insel, 2010). Suboptimal integration of factual, emotional and other types of information across brain networks results in heterotypical functional connectivity between declarative memories and their autonomic and emotional content. In chronic PTSD, the information-processing capacity of deeper layers of the PFC in particular may become compromised. As a general rule, interventions that promote adaptive neuroplasticity can mitigate or reverse this brain-based pathophysiology and promote Праці НТШ Медичні науки 2017, 2 (L) Proc. Shevchenko Sci. Soc. Medical sciences 2017, 2 (L) Огляд Review symptomatic as well as functional recovery ( Figure 5). While we await the development of more effective treatments for PTSD (Girgenti et al., 2017), it behooves us to fully integrate and exploit interdisciplinary, evidence-based treatments that are currently available. These include psychotherapeutic approaches such as EMDR and judicious use of psychotropic drugs. When economic, systemic or individual factors (e.g. medication side effects, reluctance to engage in psychotherapy) impede implementation of multimodal approaches, even limited and highly circumscribed efforts (e.g. sleep hygiene to treat sleep disorder, substance use treatment) can prove helpful in most patients. The critical tasks include i) identifying contributing factors and potential treatment targets, ii) determining which treatments are practical under given conditions, iii) continually assessing outcome and adapting treatment efforts.