PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD

IJLP-01250; No of Pages 21 International Journal of Law and Psychiatry xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

International Journal of Law and Psychiatry

PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD Gerald Young Glendon Campus, York University, Toronto, Ontario, Canada

a r t i c l e

i n f o

Article history: Received 30 January 2017 Accepted 6 February 2017 Available online xxxx Keywords: PTSD Court Biopsychosocial Models Causality Therapy

a b s t r a c t The second article in the series of three for the journal on “PTSD in Court” especially concerns the biological bases that have been found to be associated with PTSD (posttraumatic stress disorder). The cohering concepts in this section relate to risk factors; candidate genes; polygenetics; “gene × environment” interactions; epigenetics; endophenotypes; biomarkers; and connective networks both structurally and functionally (in terms of intrinsic connectivity networks, ICNs, including the DMN, SN, and CEN; that is, default mode, salience, and central executive networks, respectively). Risk factors related to PTSD include pre-event, event- and post-event ones. Some of the genes related to PTSD include: FKBP5, 5-HTTLPR, and COMT (which are, respectively, FK506-binding protein 5 gene, serotonin-transporter linked polymorphic region, catechol-O-methyl-transferase). These genetic findings give an estimate of 30% for the genetic influence on PTSD. The typical brain regions involved in PTSD include the amygdala, hippocampus, and prefrontal cortex, along with the insula. Causal models of behavior are multifactorial and biopsychosocial, and these types of models apply to PTSD, as well. The paper presents a multilevel systems model of psychopathology, including PTSD, which involves three levels — a top-down psychological construct one, a bottom-up symptom connection one, and a middle one involving symptom appraisal. Legally, causality refers to the event at issue needing to meet the bar of being materially contributory to the outcome. Finally, this section of the article reviews empirically-supported therapies for PTSD and the dangers of not receiving treatment for it. Crown Copyright © 2017 Published by Elsevier Ltd. All rights reserved.

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Précis of the second article in the series of three on “PTSD in Court” Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Introduction . . . . . . . . . . . . . . . . . . . . . . 2.2. Research . . . . . . . . . . . . . . . . . . . . . . . 2.3. Comment . . . . . . . . . . . . . . . . . . . . . . . Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Introduction . . . . . . . . . . . . . . . . . . . . . . 3.2. Genes . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Comment . . . . . . . . . . . . . . . . . . . . . . . 3.4. Epigenetics . . . . . . . . . . . . . . . . . . . . . . 3.5. Comment . . . . . . . . . . . . . . . . . . . . . . . 3.6. Brain . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Comment . . . . . . . . . . . . . . . . . . . . . . . 3.8. Connectivity . . . . . . . . . . . . . . . . . . . . . . 3.9. Comment . . . . . . . . . . . . . . . . . . . . . . . 3.10. Neurocognition . . . . . . . . . . . . . . . . . . . . 3.11. Comment . . . . . . . . . . . . . . . . . . . . . . Models of PTSD. . . . . . . . . . . . . . . . . . . . . . . . 4.1. Comment . . . . . . . . . . . . . . . . . . . . . . . Legal causality . . . . . . . . . . . . . . . . . . . . . . . . PTSD causality . . . . . . . . . . . . . . . . . . . . . . . .

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E-mail address: [email protected].

http://dx.doi.org/10.1016/j.ijlp.2017.02.002 0160-2527/Crown Copyright © 2017 Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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6.1. Standard paradigm . . . . . . . . . . . . . . . . . 6.2. New paradigm . . . . . . . . . . . . . . . . . . . 6.3. Research. . . . . . . . . . . . . . . . . . . . . . 6.4. A new approach to PTSD modeling . . . . . . . . . . 6.5. Comment . . . . . . . . . . . . . . . . . . . . . 7. Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Psychotherapy . . . . . . . . . . . . . . . . . . . 7.2. Psychopharmacology . . . . . . . . . . . . . . . . 7.3. Comment . . . . . . . . . . . . . . . . . . . . . 7.3.1. Psychotherapy . . . . . . . . . . . . . . . 7.3.2. Psychopharmacology . . . . . . . . . . . . 8. Conclusion to the second article of the three on “PTSD in Court” 8.1. Looking ahead . . . . . . . . . . . . . . . . . . . 8.2. Looking back . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Précis of the second article in the series of three on “PTSD in Court” This paper examines, in particular, the biological underpinnings of PTSD (posttraumatic stress disorder) in order to better establish its validity as a valid diagnoses and its role in adjudicating claims of psychological injury in court (Young, 2016a, 2017, being the first and third in the series). If it has an established biological basis in its genetic and epigenetic predispositions, as well as in its neurobiological, central (brain), and stress reactions (hypothalamic pituitary adrenal (HPA) axis), it will be harder to dismiss in court as a social construction or a product of a failed nosology (the DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; American Psychiatric Association, 2013). This would be true even if the research on PTSD's biological basis has not included testing and other means to exclude possible malingered cases. On the one hand, as shall be shown in the third article in the series of three in the journal on “PTSD in Court,” the percentage of malingering in disability and related forensic or court assessments is much lower relative to some higher estimates in the literature. On the other hand, the biological underpinnings are still found in the research, and would only be amplified in strength should malingered cases be tested for and excluded. This second article of the three on “PTSD in Court” considers its biological underpinnings as a prelude to presenting a model of PTSD that is biopsychosocial. That is, on the one hand, despite its biological basis, PTSD is also psychosocial in nature. This is indicated not only by its traumatic stressor initiation at the time of its inception but also by the environmental factors contributing to its risks and vulnerabilities before that event and also by the mediators and moderators that can influence its course. The latter includes psychotherapeutic interventions, which are also reviewed in this article of the three on “PTSD in Court.” However, causality as discussed in this work in relation to PTSD also includes the legal approach, which seeks to differentiate the instigating event as a material contributor to the traumatic effects at hand from among the array of multifactorial causal considerations. This article discusses a model of PTSD (and mental disorder, generally), in which PTSD as a mental construct and PTSD as a symptom complex reciprocally interact. That is, the classic point of view is a topdown one in which a mental disorder develops as an entity that creates symptom expression in context. However, bottom-up models view symptoms and their interactions as causal in and of themselves. A hybrid model would consider in PTSD bottom-up, symptom interactions and top-down mental disorder influences as reciprocal in the course of PTSD, for example. Moreover, another factor in PTSD constitutes the symptom appraisals that are individually at work in patients. Also, there might be clusters of symptoms to consider in mental disorder, such as is the case in PTSD. The present model is especially a “dynamic systems” one with multiple interacting systems, part of which evolves through emergence from lower-level interactions. In this sense, PTSD is exquisitely

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individual in nature (as well as mental disorders, generally), and it should be approached in treatment from this perspective, yet with many commonalities over patients (such as in biological underpinnings, although these, too, should reflect individual expression). This complicates any attempt to present biological measures related to PTSD in Court. For summaries of the biological underpinnings that have been found in PTSD, consult other sections of this article. 2. Risk factors 2.1. Introduction Generally, PTSD should be considered a biopsychosocial condition, and its risk factors, as well (Young, 2014). Typically, risk factors fall into two types — those that are sociodemographic or congenital and those that reflect adversity. For example, respectively, sex is a major risk factor, and early traumatization helps predispose victims to the effects of exacerbatory events, such as an event at issue (e.g., an MVA; motor vehicle accident). Risk factors should be considered as cumulative toward developing PTSD. For example, Briere, Agee, and Dietrich (2016) found that, in the general population (as well as in the prison population), exposure to increasing trauma types led to a greater likelihood of developing current PTSD. The difficulty presented to psychological assessors is to disentangle causality when there are multiple and interacting risk factors, including those that are pre-event, event, and post-event related, aside from any question of malingering. That is, in court, the event at issue must be shown to meet the threshold of material causation (not necessarily sole causation), given the multifactorial nature of psychological conditions, in general (Young, 2014). Therefore, forensically, the task is not only to diagnose the trauma reaction but also to show that the index event had contributed more than minimally to the outcome. For example, the person might have been a victim of a serious MVA, but did not experience PTSD as a result of any trauma reaction. In the area of risk in relation to PTSD claimed as a result of an index event, the person might be expressing PTSD, but due to pre-event factors and not the index event at issue. Risk factors, rather than traumatic ones addressed in court actions, might be fully responsible for the PTSD diagnosis at issue. That is, legally, risk factors might exacerbate the potential to develop PTSD or other trauma reactions. However, in court involving tort and related actions, in order for the legal bar for successful action to be met, by themselves, risk factors cannot be considered fully causative. At the other end of the spectrum, whether for the sociodemographic type or the adversity type, it would be inappropriate to consider the risk factors for PTSD in denying in a blanket way any and all PTSD claims in events at issue, or as always responsible for any PTSD that is associated with an event at claim. This would be especially egregious for the PTSD risk factor of gender. It would be unacceptable to claims that the person

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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involved is a woman, so that it is inevitable she developed PTSD because of her gender. This prelude to discussing the research on risk factors in PTSD indicates that we should let the current research speak for itself. The following considers risk factors of PTSD, such as sex and personality and, in this regard, the various roles of pre-event, event, and other factors. 2.2. Research In a cogent study of risk factors that predict posttraumatic and related symptoms after traumatic experiences, Carlson et al. (2016) studied pre-trauma, peritrauma, and post-trauma psychosocial risk and protective factors in 129 traumatically-injured hospital patients (and their family members). PTSD symptoms were assessed with the Screen for Posttraumatic Stress Symptoms (SPTSS; Carlson, 2001) keyed to the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; American Psychiatric Association, 1994). The risk factors were all significantly correlated with later posttraumatic (PT) symptoms. A hierarchical regression showed that the risks accounted for 71% of the variance in later symptoms. Pre-trauma and post-trauma risk factors accounted for most of this variance. The event-related risk factors were not predictive of outcome, unlike in prior studies that were reviewed by Carlson et al. (2016). Nevertheless, in this study, pretrauma factors were not uniquely predictive, which speaks against any argument that PTSD generally can be fully explained by pre-existing factors. Furthermore, Gorman, Engel-Rebitzer, Ledoux, Bovin, and Marx (2016) have shown how the peritraumatic experience due to traumatic stressors is quite integral to the traumatic stress response. Generally, PTSD is considered more prevalent in women (e.g., Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995; Pietrzak, Goldstein, Southwick, & Grant, 2011). Research has also studied which symptoms differ in men and women due to trauma (e.g., He, Glas, & Veldkamp, 2014); for example, the results show women feeling more detachment and men more intrusive thoughts compared to men. However, by instituting certain controls in the research, the sex differences in PTSD can be minimized. In this regard, Rivollier et al. (2015) examined the sample in the U. S. National Epidemiological Survey on Alcohol and Related Conditions (N = 23,860), using itemresponse theory and DSM-IV consistent PTSD symptoms, after stratifying for major trauma type and controlling for PTSD severity. The results showed little difference between women and men in PTSD symptom prevalence according to the design of the study, except that men felt more a “foreshortened future.” Note that the prevalence rates of all PTSD symptoms, and the overall PTSD diagnosis, were higher in women compared to men. Risk factors for PTSD relate to the traumatic events at issue themselves, as well. Ogle, Rubin, and Siegler (2016) studied communitydwelling older (mid-60s) adults in a longitudinal study, using 15 measures as PTSD risk factors and also health-related measures. They used the PCL-S (The PTSD Checklist — Stressor Specific Version; Weathers, Litz, Huska, & Keane, 1994) to measure PTSD symptom severity, which is keyed to the DSM-IV. Pretrauma factors that were measured include sociodemographic factors and history of parental psychopathology. Traumatic event analyses indicated a high rate of unexpected death of a loved one, but also life-threatening illnesses and accidents, among others. In this study, the variables that predicted PTSD symptom severity especially involved (a) post-trauma ones, including insecure attachment, depressive symptoms, lower perceptions of ability to cope with stress, and also (b) a suite of variables related to the index event (memory, severity, centrality to identity, involuntary recall, and memory-related visceral reactions). The authors concluded that index trauma memory serves as an axis in promoting and maintaining the development of PTSD symptomatology. Fletcher, O'Donnell, and Forbes (2016) showed that pre-existing lifetime history of mental disorder in reaction to trauma is not a factor

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that affects results that serve to show that pre-existing personality has an influence on the development of posttraumatic mental health problems. They examined 323 Australian adults who were hospitalized on average of about nine days for “major trauma,” according to an injury severity score (ISS; Baker, O'Neill, Haddon, & Long, 1974; also according to a registry). About 40% of these survivors had sustained an mTBI. They filled in a self-report questionnaire in their pretrauma admission, the MPQ-BF (Multidimensional Personality Questionnaire, Brief Form; Patrick, Curtin, & Tellegen, 2002). They were assessed for PTSD, depression, anxiety and substance use disorders using the SCID (Structured Clinical Interview for DSM-IV Axis I Disorders; First, Spitzer, Gibbon, & Williams, 2002). They were followed up at 3 and 12 months of age (N = 278,242, respectively). Conditional latent profile analysis (LPA) and latent change modeling (LCM) were used to group personality types and their change over time. The results showed that a three-class model best fit the data, with Class 1 representing the normative type, Class 2 having low constraint scores, and Class 3 having high negative emotionality scores. The classes were labeled normal, externalizing, and internalizing, respectively, and PTSD was associated with the latter. Surprisingly, the externalizing class appeared best protective of developing subsequent internalizing disorders although not substance abuse. The results illustrate the need to establish pretrauma personality and to consider wider trauma reactions than just PTSD. Another study that showed the value of examining pretrauma risk factors for PTSD, yet without denying the importance of the severity of the trauma itself, was authored by Feder et al. (2016). The authors examined surviving World Trade Center (WTC) 9/11 responders up to 12 years after 2001 (N = 4487; also at 3, 6, and 8 years post-trauma). Symptomatic PTSD trajectories (as evaluated with the PCL-S (Posttraumatic Checklist — Short; Ruggiero, Del Ben, Scotti, & Rabalais, 2003) were associated with ethnicity (Hispanic) and psychiatric history pretrauma, and also with greater WTC peritraumatic exposure. Furthermore, post-trauma factors included medical illness, life stressors, other traumas, and maladaptive coping (e.g., substance abuse, avoiding). Personality or dispositional factors might be involved in risk for PTSD but little implicates one personality type or disorder that is associated with PTSD. However, more subtle or less disordered characteristics, per se, such as intolerance of uncertainty (Oglesby, Boffa, Short, Raines, & Schmidt, 2016) and impulsivity (e.g., negative urgency; Roley, Contractor, Weiss, Armour, & Elhai, 2016), help predict PTSD. Morris, Hellman, Abelson, and Rao (2016) conducted a systematic review and meta-analysis of early markers for risk of PTSD symptoms. They included 26 studies with 5186 participants, and they found that soon after trauma exposure, higher heart rate was associated with greater PTSD symptoms later on. In contrast, neither measures of cortisol nor blood pressure were associated with later PTSD symptoms. The results held for younger participants only. 2.3. Comment The more recent research on PTSD risk is consistent with prior research that peri- and posttraumatic variables predict long term outcome and PTSD in trauma situations more than pre-existing variables (e.g., Weiss & Ozer, 2006). From the forensic perspective, one could argue that this type of research typically does not screen for possible malingering, so its conclusions are not valid. Some research points to more variance explained by pre-existing factors than other ones in trauma reactions (Bowman & Yehuda, 2004), and that negative affectivity is a powerful predictor of PTSD (Miller, 2003), perhaps constituting the best way to explain it. More recent research does not give such primacy to pre-event factors in the causality of PTSD development, as shown in the review above, although these factors are mentioned and certainly are often exacerbatory in any case. From a legal perspective, survivors need to be taken as they are found even if they have a “crumbling skull” (Young, 2007). If they meet the bar of having the event at issue

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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contribute materially to their present psychological condition, and there are prior exacerbatory factors complicating their presentation and recovery, the third party payor is still responsible legally for all therapies required (and perhaps more so because of the longer term therapies needed as a result), and compensation may be awarded accordingly. 3. Biology 3.1. Introduction The findings about event-related or environmental factors cannot supplant or deny the importance of biological contributions to understanding the PTSD development as a result of traumatic exposure. The bio-neuroscientific bases for PTSD development and its risk (Koenen et al., 2014; Nash, Galatzer-Levy, Krystal, Duman, & Neumeister, 2014; Rasmusson & Shalev, 2014; Vasterling & Lippa, 2014; Vogt, King, & King, 2014) suggest considering PTSD as a neurobiological disorder. However, although progress is being made in understanding its biological correlates, the field has yet to advance enough to have specified a useful biomarker for individual cases in court, despite that they “hold promise” (Kilpatrick & McFarlane, 2014). The search for the neurobiological basis for PTSD seeks not only neurological and related aspects in PTSD but also their relationship to underlying genetics. Further, the biological of PTSD includes its full-body accompaniments, and not just those of the brain. That is, a biological correlate to PTSD could result from many factors, such as a stress response to the event at issue. In fact, it is possible that one day a biomarker is found that applies to all trauma survivors diagnosed with PTSD and differentiates them from non-PTSD survivors, and their physiological reactivity might hold the key in this regard. For example, Pape and Binder (2016) maintained that genes related to the HPA axis could play a leading role in underpinning PTSD because it is the most salient system regulating the neuroendocrine stress response. Stress helps release the CRH (corticotropin-releasing hormone) in the hypothalamus, which leads to cascading adrenal and related effects, including the release of cortisol. The latter acts on the glucocorticoid receptor (GR), helping to deal with the stress, which should dissipate, thereby rendering the negative feedback loop reducing HPA activity and cortisol production adaptive. However, in PTSD, this stress hormone system is dysregulated, so that the genes involved in its regulation constitute prime candidate genes for PTSD. It is unlikely that a biomarker will be found that can apply to every individual case of PTSD, given its heterogenous nature and the multiple points in the pathway to its expression. Also, it is doubtful the marker, if found, will not be related in some way to a brain-based foundation. Downstream links to genetic bases of both stress hormone system and brain-based systems will continue to be sought. This does not imply that the environment cannot be involved, because genes do not express their protein production in a vacuum devoid of the environment (Young, 2016b). Young (2016c; citing Gottesman & Shields, 1972, 1973; Gottesman & Gould, 2003) defined an endophenotype as either one or a group of components in the pathway from distal genotype to psychiatric mental disorder. The components involved are measurable; demonstrate heritability; are expressed proportionally more in unaffected family members than in the general population; and are state-independent (even evident before the disease is fully expressed). Briefly, endophenotypes constitute transition pathways from genetics to disease/disorder, including in the case of PTSD (Sherin & Nemeroff, 2011). Michopoulos, Norrholm, and Jovanovic (2015) pointed out that the heterogeneity of PTSD symptom expression (Galatzer-Levy & Bryant, 2013) complicates the search for its biomarkers. That said, their review points to possible biomarkers related to all major organs in the body, indicating PTSD's biological roots, as well as its associated genetic bases. For example, the hippocampus and amygdala are involved in the brain, cortisol is decreased in the adrenals, heart rate increases,

testosterone reduces in the gonads, and, with further downstream effects, c-reactive protein increases in the liver and interleukin 6 (involved in inflammation) increases in the lymph nodes. The genes involved include those related to serotonin (5HTT, serotonin transporter). Potential PTSD markers, thus, involve the monoaminergic transmitter systems, the HPA axis, steroid hormones, metabolic hormonal pathways, inflammatory mechanisms, psychophysiological reactivity, and neural circuitry (neural–anatomical and neuro-activational markers). This far-reaching biological impact in PTSD helps account for its disease risk and symptom/disorder progress, as well as those for its associated medical illnesses. 3.2. Genes Genes can be considered primary biological bases for behavior, but they are downstream relative to the development of the body and brain that they regulate. They are distal mechanisms rather than proximal ones, such as in the stress response as mediated by the brain. Moreover, in searching for the genetic bases for PTSD, as with the search for epigenetic influences, one can focus on what promotes risk factors, the development of the disorder, and its recovery separately. The following examines the genetic basis of the development or expression of PTSD rather than its risk factors or responsiveness to therapy. [For work on the genetics in the risk for PTSD, see Hauser et al. (2017).] A recent study cited by Ford, Grasso, Elhai, and Courtois (2015) on genetic contributions to PTSD referred to those in the stress response (White et al., 2013). That the stress response is part of the associations with PTSD is not surprising, as mentioned. The field of forensics in the disability and related context should be aware of the research relating it to genetics either in the stress response, its precursors, or its consequences, including of possible PTSD. Simply, the danger is that a minority might emphasize that a genetic-based biomarker exists for PTSD such that this biomarker for PTSD can explain it in full beyond any traumatic stressor associated with it. That is, it is expressed more because of that vulnerability rather than any event at issue. The same forensic implications result from any research relating earlier and later portions of the endophenotypic pathway toward PTSD development. Nevertheless, forensic assessors need to know in depth how PTSD develops. The following indicates the large range of potential biomarkers for PTSD along the endophenotypic pathway toward its expression. Lebois, Wolff, and Ressler (2016) reviewed neuroimaging genetic approaches to PTSD, finding robust evidence for its neurobiological basis. They described genes related to the physiological stress response and to behavioral intermediates (e.g., in learning and memory) associated with PTSD. For them, genetic and epigenetic factors account for up to 70% of individual differences in PTSD development, with PTSD heritability estimated at 30%, and with critical brain areas including the amygdala, hippocampus, rostral ventromedial prefrontal cortex (rvPFC) and dorsal anterior cingulate cortex (dACC). Lebois et al. (2016) noted that genetic variations associated with brain structure differences in PTSD according to MRI (magnetic resonance imaging) measurement include FKBP5, COMT (catechol-O-methyl-transferase), and BDNF (brain-derived neurotrophic factor). The first one refers to the FK506-binding protein 5 gene, which modulates glucocorticoid receptor activity. It allows for inhibited glucocorticoid signaling, and it is highly expressed in the hippocampus, which is associated with memory function related to PTSD (Zannas, Wiechmann, Gassen, & Binder, 2016). The SNP (single nucleotide peptide) rs1350780 risk allele (T) is associated with increased transcription of FKBP5, leading to increased inhibition of glucocorticoid signaling, which has been related to PTSD development vulnerability (Yehuda, McFarlane, & Shalev, 1998). As for COMT, this gene codes for catechol-O-methyl-transferase, which functions in the breakdown of the neurotransmitter, dopamine, and of other catecholamines. It is highly expressed in the prefrontal cortex, which is associated with executive function. Compared to the

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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Met allele, the Val allele of COMT SNP rs4680 (Val158Met) is associated with increased dopamine breakdown, and so less dopaminergic transmission and decreased neuropsychological test performance. The BDNF gene factor encodes for a neurotrophin that facilitates the development/survival and connectivity/plasticity of neurons, the BDNF protein. The gene is quite associated with learning and memory, playing a crucial role in this regard in the hippocampus. The protective allele in this case is the SNP rs6265, with confers increased neuronal plasticity/ recovery. According to Lebois et al. (2016), fMRI (functional magnetic resonance imaging) research presents a different picture of the genetic variations involved in PTSD than is the case for MRI research, as per the above. For example, the serotonin transporter gene (SLC64A) encodes a protein in the reuptake of serotonin at the synapse. The rs16965628 G allele and also the 5-HTTLPR (serotonin-transporter linked polymorphic region) s allele are involved in decreased expression of the gene (with effects in the vlPFC (ventrolateral PFC) and the amygdala, respectively; Morey et al., 2011). As for epigenetic variations in MRI and fMRI research, once more, a different set of genes is implicated in variations associated with brain structure and function underpinning PTSD development. However, one constant in all three sets of research analyzed by Lebois et al. (2016) is the role that FKBP5 plays in PTSD. In this regard, epigenetic methylation of SNP rs1360780, with the risk allele (T), inhibits its expression, leading to increased glucocorticoid signaling (Klengel et al., 2013; who conducted a study of childhood trauma and the epigenesis mentioned). The research keeps pointing to new genes that might be involved in the development of PTSD. Often, studies on candidate genes in psychopathology have not been replicated. Nevertheless, candidate gene research is complementary to broader genetic studies in that, in candidate gene research, the molecular pathway from gene to neurobiology to behavior can be traced specifically. Moreover, consensus is emerging on certain candidate genes that are associated with PTSD, with most involving neurotransmitters and the brain, but others involving systems such as inflammation and the immune response. Pitman et al. (2012) identified 22 candidate genes in PTSD. Kolassa, Illek, Wilker, Karabatsiakis, and Elbert (2015) noted that genetic evidence suggests that there is reduced serotonin transporter binding in the amygdala in PTSD (Murrough et al., 2011), due to a polymorphism in 5-HTTLPR (the s (short) allele; Lonsdorf et al., 2009). This allele, compared to the 1 (long) one, is associated with lower gene transcription, producing less serotonin transporter activity and serotonin clearance from the synaptic cleft (Kolassa et al., 2015). This leads to greater amygdala reactivity to an emotional stimulus and, therefore, consequently, enhanced fear conditioning. Ashley-Koch et al. (2015) conducted a Genome-Wide Association Study (GWAS) of PTSD in Iraq-Afghanistan theater military veterans. PTSD was evaluated with the DSM-IV criteria. Although particular SNPs were not especially evident in the results, the genes that emerged as associated with PTSD all involved post-transcriptional regulation. There were some genes that were group-specific (Black, White, both nonHispanic), while others emerged in combined analysis (e.g., protein kinase type 1 alpha cGMP-dependent (PRKG1); and DEAD box polypeptide 60-like; (DDX60L); both genes related to the neurotransmitter serotonin). Goenjian et al. (2015) related PTSD symptomatology to the COMT and TPH-2 (tryptophan hydroxylase 2) genes. Badour et al. (2015) studied the association of a cholecystokinin (CCK) promoter polymorphism (rs1799923) and PTSD in combat veterans (N = 457). Results showed having either the heterozygous or homozygous T allele of the SNP rs1799923 relative to having the CC genotype was associated with an increased prevalence and severity of PTSD (assessed by interview). CCK is a neuropeptide related to the acquisition and extinction of fear; it has been implicated in panic attacks and panic disorder; and it is one of the most distributed neuropeptides in the brain.

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Although, candidate genes are associated with PTSD, typically, even when replicated, the variance explained is minimal. The power in associating gene loci and PTSD is increased by considering multiple genes simultaneously, especially considering that their traceable influences on pathways to PTSD interact. In this regard, Frick et al. (2016) found an overlapping expression of serotonin transporters and neurokinin-1 receptors in PTSD in a multitracer PET (positron emission tomography) study. Specifically, the serotonergic system is co-localized with and interacts with substance P/ neurokinin-1 (SP/NK1), a neuropeptidergic substance, and both have been associated with stress and anxiety. Substance P is a “back-up” system to the one involving serotonin in periods of high stress, so that both systems can be disrupted in PTSD. The results showed elevated brain serotonin transporter (SERT) and NK1 receptor availability in PTSD patients, with various correlations including with symptom severity. Of note, the interaction result was revealing. In PTSD patients, both higher and lower SERT and NK1 receptor expression were found in several brain regions, including the amygdala (the lower the overlap in the latter, the greater the symptom severity). In a diffusion tensor imaging (DTI) and a resting state MRI study, Fani et al. (2016) found that PTSD patients compared to traumatized controls showed poorer anterior cingulate cortex (ACC) — hippocampal structural connectivity (lower cingulum bundle values on the measures involved, e.g., mean fractional anisotropy, FA). The cingulum is a highly heritable white-matter tract pathway. In addition, lower cingulum FA was evident in carriers of two risk alleles for the SNP of FKBP5, rs1360780. Also, the carriers demonstrated poorer at rest ACChippocampal connectivity. The authors explained that polymorphisms of FKBP5 are likely to affect frontal-hippocampal connectivity because of their effects through glucocorticoid activity on dendritic remodeling and postsynaptic dendritic spine plasticity. The particular risk alleles of rs1360780 are the T ones, with the TT genotype being the risk one, also as mentioned above. The PTSD measure involved in this study was the CAPS (the Clinician-Administered PTSD Scale; Blake et al., 1995). The authors concluded that altered ACC-hippocampal structural connectivity could constitute a “highly salient” PTSD intermediate phenotype. Mazin et al. (2016) examined acute PTSD patients (veterans) for possible genetic biomarkers of PTSD. Relative to controls, they found differential expression levels of the transcription profiles in blood assays for the genes ERK2 and RGS2, which have been related to anxiety/mood disorders (ERK2 = Extracellular signal-related kinase 2; RGS2 = regulator of G-protein signaling 2). The GR is critical to the HPA stress axis, and the genes of interest in the present study point to, in PTSD, an affected protein-coupled receptor signaling (gPCR signaling), via ERK2 and RGS2 expression changes (cell growth stimulator, and gPCR signal duration regulator, respectively). In a GWAS, Kilaru et al. (2016) related PTSD to neuroligin 1, encoded by the gene Neuroligin 1 (NLGN1). NLGN1 has been related to synaptogenesis, learning, and memory. Sadeh et al. (2016) conducted a polygenic risk study for relevant trauma-related behavioral outcomes in trauma-exposed veterans (two studies: N = 537; N = 194, respectively). Specifically, the results implicated a role for executive dysfunction (e.g., working memory) and externalizing psychopathology (and impulsivity) in risk for PTSD. The authors found a G × E (gene by environment) interaction, such that trauma exposure in conjunction with high levels of genetic vulnerability predicted more impulsivity and less working memory. CAPS helped in the PTSD assessment. Note that in computing the polygenic risk score, 480,856 SNPs were genotyped, which illustrates the quite different approach taken in polygenic research compared to that in isolated candidate gene studies. Also, the G × E interaction itself is instructive. Genes don't necessarily work in direct pathways, and ones with liabilities might not affect phenotypic expression unless there is a concomitant environmental risk, such as early adversity or trauma exposure.

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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The polygenic nature of genetic contributions to PTSD is underlined by the study of Guardado et al. (2016). They conducted a whole genome expression analysis (for gene expression profile) of military personnel in relation PTSD and comorbidities. The results in PTSD patients relative to controls revealed 203 differentially expressed genes, of which 72% were upregulated. PTSD was assessed using the PCL-M (PTSD Checklist — Military Version; Wilkins, Lang, & Norman, 2011). The genes involved related to immune (inflammatory) and neuroendocrine function, as well as the NF-κB (nuclear factor-kappa B) systems, which regulates inflammatory gene networks. Other workers who emphasize the compromised immune system in PTSD include Rita, Young, and Wang (2016), who conducted another review implicating inflammation in PTSD. In this regard, Bersani et al. (2016), referred to affects on natural killer cells. [In this regard, O'Donovan (2016) suggested that inflammatory markers of PTSD might especially concern interleukin-6 (IL-6), IL-1β, and interferon-γ levels (IFN-γ).] Further, Zass, Hart, Seedat, Hemmings, and Malan-Müller (2016) explained the specific mechanisms involved in inflammation in PTSD. They related PTSD to neuroinflammatory genes, such that they can account for its comorbidity and medical morbidity. They considered PTSD a low-grade inflammation with heightened immune and inflammatory reactions (after Breen et al. (2015)). The genes involved lead to the overproduction of proinflammatory cytokines, then microglia activation, and then a host of effects including neurotoxic factors being produced leading to neuronal injury and cell death, thereby affecting memory consolidation and long-term potentiation. The neuroinflammatory genes involved appear to be those related to the GR, FKBP5, IL-6, IL-1β, and TNF-α (tumor necrosis factor), in particular. van den Heuvel, Suliman, Malan-Müller, Hemmings, and Seedat (2016) showed that plasma BDNF level increases with number of prior trauma exposures, indicating that it could represent a marker of past traumatic load. That is, genetic studies are now differentiating contributions to risk factors, PTSD development, and even its maintenance and therapeutic response. Zannas, Binder, and Mehta (2016) described the genomics of PTSD. Candidate genes associated with PTSD have included ones related to the HPA axis and otherwise. For the former, the gene encoding for the FKBP5 has been implicated, among others, but studying the cumulative risk effect of the involvement of multiple candidate genes provides greater statistical power (Boscarino, Erlich, Hoffman, Rukstalis, & Stewart, 2011; with the other polymorphisms related to COMT, CHRNA5 (cholinergic receptor nicotinic alpha 5 subunit), and CRHR1 (corticotrophin-releasing hormone receptor 1 gene). As for non-HPA axis PTSD-related genes, they concern the dopamine D2 receptor (DRD2), the serotonin transporter gene 5-HTT, and the gene encoding for BDNF, among others, although the results of the research appear mixed. Pape and Binder (2016) added that Rothbaum et al. (2014) have constructed a 10-gene composite risk factor score related to genes associated with the stress response, and they reported that the scores obtained predicted prospectively PTSD symptoms in emergency department trauma-exposed patients. The genes involved were: ADCYAP1R1 (pituitary peptide PACAP (pituitary adenylate cyclaseactivating peptide) receptor type 1 gene), COMT, CRHR1, DBH (dopamine beta-hydroxlase), DRD2, FAAH (fatty acid amide hydrolase), FKBP5, NPY (neuropeptide Y), NTRK2 (neurotrophic receptor tyrosine kinase 2), and PCLO (piccolo presynaptic cytomatrix protein). Part of the replicability issue in genomic studies of PTSD is that there is a G × E (gene × environment) effect to consider. For example, for the gene coding the serotonin transporter (SLC6A4), the promoter polymorphic region (5-HTTLPR) has two functional variants, the low and high expression alleles (1, respectively). The G × E interaction effect involving these alleles is illustrated by a study of PTSD in hurricane survivors (Koenen et al., 2009). The s allele was associated with a greater risk of PTSD in survivors when rates of crime and unemployment were experience as high, but with the opposite effect with low rates of crime and

unemployment. These results are consistent with the plasticity gene (differential susceptibility) hypothesis of Belsky et al. (2009). Other research found an association of epigenetic effects on early child abuse but not adult trauma survivors with FKBP5 risk variants (Klengel & Binder, 2013; Klengel et al., 2013; Zannas & Binder, 2014). In another G × E study involving PTSD, Watkins et al. (2016) found that four FKBP5 SNPs were related to PTSD symptom severity and, also, they interacted with childhood abuse in this prediction for one of the two samples studied, especially for hyperarousal symptoms. Specifically, the authors investigated 1585 U.S. military veterans in one sample from the National Health and Resilience in Veterans Study and 577 in a second one. They administered the PCL-5 (keyed to the DSM-5; Hoge, Riviere, Wilk, Herrell, & Weathers, 2014) with the second sample and the PCL-IV with the primary one (Weathers, Litz, Herman, Huska, & Keane, 1993). The four SNPs were rs9296158, rs3800373, rs1360780, and rs947008. The authors concluded that the four FKBP5 SNPs involved in conjunction with childhood abuse might be associated with a greater vulnerability to PTSD. van Rooij et al. (2016) found a G × E interaction of COMT and childhood trauma related to hippocampal activation in individuals resilient to PTSD. In particular, for 73 women who had been highly traumatized, hippocampal activation in a Go/NoGo task not only correlated negatively with PTSD symptoms but also mediated the relationship between childhood trauma and resilience for the Val/Val carrier group (not the Met carrier group). Even at press time, new findings are emerging, such as by Stein et al. (2016). They implicated the ANKRD55 (ankyrin repeat domain 55) gene (which is immune function related) in PTSD. Also, as reported in Sheerin, Lind, Bountress, Nugent, and Amstadter (2017), a GWAS investigation found an association for the PRTFDC1 (phosphoribosyl transferase domain containing 1) gene and PTSD (in rs6482463; Nievergelt et al., 2015). In the most recent research on relationship between PTSD and genetic risk mechanisms, Bharadwaj et al. (2016) found a new candidate PTSD risk SNP (rs363276), which is located in intron 14 of the SLC18A2 (solute carrier family 18 member 2) gene. The gene SLC18A2 is a transporter of monoamines and is vesicles-associated. The monoamines involved were the neurotransmitters serotonin, dopamine, and noradrenaline. The brain region associated with the SNP involved was the DLPFC (dorsal lateral prefrontal cortex). Among other results, the authors found ones involving epigenesis. The genetic procedure used was a genotype to RNA (ribonucleic acid) sequencing-derived quantitative expression analysis of normal postmortem human brains. This technique appears quite promising in elucidating the genetic and epigenetic expressions of PTSD in the brain. 3.3. Comment The research on the genetic basis for PTSD is burgeoning, is being replicated, and provides support for an integrative biopsychosocial model for PTSD. Candidate gene studies are specifying particular genetic alleles associated with PTSD expression, and which ones constitute a greater risk. However, the amount of variance explained by any one allele in candidate gene research on PTSD is minimal, so that a broader polygenic approach is needed. Moreover, Sheerin et al. (2017) reviewed only meta-analyses on candidate gene research on PTSD, and found little replicability. For 5-HTTLPR it was found to be associated with PTSD but only in a G × E effect (E = level of trauma exposure). However, the two publications were dated in 2013, which is already out of date in this fast developing field (Gressier et al., 2013; Navarro-Mateu, Escámez, Koenen, Alonso, & Sánchez-Meca, 2013). Even if candidate genes related to PTSD stand up to research scrutiny, the amount of variance any one could explain is minimal and there are many of them. This complicates search for the endophenotypic pathway in PTSD, and consequently, the application of this genetic research to court and related venues. However, forensic assessors should

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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not deny the potential biological basis for PTSD in any way, including the genetic, given its potential for finding critical biomarkers that differentiate genuine patients from non-genuine ones. In this regard, Lareau (2011) considered biomarker research as critical to forensics in PTSD assessment. The research implicates that genetic and epigenetic factors account for up to 70% of individual differences in PTSD development, with PTSD heritability estimated at 30%. The major candidate genes in PTSD development include FKBP5, COMT, and BDNF. The 5-HTTLPR gene also appears involved. A polymorphism in 5-HTTLPR (the s allele, compared to the 1 one) leads to reduced serotonin transporter binding in the amygdala in PTSD. It is associated with lower gene transcription, producing less serotonin transporter activity and serotonin clearance from the synaptic cleft, leads to a greater amygdala reactivity and enhanced fear conditioning. Other serotonin related genes implicated in PTSD include protein kinase type 1 alpha cGMP-dependent (PRKG1); and DEAD box polypeptide 60-like; (DDX60L). Also, the serotonergic system is co-localized with and interacts with substance P/neurokinin-1 (SP/NK1); substance P is a “back-up” system to the one involving serotonin in periods of high stress. Pitman et al. (2012) identified 22 candidate genes in PTSD. Guardado et al. (2016) found 203 differentially expressed PTSD genes. Other candidate genes related to PTSD include cholecystokinin (CCK) promoter polymorphism (rs1799923) (either the heterozygous or homozygous T allele of the SNP rs1799923 relative to the CC genotype) and the genes ERK2 and RGS2, which have been related to anxiety/mood. Genes vary in their effects not just due to which polymorphism is expressed but also due to the environment, in a G × E effect. Sadeh et al. (2016) found a G × E interaction — in veterans, trauma exposure in conjunction with high levels of genetic vulnerability predicted more impulsivity and less working memory. Note that in their study, in computing the polygenic risk score for PTSD, 480,856 SNPs were genotyped, which indicates the risk of focusing just on isolated candidate genes toward understanding the genetic contributions in PTSD. Typically, the research on genes in relation to PTSD does not screen for malingering, which constitutes a limitation of this type of research for court and related purposes. Moreover, the types of trauma involved that led to the PTSD in this research might not inform the ones related to trauma due to negligence, which is the typical forensic-related situation in tort and the like. Finally, the genes associated with risk for PTSD, susceptibility to the traumatic stressor that induces it in tort-like situations, the development of PTSD after the traumatic exposure, its maintenance, its response to therapy, and its functional impacts might all differ. This is evident in the initial review of this section, undertaken by Lebois et al. (2016). These types of considerations suggest that we are far from understanding the genetic contributions to PTSD at the population level, let alone in terms of the specificity needed for court and related venues. That said, generally, the findings for the biological bases underpinning PTSD are strong, as the present article demonstrates. Further, to remind, the endophenotypic pathway from genes to disorder is complicated, and tracing it requires demonstration of the molecular processes in protein production deriving from genetic activity from the early embryonic period onward in multiple neuronal and related systems. Moreover, there are gene–gene interactions at play in this regard, aside from gene-environmental ones. Other factors to consider in gene-behavioral relations concern (a) gene–environment correlations, such as evocative actions in which genes help condition environmental reactions to them, and (b) differential susceptibility, in which certain alleles of genes can lead to either more positive or more negative development, depending on environmental support, while other alleles of the genes involved are less responsive environmentally (see Young, 2016b). These types of gene–environment interactions have hardly been examined in relation to PTSD, aside from the question of screening out malingering in participants. Finally, the role that the environment might play in the development of PTSD has been demonstrated in the epigenetic processes that alter gene activity by silencing the promoter

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region of susceptible genes, as shown next. That is, genes by themselves will never be found to be biomarkers of PTSD. 3.4. Epigenetics Part of the difficulty in establishing the genetic origins and pathways to PTSD is that genetic explanations now include such factors as epigenesis (Zovkic, Meadows, Kaas, & Sweatt, 2013). Epigenetic stamps derive from three major processes: post-translational histone modifications, DNA (deoxyribonucleic acid) methylation, and micro-RNA factors. DNA methylation (modification) is the most commonly studied epigenetic process; it involves the methylation of cytosine in cytosineguanine dinucleotides. Sipahi et al. (2014) found evidence of epigenetic DNA methylation at DNA methyltransferase loci for PTSD cases. Rodgers and Bale (2015) noted that epigenetic processes allow for the intergenerational impact of parental stress experience on offspring, affecting the development of the HPA axis, and thereby altering stress reactivity and potentiating PTSD (Yehuda et al., 2014). The epigenetic marks serve to dynamically and neurally reprogram the developing HPA axis. That is, parental experience (lifetime stress exposure) even before conception can affect offspring stress reactivity. The Rodgers and Bale (2015) article explores effects of stress on the paternal germline. Other research examines the role of maternal gestational stress on offspring (Babenko, Kovalchuk, & Metz, 2015). Overall, the research suggests that epigenetic effects on the brain and the HPA stress axis confer vulnerabilities toward PTSD development but, as the authors emphasize, and as mentioned throughout, only a minority of even severe trauma-exposed individuals develop PTSD. Zannas, Provençal, and Binder (2015) reviewed studies on epigenesis and PTSD, pointing to the effects of epigenetic stamps on genes related to intermediate functions in the stress response, neurotransmitter activity, certain brain regions, and even immune regulation. For the stress response, effects on the HPA axis are crucial, as mentioned, and concern epigenetic impacts on glucocorticoid functioning, in particular. Genes involved in HPA axis regulation include NR3C1 (nuclear receptor subfamily 3 group C member 1), which is regulated in multiple promoter regions in its noncoding exon 1 variants having many glucocorticoid response elements (see Labonté, Azoulay, Yerko, Turecki, & Brunet, 2014; Vukojevic et al., 2014; Yehuda et al., 2013). More recent research by Yehuda et al. (2015) showed that altered NR3C1-1F promoter methylation is involved in trauma experiences in veterans (N = 122), leading to functional neuroendocrine alterations. In addition, this methylation was negatively correlated with the veterans' clinical markers and symptoms associated with PTSD (which was found in half the sample, with CAPS used in PTSD evaluation). The authors concluded that lower NR3C1-1F promoter methylation is a biomarker for combat-related PTSD. It could help explain, along with other epigenetic effects, why only a minority of trauma-exposed individuals continues on to develop PTSD. For further work on the topic PTSD in relation to genes, G × E, and epigenesis (see Forresi, Caffo, and Battaglia (2016) and Rusiecki, Uddin, Alexander, and Moore (2016)). As reported in Pape and Binder (2016), other research has implicated epigenetically ADCYAP1R1 in PTSD. Ressler et al. (2011) found a positive correlation between methylation of the PAC1R (pituitary adenylate cyclase type 1 gene) location of the gene and PTSD symptom severity. Kaminsky et al. (2015) found that, in conjunction with early trauma scores, SKA2 (spindle and kinetochore associated protein 2) methylation at the CpG site, cg13989295, predicted PTSD status. SKA2 is involved in activation of the GR. 3.5. Comment As with the discussion of the genetic underpinnings to PTSD, there is much more to discover in gene-endophenotypic pathway-PTSD expression. We need to determine which genes are involved, which epigenetic mechanisms, and how the results vary with population, evaluation

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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procedures and tests, and so on. Furthermore, how do they vary in terms of risk factors, the state of PTSD, its maintenance, and its response to therapy, and so on? These types of questions do not imply that genes control our behavior exclusively, or that the environment does, because there are psychological factors, too. Potentially, we do have some control of biological and genetic influences. For example, this may happen through belief in free will, coping mechanisms, curiosity and motivation, and so on. This type of modeling is biopsychosocial (Young, 2016b). That is, in PTSD, the causes of behavior include more than influences. The psychological component in behavioral causality does not refer only to simple process, such as learning and attention, but also to cognitive and affective processes that lead us to choose our behavior in ways that surpass the influences of biology and environment. One implication of this type of causal modeling of behavior, and how it can go awry, is that individuals are not inevitably hapless victims of the traumatic exposures that they experience, with trauma reactions, including possible PTSD, developing no matter what, at least to some degree. PTSD is neither inevitable to trauma exposure nor untreatable and permanent. Another implication, that runs in another direction to the one just presented, is that the minority of individuals who are not resilient to traumatic stressors and develop PTSD should not be considered as having their reactions due to “faults” that they might have in their make-up, whatever their origins in terms of biological vulnerabilities, environmental vulnerabilities, or both. That is, the trauma exposure experienced by an individual might be so overwhelming of extant resources for the person and fully account for the PTSD that develops, or at least function as a sufficient material contributor to it, despite any and all pre-existing vulnerabilities, lack of coping resources and other personal psychological mechanisms to keep psychological equilibrium, and so on. The same conclusions about the causes of behavior just addressed apply to what follows. That is, it deals extensively with the areas of the brain that have been associated with PTSD. In no way does this imply a neurocentric approach to the origins of PTSD, nor deny the possible effect of environmental and social factors, including the traumatic exposure at issue, as PTSD is initiated and develops, nor deny the personal contributions that one can make in mitigating the effects of the traumatic incident at issue or, to the contrary, succumb more readily to its effects because of a lack in this regard. That being said, the advances in understanding pathways from genes to intermediate endophenotypes, such as the brain, to behavior, are progressing rapidly in the area of brain research. The latter no longer emphasizes in a static way areas of the brain, nor simple connecting pathways between them, as underpinnings to dysfunctional behavior and mental disorder. Rather, this new perspective on the brain is emphasizing the dynamic cross-brain networks in their anatomical, structural and functional/activated connectivity. As shall be shown, the same dynamic connectivity is being studied in PTSD symptomatology. This new approach to understanding brain and also behavior has been applied to the causality of PTSD by McNally et al. (2015). Connectivity science has been applied to the brain in terms of the concept of the Connectome. As it spreads into the causal understanding of behavior, disorder, and dysfunctionality, it gives new insights into PTSD that can account both for its individual differences in expression and its causes in ongoing behavioral symptom interactions in context beyond any influence on it of biological and environmental factors grosso modo. 3.6. Brain Bremner and Pearce (2016) described the neurotransmitter, neurohormonal, and neuropeptidal factors in PTSD. For example, for the noradrenergic system, they explained a role of norepinephrine in PTSD development. For the HPA axis, they noted that corticotrophinreleasing factors and glucocorticoid (cortisol) receptors (GRs) are found in brain areas related to fear and anxiety, including the hippocampus, amygdala, and medial prefrontal cortex (mPFC). The HPA axis

neurotransmitter acetylcholine seems involved. Also, they noted that classic neurotransmitters, dopamine (increased) and serotonin (decreased) appear involved. Finally, among others, the systems that include glutamate, GABA (gamma-aminobutyric acid), and opioid peptides have been implicated in PTSD. Ford et al. (2015) reviewed the research on brain regions associated with PTSD. Multiple brain areas were mentioned, but they cautioned that they are not exclusive to PTSD. De Bellis et al. (2015) related PTSD (in maltreated youth) to smaller posterior cerebral and cerebellar gray matter volume, in particular. The HPA axis also seems implicated in PTSD (Nijdam, van Amsterdam, Gersons, & Olff, 2015). In PTSD, it is associated with cortisol dysregulation. Overall, the areas of the brain implicated in PTSD concern the classis ones of the amygdala, hippocampus, and prefrontal cortex, with effects on the inhibitory control in the latter region influencing the emotional and memory functions of the others. As well, regions such as the insula and cingulate cortex also appear involved. Diamond and Zoladz (2016) noted that the amygdala is not dysfunctional in PTSD but merely is overor hyperactive, given its role of cueing to threat and fear-related stimuli and being associated with the fight–flight–freeze response in order to optimize survival. This same message applies to the affected regulation of the other regions involved in PTSD. They are overactive or underactive because the trauma-precipitating stimulus involved had been appraised as life-threatening. Then, their continued dysregulation after that event is an evolution-mediated corollary effect allowing continued vigilance to possible further events of this nature, with the secondary cost of this potentially life-saving outcome being the detrimental effects of their prolonged dysregulation. 3.7. Comment These types of biological findings related to PTSD are undeniable, but relatively course. Newer approaches to the neuroscientific bases of PTSD revolve around intra- and interregional connectivity rather than localization conceptualizations. The following examines in depth the recent research on the brain and PTSD, which emphasizes not only particular regions but also networks, linkages, and connections. 3.8. Connectivity Kennis, van Rooij, van den Heuvel, Kahn, and Geuze (2016) conducted a study of functional network topology associated with PTSD in veterans. They found that resting state connectivity alterations especially concerned the DMN (default mode network) and SN (salience network). Some regions of the CEN (central executive network) also were involved, which is a finding not unlike that of Koch et al. (2016), who found hypoactivity in the CEN in relation to PTSD. Both Kennis et al. (2016) and Koch et al. (2016) supported a model of connectivity in PTSD that involves a triple network of dysfunction (within and between connected networks) in the three major ICNs (intrinsic connectivity networks) mentioned above (DMN, SN, and CEN), consistent with hypotheses about their general role in psychopathology (Menon, 2011; Patel, Spreng, Shin, & Girard, 2012). Lei et al. (2015) studied earthquake-exposed PTSD patients relative to controls for disrupted topographical organization in functional connectivity according to resting state fMRI. Globally, connectivity measures revealed less path length between nodes and increased clustering and efficiency. Locally, they expressed increased node centrality in nodes especially involved in the DMN and SN, including in the posterior cingulate gyrus, precunius, insula, putamen, pallidum, and temporal regions. The authors concluded that the PTSD connectivity patterns showed a “small world” topology, or disturbance of the normal global integration of whole-brain networking, in conjunction with disequilibrium between the DMN and the SN. The retrosplenial cortex might also be involved (Grupe & Heller, 2016).

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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Koch et al. (2016) conducted a systematic review of studies on aberrant task-free resting-state brain activity in PTSD. They checked for whole-brain hypo- and hyperactivations in 14 whole-brain resting state studies and nine “seed-based” temporal synchronization studies. Relative to controls, the former research studies indicated an association of PTSD with hyperactive resting state in the ventral anterior cingulate cortex (vACC) and the parahippocampus/amygdala. Also, these former studies demonstrated hypoactivity in the (posterior) insula, cerebellar pyramis, and mid frontal gyrus (MFG). In contrast, the latter research showed in PTSD, increased SN connectivity, with decreased connectivity in the DMN, suggesting more hypervigilance in these patients at the cost of reduced awareness of internal-focused thoughts; interoceptive awareness; and autobiographical memory. In an fMRI study, Rabellino, Densmore, Frewen, Théberge, and Lanius (2016) investigated the areas of the brain that have been associated with an unconscious innate rapid alarm circuitry in response to threatening stimuli, as happens in PTSD. They highlighted the role of the cerebellum and periaqueductal gray matter in these regards, as adduced in a study with subliminal (subconscious) individualized stimuli presentations. Further, they concluded that fast defense responses in PTSD are mediated by altered cerebellar–limbic–thalamic–cortical (e.g., frontal) network. Nicholson et al. (2016) studied PTSD patients with and without the dissociative subtype, along with controls, in a resting state fMRI study. The two PTSD groups displayed differential insular subregion connectivity to the amygdala complex, with connections to the left basolateral amygdala standing out in this regard. Further, both dissociative symptom and PTSD symptom severity correlated with insular subregion connectivity among the PTSD patients. PTSD was evaluated using the DSMIV-keyed SCID and the CAPS. The authors related their findings for the dissociative subtype to aberrant arousal interoceptive patterns and altered bodily state monitoring and to somatosensory processing in the insula connectivity regions involved. Sun et al. (2015) measured for abnormal connectivity in MVA survivors two days after their collisions, using resting state fMRI and DTI. Diagnoses were made at one to six months later, using the CAPS. In survivors who developed PTSD (compared to those who did not), greater WM (white matter) disruptions within two days of their collisions predicted greater symptom severity later on. Bilateral frontal regions especially were altered in those who developed PTSD in terms of their interhemispheric connectivity, leading to abnormal functional synchronization and anatomical connectivity inefficiency. The authors concluded that interhemispheric functional and structural connectivity impairment could be a biomarker of predisposition to develop PTSD. Using a Stroop task, Sadeh, Spielberg, Warren, Miller, and Heller (2014) found that PTSD symptom severity served to moderate amygdala–mPFC area coupling (especially for the hyperarousal symptoms of PTSD). Zhang et al. (2015) examined alterations in the resting state functional connectivity (FC) of PTSD patients and matched healthy controls (N = 20). PTSD was evaluated using the CAPS-DX (Clinician-Administered PTSD Scale for DSM-IV; Blake et al., 1995). The authors obtained fMRI data in order to calculate resting-state intra-network and inter-network FC. Relative to controls, the PTSD patients were found to express decreased intranetwork FC within the anterior DMN, posterior DMN, and the SN, as well as the sensorimotor network (SNM) and auditory network (AN), but not the CEN. As for inter-network alterations in the PTSD patients, they concerned increased FC between posterior DMN and SN. Other results concerned decreased FC in the SMA (supplementary motor area) and cerebellum within the SMN, decreased FC in the mPFC and PCC (posterior cingulate cortex), and decreased synchronization in the ACC within the SN. The authors related the results to behavioral/symptoms associated with PTSD. For example, the inter-network connectivity finding was associated with the hyperarousal and heightened anxiety in PTSD.

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Yoon et al. (2016) conducted a five-year longitudinal study of structural connectivity, focusing on the amygdala in 30 subway fire disaster survivors compared to 29 healthy controls (non-trauma exposure). The DTI neuroimaging took place every 1.3 years, and PTSD was evaluated using the CAPS (Blake et al., 1995) and the SCID-IV (First, Spitzer, Gibbon, & Williams, 1996). The survivor group was found to manifest improved PTSD symptomatology over the study. As for the neuroimaging results, the amygdala–insula connection was “strengthened” initially and then the amygdala–prefrontal cortex (PFC) connectivity strengthened. Among other findings, the degree of amygdala–PFC connectivity was associated with symptom severity of PTSD. The fear circuitry associated with PTSD seems to include not only each of the amygdala, PFC, and thalamus but also the insula and thalamus, in a dynamic and sequential shifting of amygdalar connectivities as PTSD symptomatology improves over time. Finally, in a study on neurotransmitters, Trousselard et al. (2016) studied 17 PTSD patients and 17 healthy controls. Plasma GABA concentrations were assessed before and after classic and emotional Stroop tests to evaluate GABA basal tone and GABA reactivity, respectively. The results showed that GABA basal tone was negatively correlated with the severity of PTSD symptoms. According to the authors, these data indicate that reduced GABA concentration in PTSD could be a biomarker of PTSD severity. Research is now investigating the relationship among PTSD severity, reduced DMN connectivity, and gene variants. Specifically, Miller et al. (2016) found that, in veterans, the genetic variant 5-HT(R)2A (5-hydroxytryptamine receptor 2A) moderated the association between PTSD severity (as measured by the CAPS-IV, keyed to the DSM-IV) and reduced DMN connectivity. That is, for the serotonin receptor/ 5-HTTLPR gene variant, the SNP 5-HT(R)2A (rs7997012) homozygous for the minor (C) allele, PTSD severity moderated, or influenced, the significant negative correlation between PTSD severity and DMN connectivity, especially between the posterior cingulate cortex (PCC) and the right middle temporal gyrus (MTG). The authors concluded that the research on the relationship between PTSD and DMN connectivity has produced different results because genetic factors have not been studied for their moderating effects. The most recent research found relating PTSD to functional connectivity differentiated local and remote connections (Ke et al., 2016). Aside from the amygdala and PFC, for the typhoon survivors involved, the PTSD group expressed regional homogeneity changes in the parahippocampal gyrus. Moreover, even survivors without PTSD expressed both local and remote functional connectivity changes relative to controls. The authors concluded that further research is needed to determine whether the results reflect pre-existing or posttraumatic stressor effects. 3.9. Comment Research is specifying the relation of the brain and PTSD, especially in terms of three ICNs, the DMN, the SN, and the CEN. Others are implicated, as well. As for the brain regions involved, they are the amygdala, hippocampus, insula, and prefrontal cortex, among others (e.g., the ACC). Each of these regions and the connectivities involved are associated with behavioral disruptions as found in PTSD. However, behaviors cannot be reduced to them and they do not regulate, control, implement, or otherwise are responsible for the behaviors and their dysregulation. PTSD is not a function of the brain but of the whole person, as a biopsychosocial response. Brain function disruption leads to neurocognitive consequences, and it could be argued that, because these are the most proximal or immediate precursors of PTSD, being the last step in the endophenotypic pathway to them, they constitute the best or ultimate endophenotypic representation of PTSD. However, the more distal the intermediate phenotype examined toward a psychiatric disorder on the endophenotypic pathway that might be involved, the less variance and consequent

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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explanatory power it should have in helping to account for the disorder endophenotypically. Moreover, the more distal the presumed intermediate phenotype on the pathway to a disorder relative to the time of onset of the gene at issue, the more likely that the environment contributes to it, rendering it less fit as a biomarker to the disorder involved. Nevertheless, neurocognitive dysfunction related to PTSD could serve to indicate its proximate mechanism that governs its symptom and dimensional profile. In this regard, the inhibitory function implicated in PTSD in the following section speaks to the broader role of inhibition in behavioral dysregulation, as discussed in Young (2016b). For further literature on PTSD in relation to the brain, HPA axis, and other biological factors, see Bukhbinder and Schulz (2016), Daskalakis, McGill, Lehrner, and Yehuda (2016), Hendler and Admon (2016), and Manns and Bass (2016). 3.10. Neurocognition In terms of the effect of PTSD on neurocognitive function, Scott et al. (2015) conducted a meta-analysis involving 60 studies (N = 4108; N = 1779 with PTSD, 1446 only trauma-exposed, and 895 healthy controls). Effect sizes were determined, with the largest ones for verbal learning, informational processing speed, attention/working memory, and verbal memory. The authors concluded the PTSD involves aberrant frontolimbic circuitry supportive of the cited cognitive functions, as well as the others (specifically causing dysregulated arousal and salience detection). Other research studies point to underlying inhibitory deficits behind the cognitive abnormalities of PTSD. Echiverri-Cohen, Zoellner, Ho, and Husain (2016) studied individuals with chronic PTSD using prepulse inhibition and attentional blink responses. They concluded that, relative to controls, PTSD group members appear to express a “general faulty inhibitory mechanism,” which allows for intrusion of irrelevant sensory information and increases demands on the allocation of attention. Contractor, Armour, Forbes, and Elhai (2016) showed that facets of impulsivity (and so inhibition) were related to underlying PTSD dimensions. Specifically, undergraduate participants were administered the SLESQ (Stressful Life Events Screening Questionnaire; Goodman, Corcoran, Turner, Yuan, & Green, 1998) to assess trauma exposure, the PCL-5 for PTSD, and the UPPS Impulsivity Scale (Whiteside & Lynam, 2001). The four PTSD factors studied were those of the DSM-5. The UPPS gave four scales (lack of premeditation, urgency, sensation seeking, and lack of perseverance). The findings supported a relationship of the PTSD dimensions of alterations in arousal and of reactivity and negative alterations in mood/cognitions with UPPS sensation seeking, in particular. The results suggest that PTSD is associated with excitement seeking irrespective of consequences, because the stimulation might be beneficial in context despite the dangers. Other results in this study suggested that PTSD is associated with tendencies to act impulsively when experiencing negative affect. Another study by this group emphasized the facet of negative urgency as much as if not more than that of sensation seeking as the critical facet in predicting PTSD, this time in a nonclinical sample of 412 trauma-exposed adults (Roley et al., 2016). Roley et al. (2016) conducted a similar study. This time, this research group emphasized negative urgency as the best UPPS facet predictor of PTSD symptoms. Once more, the difficulties in controlling behavior in the context of intense negative emotions that were evident in the data suggested to the authors that impulsivity is involved in PTSD. Consistent with the behavioral and self-reported findings of the relationship between PTSD and inhibition, Sadeh et al. (2015) studied neurobiological indicators of disinhibition or impulse dyscontrol in PTSD. Specifically, they studied trauma-exposed veterans using a Go/No-Go task with emotional stimuli, in relation to whole-brain analyses of cortical thickness. Commission errors on the task were associated with reduced cortical thickness in specified regions at higher (and not lower) levels of PTSD symptom severity (as measured by the CAPS). Resting

state fMRI implicated the right frontal gyri and pole, one of the two prefrontal cortical clusters in the first finding. The connections between right frontal regions and other networks also were aberrant. Together, the results suggest that PTSD is associated with dysfunction in brain regions activated for flexible decision-making, emotional regulation, and response inhibition, with disruptions in functional coupling in networks associated with selective attention, memory/learning, and response preparation also involved. The authors concluded that PTSD is associated with impulsivity in relation to atypical brain morphology and resting state functional coupling. 3.11. Comment This completes our survey of the biological underpinnings to PTSD. It should not lead to the conclusion that it is a biological phenomenon. Its causality is multifaceted and biopsychosocial. It should not lead to the opposite conclusion that the research on the biological bases underlying PTSD has not found anything definitive with respect to biomarkers, so is not useful for court and related purposes. To the contrary, specification of candidate alleles, genes, gene complexes, epigenetic marking, brain regions, their networking, and intermediate pathways from genes to brain and behavior, let alone how biological factors interact with environmental ones in producing the condition, are essential for understanding nomothetically PTSD and its causality. This can only help to avoid mythology and misstatement about it, while narrowing the circle of its multifactorial structure. Another point to consider about research demonstrating the biological bases of PTSD is that, forensically, there is less reason to deny its validity. However, much of the research on the matter has not considered whether the genes, brain connectivity, or stress system responses, and so on, that appear involved are differentially expressed in cases of PTSD after incidental events (and equally for all types, e.g., rape vs. MVAs), cumulative trauma, and early adversity, such as in child abuse, or populations with varying combinations of these factors. Until this research is undertaken, the support for the validity of PTSD in the forensic setting cannot be confirmed by the biological research, although the findings are generally quite strong. On another matter, to this point in the article, it has been emphasized several times already in this article that although PTSD increasingly is being shown as a mental disorder with robust biological underpinnings, this does not mean that the predominant model for PTSD must be a biocentric one. That would hearken to the medical model that psychologists typically eschew for one involving multicausal factors in the causation of mental disorder. Another example related to extreme biocentrism that is being challenged relates to neurolaw, or the use of findings about an individual's brain in order to exonerate them of a crime or to mitigate their sentencing if they are found guilty. In this regard, Morse (2011) counseled caution in use of brain data in court. The danger is that the defense in criminal cases engages in “neuroexuberance” or “brain overclaim syndrome.” In this regard, Satel and Lilienfeld (2013) noted that the brain does not make people behave, in that people potentially control their own behavior. They warned of “neurocentrism” and use of any “neurosignature” in relating brain findings associated with behavior and the causal explanation of behavior. A more general term that gives caution about biology in court might be “bioexuberance.” If PTSD is not a strictly biological phenomenon leading to its symptom expression, or a symptom expression with concomitant biological underpinnings that explain them, then what models can explain it? Psychology tends toward biopsychosocial explanations of disorder but, to my knowledge, this concept has not been applied to PTSD, per se. In this sense, the article might be presenting a novel model of PTSD causation. Even if the biopsychosocial model has been applied to PTSD, it would not have been applied by including factors such as a belief in free will, or an active personal causality beyond passive genetic and environmental causality, and so on.

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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4. Models of PTSD Models of PTSD include cognitive, emotional, and behavioral ones, aside from those that emphasize its neurobiological bases. Gillihan, Cahill, and Foa (2014) reviewed psychological theories of PTSD. Conditioning (learning) theories indicate that PTSD fear develops through the association of neutral stimuli with an aversive trauma one. Then, instrumental conditioning results in avoidance, escape, and distress reduction (Mowrer, 1960; a two-factor theory). For support for a learning model of PTSD, see Bardeen, Tull, Stevens, and Gratz (2015), who studied anxiety sensitivity and PTSD. Also, Zuj, Palmer, Lommen, and Felmingham (2016) described the centrality of impairments in fear extinction and learning in risk and PTSD. For work on the approach of alteration of worldview, see Pyszczynski and Taylor (2016). Other theories are more emotional, as in emotional processing theory (Foa & Kozak, 1985, 1986). A prominent emotion in this regard concerns fear, such as in fear generalization (Lopresto, Schipper, & Homberg, 2016). Careaga, Girardi, and Suchecki (2016) underscored that PTSD involves an exacerbated fear response, explained by dysfunctional learning and memory, fear conditioning, and either failure in extinction or abnormal memory reconsolidation. Cognitive theories concern faulty appraisals (e.g., Ehlers & Clark, 2000) and schema theory (e.g., Horowitz, 1986). Dual representation theory (Brewin, Dalgleish, & Joseph, 1996; Brewin, Gregory, Lipton, & Burgess, 2010) posit two representational systems in memory, with the sensation-based representations harder to verbalize, unlike for contextual representations, so that they are harder to deal with for the trauma survivor, to activate involuntarily, and to treat effectively. Bardeen and Fergus (2016) considered that difficulties in attentional control can contribute to posttraumatic stress symptoms, for example, by sustaining attention to threat information and increasing trauma-related distress. Liberzon and Abelson (2016) developed a model of PTSD related to aberrant contextual processing. Specifically, individuals expressing it have deficiencies in disambiguating cues and deriving situation-specific meaning from the world. This function is modulated by hippocampal– prefrontal–thalamic circuitry and can account for PTSD symptoms better than other models, for example, related to the symptoms of spontaneous intrusions, nightmares, emotional numbing, and behavioral recklessness. Keane and Barlow (2002) developed a triple vulnerability model of PTSD, involving two earlier vulnerabilities and then a trigger. The biological vulnerability involved facilitates experiencing intense negative affective states. The acquired one involves hypervigilance and cognitive bias to perceived threat. The trigger involves the trauma at issue. Other researchers have examined posttraumatic growth in situations in which PTSD might develop. Ying, Wang, Lin, and Chen (2016) provided an up-to-date literature review of the concept. According to Tedeschi and Calhoun (1996), posttraumatic growth covers five major areas: feeling of strength; becoming closer to family/friends; a greater appreciation of life; recognition of new possibilities; and spiritual development. PTSD and posttraumatic growth might delay coexisting psychological experiences (Hafstad, Kilmer, & Gil-Rivas, 2011); reciprocally opposite ones (Ickovics et al., 2006); separately (Linley & Joseph, 2004), or curvilinearly (Levine, Laufer, Hamama-Raz, Stein, & Solomon, 2008), or multiple ways (Shakespeare-Finch & Lurie-Beck, 2014). As for resilience, it refers to positive adaptation to adversity (Masten, 2011) and it might be a trait (Connor & Davidson, 2003) or a process (Luthar, Cicchetti, & Becker, 2000). The research is inconclusive on the relationship among resilience, PTSD, and posttraumatic growth (e.g., Levine, Laufer, Stein, Hamama-Raz, & Solomon, 2009; Prati & Pietrantoni, 2009). Ying et al. (2016) examined the relationship among these variables at 12, 18, and 24 months following the Chinese Wenchuan earthquake. The study included 788 survivors of the Wenchuan earthquake (15 years of age), who were assessed with the CPSS (Child PTSD Symptom Scale; Foe, Johnson, Feeny, & Treadwell, 2001), PTGI (Post-traumatic Growth Inventory; Tedeschi & Calhoun, 1996), and CD-RISC (Connor and Davidson's Resilience Scale, Chinese

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Versions; Connor & Davidson, 2003). The study found that resilience is a factor that mediates the relationship between adolescent PTSD symptoms and posttraumatic growth. Specifically, the results in Ying et al. (2016) showed that PTSD symptoms related to posttraumatic growth symptoms for low resilience individuals from 12 to 18 months post-earthquake. Also, posttraumatic growth symptoms at 12 months were related to PTSD symptoms at 18 months, but only for middle-resilience individuals. The authors concluded that the first result showed that posttraumatic growth does require dysregulation due to trauma in order for a meaning-making behavior and posttraumatic growth to take place, depending on the level of resilience. About the second finding, the authors suggest that an early experience of posttraumatic growth might be illusory in the long term even if self-protective in the short term, and also depending on the level of resilience. Blix, Birkeland, Hansen, and Heir (2016) studied the temporal relationship between levels of posttraumatic stress and levels of posttraumatic growth for a period of time of 22 months following the 2011 Oslo bombing (N = 240). To measure posttraumatic stress symptoms, they used the PCL-S (Posttraumatic Checklist-Short; Weathers & Ford, 1996) and, to measure posttraumatic growth, they used the PTGI-SF (Posttraumatic Growth Inventory-Short Form; Cann et al., 2010). They found that high levels of one were associated with high levels of the other from Time 1 to Time 2 (10 and 22 months, respectively). They concluded that posttraumatic growth appears both as an antecedent and a consequence of posttraumatic stress. Other research is investigating the relationship of PTSD and posttraumatic growth over time. For example, Wu, Leung, Cho, and Law (2016) studied their relation after MVAs and Dekel, Hankin, Pratt, Hackler, and Lanman (2016) after 9/11. A broad model of PTSD should consider it as a biopsychosocial phenomenon, as mentioned, from its origins and causes, to its expression and symptoms, and to its treatment (Young, 2016b), as well as its relationship to posttraumatic growth. PTSD's broad-ranging nature is also indicated in its corporal inflammatory relations (e.g., genetically, as has been shown, and in its expression and consequences, e.g., Brudey et al., 2015). 4.1. Comment There is a difference among (a) models about a phenomenon, (b) explanation, and (c) mechanism in understanding causality. A model might suggest contours of the origins of a phenomenon but it also deals with the description of its expression, depending on its goals. Explanation can take place at many levels, and might go beyond immediate mechanism, for example, including evolutionary origins. Explanation deals with causality, but also the contents or facts and the consequences as in models, so it is a broader term. Mechanism refers to specific immediate proximal forces acting on the phenomenon, including factors that cause it, for example, biological, neurological, learning, or environmental. Causality concerns the processes that lead to the phenomenon, and they might encompass all these mutually-influencing levels and factors in its mechanisms, yet not be as specific as accounts based on mechanisms. Recall that it refers to processes leading to a phenomenon, in general. The next part of the article moves from description of critical models in PTSD, including the biopsychosocial, to more nuanced models that suggest specific mechanisms. Before beginning, it discusses the nature of causality in law. Phenomenological and legal causality speak to different issues about PTSD in court, with the first helping to understand why it emerges and the second the legal bar needed for a court action to be recognized. 5. Legal causality According to Young (2015a), causality (or causation) is central to every legal case, yet its underlying philosophical, legal, and psychological

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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definitions and conceptions vary. In the criminal context, causality refers to establishing whether the alleged perpetrator bears the responsibility for the criminal act at issue in terms of the person's mental state (mens rea), and whether the insanity defense applies. In the forensic disability and related context, it refers to whether the index, subject, or traumatic event at issue is a material or contributing cause to the complainant's psychological condition. Usually, causal factors are multifactorial, and a civil event at issue needs to be more than minimal in causal contribution. In both the criminal and tort contexts, the legal test is a counterfactual one. Would the outcome involved have happened absent the act at issue (e.g., the voluntary criminal one, the negligent one, respectively). However, in the criminal context, the material or substantial contribution test is insufficient to establish guilt because it does not meet the bar of beyond a reasonable doubt. This maternal contribution test works in the civil context, e.g., tort, because the test is “more likely than not,” also termed the “preponderance of the evidence.” Young (2015a) continued that the psychological state of either the perpetrator of criminal conduct at issue or the survivor of the negligent act at issue can be analyzed from a biopsychosocial perspective. A biopsychosocial analysis will consider not only the array of factors involved causally but also their time line in terms of pre-existing, precipitating, and perpetuating factors, with personal and social resilience and protective factors added, as well. In the criminal context, mental competence and voluntariness are added as critical factors. Young (2015a) concluded that the danger of neurolaw in court is that it risks reducing the complexity of criminal cases to unifactorial, biological models. The same applies to advocating for a biopsychosocial approach in any legal case, civil or criminal, if only the first component of the term is considered in depth and the other aspects are considered only superficially. For a more detailed explanation of the legal term of material contributions in causality refer to Table 1. For a more detailed explanation of the biopsychosocial model as it relates to PTSD, refer to Fig. 1. The latter figure also has a forensic component. 6. PTSD causality 6.1. Standard paradigm Moving onto the topic of the causality of PTSD as a mental disorder, Ford et al. (2015) examined the spectrum of causal factors that contribute to PTSD. They considered it a multicausal phenomenon, with biological, psychological, and social factors that influence it (but without using the term biopsychosocial). In PTSD, there are both risk (e.g., genetic) and protective (e.g., coping, social support) factors, as well as preevent, peritraumatic, and post-event factors. The event itself has a dose–response relationship to the traumatic reaction, although operationalizing the variables in that relationship presents challenges. Comorbidities, such as severe physical injury and pain, lead to a greater vulnerability in PTSD development. 6.2. New paradigm The multicausal approach to mental disorder, generally, and PTSD, specifically, is the dominant paradigm in the field, at least for psychologists and most other mental health workers. However, recent approaches to mental disorder, and to PTSD, as well, are suggesting a new paradigm related to networks, linkages, or connectivities. The section of the article on the brain had introduced the concept. In the following, it is discussed with respect to PTSD and its symptom interactions. I offer a novel model of PTSD based on such concepts, and also it includes a component related to dynamical systems theory. In particular, this approach to model building affords a model both of mental disorder, in general, and PTSD, specifically, that has a hybrid top-down, upper-system level component and a bottom-up, lowersystem level component, with one or more intermediate levels, as

Table 1 Five-point scale on causation in psychological injury to guide forensic psychologists' formulation with respect to cause. Level Explanation 1

2

3

4

5

The index event is the “sole cause” of the resulting psychological condition (disorder(s) and/or functional effect(s)). There are neither overt nor latent psychological conditions evident in the pre-event state, that is, there are no pre-existing psychological vulnerabilities or risk factors. The psychological condition at issue would not have occurred, either in the present or later on, had the subject event not occurred. The event in question is the major “precipitating” factor or cause of the psychological condition involved. Disorder (or disorders) had been present as a latent pre-event potential, and the potential would not have manifested but for the psychological effects of the event at issue. The psychological event is an “aggravating” factor of a pre-existing psychological condition. Disorder had been clinically evident beforehand, but the subject event adversely affected the condition. Or, a new one psychological condition emerged as a result of the event in question to add to pre-existing concerns. That is, the event stands as a “material contributor” (proximate, dominant) to the resulting psychological condition, “substantially” contributing to it beyond the de minimus range. Either the individual had been a “thin skull” case, as in point 2, or a partial “crumbling skull” case, as in this point (so to speak, to use a legally-related metaphor), and the event at issue worsened her/his psychological condition, which would not have declined “but-for” that event. In tort and related law, the victim or survivor has to be taken “as found.” The event is a “minor,” minimal factor to the causality of the psychological condition in question. A condition had been well-developed prior to the said event, which contributed to only a small degree to the condition's post-event state. Perhaps it worsened, but might have otherwise, and the worsening is only minor at any rate. The “crumbling skill” had been quite severe. The event at issue is unrelated to any claimed psychological condition. Either the event had no bearing on it or the person had been a total crumbling skull case with no room for worsening due to any event.

Adapted from Young (2014). Note. Young and Drogin (2014) noted that Burrage v. United States (2014) elaborated the distinction in criminal and civil cases with respect to causation. In the criminal context, the event at issue must be the “actual cause,” with the effect of the event resulting from, because of, based on, or by reason of the event, or reflective of the “but-for” test (the effect would not have happened absent the event at issue). In the civil context, the event at issue must be only a “cause in fact,” or material, substantial, or contributing to the outcome in question. The standard of proof in tort is “more likely than not,” which allows for this more “permissive” type of causality, relative to the standard of “beyond a reasonable doubt” in the criminal context. Young and Drogin (2014) concluded that, for psychological injury cases, causality is usually multifactorial. For example, in MVAs, events at claim are part of an array of causal factors that could include: pre-event psychological vulnerabilities/psychopathologies; complex factors in the event (e.g., joint events, effects of individual perception or appraisal of the event), post-event factors (such as job loss due to the effects of the event), or extraneous factors (e.g., death of a family member incidental to the event).

well, and, in a reciprocal fashion, with all levels involved simultaneously interacting with and mutually influencing each other. For PTSD, one intermediate level would concern symptom clusters. Both lower and higher levels in the system involved would dynamically influence both lower and higher levels in the system involved (e.g., symptoms, overall construct). In this regard, Borsboom et al. (2016) raised the interesting point that psychiatric disorder might reflect either a categorical or dimensional architecture, depending on the individual. They argued that symptom causality resides in symptom connectivity rather than from some top-down latent construct. Moreover, strongly connected symptom networks that are found for some people are more liable to discrete kinds or types in psychiatric disorder, in contrast to weakly connected ones for other people, who would then express continuous psychiatric structures. That is, by considering the new approach of symptom networks themselves instead of any latent variable that putatively underlines them, the debate on whether psychiatric disorder reflect categorical or dimensional structures is rendered sterile, given that both might be found for any one disorder depending on symptom architecture in each individual. That being the case, for the authors, the symptom networks in both cases (strongly and weakly connected) might reflect attractor-type stable states, but

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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PTSD/ Trauma Reactions

Malingering (or related responses)

EVENT AT ISSUE

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Therapy

Society/ Culture/ Status (e.g., Gender, Age, Minority) System Factors (e.g., Litigation)

Therapy Avoidance/ Undermining

Training/ Work/ Roles Personal Life/ Support

Family, School Extracurricular, Leisure Individual (Biology; and growing personality, self, intelligence, social and coping skills)

Functional Disability

Recovery

Environment (generally)

Current Context

Psychosocial (and Political, Historical) Resilience (Posttraumatic Growth)

Variable response Biopsychosocial factors apply for each

Fig. 1. A multifactorial biopsychosocial (and forensic) model of PTSD across risk factors/cause, trauma reactions, and therapy. Another way of describing the multifactorial array of causes in psychological injury involves the biopsychosocial model (Young, 2016b), which is becoming increasingly widespread as a concept in psychology. Aside from indicating that causality is biopsychosocial, Fig. 1 indicates that, for PTSD, one can consider both the response to trauma and its treatment as multifactorial and biopsychosocial. The figure adds a forensic component by referring to malingering and related responses to trauma and also to the litigation process as an added stressor. For example, at the biological level, PTSD does not result simply from an event at issue but, in most cases, from pre-existing vulnerabilities and the like, as well. In assessment, the evaluee's history should be explored in depth in these regards, including in terms of any biological roots (e.g., child abuse has biophysical consequences). The precipitating event could elicit intense physiological reactions, such as increased heart rate/ blood pressure, or from physical injury (as well as brain injury). Biologically, the therapy that is undertaken could include medications (such as antidepressants) or concomitant physical therapies. Also, it should involve techniques aimed at controlling hyperarousal, stress responses, and so on.

with ones in the former more prone to reaching tipping points that plunge into states of psychiatric disorder. This type of conceptualization is consistent with that of nonlinear dynamical systems theory, which specifically refers to attractors and emergence. Fig. 2 offers a model of PTSD that combines the approach of PTSD as a construct and the approach that it is an interacting symptom network. Also, it includes a third level involving the appraisal or meaning of the triggering event, the construct, and the symptoms for the individual involved. About dynamical system theory in model building on the causes of disorders such as PTSD, Schwartz, Lilienfeld, Meca, and Sauvigné (2016) maintained that neuroscience, in its eliminative reductionistic form, cannot account for “emergent properties” in mental function that are irreducible to neural processes. In an approach reflective of constitutive reductionism, the brain enables or “does” the mind. It is emergent through a hierarchy of levels from lower-order ones and their properties and through complex interactions, yet with brain activity or impairment still capable of influencing it. That is, in this model, the mutual influences of brain and mind are bidirectional. 6.3. Research Frewen, Schmittmann, Bringmann, and Borsboom (2013) examined how perceptions of the causes of symptoms of anxiety, PTSD, and

depression reflect a network among the symptoms, with mediation by perceived causal relations. They had university undergraduates (N = 288) answer a questionnaire (40 items) related to Major Depressive PTSD (Construct)

Symptoms (Interactive Network)

Appraisal (Meaning)

Fig. 2. A triple level systems model of PTSD causality. The figure depicts the relationship between symptoms and mental disorder (or a symptom cluster of one) as dynamically reciprocal in causation (e.g., for PTSD). The mental disorder constitutes an underlying, higher-order level in the patient's mental state symptoms, while the symptoms interact at lower levels of the system, with both the top-down and bottom-up influences dynamically influencing each other in context and over time. A third level in the causal model concerns the person's individual appraisal or meaning given to both a disorder (e.g., PTSD) and its symptoms. Therefore, in terms of this model, PTSD causality resides in all three levels of the system, and in their interaction.

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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Episode, PTSD (DSM-IV consistent), symptoms of other anxiety disorder, and other symptoms. First, participants had to indicate the frequency of the symptoms in the past month and, then, for those symptoms that had reportedly occurred, they had to indicate how much any one symptom “caused” the others (considered one at a time; both paired possible causal directions (e.g., X → Y; Y → X) were queried). The mean cause (first of the pairs, e.g., X) and effect (outcome in the pairs, e.g., Y) association scores were calculated for each participant. Network analysis was conducted after the more classic prediction, mediation, and moderation analyses. This included calculating clustering and centrality in symptom space (e.g., outdegree, indegree, betweenness centrality, which includes directed and indirect associations), as well as coherence of the complete symptom networks. The results are complex in this study by Frewen et al. (2013), and only sample ones are given. For the perceived causal relationship analysis, the degree to which frequencies of participants' re-experiencing and anxiety symptoms concurrently predicted their depression symptom frequency varied with the degree to which the participants perceived their re-experiencing/anxiety symptoms as the causal source of their depressive symptomatology. As for the network analysis, flashbacks and avoidance of reminders of the trauma involved were evident in many feedback loops. Anxious worrying, depressed mood, and trauma memory symptoms most influenced other symptoms; and the ones most influenced were about either emotions or functional problems (e.g., numbing, work, respectively). McNally et al. (2015) applied the connectivity model to PTSD. They argued that the causality of PTSD lays in the bottom-up symptom connections that differentiate in the individual rather than from a top-down influence of a putative latent variable. McNally et al. (2015) conducted a questionnaire study of survivors of a 2008 Chinese earthquake (N = 360). According to a questionnaire, 38% met the criteria for probable PTSD (5 years after the earthquake, when the data were gathered). The data showed that strong symptom associations were evident in the survivors, for example, for hypervigilance and startle and also for avoidance of thoughts and activities (about the trauma; and associated with it, respectively). In addition, numbing and dissociation symptoms were strongly linked (loss of interest in enjoyable activities; feeling distance from others, respectively). Further, nightmares, flashbacks, and intrusive memories relating to the trauma were closely linked. Other results showed that two re-experiencing symptoms were not connected to the others (physiological reactivity, feeling upset at reminders), but quite connected to each other. Centrality calculations revealed that a highly central symptom concerns perceiving the future as foreshortened. Overall, the authors concluded that hypervigilance, future foreshortening, and sleep appear predominant symptoms in PTSD. The study by McNally et al. (2015) showed how symptom connections are revealing of PTSD dynamics. Specifically, symptom associations strengthen in their connections and reciprocally interrelate in feedback loops. They maintained that one does not need to refer to a top-down psychological construct, such as PTSD, as a causal mechanism of the symptoms constituted by it.

6.4. A new approach to PTSD modeling As initially presented, my approach to the modeling of causality of psychiatric disorder is that bottom-up symptom connectivities in the lower level(s) of a hierarchical multilevel model work in concert with the top-down level(s), such that the latent variable in this latter level interacts with the symptoms in the lower level, thereby determining the structure of the mental disorder. This hybrid network/construct model as developed in Young (2015b) is general enough to apply to PTSD. For PTSD, there might be a third level involving symptom clusters between the other two levels in such a model. The implication of this model is that underlying psychological constructs in mental disorders, such as PTSD, have validity.

But how does the top-down level develop in psychiatric disorder? Does it develop first and then direct symptom expression at lower levels, for example? The dynamical systems model provides an answer based on its concept of emergence. Systems dynamically form levels, including emergent ones that are higher up, and these can influence lower-order ones. In this sense, not only do PTSD symptoms interact and influence the latent variable at the higher level so created, but also that higher level construct, in turn, influences the dynamics of lower-order symptom interactions and connections. To summarize, the model created is a reciprocally interactive causal model between and among levels of systems related to psychiatric disorder (and PTSD), with higher-order ones not imposed by nature and carved at the joints but synergistically created in individual ways for any person suffering a mental disorder. Therefore, for PTSD, its symptoms as expressed individually lead bottom-up in its causality, but a growing complex that results from symptom dynamics can influence top-down the symptoms, too, in dynamic feedback loops. To summarize, whether for mental disorder, in general, or PTSD, specifically, the model that I have proposed combines the symptom connectivity or network approach with the latent variable one (Young, 2015b), creating a hybrid model of causality in psychopathology. The symptom network involved constitutes the bottom-up level, while the psychological construct involved constitutes the top-down one; which develops by emergence. In the following, I modify the hybrid bottom-up/top-down model of the causality of mental disorder and of PTSD as presented above. In particular, I use ideas presented in the recent research on PTSD to refine the model. Overall, I found that the types of studies on symptom connectivity by Frewen et al. (2013) and McNally et al. (2015) are intriguing and, as mentioned, they complement my own work toward expanding the symptom network/psychological construct model of psychopathology causation (Young, 2015b). In their case, Frewen et al. (2013) have elaborated the network model by trying to understand it idiographically in terms of how PTSD and comorbid symptoms cluster and why (that is, with respect to the person's causal perceptions of the symptomatology involved). Therefore, a comparison of my approach with that of Frewen et al. toward expanding network modeling of causality in psychopathology shows that my hybrid model has added superordinate influences on symptom expression related to underlying constructs (e.g., PTSD, depression) while Frewen et al. have added superordinate influences on symptom expression related to the causal interaction between networked symptoms and the person's perception of causality. A superordinate integration of the two models of Frewen et al. (2013) and Young (2015b) on the causality of psychopathology (e.g., for PTSD), would place an intermediate level of patient construals of causality as a mediator between symptoms in the lower level of the system involved and latent constructs in the higher level involved. Moreover, this new level of patient causal perception of the symptoms involved itself would be reciprocally related to the lower and higher levels in the symptom configuration through system dynamics, thereby altering dynamically over time as the three levels of the whole system reciprocally interact over time. As for McNally et al. (2015), a review of their research indicates that the causation of PTSD in relation to symptom networks and psychological constructs begins with the symptom interactions. Then, in a constructive process, the interaction leads to the emergence of higherorder levels 6.5. Comment Aside from leading to the new model of the causes of PTSD just described, this portion of article has considered the causality of PTSD in terms of risk factors or precursors, biological (genetic, neurological)

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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and environmental factors that underpin or initiate it, symptom dynamics once it is initiated, and psychological models that reflect a biopsychological model in its determination. The latter allows for individual differences in resilience, coping, and so on, with the immediate proximal mechanism in PTSD perhaps working at the level of inhibitory dynamics and dysregulation therein. From a legal perspective, the initiating trauma must meet the threshold of being materially contributory within the multifactorial array that is involved in PTSD development. Therapy can be considered a mechanism for reversing causality. The following section briefly examines the major psychotherapies for PTSD from an evidence-supported perspective. It ends the second article of the three in the journal on “PTSD in Court,” which turns to forensic and legal issues in more depth in the third article of the series.

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in treating PTSD according to their study. Hilton et al. (2016) have indicated that, in meta-analysis, meditation-based treatments can be effective in treating PTSD. The latest efforts consulted relate to two issues that need further elaboration. On the one hand, Sripada, Rauch, and Liberzon (2016) investigated the mechanisms that underlie PTSD and its treatment. In this vein, they referred to emotional engagement, extinction/contextualization, distress tolerance, and negative posttraumatic cognitions. Gutner, Galovski, Bovin, and Schnurr (2016) examined the transdiagnostic approaches in treating PTSD and posttraumatic distress. Among other aspects, they emphasized treating underlying core processes, such as emotional awareness, which is consistent with the approach of Sripada et al. (2016). 7.2. Psychopharmacology

7. Therapy The next section of the article turns to the psychological treatment of PTSD. For review of the best treatments for PTSD, consult Bryant (2014) and Resick, Monson, Gutner, and Maslej (2014). Also, it reviews psychopharmacology in treating PTSD. It does not consider other important issues, such as the effects of age, minority status, and culture; although see Schnyder et al. (2016) on culturally-sensitive psychotraumatology; Mouilso, Tuerk, Schnurr, and Rauch (2016) on gender and therapy; and Rosen et al. (2016) on treatment of combatants. 7.1. Psychotherapy Foa and McLean (2016) reviewed the research supportive of prolonged exposure therapy (ET) for PTSD. This approach is considered gold standard in the field, partly because of its evidence-based approach in RCTs (randomized control trials). Rauch and Rothbaum (2016) described innovations for exposure therapy for PTSD, especially to increase emotional engagement with the trauma memories and associated cues. Steenkamp (2016) and Yehuda and Hoge (2016), at least for veterans, called for treatment approaches to PTSD that are more flexible compared to prolonged exposure and related treatments, encompassing of clinical judgment and patient values. This tension between evidence-based (and manualized) and more flexible approaches to psychotherapy is a broad one in the field of psychopathology (Young, 2014). That said, the trauma field should exclude unverified techniques, such as emotional freedom, given their insufficient evidence base (Metcalf et al., 2016). Lee et al. (2016) conducted a meta-analytic study of research in 55 studies on first-line psychotherapy for PTSD compared to pharmacotherapy. Trauma-focused therapies stood out, including prolonged exposure, imaginal exposure, cognitive processing therapy, and EMDR (eye movement desensitization). Other therapies were less effective (e.g., interpersonal, stress inoculation). The authors concluded that medications just blunt symptoms whereas psychotherapies having a trauma focus serve to facilitate the extinction of conditioned fear responses. Cusack et al. (2016) conducted a meta-analysis of RCTs for treatment of PTSD in adults, most of whom had severe PTSD according to the DSMIV criteria. The authors found 64 such trials, which evaluated: exposure therapy (mostly prolonged exposure); cognitive therapy, cognitive processing therapy, and cognitive behavior based therapies; EMDR; and narrative exposure therapy. Considering the “graded” strength of the evidence (SOE), exposure therapy was the highest rated, with the three cognitive therapy types moderately supported, and the other two low to moderate in support. Gerger et al. (2015) also found evidence in support of cognitive behavioral therapy (CBT) and exposure therapies for PTSD. In their meta-analysis, Tran and Gregor (2016) arrived at similar conclusions to the research reviewed in this section, after having taken care to disambiguate relevant confounds in the research. In particular, prolonged exposure therapy was most effective

Hoskins et al. (2015) conducted a systematic review and metaanalysis of psychopharmatherapy for PTSD. They examined 51 RCT research studies that had fit their criteria. All the studies were doubleblinded, randomized, placebo-controlled and comparative treatment trials of PTSD. The review conducted by the authors followed appropriate guidelines (PRISMA). The DSM or ICD diagnostic criteria were part of the assessment process in all the research reviewed. The primary outcome measures in these studies related to symptom severity according to clinician-administered measures, such as the CAPS. Of the 51 studies, 31 included tests of SSRI (selective serotonin reuptake inhibitors), especially of sertraline, fluoxetine, and paroxetine. The results in the Hoskins et al. (2015) review of psychopharmacy for PTSD showed a small positive effect of treatment by SSRIs, especially for paroxetine, fluoxetine, and venlafaxine. No evidence was found to support the use of the following drugs: brofaromine, olanzapine, sertraline, and topiramate. Other medications could not be analyzed for definite conclusions because of a lack of sufficient trials. The results in the research were not conducted to allow for head-tohead comparison of pharmacological vs. psychological PTSD treatment trials. Gu, Wang, Li, Wang, and Zhang (2016) conducted another metaanalysis of pharmacotherapy for PTSD. They examined 34 reports that met their criteria. They found that fluoxetine, paroxetine, and sertraline were especially helpful to PTSD patients, with some results in the research reviewed showing that imipramine, mirtazapine, and amitriptyline were efficacious (only a few RCTs were involved). The drugs recommended as first-line for treating PTSD included fluoxetine, sertraline, paroxetine, and mirtazapine. Note that over the two recent meta-analyses conducted by Hoskins et al. (2015) and Gu et al. (2016), the two medications for treating PTSD common to both were fluoxetine and paraxetine. These medications concern serotonin, a neurotransmitter that the anti-depressants mentioned assist in being available intra-synaptically. In addition, Bernardy and Friedman (2015) also referred to SNRIs (serotonin-norepinephrine reuptake inhibitors), other anti-depressants, as efficacious in treating PTSD. Although anti-depressants have been found to be effective in treating PTSD, medications related to anxiety have not. Guina, Rossetter, DeRhodes, Nahhas, and Welton (2015) conducted a systematic review and meta-analysis on the effectiveness of benzodiazepines (BZDs) in treating PTSD. They identified 18 clinical trials that met inclusion criteria. The results showed that BZDs are “ineffective” for both treating and preventing PTSD, aside from the risks they present. Examples of BZD include alprazolam, lorezepam, and temazepam. 7.3. Comment 7.3.1. Psychotherapy The recent research on psychotherapy for PTSD patients supports trauma-focused therapy, with prolonged exposure being a prominent

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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technique in this regard. It is consistent with a cognitive behavioral approach to treating PTSD. Detractors of these types of therapies refer to clinical judgment, patient values, etc. In psychotherapy, in general, common factors and eclectic approaches account for much of the variance in outcome, even more than contained in specific techniques (Young, 2014). Therefore, instead of applying trauma-focused therapy, in particular, to PTSD patients, it should be combined with elements of a more flexible approach. We do not treat the disorder, nor do we treat from the point of view of one school of thought or another; rather, we treat the whole person in all his or her individual differences, and tailor our treatments to getting success as best we can within that perspective (Young, 2014). In this regard, Young (2014) proposed an integrated approach to treatment that is componential-based. That is, as therapists, we need to assess the psychological, emotional, cognitive, behavioral, social, coping, and other aspects involved in the patients' discourse about their conditions, including the overall narrative that integrates these components. Note that Gutner et al. (2016) also described transdiagnostic approaches in treating PTSD and posttraumatic distress. However, they concluded that there has been very limited research on transdiagnostic treatment approaches in the field of trauma. Similarly, for therapy following MVAs, Guest, Tran, Gopinath, Cameron, and Craig (2016) noted very little applicable research. The following paragraphs elaborate further this transdiagnostic model based on work on dissociation. Lanius et al. (2014) discussed the treatment implications of the emotional undermodulation and overmodulation associated with typical PTSD (nondissociative) and PTSD with dissociation. First, they noted that patients in the two groups may respond differently to treatment such that dissociation in the latter patients will affect traumatic memory reprocessing and learning. For example, in Cloitre et al. (2010), women who had experienced PTSD in relation to childhood trauma (N = 104) received either: (a) supportive counseling followed by narrative storytelling exposure-type treatment (NST); (b) skills training in affective/ interpersonal regulation followed by supportive counseling (STAIR); or, as randomly assigned, (c) NST preceding STAIR. For women with higher pre-treatment dissociation, the latter therapy helped them improve, unlike the case for the other two types. In their article, Lanius et al. maintained that the treatment of patients exposed to trauma needs to be matched to the degree of patient sympathetic nervous system activation relative to parasympathetic activation. For example, patient dissociative reactivity and “shut down” response together need a broad active engagement, enhancement, encouragement, and stimulation (e.g., motorically, in muscle tone, in speech production, and for the five senses). One therapeutic technique is to focus not only on patient reactivity but also on stimuli input processing and appraisals that can be modify the reactivity. In this regard, in relation to the modulation issue, in the reactivity phase, I encourage patients to use taught breathing exercises, visualizations, self-talk, and so on, either to bring down their arousal (e.g., after a nightmare) or bring it up (e.g., no motivation, depressed). However, also, one should work on the modulation of their appraisal of the stimuli/stressors involved and their coping mechanisms. That is, for the first of these two points, patients should learn not to catastrophize about the input into their processing. For the second, they need to learn to cope better, using problem solving as they proceed, so that the response to trauma is proactively controlled to the degree possible. In this sense, therapy for over- or under-modulation should concern not only the response phase of the stimulus-processing (organism)-response sequence but also the precursor steps of stimulus input and its processing. Therefore, for stimuli/stressors, one would work on appraising them less catastrophically; and for processing/problem solving, one would work on effective motivation, coping, and skill sets. By modulating, or finding balance, in each of input, processing, and response phases of the traumatic induction, more effective ways of dealing with trauma could take place. Separately, another contribution that I have made is to suggest the core symptoms for each of the eight

dimensions that appear in the empirical literature on PTSD (see Table 1 in Part I of “PTSD in Court”). Perhaps this idea can be used in the modulation therapy being suggested in that therapy could focus on balancing these core symptoms in the balanced modulatory way indicated. Another concept with considerable therapeutic potential is “mental scanning” (Young, 2016d). It is normal to ask patients to be aware of their psychological issues, to suggest ways of coping with them, etc. However, asking patients to scan mentally their behaviors, thoughts, emotions, relationship experiences, and bodily accompaniments to these psychological dimensions pinpoint ongoing crucial aspects of their traumatic exposure reactions and helps them use learned techniques accordingly, or to modify them as might be required. To conclude, therapy for PTSD can be effective. However, it is not always available, and it may be delayed or even refused even when it is available. In terms of not receiving treatment, Wise and Beck (2015) noted that PTSD can be chronic and unremitting if untreated, leading to a significantly reduced quality of life (Beck & Sloan, 2012). Moreover, even if the person without treatment returns to work, he or she is susceptible to chronic medical conditions and work absenteeism, injuries on the job, and eventual disability (short-term, long-term). 7.3.2. Psychopharmacology Gu et al. (2016) and Hoskins et al. (2015) have conducted metaanalyses of RCTs on medications that have been used to treat PTSD. The SSRIs have proven most effective in these regards. These sets of meta-analyses on pharmacological treatment of PTSD support the finding that PTSD often is comorbid with depression and that it is more a diagnosis related to trauma rather than anxiety. Note that research on psychopharmacy in relation to PTSD is proliferating. For example, other potentially beneficial medications for PTSD include propranolol (Giustino, Fitzgerald, & Maren, 2016), ketamine (Pradhan, D'Amico, Makani, & Parikh, 2016), cannibinoids (Berardi, Schelling, & Campolongo, 2016), and MDMA (3,4Methylenedioxymethamphetamine; Amoroso & Workman, 2016), with others for different comorbidities (e.g., naltrexone for sleep; Zandberg et al., 2016). 8. Conclusion to the second article of the three on “PTSD in Court” An interim summary to this second article on “PTSD in Court” deals with the causes of PTSD. The causes of behavior generally are considered multifactorial, biopsychosocial, and exquisitely complex over multiple levels and time frames. Causality does not constitute a secondary question in psychology, but a ubiquitous and primary one that lies at the heart of what psychology is about (Young, 2016b). One approach is to consider it from a dynamic systems perspective in which we contribute to our own development and behavior through our personal activity and inclinations, including through the free choices we make, or at least believe that we make. In this sense, I considered the biopsychosocial model essential to understanding behavior, and ascribed a role to personal factors in this regard, such as a belief in free will, coping, motivations, etc. Overall, the approach in Young (2016b) is that causality can constitute the unifying force in the study of psychology and also in related disciplines. When we speak of the causes of psychopathology, we are referring to the etiology of mental disorder. Traditionally, psychiatry functioned from the medical model, in which one causal agent induces one disorder, which in turn is dealt with by one intervention. However, mental health disciplines, in general, are moving in the direction of multifactorial biopsychosocial models. The same applies to PTSD; as mentioned, we need to consider it as biopsychosocial. Further, as previously described, we need to consider it as the product of a multilevel system with a top-down construct level, a bottom-up symptom interactive one, and an intermediate one involving symptom appraisals (aside from another level involving symptom clusters).

Please cite this article as: Young, G., PTSD in Court II: Risk factors, endophenotypes, and biological underpinnings in PTSD, International Journal of Law and Psychiatry (2017), http://dx.doi.org/10.1016/j.ijlp.2017.02.002

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The study of causation of PTSD has especially investigated the biological bases for the disorder. The biological approach to PTSD causation especially considers its genetic underpinnings and its brain-based associations. Concerning the genetic underpinnings related to PTSD, candidate genes have been found, but polygenic approaches are more powerful and indicate the scope of the genetic influence on PTSD. These influences must be considered separately for all phases of its risk and course, including which gene complexes might help promote both its initiation and its recovery, a comment that does not deny that the environment is involved, as well. The study of PTSD in terms of the brain has included structural and functional networks of areas across the brain, including those in major networks such as the default mode one, the salience one, and the central executive one. The new approach to understanding the brain as a Connectome has filtered into understanding the dynamic symptom linkages in psychopathology, including in PTSD, as causal influences on their expression, as mentioned. The other areas discussed in this article include risk factors and genes. It is quite possible that the interactive dynamics within each of these areas and across them reflect connectivity dynamics. Moreover, their relationship to more distal intermediate phenotypes in the endophenotypic pathway to PTSD might also involve network dynamics worthy of investigation. Another aspect of this section of the article on causality in PTSD relates to its legal conceptualization. In court and related venues, the evidence proffered must indicate that the event at issue in tort and related claims must meet the bar of being a material contributor to the elicited disorder claimed, including of PTSD. For detailed review of causality in the forensic disability and related assessment contexts, refer to Young and Drogin (2014) and Young (2015a). Essentially, once cases are determined as valid after ruling out malingering and related feigning, the event at issue needs to be established as a contributor greater than the minimal level to the psychological condition at issue, notwithstanding the multifactorial impacts in the causation involved, including preexisting ones. 8.1. Looking ahead There are multiple other complications in assessing PTSD, including related to the causal traumatic stressor that had induced it. Is it traumatic to the degree required by the DSM-5 diagnostic manual? Is the presentation by the evaluee indicative of possible malingering and, if so, how does one best detect it? Which tests detect best PTSD and which ones are useful in detecting PTSD malingering? How can one have the evidence we present to court accepted and stand up either to admissibility challenges or, if accepted, to cross-examination on its weight and credibility? The third article in the series of three articles on “PTSD in Court” published in this journal (Young, 2017) tackles these and related issues, such as assessor biases and systemic influences in the court process. The question of causality in cases of psychological injury is deeply embedded with the one of malingering and related negative response biases and symptom exaggerations. The third article concludes by examining litigation science, the narratives about PTSD told in court (and to ourselves as forensic psychological assessors), including about the pervasiveness of malingering in tort and related cases at court, or its lack, as the case may be on one side of the adversarial divide or the other. Given this preamble, in the following, I examine more closely the topic of malingering and other relevant legal topics. 8.2. Looking back To give a brief synopsis of the first and articles on “PTSD in Court” in the journal as a prelude to the third, note that the first one gave introductory material on its history, diagnostic structure in the DSM-5

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(American Psychiatric Association, 2013) and the proposed ICD-11 (International Classification of Diseases, 11th Edition; World Health Organization, 2018), which differ in the number of PTSD symptoms and clusters, and current research on the number of dimensions among the 20 DSM-5 PTSD symptoms, which might even number seven or eight and not the four used in the DSM-5. Also, forensic cautions were provided. As for this second article, it focused on the biological underpinnings to PTSD, from risk factors to genes to brain and to behavior. This part included the concept of endophenotypes as a cohering one. The biological focus on PTSD should not be taken to deny environmental contributions, including of traumatic events at issue and in epigenetics and “gene x environment” interactions, nor lead to the conclusion that biomarkers have been found for PTSD that would be useful in court. The vulnerabilities in PTSD speak to post-event factors as much as pre-event ones. The causality models for PTSD that were supported considered the biopsychosocial and systems perspectives. The evidencesupported therapies helpful for PTSD were discussed, as well.

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