The Reward System and Post-Traumatic Stress Disorder: Does Trauma Affect the Way We Interact With Positive Stimuli?

Abstract

Post-traumatic stress disorder (PTSD) is a highly prevalent disorder and a highly debilitating condition. Although anhedonia is an important construct of the disorder, the relationship between PTSD and reward functioning is still under-researched. To date, the majority of research on PTSD has focused on fear: fear learning, maintenance, and extinction. Here we review the relevant literature—including clinical observations, self-report data, neuroimaging research, and animal studies—in order to examine the potential effects of post-traumatic stress disorder on the reward system. Our current lack of sufficient insight into how trauma affects the reward system is one possible hindrance to clinical progress. The current review highlights the need for further investigation into the complex relationship between exposure to trauma and the reward system to further our understandings of the ethology of PTSD.

Keywords

anhedonia emotional numbing MDD negative valence positive valence PTSD reward system stress trauma

Introduction

Post-traumatic stress disorder (PTSD) was established as a psychiatric disorder in 1980.¹ Approximately 6–8% of the general population will be diagnosed with PTSD at some point in their lives,^2–5 which makes the diagnosis quite prevalent. This is slightly lower than previous estimates because the 5th edition of the American Psychological Association’s (APA) Diagnostic Statistical Manual (DSM) narrowed its diagnostic parameters on criterion A (see Table 1) by excluding illness-related traumas and traumas witnessed only via electronic media.^3,6

Table 1.

PTSD criteria across DSM editions.

Criteria	DSM III (1980)	DSM III-R (1987)	DSM IV (1994), DSM IV-R (2000)	DSM V (2013)
A	Significant stressor	Significant stressor• Outside of normal experience	Significant stressor • Possibility of death, serious injury, or risk to physical integrity (e.g. sexual assault) • Induced fear, helplessness, or horror• Was experienced, witnessed, or learned about• Can be illness-related	Significant stressor• Possibility of death, serious injury, sexual violence• Must be violent or accidental (not medical or illness-related) • Was experienced, witnessed, or learned about (not through media)

B	(1x) • Intrusive memories• Nightmares• Flashbacks	(1x) • Intrusive memories• Nightmares• Flashbacks• Symptom triggering	(1x) • Intrusive memories• Nightmares• Flashbacks• Symptom triggering• Physiological reactivity	(1x) • Intrusive memories• Nightmares• Flashbacks• Symptom triggering• Physiological reactivity

C	(1x) • Anhedonia• Detachment • Limited affect	(3x) • Anhedonia • Detachment • Limited affect• Dread• Avoidance (thoughts/feelings) • Avoidance (activities/situations) • Inability to recall trauma details	(3x) • Anhedonia • Detachment• Limited affect• Dread• Avoidance (thoughts/feelings) • Avoidance (activities/situations) • Inability to recall trauma details	(1x) • Avoidance (thoughts/feelings) • Avoidance (activities/situations)

D	(2x) • Hypervigilance • Sleep disturbance• Guilt• Impaired memory• Avoidance • Symptom triggering	(2x) • Hypervigilance • Sleep disturbance• Anger• Impaired concentration• Exaggerated startle • Physiologic reactivity	(2x) • Hypervigilance • Sleep disturbance• Anger• Impaired concentration• Exaggerated startle	(2x) • Guilt/blame• Anhedonia • Detachment• Inability to recall trauma details• Emotional numbing • Negative beliefs• Negative emotional state

E	N/A	N/A	N/A	(2x) • Hypervigilance • Sleep disturbance• Anger• Impaired concentration• Exaggerated startle • Impulsivity
Classification	Anxiety disorder	Anxiety disorder	Anxiety disorder	Trauma/stress disorder

DSM: Diagnostic and Statistical Manual of Mental Disorders.

PTSD is often characterized by its maladaptive fear responses following a traumatic event (e.g., a combat veteran with a startle response to ordinary noises and movements). To date, the majority of PTSD research has focused on the inhibition system—fear learning, maintenance, and extinction—due to the conspicuous nature of the disorder’s fear-related symptoms. Though less researched, PTSD also involves depressive symptoms, such as anhedonia and emotional numbing (which relate to the reward system). The relationship between PTSD and the reward system is not well characterized,^7–10 and current research is not definitive regarding whether reward system deficits are distinct from negative valence symptoms.^11–13

Appropriately characterizing PTSD symptomatology related to the reward system enables professionals in the field to effectively identify predictive factors for PTSD and properly diagnose the disorder. Additionally, diagnostic clarity would enable the development of treatments that go beyond reversal of fear,^8,14 which may assist in avoiding poor outcomes, such as health risk behaviors and chronic PTSD (which have been positively correlated with depressive symptoms in PTSD^8,15). The aim of this article is to synthesize relevant literature and aid in the overall understanding of the effect of trauma on the reward system.

The Reward System: Function and Dysfunction

The reward system refers to the aggregate of neural circuits that process appetitive stimuli—including the limbic system (septal area, thalamus, hypothalamus, amygdala), basal ganglia (containing the ventral and dorsal striatum), prefrontal cortex (ventromedial prefrontal cortex, in particular), ventral tegmental area (VTA), and substantia nigra.⁸

Neural structures were first implicated in reward processes in the mid-1900s when studies started employing deep-brain stimulation^16–23 to elicit reward responses, resulting in self-reported feelings of pleasure and a disinclination to cease self-stimulation.^17,18,24 Findings were replicated across settings with the use of multiple neuroimaging technologies.^18,25

The reward system is now understood to rely on the functioning of neural structures, circuits, and neurotransmitters including dopamine, serotonin, and norepinephrine. In a properly functioning reward system, the anticipation or acquisition of a reward will catalyze a cascade of events, eventuating in the release of dopamine, which travels along the dopaminergic pathways^26–30 to critical structures (the cerebral cortex, striatum, and pituitary gland).^29,31–33 Dopamine is involved in signaling reward prediction error and creating incentive salience, therefore motivating and reinforcing behavior.^29,33–37 Serotonin has a large role in mediating reward enjoyment, motivation, and learning. High serotonin levels will increase inhibition and feelings of satiation, modulating dopamine’s effects on reward reinforcement.^38–42 Norepinephrine affects the mobilization efforts required to obtain a reward.^32,43 The cannabinoid and opioid systems are also implicated in this process. Some evidence exists to suggest that the cannabinoid system has a role in reward signaling and in modulating one’s risk for developing reward-related deficits following stressors.^44,45 Additionally, the opioid system may help to regulate motivation and reward seeking.^46–48 All of these mechanisms work in tandem to create reward satisfaction and encourage reward-seeking behavior—though the scientific community’s understanding of these mechanisms is relatively new, and further research is warranted.

Dysfunction in reward mechanisms can occur naturally (e.g., natural dopamine decline caused by social isolation^49–51 or serotonin decline caused by aging⁵²), or artificially (e.g., introduction of dopamine antagonist,^53–55 drug-induced blocking of CB1 receptors,⁴⁵ or opioids modifying their receptors as addiction develops⁴⁶), or caused by illness^34,56,57 and genetic disorders (e.g., genetic depletion or malformation of the CB1 receptors^44,45). Dysfunction in these mechanisms is characterized by reward learning and motivation deficits⁵⁶ and emotional abnormalities:⁸ a lack of pleasure or satisfaction (anhedonic symptoms^34,57,58), reduction in motivation,^29,33,37,59 and emotional numbing.⁶⁰

PTSD and Dysfunction in Reward System Mechanisms

Researchers are still trying to understand if and to what extent trauma may be a natural cause of reward system dysfunction. Evidence does support the existence of reward learning deficits in the neural circuitry of those with PTSD, as demonstrated by limited activation in brain regions during both the anticipation of (“expectancy phase”) and experiencing of (“outcome phase”) reward.^61–63 When actively participating in a rewards task, participants with PTSD displayed reduced neural activation in the nucleus accumbens and in the mesial prefrontal cortex, and they were slow to learn which series of responses would lead them to a reward.⁶⁴ When passively experiencing rewards, PTSD-sufferers have shown limited blood oxygen level-dependent (BOLD) changes in the amygdala and striatal subregions (bilateral nucleus accumbens, bilateral caudate, bilateral putamen) in comparison to healthy controls.⁶² Abnormalities, varying by factors such as age of trauma onset, brain region, and sex, also exist in the cannabinoid^65,66 and opioid systems as a result of trauma.^67,68 Neurobiological symptoms are supported by animal model research, which correlates core PTSD symptomatology (e.g., mouse behaviors related to avoidance, fear extinction, arousal) to impaired neurocircuitry in the amygdala, nucleus accumbens, caudate, and putamen.⁶⁹

Trauma is also associated with emotional abnormalities in neural structures. One study found that, compared to their healthy counterparts, those with PTSD have less activation in left parahippocampal gyrus, left fusiform gyrus, left bilateral temporal pole (regions often indicated in emotional processing), when they are exposed to positive valence images.⁷⁰ Another study found that participants with PTSD had less activation in their amygdala and in their ventral striatal-limbic networks than healthy controls did when passively presented with a happy face. The PTSD group also reported the faces as appearing less happy than they appeared to the control group.⁷¹

Clinical observation has supported the relationship between trauma and emotional abnormalities: anhedonia,⁷² emotional numbing,^72,73 diminished positive affect⁸ (present even without comorbid diagnoses of MDD⁷⁴), and deficits in motivation (present without any coexisting cognitive deficits that could be confounding⁶⁴). Similar symptoms are observed in animal models. (When stress is introduced, rats show a decreased interest in rewards⁷⁵).

Self-report data corroborates these findings, further suggesting a correlation between PTSD and deficits in reward learning. Those with PTSD report getting less satisfaction from rewards than their healthy control counterparts report getting; this includes both passively and actively experiencing the anticipation and outcome of a reward.^62,76 Participants with PTSD have reported fewer positive emotions associated with rewards⁷⁶ and less satisfaction with the rewards even when there was little expectation of receiving a reward at all.⁷⁷ Healthy controls, comparatively, reported experiencing more pleasure from and satisfaction with the rewards, and they were particularly pleased when the reward was unexpected.⁷⁷ One theory postulates that this phenomenon exists because those with PTSD have a higher threshold for positive stimuli and require stronger positive stimuli to meet said threshold.⁷⁸

In addition to trauma being linked to emotional abnormalities and reward learning deficits, there is also a connection between PTSD and dysfunction in reward-related neurobiology. Dopamine is crucial to reward functioning,^55,58 and severe stress has been associated with a reduction in dopaminergic neural activity in humans and in animal models.^75,79–82 The reciprocal is also true: In mice, the introduction of dopamine agonists has been shown to reduce PTSD-like stress symptoms.⁸³ In human neuropharmacological studies, artificial increases in dopamine, norepinephrine, or serotonin can have antidepressant effects in PTSD.^84,85

PTSD and External Reward Seeking

Abnormal reward-seeking and maintenance behaviors (risky behaviors) are innate in the PTSD diagnosis (criterion E2⁶). PTSD symptom severity positively correlates with risk-taking behaviors, including thrill seeking and risky sexual behaviors.^86–88 Notably, PTSD is also highly comorbid with substance abuse:^80,89–92 According to the American Addiction Center, 50–66% of PTSD-sufferers have comorbid substance abuse issues. According to the European Monitoring Centre for Drugs and Drug Addiction, depression—a disorder highly defined by its reward-system deficits—has the highest substance abuse comorbidity prevalence of all psychiatric disorders.⁹³)

High levels of external reward seeking may be evidence of reward system dysfunction in PTSD. Dopamine-inducing behaviors and substances (such as alcohol, opioids, nicotine, and cannabis) are self-reinforcing.^37,94 The self-proctoring of external thrills and psychoactive substances is an in-vivo representation of neurobiological self-stimulation studies,^93,95 which have been mainstays in reward system research. Those experiencing emotional abnormalities may be in search of external stimulation. This can lead to risky behaviors and addictive substances—as dopamine levels increase as a result of reward system activation, serotonin levels decrease,^38,41 and leave the individual without a sense of satiation and in search of additional stimulation.^39,42,96 Possibly adding to the effect: High levels of dopamine are thought to encourage impulsive behaviors, while high levels of serotonin will suppress them.⁹⁷ With low levels of serotonin and high levels of dopamine, reward seekers are left unencumbered by inhibition and in search of an ever-elusive feeling of satiation.

Opposing Theories

Despite strong evidence, the theory that trauma affects the reward system is not universally accepted. There have been alternative theories as to why neural correlates present differently in PTSD patients than they do in healthy controls. One theory speculates that hyperarousal (a negative valence symptom associated with PTSD (see Table 1)) uses up cognitive resources, diverting resources away from tasks and non-trauma-related topics.⁷⁸ Animal model studies have suggested that performance in cognitive and memory-based tasks is impaired when there is exposure to high stress,⁹⁸ which could explain why human research studies detect limited BOLD activation during reward learning tasks.^61–63

Another theory states that PTSD sufferers are not lacking the ability to feel positive emotions. Rather, they lack the ability to label and/or express these emotions. Comparisons between PTSD and non-PTSD samples have suggested a correlation between alexithymia and a diagnosis of PTSD.^99–101 Alternatively, individuals could be strategically concealing their emotions. One study found that veterans with PTSD reported purposely concealing their emotions more often and more intensely than veterans without PTSD did.¹³ Researchers in this study, however, did acknowledge that any active retention of emotion was most likely a facet of an overarching emotional deficiency and not a primary symptom in itself.

Another differential conclusion is that comorbidities are the primary contributor to reward deficits in PTSD, given the high rate of comorbidity with substance abuse^89–91 and MDD.¹⁰² With this explanation, comorbid disorders would explain a majority of the observed reductions in appetitive functioning.¹² PTSD symptomatology is complex and can have significant overlap with other disorders, which makes understanding the source of reward system deficiencies challenging.

Complexity and Heterogeneity

If the field is to carefully consider the possible effects of PTSD on the reward system, it will be important to reconcile these opposing theories, potentially by transparently acknowledging the disorder’s complexity and heterogeneity. One facet to consider is that the existence and severity of reward dysfunction in PTSD may vary across demographic categories. Research has suggested that older adults may suffer more reward dysfunction following trauma than younger adults will.^103,104 Although not fully studied, broader research does support the existence of variation in PTSD symptom expression across race, gender, and age—affecting arousal,^105–107 avoidance behaviors,^{103,107–109} and emotional regulation^110,111): Evidence suggests that Black individuals are generally likely to experience more avoidance symptoms than white individuals will,^108,109 and women more so than men.^103,107 Also suggested is that Black individuals are generally likely to experience more hyperarousal symptoms than white individuals will,¹⁰⁵ elderly adults more than younger adults,¹⁰⁶ and women more than men.¹⁰⁷ More research in this area is warranted, specifically as it relates to the reward system.

Symptom variation may, in part, be explained by differing trauma types across populations.^109–114 For example, racial trauma may produce a different set of coping strategy than other traumas¹⁰⁹ and sexual trauma may affect emotional regulation skills, mitigating gender differences.^110–112

Heterogeneity across populations is important to address, as ignoring it could lead to systematically underdiagnosing or overdiagnosing certain groups, which may further result in undertreating or mistreating. Chart-review research on the detection of PTSD offers a look into the real-world consequences involved when diagnostic criteria do not equally represent different groups of people and their respective symptomatology: Among those with a confirmed diagnosis of PTSD, women, Native Americans, and Black men were most likely to have been diagnosed with PTSD upon first consulting with a mental healthcare professional (as opposed to later on in treatment).^2,115 A gap in knowledge exists when it comes to understanding presentations of PTSD across groups.

Some theories propose that heterogeneity in PTSD symptomatology would be best explained and controlled for in diagnosis by considering the possible existence of PTSD subtypes. The theory that PTSD has two emotional dysregulation subtypes^68,116,117 is already relatively accepted in the literature. Relevant theories propose that there are also subtypes of PTSD that can be characterized by reward dysfunction.^90,116,118 Neuroimaging research also shows that individuals with PTSD can display both overmodulation and under-modulation of the medial prefrontal cortex (PFC), which dynamically and continuously regulates the limbic system (relating to emotional modulation).¹¹⁶ These findings suggest that the expression of PTSD not only varies across people but is also dynamic within subjects. A unipolar definition of any PTSD symptomatology may be neglecting these complex aspects of PTSD presentation.

Limitations

Current research on PTSD’s effect on the reward system is limited, and there are a number of obstacles involved in exploring the topic—barriers that stunt research but are also a reflection of gaps in knowledge and the need for further exploration. For one, researchers face a lack of definitional clarity.¹⁴ The American Psychological Association offers vague—if not conflicting—information about the current PTSD diagnosis criteria as they relate to the valence systems; the DSM 5 cites examples of valence over-reactivity and valence under-reactivity.⁶ Looking specifically at emotional abnormalities, we see DSM discussion of both increased emotional reactivity (criterion B) and emotional numbing (D) (see Table 1). And while some reward system dysfunction is acknowledged (e.g., emotional numbing, anhedonia), the DSM evades a commitment to these criteria by allowing a diagnosis in the absence of any reward deficit symptoms.

Substantial changes between DSM editions (see Table 1) pose a similar obstacle. The DSM IV, for example, presents emotional numbing and avoidance in a single cluster of PTSD symptoms, whereas the DSM V separates these symptoms and goes on to define emotional numbing solely as the numbing of positive emotions—a specification not previously noted and one that is still not ubiquitously accepted or unanimously utilized in discourse.^{4,6,119–121} What may seem like technicalities create barriers in communication and can ultimately affect the reexamination of PTSD criteria and treatment.

Future Directions

Nonresponse and drop-out rates are high in PTSD treatments,^122–127 and only about a third of people diagnosed with PTSD fully recovered from it.¹²⁸ Much work needs to be done on researching the disorder and its treatment, and part of this work needs to be on understanding trauma and the reward system. In line with the Research Domain Criteria (RDOC^10,100), future research could use multi-method procedures to assess the effects of PTSD on the reward system as well as potential bidirectional effects.

Research should, first, work to confirm if there are reward system deficits that accompany PTSD. While there is evidence to this end, some suggest alternative readings of the findings.^{78,98,99,101,102,129} One method to approach this question might be to try to measure reward deficits in PTSD subjects when comorbidities, such as threshold and subthreshold substance abuse, MDD, and alexithymia, are controlled for.

If reward dysfunction in PTSD attracts further scientific support, the next step may be to work toward understanding the heterogeneity of reward functioning in PTSD. Not understanding how the presentation of PTSD can differ across individuals and groups will affect diagnosis prevalence and may leave certain groups of people underdiagnosed or overdiagnosed. A proper diagnosis is a gateway to a proper treatment. If certain groups of people are underdiagnosed or misdiagnosed due to their symptom presentation, clinicians may be systematically excluding these groups from receiving appropriate treatment.^105,108,112 Does chronic trauma put an individual at risk of developing reward deficits more than an acute trauma does? Does one’s age, gender, race, ethnicity, or type of trauma increase the chances of developing these deficits?

Once these steps are taken, future research may include efforts to improve the effectiveness and tolerability of PTSD treatments by targeting reward-related symptoms. Prolonged exposure is currently considered to be the gold standard of PTSD-targeted psychotherapies, particularly for those with chronic PTSD.¹²³ While generally considered effective, aiding in about a 40%-70% reduction in symptoms,¹³⁰ up to 50% of patients do not respond, and the treatment’s rigor results in high drop-out rates.^123–126 Medication trails also result in high rates of discontinuation prior to completion of the recommended course.¹³¹ If reward-related deficits in PTSD were better correlated to certain factors (e.g., trauma type or age increasing the likelihood of developing reward dysfunction) or if subtypes were identified and clearly defined, perhaps treatments could be better targeted. More precise treatments would not only carry the potential to become more effective than generalized treatments but would also aid in possibly attenuating patient exhaustion. One avenue to explore may be investigating the use of rapid-acting medications and their use in augmenting traditional psychotherapies. Ketamine, in particular, is promising, as it has been lauded for its antidepressant effects in patients with severe MDD^132,133 and is currently being researched for its potential use in PTSD treatment.^{122,134–136} As a fast-acting antidepressant with potential long-term benefits, ketamine could make for a tolerable and effective therapeutic tool for addressing reward dysfunction in PTSD.

A final suggestion of future directions is to study the bidirectionality of trauma and reward dysfunction. Studies have shown both predisposing and acquired neural abnormalities related to PTSD. Hyperactivity in the amygdala and the dorsal anterior cingulate cortex are recognized as predisposing factors for vulnerability to PTSD; while decreased connection between the hippocampal and ventromedial prefrontal cortex is regarded as acquired impairment.¹³⁶ This line of research has historically focused on the processing of threats and fear, and more needs to be studied regarding the processing of positive rewards. While it is important to recognize the contribution of trauma to reward system impairments, it is likewise useful to be aware of the concern that this relationship could move in both directions. Does an altered reward system predispose an individual to be more susceptible or more resilient to psychopathology following a traumatic event? Understanding such questions will give new insights to preventive interventions and treatments for PTSD.

Conclusion

It has been 40 years since the term “post-traumatic stress disorder” was coined. PTSD remains highly prevalent.^2–4 Our lack of insight into trauma’s effect on the reward system is one possible hindrance to clinical progress. When we start examining the relationship between trauma and the reward system, important questions come about regarding the diagnosis and treatment of PTSD. For example: Should reward system deficits be more central in PTSD diagnostic criteria? Should we be treating PTSD based on its subtype? Should psychotherapy for PTSD include affect-focused treatment? What is known is that those with PTSD have low levels of dopamine, reduced reactivity in neural areas associated with the reward system, lower reports of reward satisfaction, and a higher tendency to seek external—sometimes risky—rewards. These correlations merit some attention. Ultimately, further research is necessary in order to address PTSD in a more complete way, one that appreciates the heterogeneity of the disorder and is culturally competent. When more is known about PTSD criteria, including their relation to reward system deficits, the field will be better enabled to create targeted, effective, and efficient treatments for the disorder.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was partly funded by VA CSR&D Grant CX001538 to IHR.

ORCID iDs

Rebecca Seidemann

Ilan Harpaz-Rotem

References

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-III). Washington, DC: APA Publishing; 1980.

Goldstein

Smith

Chou

, et al. The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the national epidemiologic survey on alcohol and related Conditions-III. Soc Psychiatry Psychiatr Epidemiol. 2016; 51(8): 1137–1148.

Gradus

JL.

Epidemiology of PTSD: From the National Center for Post-Traumatic Stress Disorder, Department of Veterans Affairs. West Haven, CT: National Center for PTSD; 2013.

Kilpatrick

DG.

The DSM-5 got PTSD right: comment on Friedman (2013). J Trauma Stress. 2013; 26(5): 563–566.

Pietrzak

Goldstein

Southwick

, et al. Prevalence and axis I comorbidity of full and partial posttraumatic stress disorder in the United States: results from wave 2 of the national epidemiologic survey on alcohol and related conditions. J Anxiety Disord. 2011; 25(3): 456–465.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM V), Fifth Edition. Washington, DC: Author; 2013. https://psychiatryonline.org/doi/book/10.1176/appi.books.9780890425596. Accessed February 4, 2021.

Finucane

Dima

Ferreira

, et al. Basic emotion profiles in healthy, chronic pain, depressed and PTSD individuals. Clin Psychol Psychother. 2012; 19(1): 14–24.

Fonzo

GA.

Diminished positive affect and traumatic stress: a biobehavioral review and commentary on trauma affective neuroscience. Neurobiol Stress. 2018; 9: 214–230.

Insel

Cuthbert

Garvey

, et al. Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry. 2010; 167(7): 748–751.

10.

The National Institute for Mental Health. Research Domain Criteria [RDOC]. Bethesda, MD: Author; 2009.

11.

Nawijn

van Zuiden

Frijling

, et al. Reward functioning in PTSD: a systematic review exploring the mechanisms underlying anhedonia. Neurosci Biobehav Rev. 2015; 51: 189–204.

12.

Pietrzak

Tsai

Armour

, et al. Functional significance of a novel 7-factor model of DSM-5 PTSD symptoms: results from the national health and resilience in veterans study. J Affect Disord. 2015; 174: 522–526.

13.

Roemer

Litz

Orsillo

, et al. A preliminary investigation of the role of strategic withholding of emotions in PTSD. J Traum Stress. 2001; 14(1): 149–156.

14.

Galatzer-Levy

Bryant

RA.

636,120 Ways to have posttraumatic stress disorder. Perspect Psychol Sci. 2013; 8(6): 651–662.

15.

Hassija

Jakupcak

Gray

MJ.

Numbing and dysphoria symptoms of posttraumatic stress disorder among Iraq and Afghanistan war veterans: a review of findings and implications for treatment. Behav Modif. 2012; 36(6): 834–856.

16.

Berridge

KC.

The debate over dopamine’s role in reward: the case for incentive salience | SpringerLink. Psychopharmacology (Berl). 2007; 191(3): 391–431.

17.

Bishop

Elder

Heath

RG.

Intracranial self-stimulation in man. Science. 1963; 140(3565): 394–396.

18.

Heath

RG.

Pleasure and brain activity in man: deep and surface electroencephalograms during orgasm. J Nerv Ment Dis. 1972; 154(1): 3–18.

19.

Olds

Milner

Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J Comp Physiol Psychol. 1954; 47(6): 419–427.

20.

O’Neal

Baker

Glenn

, et al. Dr. Robert G. Heath: a controversial figure in the history of deep brain stimulation. Neurosurg Focus. 2017; 43(3): E12.

21.

Sem-Jacobsen

CW.

Depth‐electrographic observations in psychotic patients. Acta Psychiatr Scand Suppl. 1959; 34(136): 412–416.

22.

Sorge

Clarke

PBS.

Rats self-administer intravenous nicotine delivered in a novel smoking-relevant procedure: effects of dopamine antagonists. J Pharmacol Exp Ther. 2009; 330(2): 633–640.

23.

Sem-Jacobsen CW, Torkildsen A. Depth Recording and Electrical Stimulation in the Human Brain. In: Ramey ER, Doherty DS, eds. Electrical Studies on the Unanesthetized Brain: A Symposium with 49 Participants. New York: Hoeber, Harper & Row; 1960: 280–288.

24.

Heath

RG.

Pleasure response of human subjects to direct stimulation of the brain. In: Health RG, ed. The Role of Pleasure in the Brain. New York, NY: Hoeber ; 1964: 219–243.

25.

McClure

Berns

Montague

PR.

Temporal prediction errors in a passive learning task activate human striatum. Neuron. 2003; 38(2): 339–346.

26.

Hudepohl

Nasrallah

HA.

Chapter 39 - antipsychotic drugs. In: Aminoff MJ, Boller F, Swaab DF, eds. Handbook of Clinical Neurology. Amsterdam, Netherlands: Elsevier; 2012: 657–667 (Neurobiology of Psychiatric Disorders; Vol. 106). http://www.sciencedirect.com/science/article/pii/B9780444520029000395. Accessed February 4, 2021.

27.

Hull

Rodriguez-Manzo

Male Sexual Behavior. In: Pfaff DW, Etgen AM, Etgen AM, Arnold AP, Fahrbach SE, eds. Hormones, Brain and Behavior, 2nd ed. San Diego, CA: Academic Press; 2009: 5–66.

28.

Kandel

Schwartz

Jessell

Principles of Neural Science. 5th ed. New York, NY: McGraw-Hill; 2013.

29.

Schultz

Dayan

Montague

PR.

A neural substrate of prediction and reward. Science. 1997; 275: 1593–1599.

30.

Wise

RA.

Drug-activation of brain reward pathways. Drug Alcohol Depend. 1998; 51(1–2): 13–22.

31.

Adinoff

Neurobiologic processes in drug reward and addiction. Harv Rev Psychiatry. 2004; 12(6): 305–320.

32.

Reward and aversion. Annu Rev Neurosci. 2016; 39(1): 297–324.

33.

Tsai

H-C

Zhang

Adamantidis

, et al. Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science. 2009; 324(5930): 1080–1084.

34.

Belujon

Grace

AA.

Dopamine system dysregulation in major depressive disorders. Int J Neuropsychopharmacol. 2017; 20(12): 1036–1046.

35.

Connecticut College. Student-Faculty Research Suggests Oreos Can Be Compared to Drugs of Abuse in Lab Rats. New London, CT: Connecticut College; 2013. http://www.conncoll.edu/news/news-archive/2013/. Accessed February 4, 2021.

36.

Olsen

CM.

Natural rewards, neuroplasticity, and non-drug addictions. Neuropharmacology. 2011; 61(7): 1109–1122.

37.

Schultz

Dopamine reward prediction error coding. Dialogues Clin Neurosci. 2016; 18(1): 23–32.

38.

Daw

Kakade

Dayan

Opponent interactions between serotonin and dopamine. Neural Netw. 2002; 15(4–6): 603–616.

39.

Fischer

Ullsperger

An update on the role of serotonin and its interplay with dopamine for reward.

Front Hum Neurosci. 2017; 11: 484. https://www.frontiersin.org/articles/10.3389/fnhum.2017.00484/full. Accessed February 4, 2021.

40.

Kranz

Kasper

Lanzenberger

Reward and the serotonergic system. Neuroscience. 2010; 166(4): 1023–1035.

41.

Seo

Patrick

Kennealy

PJ.

Role of serotonin and dopamine system interactions in the neurobiology of impulsive aggression and its comorbidity with other clinical disorders. Aggress Violent Behav. 2008; 13(5): 383–395.

42.

Wee

Anderson

Baumann

, et al. Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs. J Pharmacol Exp Ther. 2005; 313(2): 848–854.

43.

Varazzani

San-Galli

Gilardeau

, et al. Noradrenaline and dopamine neurons in the reward/effort trade-off: a direct electrophysiological comparison in behaving monkeys. J Neurosci. 2015; 35(20): 7866–7877.

44.

Martin

Ledent

Parmentier

, et al. Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl)). 2002; 159(4): 379–387.

45.

Solinas

Goldberg

Piomelli

The endocannabinoid system in brain reward processes. Br J Pharmacol. 2008; 154(2): 369–383.

46.

Le Merrer

Becker

JAJ

Befort

, et al. Reward processing by the opioid system in the brain. Physiol Rev. 2009; 89(4): 1379–1412.

47.

Nummenmaa

Saanijoki

Tuominen

, et al. μ-opioid receptor system mediates reward processing in humans. Nat Commun. 2018; 9(1): 1500.

48.

Schreckenberger

Klega

Gründer

, et al. Opioid receptor PET reveals the psychobiologic correlates of reward processing. J Nucl Med. 2008; 49(8): 1257–1261.

49.

Depue

On the nature of extraversion: variation in conditioned contextual activation of dopamine-facilitated affective, cognitive, and motor processes. Front Hum Neurosci. 2013; 7: 288.

50.

Eisenberger

NI.

The pain of social disconnection: examining the shared neural underpinnings of physical and social pain. Nat Rev Neurosci. 2012; 13(6): 421–434.

51.

Matthews

Nieh

Vander Weele

, et al. Dorsal raphe dopamine neurons represent the experience of social isolation. Cell. 2016; 164(4): 617–631.

52.

Meltzer

Smith

DeKosky

, et al. Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology. 1998; 18(6): 407–430.

53.

Fouriezos

Wise

RA.

Pimozide-induced extinction of intracranial self-stimulation: response patterns rule out motor or performance deficits. Brain Res. 1976; 103(2): 377–380.

54.

Galistu

D'Aquila

PS.

Effect of the dopamine D1-like receptor antagonist SCH 23390 on the microstructure of ingestive behaviour in water-deprived rats licking for water and NaCl solutions. Physiol Behav. 2012; 105(2): 230–233.

55.

Kirsch

Ronshausen

Mier

, et al. The influence of antipsychotic treatment on brain reward system reactivity in schizophrenia patients. Pharmacopsychiatry. 2007; 40(5): 196–198.

56.

Bódi

Kéri

Nagy

, et al. Reward-learning and the novelty-seeking personality: a between- and within-subjects study of the effects of dopamine agonists on young Parkinson’s patients. Brain. 2009; 132(Pt 9): 2385–2395.

57.

Pizzagalli

Jahn

O'Shea

JP.

Toward an objective characterization of an anhedonic phenotype. Biol Psychiatry. 2005; 57(4): 319–327.

58.

Isella

Iurlaro

Piolti

, et al. Physical anhedonia in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2003; 74(9): 1308–1311.

59.

Salamone

Correa

The mysterious motivational functions of mesolimbic dopamine. Neuron. 2012; 76(3): 470–485.

60.

Berridge

Kringelbach

ML.

Pleasure systems in the brain. Neuron. 2015; 86(3): 646–664.

61.

Boukezzi

Baunez

Rousseau

P-F

, et al. Posttraumatic stress disorder is associated with altered reward mechanisms during the anticipation and the outcome of monetary incentive cues. NeuroImage Clin. 2020; 25: 102073102073.

62.

Elman

Lowen

Frederick

, et al. Functional neuroimaging of reward circuitry responsivity to monetary gains and losses in posttraumatic stress disorder. Biol Psychiatry. 2009; 66(12): 1083–1090.

63.

Oldham

Murawski

Fornito

, et al. The anticipation and outcome phases of reward and loss processing: a neuroimaging meta-analysis of the monetary incentive delay task. Hum Brain Mapp. 2018; 39(8): 3398–3418.

64.

Sailer

Robinson

Fischmeister

FPS

, et al. Altered reward processing in the nucleus accumbens and mesial prefrontal cortex of patients with posttraumatic stress disorder. Neuropsychologia. 2008; 46(11): 2836–2844.

65.

Hill

Bierer

Makotkine

, et al. Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the world trade center attacks. Psychoneuroendocrinology. 2013; 38(12): 2952–2961.

66.

Liberzon

Taylor

Phan

, et al. Altered central micro-opioid receptor binding after psychological trauma. Biol Psychiatry. 2007; 61(9): 1030–1038.

67.

Torres-Berrio

Nava-Mesa

MO.

The opioid system in stress-induced memory disorders: from basic mechanisms to clinical implications in post-traumatic stress disorder and Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2019; 88: 327–338.

68.

Fenster

Lebois

LAM

Ressler

, et al. Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man. Nat Rev Neurosci. 2018; 19(9): 535–551.

69.

Bassir Nia

Bender

Harpaz-Rotem

Endocannabinoid system alterations in posttraumatic stress disorder: a review of developmental and accumulative effects of trauma. Chronic Stress. 2019; 3: 247054701986409.

70.

Jatzko

Schmitt

Demirakca

, et al. Disturbance in the neural circuitry underlying positive emotional processing in post–traumatic stress disorder (PTSD). Eur Arch Psychiatry Clin Neurosci. 2006; 256(2): 112–114.

71.

Felmingham

Falconer

Williams

, et al. Reduced amygdala and ventral striatal activity to happy faces in PTSD is associated with emotional numbing. PLoS One. 2014; 9(9): e103653.

72.

Kashdan

Elhai

Frueh

Anhedonia and emotional numbing in combat veterans with PTSD - ScienceDirect. Behav Res Ther. 2006; 44(3): 457–467.

73.

Feeny

Zoellner

Fitzgibbons

, et al. Exploring the roles of emotional numbing, depression, and dissociation in PTSD. J Trauma Stress. 2000; 13(3): 489–498.

74.

Franklin

Zimmerman

Posttraumatic stress disorder and major depressive disorder: investigating the role of overlapping symptoms in diagnostic comorbidity. J Nerv Ment Dis. 2001; 189(8): 548–551.

75.

Enman

Arthur

Ward

, et al. Anhedonia, reduced cocaine reward, and dopamine dysfunction in a rat model of posttraumatic stress disorder. Biol Psychiatry. 2015; 78(12): 871–879.

76.

Amdur

Larsen

Liberzon

Emotional processing in combat-related posttraumatic stress disorder: a comparison with traumatized and normal controls. J Anxiety Disord. 2000; 14(3): 219–238.

77.

Hopper

Pitman

, et al. Probing reward function in posttraumatic stress disorder: expectancy and satisfaction with monetary gains and losses. J Psychiatr Res. 2008; 42(1010): 802–807.

78.

Litz

Gray

Emotional numbing in posttraumatic stress disorder: current and future research directions. Aust N Z J Psychiatry. 2002; 36(2): 198–204.

79.

Elman

Upadhyay

Langleben

, et al. Reward and aversion processing in patients with post-traumatic stress disorder: functional neuroimaging with visual and thermal stimuli. Transl Psychiatry. 2018; 8(1): 1–15.

80.

María-Ríos

Morrow

JD.

Mechanisms of shared vulnerability to post-traumatic stress disorder and substance use disorders. Front Behav Neurosci. 2020; 14: 6. https://www.frontiersin.org/articles/10.3389/fnbeh.2020.00006/full#B238. Accessed February 4, 2021.

81.

Moriam

Sobhani

ME.

Epigenetic effect of chronic stress on dopamine signaling and depression. Genet Epigenet. 2013; 5: 11–16.

82.

Zhu

Peng

Zhang

, et al. Stress-induced depressive behaviors are correlated with par-4 and DRD2 expression in rat striatum. Behav Brain Res. 2011; 223(2): 329–335.

83.

Malikowska-Racia

Sałat

Nowaczyk

, et al. Dopamine D2/D3 receptor agonists attenuate PTSD-like symptoms in mice exposed to single prolonged stress. Neuropharmacology. 2019; 155: 1–9.

84.

Krystal

Neumeister

Noradrenergic and serotonergic mechanisms in the neurobiology of posttraumatic stress disorder and resilience. Brain Res. 2009; 1293: 13–23.

85.

Thase

Entsuah

Rudolph

RL.

Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001; 178(3): 234–241.

86.

Contractor

Weiss

Dranger

, et al. PTSD’s risky behavior criterion: relation with DSM-5 PTSD symptom clusters and psychopathology. Psychiatry Res. 2017; 252: 215–222.

87.

Strom

Leskela

James

, et al. An exploratory examination of risk-taking behavior and PTSD symptom severity in a veteran sample. Mil Med. 2012; 177(4): 390–396.

88.

Weiss

Tull

Borne

MER

, et al. Posttraumatic stress disorder symptom severity and HIV-risk behaviors among substance-dependent inpatients. AIDS Care. 2013; 25(10): 1219–1226.

89.

Debell

Fear

Head

, et al. A systematic review of the comorbidity between PTSD and alcohol misuse. Soc Psychiatry Psychiatr Epidemiol. 2014; 49(9): 1401–1425.

90.

Flory

Yehuda

Comorbidity between post-traumatic stress disorder and major depressive disorder: alternative explanations and treatment considerations. Dialogues Clin Neurosci. 2015; 17(2): 141–150.

91.

Walton

Raines

Cuccurullo

L-AJ

Vidaurri

, Villarosa-Hurlocker MC, Franklin CL. The relationship between DSM-5 PTSD symptom clusters and alcohol misuse among military veterans. Am J Addict. 2018; 27(1): 23–28.

92.

Weiss

Tull

Anestis

, et al. The relative and unique contributions of emotion dysregulation and impulsivity to posttraumatic stress disorder among substance dependent inpatients. Drug Alcohol Depend. 2013; 128(1–2): 45–51.

93.

Torrens

Mestre-Pinto

J-I

Domingo-Salvany

Comorbidity of Substance Use and Mental Disorders in Europe. Lisbon: EMCDDA; 2015.

94.

Ikemoto

Panksepp

The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res Brain Res Rev. 1999; 31(1): 6–41.

95.

Harvard Health Publishing. How Addiction Hijacks the Brain. Boston, MA: Author; 2011. https://www.health.harvard.edu/newsletter_article/how-addiction-hijacks-the-brain. Accessed February 4, 2021.

96.

Voigt

J-P

Fink

Serotonin controlling feeding and satiety. Behav Brain Res. 2015; 277: 14–31.

97.

Eske

Dopamine and serotonin: brain chemicals explained. Medical News Today. August 19, 2019. https://www.medicalnewstoday.com/articles/326090. Accessed February 4, 2021.

98.

Shansky

Rubinow

Brennan

, et al. The effects of sex and hormonal status on restraint-stress-induced working memory impairment | behavioral and brain functions | full text. Behav Brain Funct. 2006; 2(8). doi: 10.1186/1744-9081-2-8.

99.

Eichhorn

Brähler

Franz

, et al. Traumatic experiences, alexithymia, and posttraumatic symptomatology: a cross-sectional population-based study in Germany. Eur J Psychotraumatology. 2014; 5: 27.

100.

Frewen

Pain

Dozois

DJA

, et al. Alexithymia in PTSD: psychometric and FMRI studies. Ann N Y Acad Sci. 2006; 1071: 397–400.

101.

Hyer

Woods

Boudewyns

PA.

PTSD and alexithymia: importance of emotional clarification in treatment. Psychotherapy. 1991; 28(1): 129–139.

102.

Angelakis

Nixon

RDV.

The comorbidity of PTSD and MDD: implications for clinical practice and future research. Behav Change. 2015; 32(1): 1–25.

103.

Hagströum

The acute psychological impact on survivors following a train accident. J Traum Stress. 1995; 8(3): 391–402.

104.

Tanskanen

Hintikka

Honkalampi

, et al. Impact of multiple traumatic experiences on the persistence of depressive symptoms – a population-based study. Nord J Psychiatry. 2004; 58(6): 459–464.

105.

Mainous

Smith

Acierno

, et al. Differences in posttraumatic stress disorder symptoms between elderly non-Hispanic whites and African Americans. J Natl Med Assoc. 2005; 97(4): 546–549.

106.

Goenjian

Najarian

Pynoos

, et al. Posttraumatic stress disorder in elderly and younger adults after the 1988 earthquake in Armenia. Am J Psychiatry. 1994; 151(6): 895–901.

107.

Ditlevsen

Elklit

The combined effect of gender and age on post traumatic stress disorder: do men and women show differences in the lifespan distribution of the disorder?

Ann Gen Psychiatry. 2010; 9(1): 32.

108.

Weiss

Johnson

Contractor

, et al. Racial/ethnic differences moderate associations of coping strategies and posttraumatic stress disorder symptom clusters among women experiencing partner violence: a multigroup path analysis. Anxiety Stress Coping. 2017; 30(3): 347–363.

109.

Plummer

Slane

Patterns of coping in racially stressful situations. J Black Psychol. 1996; 22(3): 302–315.

110.

Ditlevsen

Elklit

Gender, trauma type, and PTSD prevalence: a re-analysis of 18 nordic convenience samples. Ann Gen Psychiatry. 2012; 11(1): 26.

111.

Raudales

Short

Schmidt

NB.

Emotion dysregulation mediates the relationship between trauma type and PTSD symptoms in a diverse trauma-exposed clinical sample. Personal Individ Differ. 2019; 139: 28–33.

112.

Guina

Nahhas

Kawalec

, et al. Are gender differences in DSM-5 PTSD symptomatology explained by sexual trauma? J Interpers Violence. 2019; 34(21–22): 4713–4740.

113.

Mock

Arai

SM.

Childhood trauma and chronic illness in adulthood: mental health and socioeconomic status as explanatory factors and buffers. Front Psychol. 2011; 1: 246. https://www.frontiersin.org/articles/10.3389/fpsyg.2010.00246/full. Accessed February 4, 2021.

114.

Olff

Sex and gender differences in post-traumatic stress disorder: an update. Eur J Psychotraumatology. 2017; 8(sup4): 1351204. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632782/. Accessed February 4, 2021.

115.

Koo

Hebenstreit

Madden

, et al. PTSD detection and symptom presentation: racial/ethnic differences by gender among veterans with PTSD returning from Iraq and Afghanistan. J Affect Disord. 2016; 189: 10–16.

116.

Lanius

Vermetten

Loewenstein

, et al. Emotion modulation in PTSD: clinical and neurobiological evidence for a dissociative subtype. Am J Psychiatry. 2010; 167(6): 640–647.

117.

Campbell

Trachik

Goldberg

, et al. Identifying PTSD symptom typologies: a latent class analysis. Psychiatry Res. 2020; 285: 112779112779.

118.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), Fourth Edition. Washington, DC: Author; 1994.

119.

Brewin

CR.

I wouldn’t start from here”–an alternative perspective on PTSD from the ICD-11: comment on Friedman (2013). J Trauma Stress. 2013; 26(5): 557–559.

120.

Friedman

MJ.

Finalizing PTSD in DSM-5: getting here from there and where to go next. J Trauma Stress. 2013; 26(5): 548–556.

121.

Kelmendi

Adams

Southwick

, et al. Posttraumatic stress disorder: an integrated overview of the neurobiological rationale for pharmacology. Clin Psychol (New York)). 2017; 24(3): 281–297.

122.

McSweeney

Rauch

Norman

, et al. Prolonged Exposure for PTSD. West Haven, CT: National Center for PTSD; 2019. https://www.ptsd.va.gov/professional/treat/txessentials/prolonged_exposure_pro.asp. Accessed February 4, 2021.

123.

Najavits

LM.

The problem of dropout from “gold standard” PTSD therapies. F1000Prime Rep. 2015; 7: 43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447050/. Accessed February 4, 2021.

124.

Rauch

SAM

Kim

Powell

, et al. Efficacy of prolonged exposure therapy, sertraline hydrochloride, and their combination among combat veterans with posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2019; 76(2): 117–126.

125.

Schottenbauer

Glass

Arnkoff

, et al. Nonresponse and dropout rates in outcome studies on PTSD: review and methodological considerations. Psychiatry Interpers Biol Process. 2008; 71(2): 134–168.

126.

Stein

Ipser

Seedat

Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2006; (1): CD002795.

127.

Harvard Health Publishing. Post-Traumatic Stress Disorder. Boston, MA: Author; 2018. https://www.health.harvard.edu/a_to_z/post-traumatic-stress-disorder-a-to-z. Accessed February 4, 2021.

128.

Cuthbert

BN.

The RDoC framework: facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology. World Psychiatry. 2014; 13(1): 28–35.

129.

Bradley

Greene

Russ

, et al. A multidimensional meta-analysis of psychotherapy for PTSD. Am J Psychiatry. 2005; 162(2): 214–227.

130.

Duek

Pietrzak

Petrakis

Hoff

Harpaz-Rotem

Early discontinuation of pharmacotherapy in U.S. veterans diagnosed with PTSD and the role of psychotherapy. J Psychiatr Res. 2021; 132: 167–173.

131.

Office of the Commissioner. FDA Approves New Nasal Spray Medication for Treatment-Resistant Depression; Available Only at a Certified Doctor’s Office or Clinic. Silver Spring, MD: FDA; 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified. Accessed February 4, 2021.

132.

Chen

How new ketamine drug helps with depression. Yale Medicine. March 21, 2019. https://www.yalemedicine.org/news/ketamine-depression. Accessed February 4, 2021.

133.

Duek

Kelmendi

Pietrzak

Harpaz-Rotem

. Augmenting the treatment of PTSD with ketamine—a review. Curr Treat Options Psych. 2019; 6(2): 143–153.

134.

Feder

Parides

Murrough

, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014; 71(6): 681–688.

135.

Krystal

Abdallah

Averill

, et al. Synaptic loss and the pathophysiology of PTSD: implications for ketamine as a prototype novel therapeutic. Curr Psychiatry Rep. 2017; 19(10): 74.

136.

Admon

Milad

Hendler

A causal model of post-traumatic stress disorder: disentangling predisposed from acquired neural abnormalities. Trends Cogn Sci. 2013; 17(7): 337–347.