The association of prefrontal cortex response during a natural reward cue-reactivity paradigm, anhedonia, and demoralization in persons maintained on methadone
Introduction
The United States continues to face a deadly and protracted opioid crisis that claimed over 48,000 lives in opioid-related overdose deaths in 2018 (Wilson, 2020). This unprecedented crisis has motivated the field of opioid use disorder (OUD) treatment to search for ways to enhance existing OUD treatment strategies to improve outcomes for those who are struggling to establish recovery from OUD (Bell & Strang, 2019). Maintenance on the OUD pharmacotherapy methadone remains a gold standard treatment for OUD (Volkow, Frieden, Hyde, & Cha, 2014). However, the primary goal of many methadone treatment programs is to reduce or eliminate illicit opioid use – which is highly important – but might not include interventions to improve other physical and mental health outcomes that promote healthy, sustained recovery from OUD.
There is an emerging body of literature regarding anhedonia, or an impaired capacity to experience pleasure (Snaith et al., 1995), as a key clinical feature in the progression and treatment of OUD (Destoop et al., 2019, Kiluk et al., 2019, Koob and Le Moal, 1997, Stevens et al., 2007). Previous studies have reported associations between anhedonia or low positive affect and opioid-specific treatment outcomes including increased craving and illicit drug relapse (Garfield et al., 2017, Huhn et al., 2016, Huhn et al., 2019). While there are relatively robust preclinical data regarding the neurobiology of devaluation of natural reward in favor of misused or illicit drugs (Carroll et al., 2002, Grigson and Twining, 2002, Koob and Volkow, 2010), relatively few studies have assessed the underlying pathophysiology of response to natural rewards in human models of OUD. In human laboratory studies, individuals with current heroin use have self-reported lower ratings of positively-valanced visual stimuli compared with persons who had recently achieved abstinence (De Arcos et al., 2008), and in brain imaging studies, persons with OUD displayed decreased neural activity in the left amygdala and posterior cortex (Wang et al., 2010), and in the ventromedial (VM) and dorsolateral (DL) prefrontal cortices (PFC) in response to naturally rewarding visual stimuli compared with healthy controls (Huhn et al., 2016, Zijlstra et al., 2009).
These findings are consistent with a more general neurobiological model of anhedonia suggesting that responses to natural rewards are blunted as a result of decreased activity in neural reward circuits. For example, self-reported anhedonia is associated with decreased dopamine signaling from the ventral tegmental area to the nucleus accumbens and downregulation of μ opioid receptors in the nucleus accumbens, as well as decreased activity in areas associated with allocation of attention and reward processing including the rostral anterior cingulate cortex, VMPFC, and DLPFC (Der-Avakian and Markou, 2012, Park et al., 2009, Zijlstra et al., 2009). There is some evidence that self-reported anhedonia improves during protracted abstinence in opioid and other substance use disorders (Janiri, Martinotti, Dario, Reina, Paparello, Pozzi, & De Risio, 2005), yet neuroimaging studies on persons with methamphetamine use disorder suggests that even though there is some evidence of neural reregulation during protracted abstinence, decreased neural reward activity associated with anhedonia might persist for over a year (Wang et al., 2004). Moreover, there is little information available regarding anhedonia in patients on opioid maintenance therapies such as methadone, given that the majority of research on anhedonia and OUD has been in the context of post-withdrawal sequelae in abstinence-only treatment models.
Many individuals maintained on methadone might also experience feelings of demoralization, which is defined as a deprivation of spirit, courage, morale, or discipline and often conceptualized as an existential challenge (Robinson et al., 2016). Similar to anhedonia, research on the experience of demoralization in persons with OUD and specifically persons maintained on methadone is scarce. Higher levels of demoralization have been associated with more perceived psychosocial stress and greater risk for alcohol and drug use among veterans (Harling, Strehmel, Schablon, & Nienhaus, 2009), though the role of demoralization has often been lumped in with other measures of psychosocial stress (Moos, 2003). In addition, demoralization has been noted in relation to the economic burden on geographic areas or communities affected by opioid use (Mark, Woody, Juday, & Kleber, 2001). To our knowledge, the discrete pathophysiology of demoralization has not been reported. In general, demoralization and anhedonia are seen as independent constructs that are distressing to patients and may either contribute to the experience of depressive symptoms or be experienced in the context of other chronic illnesses, such as major depressive disorder or cancer (Angelino and Treisman, 2001, Clarke et al., 2005).
Persistent anhedonia and feelings of demoralization are important yet often overlooked treatment outcomes for OUD patients, and understanding more about these constructs from a biopsychosocial perspective is imperative to developing interventions that improve OUD recovery. We previously reported that greater self-reported anhedonia and demoralization were associated with more illicit drug use in persons maintained on methadone (Huhn et al., 2019), however the biological underpinnings of anhedonia and demoralization in these individuals are not well-understood. The current study combined a natural reward cue reactivity task with functional near-infrared spectroscopy (fNIRS) imaging to examine the relationship among PFC function, anhedonia, and demoralization. We hypothesized that individuals maintained on methadone with clinically-significant levels of self-reported anhedonia would display decreased neural response to natural reward cues in the right DLPFC and VMPFC. We further hypothesized that decreased neural response to positive social cues in the VMPFC would be associated with increased self-reported anhedonia and demoralization.
Section snippets
Participants
Persons maintained on methadone were recruited from an opioid treatment program for a single study session that included an fNIRS-adapted cue reactivity task and self-reported questionnaires, and participants were tracked for 90-days post-study session to determine opioid and other drug use outcomes e.g., percent negative urine screens for opioids or any illicit drugs, which were collected as part of routine treatment; primary opioid use outcomes have been previously reported (Huhn et al., 2019
Results
Thirty individuals maintained on methadone were recruited into this study and one was excluded for excessive head movement during fNIRS imaging, resulting in a final N = 29. Regarding drug use outcomes, 12/29 participants tested positive for opioids during the 90-day follow-up and these individuals provided a mean (SD) 41.5% (28.6) opioid-positive urine drug screens; 17/29 participants tested positive for any illicit drug, including opioids, cocaine, marijuana, and/or benzodiazepines during
Discussion
This study provides initial evidence that the prefrontal cortex is involved in the pathophysiology of anhedonia and demoralization in persons in recovery from OUD. More specifically, the results of this study demonstrated that persons maintained on methadone who self-reported clinically-significant levels of anhedonia display decreased neural activity in the right PFC when compared with methadone patients who did not report clinically significant anhedonia (Fig. 1). Moreover, study results
Conclusion
In conclusion, this study provides initial evidence that PFC response to natural rewards could be used as a biological marker of anhedonia and demoralization in persons receiving methadone for the treatment of OUD. This study demonstrated that decreased PFC activity in response to natural rewards - and specifically positive social interactions – was associated with increased self-reported anhedonia and demoralization. Anhedonia and demoralization are, in and of themselves, distressing to
Contributors
AH, RB, and KD designed the study. All authors contributed to manuscript preparation and revision of the manuscript. AH and HA are responsible for data processing and data analyses.
CRediT authorship contribution statement
Andrew S. Huhn: Conceptualization, Funding acquisition, Supervision, Investigation, Writing - review & editing, Formal analysis, Validation, Visualization, Data curation, Investigation, Methodology. Robert K. Brooner: Conceptualization, Funding acquisition, Supervision, Investigation, Writing - review & editing. Mary M. Sweeney: Data curation, Investigation, Methodology, Writing - original draft, Writing - review & editing. Denis Antoine: Writing - original draft, Writing - review & editing.
Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HA was involved in the technology development of the brain-imaging instrument manufactured by fNIR Devices, LLC and owns a minor share of the firm. fNIR Devices, LLC manufactures the optical brain imaging instrument and licensed IP and know-how from Drexel University. ASH receives research funding from Ashley Addiction Treatment through his university. The
Acknowledgements
We thank Kori Kindbom and her clinical research support team for their help in conducting this study, and the Addiction Treatment Services program patients whose participation made it possible. The work described in this manuscript was funded by the National Institute on Drug Abuse: NIDA R01DA034047 (Dunn) and UG3DA048734 (Huhn). The National Institute on Drug Abuse had no role in data collection, interpretation, or in the writing of this manuscript.
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2022, Brain Research BulletinCitation Excerpt :Using a subset of the current sample, Huhn, Meyer, et al. (2016), found reduced activation in the right dlPFC (optodes 9, 11, 12, 13) to positive social interaction stimuli in patients self-reporting anhedonia relative to patients who did not endorse anhedonia. In a study of patients being treated for OUD with methadone, Huhn et al. (2021) also found reduced activation in the right dlPFC (optodes 11, 12, 14, 15, 16) in response to natural reward cues in patients who self-reported anhedonia, relative to patients who did not endorse anhedonia. Given these findings, we chose optodes 11–14 in the right dlPFC for analyses.