Prefrontal cortical response to natural rewards and self-reported anhedonia are associated with greater craving among recently withdrawn patients in residential treatment for opioid use disorder
Introduction
The rapid escalation of opioid misuse and overdose deaths in the U.S. over the last two decades led to the opioid epidemic being declared a national emergency in 2017 (Exec. Order No. 13784, 2017). National data from 2019 found that 1.6 million Americans aged 12 years or older had an opioid use disorder (OUD) (SAMHSA, 2020). Despite evidence-based pharmacological and behavioral treatment for OUD (see Sofuoglu et al., 2019 for review), relapse rates continue to be unacceptably high (Zhu et al., 2018), indicating the need for a better understanding of the factors contributing to relapse.
The construct of craving, typically described as a subjective urge or desire to use substances (Kozlowski and Wilkinson, 1987), has been central to theories of addiction and relapse for more than seven decades, particularly as a predictor of continued use and relapse (Kakko et al., 2019; for a recent review see Kleykamp et al., 2019). Initially conceptualized in relatively simplistic terms, and as a purely subjective phenomenon, craving was historically measured almost exclusively with single timepoint self-report questionnaires (Drummond, 2000). However, outside of the laboratory, the empirical relationship between self-reported craving and actual drug use has not been found to be as robust as initially proposed (Pickens and Johanson, 1992), leading researchers to question the utility of unidimensional assessments of craving (e.g., Anton, 2000; McEvoy et al., 2004) and a call for considering the construct’s multi-dimensionality.
The failure of commonly used subjective, unidimensional measures of craving to consistently predict relapse (Goldstein et al., 2009) led investigators to incorporate more complex assessments (e.g., ecological momentary assessment; EMA) and more objective psychophysiological and neuroimaging measures of craving into their studies. Such studies have significantly increased our understanding of the neurobiological basis of addiction and relapse. First, a broader definition of craving emerged, as a multidimensional phenomenon with physiological, neurochemical, subjective and behavioral correlates (Mezinskis et al., 2001). Multidimensional self-report models of craving (EMA) have since shown that craving precedes drug use among individuals being treated for cocaine and heroin use (Preston and Epstein, 2011) as well as OUD (Preston et al., 2018). EMA assessments of craving during residential OUD treatment have been shown to have high reliability, sensitivity, and utility, suggesting EMA is an effective way to measure craving in this population (Cleveland et al., 2021). EMA data obtained from inpatient OUD treatment populations have shown that craving is associated with negative social exchanges (Knapp et al., 2020), negative affect (Jenkins et al., 2021), and positive affect (Huhn, Harris, et al., 2016), as well as stress (Kowalczyk et al., 2015). These studies suggest the multidimensional framework of EMA approaches to assessing subjective craving among treatment populations provide an important metric for a better understanding of craving.
Second, these studies have identified and begun to elucidate the roles of a distributed network of brain areas related to craving (Volkow et al., 2004). Importantly, whereas addiction was thought to involve primarily reward processes mediated by subcortical limbic circuits, a large number of cue reactivity studies that exposed substance use disorder (SUD) patients to stimuli designed to elicit craving, have implicated other brain regions as well, especially the prefrontal cortex (Goldstein and Volkow, 2002, Goldstein and Volkow, 2011). In a recent review, Moningka et al. (2019) found that functional magnetic resonance imaging (fMRI) studies using the cue-reactivity paradigm in individuals with OUD have found widespread, heightened neural activation in response to drug related cues relative to healthy control participants in the midbrain, parietal, limbic, and frontal cortical regions. In contrast, individuals with SUD (including OUD) have lower neural responses to natural (non-drug) reward cues relative to healthy controls (Garavan et al., 2000, Gradin et al., 2014, Yip et al., 2016, Zijlstra et al., 2009). In addition, individuals with OUD have displayed reduced electrophysiological brain activity (Lubman et al., 2008, Lubman, Dan et al., 2007), heart rate variability (Garland et al., 2015, Garland et al., 2017, Hudak et al., 2021), and attentional bias (Garland et al., 2015) in response to images of hedonic rewards relative to individuals without OUD. Such blunted response patterns have, in turn, been associated with future opioid use (Lubman et al., 2009). Studies employing functional near-infrared spectroscopy (fNIRS), a translational neuroimaging technology that uses light to measure changes in the blood oxygen level dependent (BOLD) signal, have generally found results similar to the studies using fMRI, i.e., differential activation patterns in response to drug-related cues vs natural reward cues in participants with SUD relative to control participants (Bunce et al., 2015, Bunce et al., 2012, Bunce et al., 2013, Kroczek et al., 2017). These cue-reactivity studies suggest that participants with OUD commonly show heightened activity in PFC response to drug cues, and decreased neural activity in response to natural reward cues, relative to healthy controls.
Whereas the craving construct and cue reactivity paradigms have held a central role in theories of SUD and relapse for decades, only recently has anhedonia begun to receive similar attention in the addiction literature. Defined as the inability, or significantly decreased capacity, to experience pleasure (Snaith et al., 1995), anhedonia has gained recognition as a key risk factor in SUD treatment (Blum et al., 2014, Garfield et al., 2014, Garfield et al., 2017, Hatzigiakoumis et al., 2011, Kiluk et al., 2019, Lubman, Dan et al., 2018). Anhedonia has been associated with a heightened susceptibility of relapse to opioids (Kakko et al., 2019, Kiluk et al., 2019), cocaine (Crits-Christoph et al., 2018) and tobacco (Cook et al., 2010). Anhedonia has also been shown to have a positive correlation with craving among patients with opioid use disorder (Martinotti, Cloninger, et al., 2008), recently withdrawn patients with alcohol use disorder, (Martinotti et al., 2008, Martinotti et al., 2008), and in recently abstinent people quitting tobacco smoking (Cook et al., 2010, Leventhal et al., 2009). Anhedonia has been identified as both a diathesis for substance misuse (Blum et al., 2012, Blum et al., 2014), and as a consequence of the allostatic neuroadaptations of substance use that drive SUD and relapse through an elevation of reward thresholds (Koob, 2020, Koob and Le Moal, 2001). The elevated reward thresholds characteristic of anhedonia are thought to play a critical role in the treatment of OUD, in that patients who cannot derive gratification from typical natural rewards in their everyday lives are more likely to return to the highly rewarding use of opioids, or other substances of abuse.
Clinical studies using neuroimaging techniques have assessed the relationship between neural activation during hedonic cue-reactivity paradigms and anhedonia. FMRI studies have indicated that anhedonia severity was negatively linked with cortico-striatal activity in response to hedonically positive stimuli in patients with major depressive disorder (Keedwell et al., 2005), and schizophrenia (Harvey et al., 2010; for a meta-analysis see Zhang et al., 2016). These fMRI findings have been corroborated with structural MRI findings among OUD patients; whereby decreases in striatal volume were correlated with increases in anhedonic severity (Schaub et al., 2021). In sum, there is growing evidence that (1) individuals with OUD commonly display blunted emotional, autonomic, neural and psychophysiological processing in response to positive emotions or stimuli indicative of natural rewards, and (2) self-endorsed anhedonia is related to these decreased neuro- and psychophysiological reward processes.
Unfortunately, despite the theoretical overlap of the these two constructs (Koob, 2020, Koob and Le Moal, 2001) and evidence suggesting that these two phenomena may share similar neurobiological mechanisms (Gold et al., 2018, Zijlstra et al., 2009), anhedonia and craving are often studied independently within SUD populations. The chronic use of opioids can result in both increased salience of opioid-related stimuli, opioid cue-reactivity, and subsequent craving (Robinson and Berridge, 2008), as well as decreased sensitivity to natural rewards (Koob and Le Moal, 2008) which can result in anhedonic states (Gold et al., 2018). The linked nature of these phenomena is clearly set out in Koob and Le Moal’s allostasis model, as well as Goldstein and Volkow, 2002, Goldstein and Volkow, 2011 impaired Response Inhibition and Salience Attribution (iRISA) model. Importantly, the iRISA model also posits that the PFC plays a critical role in the addiction and recovery processes through its top-down regulation of limbic reward regions, and its involvement in the maintenance of goal-directed behavior (Ceceli et al., 2022, Goldstein and Volkow, 2002, Goldstein and Volkow, 2011, Koob and Volkow, 2010). In this model, symptoms of anhedonia, lack of motivation, negative affect, and enhanced stress reactivity may develop as neuroadaptations to repeated drug use (Koob and Volkow, 2010, Goldstein and Volkow, 2011). Drug craving can develop as a drive to alleviate these negative symptoms, which is associated with increased risk of relapse. Thus, the iRISA model suggests that there are interrelationships among anhedonia, craving, and PFC neurocircuitry, which are relatively understudied.
Data for the current investigation were drawn from a larger study of patients in residential treatment for OUD. In a previously published investigation using fNIRS with these data, Huhn, Meyer, et al. (2016) found that patients who self-reported anhedonia displayed reduced activation to positive social interaction stimuli in areas of the right and left prefrontal cortex relative to patients who did not self-report anhedonia. Similar findings were demonstrated for the highly palatable food stimuli in the medial prefrontal cortex. Using EMA data from this sample (Huhn, Harris, et al., 2016), our group has also found that on days when patients’ positive affect was lower than their average, they had higher levels of craving on that day. In the current study, we have expanded on these prior studies by using a multimodal approach to examine the relationship among self-reported anhedonia, PFC activity in response to a hedonically positive cue reactivity task assessed via fNIRS, and EMA-reported craving. The current study was based on the approach that, although both fNIRS and EMA methods are valuable when used independently, integrating these modalities may offer unique insight into the way in which aspects of the iRISA model transact. This study had two goals. The first goal was to assess whether PFC responses to hedonically positive stimuli during the cue reactivity task were associated with EMA-based assessments of craving. Noori and colleagues (2016) conducted a meta-analysis of 175 studies and found that there are overlapping brain activation patterns in response to natural and drug cues, including the prefrontal cortex. Thus, as per Noori et al. (2016), we expected to find brain responses in the dlPFC to hedonically positive stimuli. We hypothesized that, anhedonia (i.e., reduced response neural rewards), might result in a compensatory craving for a substance that could elicit reward (e.g., opioids; Koob and Volkow, 2010), and that anhedonia would moderate the association between PFC response during cue-reactivity and craving. As such, low PFC activity would be expected to be associated with higher craving in people with higher anhedonia, to the degree that reduced neural activation to hedonic rewards is part of the neural substrate underlying anhedonia. The second goal was to assess whether self-reported anhedonia moderated the association between PFC activity and EMA-based craving. We hypothesized that self-reported anhedonia would moderate the association between PFC responses to hedonically positive stimuli during the cue reactivity task and craving, such that lower PFC activity would be associated with higher average craving in patients who self-reported more anhedonic symptoms relative to patients who self-reported fewer anhedonia symptoms.
Section snippets
Participants
Participants (n = 71; 24 % female, Mage = 30.32, Range = 19–61) were patients recruited from the Caron Treatment Centers’ drug and alcohol treatment facility. All participants completed medically assisted withdrawal prior to enrollment, approximately 10–14 days before data collection. Participants provided written informed consent following a detailed explanation of the study protocol, which was approved by the Penn State Hershey Medical Center Institutional Review Board. Inclusion criteria
Zero-order correlations and descriptive statistics among variables in the study
Zero-order correlations and descriptive statistics of all variables in the current study are presented in Table 1. Patients reported an average craving score of 2.16 (SD = 1.02) on a 1–5 scale, an average SHAPS score of 1.62 (SD = 1.98) on a 0–14 scale, average activity in right dlPFC while viewing images of positive social interactions of − 0.04 (SD = 0.11), average activity in right dlPFC while viewing images of palatable foods of − 0.07 (SD = 0.13), and average activity in right dlPFC while
Discussion
The current study used a multimodal approach to examine the associations among self-reported anhedonia, prefrontal cortical responses to hedonically pleasant visual cues, and craving as measured via EMA, among patients in residential treatment for prescription OUD. A linear regression model was used to evaluate whether dlPFC activation while viewing hedonically positive stimuli was associated with anhedonia and average craving in patients with OUD. Out of three categories of hedonically
CRediT authorship contribution statement
D.J. Petrie: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing, Visualization. K.S. Knapp: Data curation, Writing – review & editing. C.S. Freet: Data curation, Project administration. E. Deneke: Project administration. T.R. Brick: Writing – review & editing, Supervision. H.H. Cleveland: EMA design, Writing – review & editing, Supervision. S.C. Bunce: Study design, Funding acquisition, Project administration, Writing – original draft,
Funding
This study was supported by Grant R01 DA035240 from the National Institute on Drug Abuse (Multi-PIs: S.C. Bunce & R.E. Meyer). Authors D.J. Petrie and K.S. Knapp were supported by the Prevention and Methodology Training Program (T32 DA017629; MPIs: J. Maggs & S. Lanza) with funding from the National Institute on Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National
Declaration of Interest
S.C. Bunce owns equity in fNIR Devices, LLC (Potomac, MD).
Acknowledgements
The authors thank the Caron Treatment Centers and its staff for their collaboration in hosting the research study.
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