Emotionally valenced stimuli impact response inhibition in those with substance use disorder and co-occurring anxiety and depression symptoms

Journal Pre-proof

Emotionally Valenced Stimuli Impact Response Inhibition in Those with Substance Use Disorder and Co-Occurring Anxiety and Depression Symptoms Alison Legrand , Matthew Price PII: DOI: Reference:

S0165-0327(19)31706-9 https://doi.org/10.1016/j.jad.2020.02.008 JAD 11639

To appear in:

Journal of Affective Disorders

Received date: Revised date: Accepted date:

28 June 2019 23 January 2020 1 February 2020

Please cite this article as: Alison Legrand , Matthew Price , Emotionally Valenced Stimuli Impact Response Inhibition in Those with Substance Use Disorder and Co-Occurring Anxiety and Depression Symptoms, Journal of Affective Disorders (2020), doi: https://doi.org/10.1016/j.jad.2020.02.008

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE Highlights 

Psychopathology is associated with poor response inhibition in SUD history.



Depression moderated the relation between emotional stimuli and response inhibition.



Low anxiety was associated with poor response inhibition to emotional stimuli.



Response inhibition did not differ between positive and negative emotional stimuli.

2

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE Emotionally Valenced Stimuli Impact Response Inhibition in Those with Substance Use Disorder and Co-Occurring Anxiety and Depression Symptoms

Alison Legrand*, Matthew Price Department of Psychological Science, University of Vermont

Corresponding Author: Alison Legrand, BA Department of Psychological Science, Room 248 University of Vermont 2 Colchester Ave Burlington, VT 05405 [email protected] 802-656-1341 Abstract Background: Substance use disorder (SUD) is associated with impaired response inhibition. Given the deficits in emotion regulation associated with SUD, it is unclear if this impairment is exacerbated by emotionally valenced stimuli. Co-occurring conditions may further exacerbate these impairments as

3

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

4

many co-occurring conditions further impact emotion regulation. It was hypothesized that negative stimuli may further impact response inhibition for this population. Methods: The current study used the stop-signal task to examine response inhibition to negative, neutral and positive stimuli in a sample of those with a history of SUD and co-occurring depression and anxiety symptoms. Results: Response inhibition was poorer for negative stimuli relative to neutral stimuli. There was no difference between negative and positive stimuli. Depression severity moderated the difference between response inhibition for negative and neutral stimuli. At elevated depression, response inhibition was worse and there was no difference across emotional stimuli. At low depression, there was a significant difference between negative and neutral stimuli. This effect was not found for anxiety symptoms. Limitations: Study participants presented with polysubstance use of varying duration and amount. It is unclear whether findings are attributed to specific substances, or substance use broadly. Additionally, happy, angry, and calm facial emotions were used to represent positive, negative, and neutral valences respectively. It is unclear whether these findings are generalizable to other emotional expressions. Conclusion: Results suggested that emotionally valenced stimuli affected response inhibition among those with low symptom severity. At elevated symptom severity, response inhibition to all stimuli were impaired.

Substance use disorder (SUD) is associated with significant impairment across the lifespan and increased mortality and is thus a major public health concern (Onyeka, 2015; Borges, Walters, & Kessler, 2000; Whiteford et al., 2013). Co-occurring conditions are common among those with SUD with depression (35%) and anxiety disorders (45%) being the most

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

5

common (Merikangas et al., 1998; Grant et al., 2004). Those with co-occurring disorders experience more severe mood and anxiety symptoms as well as substance-related impairments (Merikangas et al., 1998; Regier et al., 1990; Swendsen & Merikangas, 2000). Understanding the processes that underlie this impairment is necessary to improve treatments for these conditions. One such factor that may be impacted is inhibitory functioning, defined as the ability to suppress a behavioral response (Verbruggen & Logan, 2009). Poor inhibitory functioning in those with SUD is thought to map onto altered responding to salient drug cues (Nigg, 2000; Jentsch & Taylor, 1999; de Wit, 2009). Several studies examining participants who reported substance use found that these individuals had poorer response inhibition relative to individuals who did not use substances (Fillmore & Rush, 2002; Monterosso, Aron, Cordova, Xu, & London, 2005). A study examining response inhibition in adolescents with substance use using fMRI and the Go-No-Go Task (GNG) discovered atypical activation in areas outside of the ventromedial prefrontal (vmPFC) and anterior cingulate cortices (ACC) (Mahmood, et al., 2013). Activation of the vmPFC and ACC during the GNG task was shown to be predictive of increased substance use at an 18-month follow up. Taken together, these results suggest that poorer response inhibition is associated with sustained SUD. Much of the work examining response inhibition in those with a history of SUD have used neutral stimuli, such as arrows, shapes, or letters, to control for extraneous effects, such as emotional reactivity (Lawrence, Luty, Bogdan, Sahakian, & Clark, 2009; Mahmood et al., 2013; Heitzeg et al., 2014). There is considerable evidence to suggest that those with SUD often have a strong reaction to emotionally relevant stimuli, however. Several studies examining those who reported substance use found that pertinent trauma-related stimuli increased drug cravings, arousal, and increased negative affect (Coffey et al., 2002; McHugh, Gratz, & Tull, 2017). In a

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

6

recent study of those with current opioid dependence, exposure to a stressful stimulus was associated with greater cue reactivity as defined by elevated stress, anger, and craving (Back et al., 2015). This elevated reactivity to emotional stimuli among those with a history of SUD may impact response inhibition toward such stimuli. Specifically, stronger reactions to negative stimuli may further impair response inhibition relative to neutral stimuli. Prior work with healthy adults has suggested that the emotional valence of a stimulus affects response inhibition. Kalanthroff, Cohen, and Henik (2013) used peripheral negative images during the stop signal task (SST) and found that reaction times on stop trials were worse if preceded by a negative image as opposed to a neutral image. A study completed by Pessoa, Padmala, Kenzer, and Bauer (2012) found that when healthy participants were exposed to lowthreat faces, their SST worsened relative to neutral faces. Rebetez, Rochat, Billieux, Gay, & Van der Linden (2015) used emotional faces as stimuli in the SST with healthy adults and found that SSRT for angry faces was longer than that for neutral faces. In an fMRI study with healthy adults, participants were asked to complete the SST using neutral or fearful faces (Sagaspe, Schwartz, & Vuilleumier, 2011). GORT for fearful faces was slower than for neutral faces, however there were no differences in response inhibition. Despite the lack of a behavioral difference in response inhibition, there were differences in brain activity such that trials involving negative stimuli recruited the orbitofrontal cortex (OFC), which is involved in outcome expectations for emotional stimuli (Davidson, Putnam, & Larson, 2000). This difference in brain activation suggests that the lack of a difference in response inhibition may be attributed to the recruitment of emotion regulation areas of the brain. Persistent use of substances has been shown to affect these regions, especially the orbitofrontal cortex (OFC) (Schoenbaum,

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

7

Roesch, & Stalnaker, 2006). As such, it is hypothesized that response inhibition to emotionally valenced stimuli may be further impacted among those with a history of SUD. In understanding how emotionally valenced stimuli affects response inhibition, it is necessary to consider how response inhibition is impacted by the presence of co-occurring psychopathology. There has been relatively little work examining the effect of mood and anxiety disorders on response inhibition. Several studies have suggested that those with depression demonstrate slowed SSRT to neutral stimuli when compared to non-depressed controls (Aker, Bø, Harmer, Stiles, & Landrø, 2016; Bredemeier, Warren, Berenbaum, Miller, & Heller, 2016). Taken together, these findings suggest that depression symptoms may further impair response inhibition in those with SUD, with the worst response inhibition observed for negative stimuli. The effect of anxiety pathology on response inhibition is unclear. Initial pre-clinical work suggested that elevated anxiety may facilitate response inhibition, presumably because the individual is better primed to withhold a response to a possible threat (Grey & McNaughton, 2000). Consistent with this hypothesis, two studies found that elevated state anxiety during a GNG task improved response inhibition (Robinson, Krimsky, & Grillon, 2013; Grillon, Robinson, Mathur, & Ernst, 2016). State anxiety in these studies was induced by threat of electrical shock for incorrect responses. In contrast, several studies demonstrated that elevated trait anxiety was unrelated to response inhibition (Karch et al., 2008; Righi et al., 2009; Li, Zinbarg, Boehm, & Paller, 2008). Recently, it was suggested that elevated state and trait anxiety may have an interactive effect on response inhibition such that when both are elevated, response inhibition is further impaired (Grillon et al., 2017). Preliminary data suggest that this hypothesis is supported in that those with anxiety disorders presented with excessive response inhibition (Grillon et al., 2017). Excessive response inhibition is defined as improved response inhibition at

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

8

the expense of overall reaction time when perceiving threat. In contrast, when healthy individuals were under threat, response inhibition improved but overall reaction time was unaffected. These results suggest that the type of stimulus (threatening vs non-threatening) may interact with anxiety to affect response inhibition. It is unclear how the presence of comorbid SUD may further affect these factors. Given that those with SUD are prone to having elevated anxiety symptoms, it is hypothesized that elevated trait anxiety would further impair response inhibition for negative stimuli. The present study had two primary aims. The first was to examine how response inhibition was affected by stimuli of a specific emotional valence in those with a history of SUD. It was hypothesized that response inhibition would be worse for negative stimuli relative to neutral stimuli. To determine if this difference is attributed to negative emotional stimuli as opposed to emotional stimuli, positive emotional stimuli were also included. The second aim was to determine if the presence of co-occurring psychopathology further impacted response inhibition to emotional stimuli. It was hypothesized that participants with higher levels of selfreported anxiety and depression would demonstrate poorer response inhibition towards negative stimuli. Method Data for the current study came from a larger study conducted from the Northeastern United States designed to examine the relation between substance use, mental health disorders, and response inhibition (Price et al., 2018). For the study visit, participants completed diagnostic interviews, self-report measures, and the SST. Participants

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

9

Participants were 72 individuals with a history of SUD. All participants recruited because they had a prior history of opioid use, defined as misusing prescription opioids or heroin for at least 1 year (Heroin M = 4.12 years, SD = 4.52; Prescription opioids: M = 6.95 years, SD = 6.21), and opioids being the drug of choice. A majority of participants (n = 46, 69%) reported misusing opioids in the last month. Predominantly, participants were also involved in methadone maintenance treatment (n = 52, 72%). Furthermore, history in years of lifetime use of other substances were as follows: Alcohol: M = 10.56, SD = 8.81; Cocaine: M = 6.12, SD = 6.59; Cannabis: M = 13.34, SD = 9.45. Taken together, although the sample all had a history of opioid misuse, there was evidence of consistent chronic substance use. No participants were under the influence of substances at the time of the clinical interview. Clinical interviews were used to corroborate participants’’ reports of depression and anxiety. These ratings mirrored rates of self-reported depression and anxiety used in the study. The sample mean for the BAI was 27.79 (SD = 15.51) falling within the “Severe” range of anxiety (Beck & Steer, 1990). The sample mean for the PHQ was 13.31 (SD = 6.73) falling within the “Moderate” range for depression (Kroenke, Spitzer, & Williams, 2001). This data suggests that self-reported rates of depression and anxiety were similar to clinician-rated diagnostic information for depression and anxiety. Of the N = 72 participants, 84.7% (n = 61) met diagnostic criteria for at least one anxiety disorder or PTSD as determined by clinical interviews. Prevalence of these diagnoses were as follows: generalized anxiety disorder (n = 29), social anxiety disorder (n = 32), panic disorder (n = 24), agoraphobia (n = 10), obsessive compulsive disorder (n = 15), posttraumatic stress disorder (n = 50), and specific phobias (n = 13). Approximately one third met criteria for major depression (n=28). The majority of the sample met diagnostic criteria for at least 1 or more diagnosis: 1 (n = 12, 16%), 2 (n = 15, 21%),

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

10

3 (n = 12, 16%), 4 (n = 13, 18%), 5 (n = 4, 7%), 6 (n = 6, 8%). A small portion of the sample did not meet criteria for any diagnosis (n = 10, 14%). The average number of years of education was 12.67 (SD = 2.14) years and the majority of participants (n = 41, 56.2%) earned less than $10,000 per year, which is below the federal poverty level. The sample was predominantly male (n = 41), 56.2% with an average age of 34 (SD = 7.25). Participants self-identified as White 86% (n = 61), African American 1.4% (n = 1), Pacific Islander/Native Alaskan 1.4% (n = 1), Asian American 2.8% (n = 2), Native American 5.6% (n = 4), and Bi-Racial 2.8% (n = 2). Exclusion criteria included a lack of English fluency and active psychosis. Procedure Participants attended an in-person study visit during which they completed a battery of questionnaires as part of a larger study examining how PTSD effects behavior inhibition in those who habitually use opioids. Trained research assistants administered the Structured Clinical Interview for DSM-5 (SCID-5) and Addiction Severity Index Lite (ASI-Lite) and reviewed for consistency by a licensed clinical psychologist (First, Williams, Karg, & Spitzer, 2015; McLellan et al., 1992). Later, participants were asked to complete the SST. Before beginning the experimental trials, participants had to achieve at least 80% accuracy on a practice trial. The experimental trial SST paired the trained visual stimuli with images of faces with one of 3 emotional valences; angry, happy, or calm. Measures Stop-Signal Task (SST; Logan, 1985). The SST is a cognitive task designed to measure a participant’s ability to inhibit behaviors in response to an auditory signal in STOP trials (87) and their reaction time to visual stimuli in GO trials (177). A variant of the SST developed by

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

11

Logan (1994) was used. Each task trial began with a fixation cross presented for 250 milliseconds (ms). A target stimulus was then presented that consisted of a face from the NimStim stimulus set for 1400 ms (Tottenham et al., 2009). Color images were of men and women who were making neutral, happy, or angry facial expressions with open and closed mouths and were equally divided and randomized across trial types. Angry faces were chosen to represent negative stimuli in this study. Although some previous research on depression and negative stimuli have utilized sad faces, multiple studies have used angry faces (Goldstein et al., 2007; Hare et al., 2005; Pawliczek et al., 2013; Shafritz et al., 2006) or have found no difference between anger and other negative facial emotions on reaction time tasks (Leyman, De Raedt, Schacht, & Koster, 2006; Domes, Normann, Heinrichs, 2016; Mogg, Millar, Bradley, 2000). Participants were asked to identify the gender of the individual as quickly as possible. For STOP trials, the onset of the stop signal was dynamic in that successful STOP trials resulted in an increase in the onset of the stop signal by 50ms and failed STOP trials reduced the onset of the stop signal by 50ms. This adaptive timing was used to obtain a successful stop rate of approximately 50%. The three outcomes of interest were: (1) GO RT on correct GO trials, (2) GOSD variability in the reaction time for GO trials, and (3) SSRT, which is the difference between the mean GORT and the mean STOP signal presentation for trials in which the participant successfully stopped. Longer SSRTs indicate poorer response inhibition. Addiction Severity Index Lite (ASI-Lite; McLellan et al., 1992). The ASI-Lite is an abbreviated adaptation of the ASI-5. It is a 169-item structured interview designed to assess rates of drug or alcohol addiction as well as levels of associated impairment in life domains such as alcohol use, drug use, legal history, family/social history, psychological history, medical history,

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

12

and employment status. The ASI-Lite was used in this study to determine substance use frequency. Patient Health Questionnaire (PHQ-9; Kroenke, Spitzer, & Williams, 2001). The PHQ-9 is a widely used 9-item self-report tool used to assess depression as defined by DSM-IV. It is used to determine severity and frequency of depressive symptoms as well as the patient’s level of function. The PHQ-9 uses a Likert scale (0-3) to indicate how often patients are experiencing symptoms. This measure demonstrated excellent internal reliability (a = .93). Beck Anxiety Inventory (BAI; Beck & Steer, 1990). The BAI is comprised of 21 selfreport items used to assess common symptoms of anxiety, including physical symptoms. Answers are based on a Likert scale (0-3), with higher scores indicating higher levels of symptom severity. The BAI demonstrated excellent internal consistency (a = .96). Data Analysis Plan Repeated-measures analyses of variance (RM-ANOVAs) were used to determine if there was a difference between SSRT, go reaction times (GORT), and go standard deviation (GOSD), for each emotional face (angry, happy, and calm). To determine the moderating effect of depression and anxiety, mixed models were used to examine the interaction between anxiety, depression, and SSRT to emotional faces. Models contained main effects for valence in which emotional stimuli were compared to calm stimuli and for psychopathology. Interaction terms were included between emotional valence (neutral/emotional) and the psychopathology variable (depression and anxiety). Separate models were used for anxiety and depression. For significant interactions the models were probed at high (+1 SD) and low (-1SD) levels of psychopathology. Results

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

13

Mean scores and standard deviations of SST performance are reported in Table 1. These data indicated that the SST was administered correctly. The proportion of correct stop trials was M = 44%, SD = 9%, which suggested that the task maintained a consistent stop rate. There were relatively few omissions (3%), which suggested that participants consistently responded to GO trials. These data suggest that, in aggregate, this modified SST performed correctly. There was a significant difference in SSRT across emotional faces, F (2, 71) = 6.17, p < .01. Post-hoc pairwise comparisons indicated that the difference between SSRT to negative faces (M = 262.00, SD = 71.28) was significantly longer than that to neutral faces (M = 244.37, SD = 76.12, p < .01, d = 0.41). The difference between SSRT to positive faces (M = 255.32, SD = 68.95) and neutral faces (p = .06, d = 0.26) was not significant. There were also no differences in SSRT between negative and positive faces (p = .34, d = 0.13). For GORT, there was a significant difference across emotional stimuli, F (2, 71) = 5.67, p < .01. There was a significant difference between GORT for negative faces (M = 762.59, SD = 215.12) and neutral faces (M = 748.84, SD = 211.93, p < .01, d = 0.38) such that negative GORT was slower than GORT for neutral faces. GORT for negative faces was slower than for positive faces (p = .04, d = 0.25). There were no differences in GORT between positive and neutral faces (p < .72, d = 0.08). Finally, there were significant differences in GOSD across emotional faces, F (2, 71) = 3.96, p = .02. There was a significant difference between GOSD for neutral (M = 189.22, SD = 66.93) and positive faces (M = 201.95, SD = 71.8), such that the GOSD for positive faces was larger than for neutral faces (p = .01, d = 0.30). There were other no significant differences for GOSD. Mean scores, standard deviations, and correlations for psychopathology variables can be found in Table 2. There was a significant depression by negative face interaction (B = -1.50, SE = 0.69, p = .03) as well as a significant depression by positive face interaction (B = -1.51, SE =

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

14

0.69, p = .03). The moderating effect of depression scores on the relation between faces and SSRT was then examined. The significant interactions were probed at high and low (± 1 SD) levels for psychopathology (Table 3). These methods were chosen in accordance with guidelines suggested by Aiken, West, and Reno in 1991 and have been found acceptable to be used to probe interactions. Graphs in Figure 1 are in reference to the categorical variables created by the standard deviation split and are meant to aid in interpretation of reported continuous interactions. In the low depression group, there was a significant difference between both negative (B = 30.78, SE = 5.64, p < 0.01) and positive faces (B = 19.48, SE = 6.13, p < .01) from neutral faces. These findings suggest that at low depression, SSRT for negative and positive faces were significantly longer than for neutral faces. For the high depression group, there were no differences between negative (B = 1.96, SE = 6.41, p = 0.76) or positive (B = 2.07, SE = 7.06, p = 0.77) faces relative to neutral faces. This finding suggests there were no difference between emotional faces at high levels of depression (Figure 1). Also, SSRTs increased for all emotional faces at high depression. A different set of findings was obtained for anxiety. There was a significant anxiety by positive face interaction for SSRT (B = -0.79, SE = 2.98, p = .009). The negative face by anxiety score interaction for SSRT was not significant (B = -0.47, SE = 2.98, p = .12). At low levels of BAI, there was a significant difference between negative faces and neutral faces (B = 21.11, SE = 5.43, p < 0.01) and between positive faces and neutral faces (B = 23.74, SE = 5.70, p < 0.01). This suggested that at low anxiety, SSRT for both negative and positive faces were significantly longer than for neutral faces. However, at high levels of anxiety there was no effect of emotional faces for SSRT in the high anxiety group for either negative (B = 11.62, SE = 7.23, p = 0.12) or positive faces (B = -1.38, SE = 6.99, p = 0.85). Discussion

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

15

The current study contributes to a small body of literature on the impact of emotionally valenced stimuli on response inhibition. It is among the first to demonstrate that, among those with a history of SUD, the presence of a negative stimulus (angry face) slows overall reaction times and reduces response inhibition. Others (Rebetez et al., 2015) have described this difference as interference such that the processing of the emotional component of the stimulus supersedes the inhibition component of the task. The effect size of the difference in emotional responding for negative stimuli was comparable to that obtained in a sample with healthy controls (d = 0.51, Rebetez, et al., 2015), suggesting that this interference effect may be comparable across populations. These findings are relevant to those with SUD as it suggests that the ability to appropriately withhold a response may be further compromised to a negative stimulus, which is a possible mechanism by which the disorder is maintained. The present study did not find a significant difference between response inhibition for positive stimuli relative to neutral stimuli. However, the effect size of the difference between positive and neutral stimuli was in the small-medium range (d = 0.26), suggesting this difference is potentially meaningful. Although less examined than negative stimuli, prior work on positive stimuli and response inhibition has suggested these stimuli may also have an interference effect, albeit smaller (Rebetez et al., 2015). Continued exploration of the role of positive stimuli on response inhibition is warranted, especially in the SUD population. Recent reviews have highlighted the importance of understanding how reactions to positive stimuli are altered in those with SUD (Weiss, Tull, Sullivan, Dixon-Gordon, & Gratz, 2015; Weiss, Forkus, Contractor, & Schick, 2018). Depression moderated the difference in response inhibition in a manner that was different than hypothesized. At low levels of depression, there was evidence of an interference effect for

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

16

emotional stimuli relative to neutral stimuli. Specifically, response inhibition to emotional stimuli was slower than that to neutral stimuli. However, at elevated levels of depression, two differences were observed. First, there was no significant difference in response inhibition across stimuli. Second, response inhibition worsened, suggesting that elevated depression further impaired response inhibition. Related work has suggested that those with depression are less impacted by the emotional valence of stimuli, particularly faces (Stuhrmann, Suslow, & Dannlowski, 2011). Specifically, neutral faces are interpreted comparably to emotional faces (for review see Bourke, Douglas, & Porter, 2010). This phenomenon may explain the reduction in the difference between SSRTs across emotional stimuli associated with increased depression. Brain-based studies provide additional information on how emotional stimuli may impacts response inhibition. As discussed previously, work with healthy controls on response inhibition has shown that when the emotional valence of the stimuli varies, the orbitofrontal cortex (OFC) is recruited for inhibition (Sagaspe et al., 2011). The OFC is involved in numerous executive and emotional functions with its primary role being learning and consolidating outcome expectations for emotionally relevant stimuli (for a review see Schoenbaum et al., 2006). Those with a history of SUD have been shown to have impaired OFC functioning, which is thought to maintain the disorder. OFC impairment in this population has been associated with limited recognition of reward reduction and increased negative outcomes associated with continued substance misuse. Reviews have suggested that unipolar depression is also associated with diminished OFC functioning (Rogers et al., 2004). Specifically, those with depression have reduced OFC volume (Drevets, 2007) and fail to show a shift in responding when the reward or punishment contingences for a given task change. The presence of both a history of SUD and elevated depression symptoms may be attributed to significantly altered functioning of the OFC.

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

17

This impairment may be associated with the overall worsening of response inhibition that was observed in the current study. Additional neuroimaging work is necessary to test this hypothesis, however. Anxiety symptoms were found to moderate the difference in SSRT between positive and neutral stimuli, but not between negative and neutral stimuli. This result is consistent with related work suggesting that state anxiety alone has a minimal impact on response inhibition (Grillon et al., 2017). However, elevated trait and state anxiety further impair response inhibition. A similar effect was found in the current study in that the highest SSRTs were found for those with elevated trait anxiety when inhibiting to a negative stimulus. However, elevated state anxiety alone did not further exacerbate this difference. Participants with elevated anxiety did, however, demonstrate less of a difference between neutral and positive stimuli than those with low anxiety. This shift is attributed to the speed with which those with anxiety process threat. Anxiety disorders are associated with a bias towards threatening stimuli that is characterized by faster processing of threatening information (Shechner & Bar-Haim, 2016). For those with elevated anxiety, positive faces in the current study were likely quickly interpreted as nonthreatening, which allowed for improved SSRT. However, negative and neutral faces were likely processed as threatening, which resulted in an interference effect. Additional work on the processing of positive information, however, is needed to verify this hypothesis. The current study had several limitations of note. First, all participants presented with a history of polysubstance use. It is unclear if these findings are specific to the use of a specific substance or set of substances or if they are characteristic of substance use more broadly. Second, the amount and duration of substance use varied considerably across participants. It is unclear if these findings would be obtained in a sample of those with a history of chronic use or

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

18

in a sample of those using actively. Participants’ psychopathology was measured by self-report surveys. Use of clinician-administered measures of psychopathological severity should be considered for future studies. Finally, the current study used angry facial expressions as the negative stimuli. Related work has used more salient emotional stimuli such as images of traumatic events or drug related cues to evoke a particular emotion. It is unclear how more salient emotional stimuli would affect the results. In addition, happy, calm, and angry facial expressions were chosen to represent positive, neutral, and negatively valenced stimuli respectively. It is unclear to what extent other types of emotional expressions (e.g., excitement, fear, sadness, etc.) may impact SST performance in this population. Finally, the ethnic and racial diversity of the sample was quite low due to the location in which the study was conducted. Efforts should be taken to replicate these findings in a more diverse set of individuals to determine the presence or absence of cultural variables on the observed effects. In conclusion, the findings of the present study demonstrate how psychopathology, particularly depression, and emotional stimuli interact to affect response inhibition in those with a history of SUD. The results highlight that both emotion regulation and an understanding of the context in which stimuli are encountered are necessary to determine an individual’s ability to appropriately inhibit a response. Poorer response inhibition among those with depression and anxiety towards negative stimuli may explain why individuals with co-occurring SUD and psychopathology have greater impairment and poorer treatment outcomes (Davis et al., 2010). The results highlight the need for treatment that addresses co-occurring conditions.

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

19

Author Statement We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We acknowledge funding provided by NIMH 1K08MH107661-01A1 (PI: Price). This work was also supported by a UVM small faculty award (PI: Price) and a Summer Undergraduate Research Fellowship (PI: Mirhashem). We have no further acknowledgements. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. Role of Funding Source Matthew Price and Alison Legrand were supported by NIMH 1K08MH107661-01A1 (PI: Price). This work was also supported by a UVM small faculty award (PI: Price) and a Summer Undergraduate Research Fellowship (PI: Mirhashem). NIMH had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. Contributors Dr. Matthew Price oversaw this study. Alison Legrand contributed to drafting the manuscript and preparing tables and figures. Dr. Matthew Price reviewed drafts of the manuscript. Conflict of Interest Both authors declare that they have no conflicts of interest

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

20

References Aker, M., Bø, R., Harmer, C., Stiles, T. C., & Landrø, N. I. (2016). Inhibition and response to error in remitted major depression. Psychiatry research, 235, 116-122. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Pub. Back, S. E., Gros, D. F., Price, M., LaRowe, S., Flanagan, J., Brady, K. T., ... & McCauley, J. L. (2015). Laboratory-induced stress and craving among individuals with prescription opioid dependence. Drug and alcohol dependence, 155, 60-67. Beck, A. T., & Steer, R. A. (1990). Manual for the Beck anxiety inventory. San Antonio, TX: Psychological Corporation. Borges, G., Walters, E. E., & Kessler, R. C. (2000). Associations of substance use, abuse, and dependence with subsequent suicidal behavior. American Journal of Epidemiology, 151(8), 781-789. Bourke, C., Douglas, K., & Porter, R. (2010). Processing of facial emotion expression in major depression: a review. Australian and New Zealand Journal of Psychiatry, 44(8), 681-696. Bredemeier, K., Warren, S. L., Berenbaum, H., Miller, G. A., & Heller, W. (2016). Executive function deficits associated with current and past major depressive symptoms. Journal of Affective Disorders, 204, 226-233. Coffey, S. F., Saladin, M. E., Drobes, D. J., Brady, K. T., Dansky, B. S., & Kilpatrick, D. G. (2002). Trauma and substance cue reactivity in individuals with comorbid posttraumatic stress disorder and cocaine or alcohol dependence. Drug and alcohol dependence, 65(2), 115-127.

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

21

Davidson, R. J., Putnam, K. M., & Larson, C. L. (2000). Dysfunction in the neural circuitry of emotion regulation--a possible prelude to violence. science, 289(5479), 591-594. De Wit, H. (2009). Impulsivity as a determinant and consequence of drug use: a review of underlying processes. Addiction biology, 14(1), 22-31. Domes, G., Normann, C., & Heinrichs, M. (2016). The effect of oxytocin on attention to angry and happy faces in chronic depression. BMC psychiatry, 16(1), 92. Donders, F. C. (1969). On the speed of mental processes. Acta psychologica, 30, 412-431. Drevets, W. C. (2007). Orbitofrontal cortex function and structure in depression. Annals of the New York Academy of Sciences, 1121(1), 499-527. Fillmore, M. T., & Rush, C. R. (2002). Impaired inhibitory control of behavior in chronic cocaine users. Drug and alcohol dependence, 66(3), 265-273. Goldstein, M., Brendel, G., Tuescher, O., Pan, H., Epstein, J., Beutel, M., ... & Clarkin, J. (2007). Neural substrates of the interaction of emotional stimulus processing and motor inhibitory control: an emotional linguistic go/no-go fMRI study. Neuroimage, 36(3), 1026-1040. Gray, J. A., & McNaughton, N. (2000). The psychology of Anxiety and Enquiry in to the functions of the septohippocampus system. Grant, B. F., Stinson, F. S., Dawson, D. A., Chou, S. P., Dufour, M. C., Compton, W., ... & Kaplan, K. (2004). Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: Results from the national epidemiologic survey on alcohol and related conditions. Archives of general psychiatry, 61(8), 807-816. Grillon, C., Robinson, O. J., Mathur, A., & Ernst, M. (2016). Effect of attention control on sustained attention during induced anxiety. Cognition and emotion, 30(4), 700-712.

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

22

Grillon, C., Robinson, O. J., O'connell, K., Davis, A., Alvarez, G., Pine, D. S., & Ernst, M. (2017). Clinical anxiety promotes excessive response inhibition. Psychological medicine, 47(3), 484-494. Hare, T. A., Tottenham, N., Davidson, M. C., Glover, G. H., & Casey, B. J. (2005). Contributions of amygdala and striatal activity in emotion regulation. Biological psychiatry, 57(6), 624-632. Heitzeg, M. M., Nigg, J. T., Hardee, J. E., Soules, M., Steinberg, D., Zubieta, J. K., & Zucker, R. A. (2014). Left middle frontal gyrus response to inhibitory errors in children prospectively predicts early problem substance use. Drug and alcohol dependence, 141, 51-57. Jentsch, J. D., & Taylor, J. R. (1999). Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology, 146(4), 373-390. Kalanthroff, E., Cohen, N., & Henik, A. (2013). Stop feeling: inhibition of emotional interference following stop-signal trials. Frontiers in human neuroscience, 7, 78 Karch, S., Jäger, L., Karamatskos, E., Graz, C., Stammel, A., Flatz, W., ... & Pogarell, O. (2008). Influence of trait anxiety on inhibitory control in alcohol-dependent patients: simultaneous acquisition of ERPs and BOLD responses. Journal of Psychiatric Research, 42(9), 734-745. Kroenke, K., Spitzer, R. L., & Williams, J. B. (2001). The PHQ‐9: validity of a brief depression severity measure. Journal of general internal medicine, 16(9), 606-613.

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

23

Lawrence, A. J., Luty, J., Bogdan, N. A., Sahakian, B. J., & Clark, L. (2009). Impulsivity and response inhibition in alcohol dependence and problem gambling. Psychopharmacology, 207(1), 163-172. Leyman, L., De Raedt, R., Schacht, R., & Koster, E. H. (2007). Attentional biases for angry faces in unipolar depression. Psychological medicine, 37(3), 393-402. Li, W., Zinbarg, R. E., Boehm, S. G., & Paller, K. A. (2008). Neural and behavioral evidence for affective priming from unconsciously perceived emotional facial expressions and the influence of trait anxiety. Journal of Cognitive Neuroscience, 20(1), 95-107. Logan, G. D. (1985). Executive control of thought and action. Acta Psychologica, 60(2-3), 193210. Logan, G. D., Cowan, W. B., & Davis, K. A. (1984). On the ability to inhibit simple and choice reaction time responses: a model and a method. Journal of Experimental Psychology: Human Perception and Performance, 10(2), 276. Mahmood, O. M., Goldenberg, D., Thayer, R., Migliorini, R., Simmons, A. N., & Tapert, S. F. (2013). Adolescents' fMRI activation to a response inhibition task predicts future substance use. Addictive behaviors, 38(1), 1435-1441. McHugh, R. K., Gratz, K. L., & Tull, M. T. (2017). The role of anxiety sensitivity in reactivity to trauma cues in treatment-seeking adults with substance use disorders. Comprehensive psychiatry, 78, 107-114. McLellan, A. T., Kushner, H., Metzger, D., Peters, R., Smith, I., Grissom, G., ... & Argeriou, M. (1992). The fifth edition of the Addiction Severity Index. Journal of substance abuse treatment, 9(3), 199-213.

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

24

McNaughton, N. (1993). Stress and behavioural inhibition. Stress: an integrated approach (Stanford SC, Salmon P, eds), 191-206. McNaughton, N., & Gray, J. A. (2000). Anxiolytic action on the behavioural inhibition system implies multiple types of arousal contribute to anxiety. Journal of affective disorders, 61(3), 161-176. Merikangas, K. R., & McClair, V. L. (2012). Epidemiology of substance use disorders. Human genetics, 131(6), 779-789. Merikangas, K. R., Mehta, R. L., Molnar, B. E., Walters, E. E., Swendsen, J. D., AguilarGaziola, S., ... & Kolody, B. (1998). Comorbidity of substance use disorders with mood and anxiety disorders: results of the International Consortium in Psychiatric Epidemiology. Addictive behaviors, 23(6), 893-907. Mogg, K., Millar, N., & Bradley, B. P. (2000). Biases in eye movements to threatening facial expressions in generalized anxiety disorder and depressive disorder. Journal of abnormal psychology, 109(4), 695. Monterosso, J. R., Aron, A. R., Cordova, X., Xu, J., & London, E. D. (2005). Deficits in response inhibition associated with chronic methamphetamine abuse. Drug and alcohol dependence, 79(2), 273-277. Nigg, J. T. (2000). On inhibition/disinhibition in developmental psychopathology: views from cognitive and personality psychology and a working inhibition taxonomy. Psychological bulletin, 126(2), 220. Onyeka, I. (2015). Premature deaths among illicit drug users: a follow-up study on treatment seeking clients in Finland (Doctoral dissertation, Väitöskirja. Kuopio: Itä-Suomen yliopisto).

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

25

Pawliczek, C. M., Derntl, B., Kellermann, T., Kohn, N., Gur, R. C., & Habel, U. (2013). Inhibitory control and trait aggression: neural and behavioral insights using the emotional stop signal task. Neuroimage, 79, 264-274. Pessoa, L., Padmala, S., Kenzer, A., & Bauer, A. (2012). Interactions between cognition and emotion during response inhibition. Emotion, 12(1), 192. Price, M., Brier, Z. M., Mirhashem, R., & Allen, H. C. (2018). The impact of co-occurring opioid misuse and PTSD on response inhibition. Drug and alcohol dependence, 189, 187-192. Rebetez, M. M. L., Rochat, L., Billieux, J., Gay, P., & Van der Linden, M. (2015). Do emotional stimuli interfere with two distinct components of inhibition? Cognition and Emotion, 29(3), 559-567. Regier, D. A., Farmer, M. E., Rae, D. S., Locke, B. Z., Keith, S. J., Judd, L. L., & Goodwin, F. K. (1990). Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study. Jama, 264(19), 2511-2518. Righi, S., Mecacci, L., and Viggiano, M. P. (2009). Anxiety, cognitive self-evaluation and performance: ERP correlates. J. Anxiety Disorders. 23, 1132–1138. Robinson, O. J., Krimsky, M., & Grillon, C. (2013). The impact of induced anxiety on response inhibition. Frontiers in Human Neuroscience, 7, 69. Rogers, M. A., Kasai, K., Koji, M., Fukuda, R., Iwanami, A., Nakagome, K., ... & Kato, N. (2004). Executive and prefrontal dysfunction in unipolar depression: a review of neuropsychological and imaging evidence. Neuroscience research, 50(1), 1-11. Sagaspe, P., Schwartz, S., & Vuilleumier, P. (2011). Fear and stop: a role for the amygdala in motor inhibition by emotional signals. Neuroimage, 55(4), 1825-1835.

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

26

Shafritz, K. M., Collins, S. H., & Blumberg, H. P. (2006). The interaction of emotional and cognitive neural systems in emotionally guided response inhibition. Neuroimage, 31(1), 468-475. Shechner, T., & Bar-Haim, Y. (2016). Threat monitoring and attention-bias modification in anxiety and stress-related disorders. Current Directions in Psychological Science, 25(6), 431-437. Schoenbaum, G., Roesch. M. R., Stalnaker, T. A., (2006). Orbitofrontal cortex, decision‐making and drug addiction. Trends Neuroscience, 29, 116–124. Stuhrmann, A., Suslow, T., & Dannlowski, U. (2011). Facial emotion processing in major depression: a systematic review of neuroimaging findings. Biology of mood & anxiety disorders, 1(1), 10. Substance Abuse and Mental Health Services Administration. (2014). Results from the 2013 National Survey on Drug Use and Health: Summary of national findings. NSDUH Series H-48, HHS Publication No. (SMA) 14-4863. Swendsen, J. D., & Merikangas, K. R. (2000). The comorbidity of depression and substance use disorders. Clinical psychology review, 20(2), 173-189. Verbruggen, F., & Logan, G. D. (2009). Models of response inhibition in the stop-signal and stop-change paradigms. Neuroscience & Biobehavioral Reviews, 33(5), 647-661. Weiss, N. H., Forkus, S. R., Contractor, A. A., & Schick, M. R. (2018). Difficulties regulating positive emotions and alcohol and drug misuse: A path analysis. Addictive behaviors, 84, 45-52. Weiss, N. H., Tull, M. T., Sullivan, T. P., Dixon-Gordon, K. L., & Gratz, K. L. (2015). Posttraumatic stress disorder symptoms and risky behaviors among trauma-exposed

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE inpatients with substance dependence: the influence of negative and positive urgency. Drug and alcohol dependence, 155, 147-153. Wessel, J. R. (2018). Prepotent motor activity and inhibitory control demands in different variants of the go/no‐go paradigm. Psychophysiology, 55(3), e12871. Whiteford, H. A., Degenhardt, L., Rehm, J., Baxter, A. J., Ferrari, A. J., Erskine, H. E., ... & Burstein, R. (2013). Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. The Lancet, 382(9904), 1575-1586.

27

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE Figure 1 A)

B)

___________________________________________________________________________ Note. Relation between anxiety and depression symptom classification and SSRT across emotional valence. SSRT = Stop Signal Reaction Time. PHQ = Patient Health Questionnaire. BAI = Beck Anxiety Inventory

28

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE Table 1 Descriptive statistics for stop signal tasks

Task Variable

Mean (SD)

GORT

758.49 (214.77)

Angry

762.59 (215.12)

Happy

752.17 (208.59)

Calm

748.84 (211.93)

GOcRT

738.66 (198.93)

GOSD

197.50 (62.30)

SSRT

253.83 (68.22)

Angry

262.10 (71.28)

Happy

255.32 (68.95)

Calm

244.37 (76.12)

SSRT PRS

0.44 (0.09)

SSRT Delay

418.88 (176.08)

Omission Error Rate

0.03 (0.04)

Note. GORT = Go Reaction Time. GOcRT = Go Reaction Time on correct trials. GOSD = Go Reaction Time Standard Deviation. SSRT PRS= Probability of responding on a stop trial. SSRT Delay = Delay between presentation of the go stimulus and the stop-signal.

29

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

30

Table 2 Correlation Matrix and Descriptive Statistics Measure

1.

2.

3.

4.

5.

6.

.7

1. PHQ

-

2. BAI

0.76

-

3. SSRT Angry

0.02

0.06

4. SSRT Calm

0.23

0.15

0.85

-

5. SSRT Happy

0.11

-0.01

0.83

0.85

-

6. GORT

0.02

0.06

0.13

0.06

0.08

-

7. GOSD

0.28

0.30

0.26

0.22

0.19

0.73

-

M (SD)

1.

2.

3.

4.

.5

.6

.7

13.31

27.79

262

244.37

255.32

754.65

197.5

(6.73)

(15.51)

(71.28)

(76.12)

(68.95)

(210.87)

(62.30)

-

Note. PHQ = Patient Health Questionnaire. BAI = Beck Anxiety Inventory. SSRT = Stop Signal Reaction Time. GORT = Go Reaction Time. GOSD = Go Reaction Time Standard Deviation.

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

31

Table 3

Interactions and Simple Effects Emotion BAI interaction

B

SE

p

BAI

0.75

0.55

.18

Angry

29.11

9.48

<.01

Happy

32.50

9.48

<.01

Angry*BAI

-0.47

2.98

.12

Happy*BAI

-.079

2.98

<.01

PHQ

2.55

1.27

.05

Angry

36.03

10.21

<.01

Happy

30.54

10.21

<.01

Angry*PHQ

-1.50

0.69

.03

Happy*PHQ

-1.51

0.69

.03

High BAI*Angry

11.62

7.23

.12

Low BAI*Angry

21.11

5.43

<.01

High BAI*Happy

-1.38

6.99

.85

Low BAI*Happy

23.74

5.70

<.01

Emotion PHQ interaction

Emotion BAI simple effects

EMOTIONAL STIMULI, RESPONSE INHIBITION IN SUBSTANCE USE

32

Emotion PHQ simple effects High PHQ*Angry

1.96

6.41

.76

Low PHQ*Angry

30.78

5.64

<.01

High PHQ*Happy

2.07

7.06

.77

Low PHQ*Happy

19.48

6.13

<.01

Note. PHQ = Patient Health Questionnaire. BAI = Beck Anxiety Inventory.