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Published in final edited form as: Am J Primatol. 2016 Jun 10;79(1):1–8. doi: 10.1002/ajp.22569

Rhesus Macaques (Macaca mulatta) With Self-Injurious Behavior Show Less Behavioral Anxiety During the Human Intruder Test

EMILY J PETERSON 1, JULIE M WORLEIN 2, GRACE H LEE 2, AMANDA M DETTMER 3, ELANA K VARNER 4, MELINDA A NOVAK 4,*
PMCID: PMC7652060  NIHMSID: NIHMS1631524  PMID: 27286311

Abstract

Self-injurious behavior (SIB) has been linked to anxiety in the human literature, but relatively few studies have explored this link in rhesus macaques. A widely used behavioral assessment of anxiety, the human intruder test (HIT), employs the mildly stressful stimulus of an unfamiliar experimenter to assess anxious behavior in macaques. The HIT was conducted on 59 (20 male) laboratory housed rhesus macaques, 30 with a record of SIB (10 male). If monkeys with SIB have a more anxious phenotype, they should show stronger reactions to the HIT. However, contrary to our predictions, monkeys with SIB did not show higher levels of anxious behavior compared to controls. They spent significantly less time showing anxious behavior and displayed little aggression in response to the stare of the intruder. SIB and control monkeys did not differ in a range score (number of unique behaviors expressed per phase); however, SIB monkeys had a lower change score (total number of behaviors expressed including repetitions) than controls. In general, monkeys that paced regardless of SIB status, showed a reduction in pacing when the intruder entered the room. Possible explanations for the failure of SIB monkeys to show increased anxiety in the HIT include greater exposure of SIB monkeys to unfamiliar humans because of their condition, evidence for a subtype of SIB which is not anxiety related, and/or the presence of comorbid depressive-like symptoms.

Keywords: self-injury, rhesus macaques, anxiety, human intruder test, blunted affect

INTRODUCTION

Self-injurious behavior (SIB) is a serious human health concern, that has been studied in both human and nonhuman primates. In rhesus monkeys, SIB is usually manifested as self-directed biting leading to wounds that may require veterinary care [Novak, 2003], and in some facilities, it occurs in about 10% of the population [Bellanca and Crockett, 2002; Lutz et al., 2003]. There are some similarities between SIB in rhesus macaques and the non-suicidal self-injury (NSSI) reported in the general human population, and SIB reported in individuals with severe developmental delays [Novak et al., 2014; Symons et al., 2012]. These include similar targets for injury (i.e., arms and legs), albeit using different means, presence of early life stress events [Lutz et al., 2003], and somewhat similar responses to treatment, for example, some efficacy with fluoxetine [Fontenot et al., 2009] and naltrexone [Kempf et al., 2012] in rhesus monkeys along with a meta-analysis of research on humans suggesting treatment efficacy with SSRIs, and naltrexone [see Turner et al., 2014 for a review].

A variety of environmental factors and physiological correlates have been explored to gain a better understanding of this behavioral pathology in monkeys [Novak, 2003; Novak et al., 2014]. Restrictive environments and atypical rearing conditions are associated with the development of SIB in monkeys [Bellanca & Crockett, 2002; Kraemer et al., 1997; Lutz et al., 2003]. For example, nursery reared monkeys are more likely to develop SIB than mother-reared monkeys [Gottlieb et al., 2013; Lutz et al., 2003]. Monkeys with SIB appear to have a blunted hypothalamic-pituitary-adrenal (HPA) axis as manifested by an attenuated response to stimulation by adrenocorticotrophic hormone (ACTH) compared to control monkeys [Tiefenbacher et al., 2004]. Additionally, major life stress (relocation to a new building) resulted both in increased HPA axis activation, and SIB [Davenport et al., 2008].

Although, anxiety has been implicated as one factor in the maintenance of NSSI in some human populations [Klonsky et al., 2003; Ross & Heath, 2003], a relationship between anxiety and SIB has not been fully established in monkeys. Early life stress is known to be a risk factor in developing both anxious behavior and SIB in monkeys [Dettmer et al., 2012; Lutz et al., 2003], suggesting a link between the two pathologies. The only clear evidence that monkeys with SIB show increased anxious behavior comes from pharmacological investigations with anxiogenic, and anxiolytic compounds. Monkeys with SIB showed a mild increase in biting behavior with the anxiogenic drug FG7142 [Major et al., 2009], and a reduction in biting and wounding when treated with the anxiolytic drug, diazepam [Tiefenbacher et al., 2005]. However, only a subset of monkeys reacted to these drugs in the above described manner. Nearly, half of the SIB monkeys showed no response to the anxiogenic drug FG7142, and half of the SIB monkeys treated with diazepam actually got worse. It is possible, as has been reported in the human population, that there may be different subtypes of SIB. The objective of this study, was to more directly examine the hypothesis that monkeys with SIB might also show heightened anxiety compared to monkeys without this pathology. To measure anxiety, we used a standard behavioral anxiety assessment, the human intruder test (HIT).

The HIT, developed by Kalin and Shelton, is a provoked response test widely used to identify an anxiety-like endophenotype in macaques [Coleman & Pierre, 2014; Kalin & Shelton, 1989]. The HIT was originally developed for use with infant monkeys to examine the effects of early social experience on temperament and behavior. It was subsequently modified for use in adult monkeys, and adults, like infants, show phase dependent reactions to the test [Coleman et al., 2011; Corcoran et al., 2012; Kalin et al., 1998; Mason et al., 2006]. The test involves exposure to an unfamiliar human (intruder), who assumes various positions relative to the monkey being assessed. The test is divided into a number of phases: baseline (no intruder present), profile (intruder enters the room, approaches the monkey, and stands in profile to the monkey), stare (intruder turns to face the monkey and looks directly at the animal), and back (intruder turns their back to the monkey). The stare phase is generally the most provocative part of the test, although additional information can be gained as the intruder first enters the room, particularly in terms of how much time monkeys spend in the back of the cage during both the profile and stare phases. An anxious phenotype is identified by an exaggerated response to the stare of the intruder as manifested by increased threatening behavior, fear responses, and/or freezing [Coleman & Pierre, 2014]. Because two other behaviors, scratching and yawning, have been shown to increase with anxiogenic compounds, and decrease with anxiolytic compounds [Schino et al., 1991, 1996], changes in these target behaviors are often examined during the HIT.

Several variants of the HIT have been used to test adult monkeys. In the variant most similar to the infant version, an adult is moved to a testing environment and five 2-min phases are conducted: alone, profile (intruder enters the room and stands in profile, and then exits), alone, stare (intruder reenters the room and faces the monkey, and then exits), and alone. However, Coleman et al. [2016] refined the original HIT protocol to generate a cage-side variant that could be conducted on adult macaques in a large research facility. In this variant of the HIT, monkeys are tested in their home cage, and the intruder enters only once (no intervening alone phases between profile and stare). All intruder phases are run in sequence starting with profile, moving to stare, and ending with the intruder turning around such that her back faces the intruder. The back phase was added to the end of the test to assess the importance of facial exposure.

In order to gain further knowledge about the relationship between SIB and anxiety in laboratory macaques from three large primate facilities across the country, we utilized the cage-side HIT. We predicted that if an anxiety-like phenotype were a characteristic of SIB, monkeys with this condition would show a stronger reaction to this test. Specifically, they would react more to the intruder’s stare by showing heightened levels of aggression compared to monkeys without this condition. We also predicted that monkeys with SIB would spend more time displaying anxious behavior when the intruder was in the room, regardless of phase, as compared to normal controls.

METHODS

Subjects

The subjects were 59 rhesus macaques (Macaca mulatta) from the Washington National Primate Research Center. Thirty subjects that exhibited SIB, as manifested by biting and mild wounding, were identified using health records, and behavioral assessments. Twenty-nine control subjects were chosen to match the age and sex of the SIB subjects. Twenty of 59 subjects were male, and all subjects were between the ages of 4 and 16 with a mean age of 8.3. Of the males, 10 had a record of SIB and of the females, 20 had a record of SIB. All 59 subjects were housed indoors, experienced similar enrichment routines, had water ad libitum, and received Lab Diet 5038 chow twice daily. All subjects were housed in accordance with the National Research Council Guide for the Care and Use of Laboratory Animals, and all research conducted conformed to the American Society of Primatologists for the Ethical Treatment of Nonhuman primates.

THE HUMAN INTRUDER TEST

The cage side version of the HIT was employed to assess anxious behavior, and was video recorded. The intruder was a female experimenter unfamiliar to the subjects. Any pair housed subjects were separated from each other for the duration of the test (~15 min), and the monkeys at all facilities were thoroughly habituated to brief separations as a part of basic husbandry procedures. At the beginning of the test, a camera was placed in the room. The test consisted of a 10-min camera-only period of which the last 2-min were scored as a baseline, followed by three 2-min intruder phases. During the intruder phases, the intruder stood 60 cm from the subject’s cage in three orientations without leaving the room. The intruder initially stood obliquely to the subject (profile), then turned to face the subject (stare), and then turned directly opposite to the monkey (back). After the back phase, the intruder left the room and the test was complete. A timer held by the intruder cued the start of each 2-min phase.

BEHAVIORAL SCORING

Video recordings were sent to the University of Massachusetts Amherst for scoring. Videos were scored using MPEG Streamclip, free downloadable software provided by Squared5, which permits frame-by-frame analysis of videos. All scorers were blind to the facility and SIB status of the subjects. All behaviors were scored for frequency and duration. Inter-observer reliability was calculated as 90% agreement score such that behavioral duration scores were within a range of 15 frames (equal to 0.5 sec). The last 2 min of the baseline phase and the three 2-min intruder phases were scored for the duration of 12 behaviors: back of cage, pace, freeze, fear grimace, yawn, scratch, threat/cage-shake, self-groom, self-bite, eye poke, floating limb, and self-mouth. Combining the behaviors fear grimace, yawn, scratch, back of cage, and freeze created an anxiety behavior score. Self-bite, eye-poke, floating limb, and self-mouth occurred rarely, and these behaviors were combined to create a category of self-directed stereotypy behavior.

DATA ANALYSIS

The following behaviors were analyzed for duration: threat/cage-shake, anxiety, and two abnormal behaviors, pace and self-directed stereotypy. Additionally, two global categories were created: (i) the range which reflected the number of unique behaviors expressed during each phase of the HIT; and (ii) the change which reflected the total frequency of all behavioral events regardless of whether they were repeated, during each phase.

For each subject, behavior durations were rounded to the nearest second and summed to create totals for each phase. The statistical software SYSTAT 12 was used for all analyses. Because the data were not normally distributed (Shapiro–Wilks Test), a log transformation was used to normalize the distributions. The data were analyzed using General Linear Model (GLM) Analysis of Variance on the transformed data with HIT phase as the within subject variable and sex, and SIB status as the between subjects variables for the behaviors: threat/cage-shake, anxiety, pace, self-directed stereotypies, range, and change. Significant main effects of phase were then examined by pairwise comparisons using a Bonferroni correction. Significant interactions of phase with SIB status were subjected to three post hoc Contrasts (F-Tests). The first compared the baseline values with the profile and stare phases, the second compared the profile to the stare phase, and the third compared the baseline and back phases.

RESULTS

Four of the subjects identified as having SIB showed mild biting behavior, which did not result in wounding during the HIT. Biting behavior was spread idiosyncratically across all phases, occurring in one subject once during the baseline, in another subject once during the profile phase, and another subject twice during the back phase. Only one subject appeared to react to the intruder, showing mild wrist biting five times spread across the phases in which the intruder was in the room.

Responsiveness to the HIT

We first report the reactions of all monkeys, regardless of SIB status, to the test. For every behavior analyzed, there was a significant phase effect (see Fig. 1). As expected the duration of threats varied significantly across phase (F = 20.05(3,165); P < 0.01) with most of the threatening behaviors occurring during the stare phase. Subsequent pairwise comparisons revealed that the threatening behavior was elevated in the stare phase compared to the baseline (P < 0.01), profile (P < 0.01), and back (P < 0.01) phases. Anxiety responses also varied significantly across phase (F(3,165) = 10.19, P < 0.01) such that anxious behavior was higher in all intruder phases compared to the baseline (profile vs. baseline, P < 0.01, stare vs. baseline P < 0.01, back vs. baseline, P = 0.03). Additionally, anxious behavior was higher in the profile and stare phase compared to the back phase (P < 0.01 and P = 0.02, respectively).

Fig. 1.

Fig. 1.

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Phase Dependent Effects. (A) threatening behavior, (B) anxious behaviors, (C) pacing, (D) self-directed stereotypies, (E) change (total number of behavioral events), and (F) range (number of unique behaviors).

Abnormal behavior was generally suppressed in the presence of an intruder. Pacing varied significantly by phase (F(3,165) = 10.77, P < 0.01), such that time spent pacing was higher during baseline compared to the profile (P < 0.01), stare (P < 0.01), and back (P < 0.01) phases. Self-directed stereotypies varied significantly across phase (F(3,165) = 3.44, P = 0.02) with higher durations in the baseline compared to the profile phase (P = 0.02) and the stare phase (P = 0.03). Additionally, self-directed stereotypies were higher in the back phase compared to the profile phase (P = 0.02) and stare phase (P = 0.04).

An examination of the two global categories also revealed significant phase effects (change F(3,165) = 5.47, P < 0.01, and range F(3,165) = 2.63, P = 0.05). Pairwise comparisons showed that the number of times monkeys changed behaviors was significantly higher in the stare phase compared to the baseline (P = 0.04), profile (P < 0.01), and back (P < 0.01) phases. The range score (the total number of discrete categories that was observed) was significantly lower in the profile compared to the stare phase (P = 0.01).

Effects of SIB Status

Monkeys with SIB responded differently than controls on three of the six measures (see Fig. 2). Contrary to expectations, monkeys with SIB spent less time in threatening behavior (F(1,55) = 4.04, P = 0.05) showed lower durations of anxious behavior (F(1,55) = 10.38, P < 0.01), and fewer behavioral changes (F(1,55) = 6.48, P < 0.01) over the entire test compared to control monkeys. The difference in anxious behavior was further explained by a significant interaction of SIB status with phase (F(3,165) = 4.79, P < 0.01). Subsequent post hoc F-tests, revealed that monkeys with SIB spent less time in anxious behavior during the profile and stare phase versus the baseline phase than control monkeys (F(1,55) = 4.56, P = 0.04). SIB monkeys also showed lower durations of anxious behavior during both the profile and stare phase (F(1,55) 6.39, P = 0.01) and spent less time in anxious behavior during the back phase (F(1,55) = 7.93, P = 0.01) compared to controls.

Fig. 2.

Fig. 2.

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SIB Status Effects: (A) threatening behavior, (B) anxious behavior, and (C) change (total number of behavioral events).

ANOVA results for all main effects and interactions are presented in Table I.

TABLE I.

ANOVA Results for all Main Effects and Interactions

Behavior SIB Sex SIB × Sex Phase SIB × Phase Sex × Phase SIB × Sex × Phase
Anxiety F = 10.38 F = 0.03 F = 0.35 F = 10.19 F = 4.79 F = 0.33 F = 1.06
P = 0.01 P = 0.87 P = 0.56 P = 0.01 P = 0.01 P = 0.81 P = 0.37
Cageshake/threat F = 4.04 F = 0.20 F = 2.19 F = 20.05 F = 1.72 F = 0.39 F = 1.53
P = 0.05 P = 0.66 P = 0.14 P = 0.01 P = 0.17 P = 0.76 P = 0.21
Pace F = 3.09 F = 0.49 F = 0.35 F = 10.77 F = 0.04 F = 0.05 F = 0.11
P = 0.08 P = 0.49 P = 0.56 P = 0.01 P = 0.99 P = 0.99 P = 0.96
Self-directed stereotypy F = 2.55 F = 0.65 F = 1.14 F = 3.44 F = 0.65 F = 0.01 F = 0.38
P = 0.12 P = 0.42 P = 0.29 P = 0.02 P = 0.59 P = 1.00 P = 0.77
Change F = 6.48 F = 2.05 F = 1.36 F = 5.47 F = 1.42 F = 1.01 F = 1.89
P = 0.01 P = 0.16 P = 0.25 P = 0.01 P = 0.24 P = 0.39 P = 0.13
Range F = 2.53 F = 1.39 F = 0.13 F = 2.63 F = 1.78 F = 0.96 F = 1.29
P = 0.12 P = 0.24 P = 0.72 P = 0.05 P = 0.15 P = 0.41 P = 0.28
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Significant effects highlighted in bold.

DISCUSSION

We found little evidence to suggest that monkeys with SIB are more anxious than controls as measured by their reactions to the HIT. To the contrary, the data revealed that monkeys with SIB were significantly less reactive to the intruder phases of this test than the controls as shown by the duration they spent displaying anxiety, and aggressive behavior. This difference could not be attributed to variation in the range (total number of unique behaviors) expressed; however, controls showed a higher frequency of behavioral change (rate of iterating through behaviors) during the test.

SIB in macaques can vary widely in terms of the frequency of biting and the extent of skin damage (either requiring or not requiring suturing). All of the SIB monkeys in this study, were identified as biters through routine behavioral assessments by the Behavioral Management Team or came to the attention of the Behavioral Management Team as a result of care staff reports. However, none of the SIB monkeys in the study, with the exception of one male, produced wounds that were serious enough to require suturing. Most wounds consisted of minor skin abrasions or small cuts. It is possible that different results might have been obtained with monkeys who had a more severe form of SIB. However, studying such a population might be difficult given that severe wounders usually undergo pharmacotherapy; for example, naltrexone [Kempf et al., 2012], fluoxetine [Fontenot et al., 2009], or guanfacine [Freeman et al., 2015]. Nonetheless, it was not that we failed to find effects with this population; rather the effects were the opposite of what was expected.

Thus, we also consider several other possible explanations that include differential exposure to strangers, subtypes of SIB, and depressive symptomatology. With respect to novelty, the HIT involves exposing monkeys briefly to an unfamiliar human who stands in front of their cage. It is possible and perhaps likely that exposure to unfamiliar humans differed between monkeys with SIB, and controls prior to the test. Because of their condition, monkeys with SIB may be seen more often by veterinary staff and behavioral management technicians as compared to controls. Typically monkeys with SIB receive more behavioral assessments and extra enrichment as a means of tracking, and ameliorating the condition. This facility engaged in both these practices. Thus, monkeys with SIB experienced increased human contact and may have become habituated to relatively unfamiliar humans standing near their cage. If such habituation occurred, the HIT may not be suitable for evaluating anxious behavior in these monkeys.

A second explanation for our results is that the population of SIB monkeys in our study consists of a non-anxious subtype. Multiple subtypes of SIB have been defined in human populations including compulsive and impulsive subtypes [Favaro et al., 2007]. The presence of a second possible subtype of SIB that may be unrelated to anxiety is strongly suggested in our pharmacological studies of macaques using anxiolytic and anxiogenic compounds. Only a subgroup of monkeys with SIB responded in the expected manner to these manipulations, showing an elevation of mild biting to the anxiogenic drug [Major et al., 2009], and a reduction in biting and wounding to the anxiolytic drug, diazepam [Tiefenbacher et al., 2005]. The remaining SIB monkeys were unaffected by the anxiogenic drug, and SIB symptoms actually increased when these monkeys were treated with diazepam. These two subgroups also differed in the presence of an early life stress event. SIB monkeys that responded to the drugs in the expected manner were exposed to an early life stress event (early social separation), whereas, as the remaining monkeys did not have this experience. These findings suggest that there may be a separate population of monkeys with SIB in which anxiety is not comorbid with this condition.

Because monkeys with SIB showed a reduced reaction to the HIT, particularly with respect to threatening the intruder and with respect to behavioral change, a third possible explanation is that this blunted response is a manifestation of depressive like behavior. A link between depressive behavior and NSSI has been reported in teenagers [Asarnow et al., 2011; Baetens et al., 2015; Nock et al., 2006]. In macaques, a common posture associated with depression is sitting with head bent toward the body for prolonged periods of time [Shively & Willard, 2012]. However, this pattern was not observed during the scoring of the HIT. Thus, it seems unlikely that the blunted response to the HIT in SIB monkeys is related to depressive-like behavior. However, further study of these monkeys using other procedures (e.g., novel object testing) would be valuable in assessing possible depressive-like states.

There was little relationship between other forms of abnormal behavior and SIB. In general, abnormal behavior was suppressed in the presence of the intruder. All monkeys showed a suppression of pacing behavior throughout the period of time in which the intruder was in the room compared to the baseline. Like pacing, self-directed stereotypy was lower in the profile and stare phases compared to baseline. However, unlike pacing, self-directed stereotypy significantly increased in the back phase compared to the profile and stare phases. This differential response in the back phase is interesting because it suggests that certain kinds of activity revert to baseline when the intruder’s face is unavailable (e.g., self-directed stereotypies, and not surprisingly, threats), whereas, others continue to remain suppressed (e.g., pacing) or elevated (e.g., anxiety) as compared to baseline.

There are several limitations of this study. We studied a clinical population of monkeys with a pre-existing condition of SIB, whereupon the factors that might have caused the development of this condition are largely unknown. Additionally, our subject population should be considered a convenience sample, which only included the monkeys at the facility that were available for study because they were currently unassigned or assigned to non-drug related, or non-disease related research for which we received investigator approval. Additionally, background information on some subjects was limited. First, we were unable to determine reliably the exact age at which the biting pathology started because some of the monkeys had been transferred from other facilities years before with little information on behavioral histories. To examine the subtype hypothesis more fully, we needed information on early social history and stress exposure which was again not available for a number of subjects. Of significance to the depression hypothesis would be other behavioral data and tests on these monkeys, some of which are being conducted now. Additionally, although we know that the SIB monkeys were exposed to a higher frequency of humans standing near their cage, this number was not strictly quantified, and thus, we could not examine correlations between actual frequencies of extra human contact the SIB monkeys received in relation to their behavioral responses on the HIT.

A greater understanding of SIB pathology in macaques, particularly with respect to possible subtypes, would have value for the use of macaques as a translational model, as well as have implications for improving the welfare of laboratory macaques. Monkeys with SIB are a challenge to care for, and treatment outcomes are quite variable. Further exploration into alternative anxiety assessments and for determining whether a non-anxious subtype of SIB exists in monkeys is essential for the development of effective prevention, and intervention strategies.

ACKNOWLEDGMENTS

The authors thank Olivia Forshtay and Mark Menard for helping with project support and organization; Saif El-Mallah, Bianca Corey, Lauren Stanwicks, and Lily Augustini who spent many hours scoring videotapes; and to everyone involved in running and filming the HIT. This project was funded by the National Institutes of Health grant R24-OD11180 to Melinda Novak. All research reported in this manuscript has been approved by an Institutional Animal Care and Use Committee (IACUC) at each facility, conducted in accordance with the Guide for the Care and Use of Laboratory Animals, and complied with the Animal Welfare Act of the United States as well as the American Society of Primatologists Principles for the Ethical Treatment of Non-human Primates.

Footnotes

Conflicts of interest: None.

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