Dysregulation of Regional Endogenous Opioid Function in Borderline Personality Disorder

Participants were 18 right-handed female patients with borderline personality disorder (mean age=28 years [SD=9], mean educational level=14 years [SD=2]) and 14 age-matched healthy female comparison subjects (mean age=35 years [SD=10], mean educational level=17 years [SD=2]). Nine comparison subjects were in a previous study (19), and nine in a second study (20), with an overlap of 10 comparison subjects between the present study and previously published work; four comparison subjects were unique to this study. Axis I and axis II diagnoses were made via the Structured Clinical Interview for DSM-IV Axis I Disorders (25) and the Structured Clinical Interview for DSM-IV Axis II Disorders (26) and confirmed by an experienced clinician (K.R.S.). Patients with borderline personality disorder also met the DSM-IV borderline personality disorder criterion of affective instability. Exclusion criteria were concurrent axis I and III diagnoses (except for mood disorder); history of psychosis or head trauma; and current or recent (within 3 months) illicit substance use, abuse, or dependence. All participants were medication free for at least 3 months. Comprehensive urine drug screens were negative prior to the PET scan.

Participants completed the NEO Personality Inventory–Revised (NEO-PI-R; 27), the Barratt Impulsiveness Scale (28), and the Dissociative Experiences Scale (29) prior to scanning. To reduce phenotypic and neurobiological variability, only women were studied (30).

All participants provided written informed consent. Protocols were approved by the Investigational Review Board and the Radioactive Drug Research Committee at the University of Michigan.

Neutral and sadness states were randomized, counterbalanced, and initiated either 5 minutes or 45 minutes after administration of the radiotracer. During the neutral condition, participants were instructed to try to create passive relaxation while avoiding any active cognitive process. During sadness induction, participants recalled a previously rehearsed past autobiographical vignette associated with sadness. Both states were practiced prior to the actual scan and the specific events recorded. Participants rated their experience every 10 minutes on the sadness subscale of the Positive and Negative Affect Schedule (PANAS; 31) to ascertain maintenance of their emotional state; the subscale includes the adjectives "sad," "blue," "downhearted," "alone," and "lonely." The full PANAS (60 adjectives, 20 of which are grouped into two main affective subscales, positive and negative) was completed by participants at baseline and after completion of neutral and sadness states (45 minutes and 90 minutes after administration of the radiotracer).

One PET scan was acquired over 90 minutes with a Siemens (Knoxville, TN) HR+ scanner in three-dimensional mode (reconstructed full width at half maximum resolution, ∼5.5 mm). [¹¹C]carfentanil, a selective μ-opioid receptor radiotracer, was administered at a dose of 10–15 mCi and mass <0.03 μg/kg (tracer quantities). Acquisition, reconstruction, and emission image coregistration protocols were identical to those used in previous studies (19, 20).

Image data were transformed on a voxel-by-voxel basis into two sets of parametric maps: a tracer transport measure (K₁ ratio) and receptor-related measures during neutral and sadness states. To avoid arterial blood sampling, these measures were calculated employing a modified Logan graphical analysis (32) using the occipital cortex (an area devoid of μ-opioid receptors) as the reference region. The slope of the Logan plot is proportional to [(B_max/K_d) +1] for this receptor site (B_max= receptor concentration; K_d= receptor affinity for the radiotracer); B_max/K_d is the "in vivo receptor availability" measure, or nondisplaceable binding potential, BP_ND. With the bolus-continuous infusion protocol, the Logan plot becomes linear approximately 4–6 minutes after administration of the radiotracer, allowing for quantification of receptor sites. BP_ND values for neutral and sadness states were calculated from data from 10–45 minutes and 50–90 minutes after radiotracer administration. Anatomical MRI scans were acquired on a GE 3-T scanner (General Electric, Milwaukee). Acquisition sequences were axial spoiled gradient-recall acquisition (echo time=3.4 msec, repetition time=10.5 msec, inversion time=200 msec, flip angle =25°, number of excitations=1, using 124 contiguous images 1.5 mm thick). K₁ and BP_ND images for each experimental period and MR images were coregistered to each other and to the Montreal Neurological Institute (MNI) stereotactic atlas orientation (33). Statistical parametric maps of differences between conditions were generated by anatomically standardizing the T₁ spoiled gradient-recall acquisition MRI of each participant to the MNI stereotactic atlas coordinates, with subsequent application of this transformation to the receptor binding maps. The accuracy of coregistration and nonlinear warping algorithms was confirmed for each participant by comparing the transformed MRI and PET images to each other and to the atlas template.

Differences between groups and conditions were calculated with subtraction analyses and mapped into stereotactic space with t maps of statistical significance using the SPM2 (Wellcome Department of Cognitive Neurology, University College, London) and MATLAB (MathWorks, Natick, Mass.) software packages with a general linear model and correction for multiple comparisons. No global normalization was applied to the data; calculations presented are based on absolute BP_ND estimates. Only regions with specific μ-opioid receptor binding were included in the analyses (voxels with BP_ND values >0.1). Subtraction analyses were performed on μ-opioid BP_ND images separately to assess main effects. For each subtraction analysis, one-sample paired t values were calculated for each voxel using pooled variance across voxels. Significant differences were detected using a statistical threshold of p<0.0001 for regions known to be involved in opioid modulation of affective and stress responses (the rostral anterior cingulate, medial prefrontal and orbitofrontal cortex, inferior temporal cortex, insula, posterior thalamus, nucleus accumbens/ventral pallidum, and amygdala [19, 20]). Statistical thresholds for other regions were corrected for type I error rate at p=0.05 for multiple comparisons (34). The BP_ND values were extracted from image data by averaging the voxel values contained in an area where significant differences were obtained down to a threshold of p<0.01. These values were then used to plot the data and perform correlation analyses, ruling out the presence of outliers. Planned analyses included Spearman rank correlations between regional BP_ND values or sadness-induced changes in BP_ND and the NEO-PI-R neuroticism subscore, the Barratt Impulsiveness Scale score, and the Dissociative Experiences Scale score and change in PANAS scores at p<0.05 with subsequent Bonferroni corrections for multiple comparisons.

Baseline data (neutral state) comparisons between groups showed significantly greater μ-opioid BP_ND in borderline personality disorder patients in the orbitofrontal cortex bilaterally; the caudate nucleus bilaterally, extending into the nucleus accumbens on the right; the left nucleus accumbens; and the left amygdala (Table 1, Figure 2). These corresponded to average between-group differences of 44% and 47% for right and left orbitofrontal cortex, respectively; 44% and 32% for right and left caudate, respectively; 25% for left nucleus accumbens; and 35% for left amygdala. The comparison group demonstrated greater BP_ND in the posterior thalamus bilaterally (Table 1), corresponding to group differences of 39% on the right and 37% on the left.

No significant correlations were obtained between Barratt Impulsiveness Scale scores or NEO-PI-R neuroticism subscale scores and baseline regional μ-opioid BP_ND. Dissociative Experiences Scale scores were negatively correlated with BP_ND in the right caudate region (r=–0.57, p=0.02), but this correlation did not persist after correction for multiple comparisons.

Consistent with a previous report (19), significant regional increases in BP_ND were observed in the comparison group during the sadness state compared to the neutral state. These were localized in the pregenual and subgenual anterior cingulate (x, y, z coordinates in mm=3, 31, 4; cluster size=862 mm³; z=5.91; average change 20%), the right nucleus accumbens/ventral pallidum (x, y, z=3, –3, –5; cluster size=300 mm³; z=6.29; change 7%), the left nucleus accumbens (x, y, z=–16, 3, 1; cluster size=444 mm³; z=4.74; change 12%), and the right hypothalamus (x, y, z=3, –3, –5; cluster size=300 mm³; z=6.29; change 15%). This directionality (increase in BP_ND) is thought to reflect an acute reduction in endogenous opioid system tone (deactivation of neurotransmission) (19, 20).

The borderline personality disorder sample showed increases in BP_ND that were localized in the left nucleus accumbens (x, y, z=–8, 10, –11; cluster size=220 mm³; z=4.10; change 5%), the hypothalamus (x, y, z=–1, –3, –10; cluster size=506 mm³; z=4.42; change 5%), and an area of brainstem in the approximate location of the periaqueductal gray and subjacent dorsal raphe (x, y, z=4, –21, –10; cluster size=418 mm³; z=3.35; change 12%); the latter was not significant after correction for multiple comparisons.

Increases in negative affect during sadness were correlated with reductions in opioid neurotransmission in the hypothalamus area in the comparison group (r=0.57, p=0.03) but not in the borderline personality disorder group. No significant correlations were observed between regional opioid system deactivation and scores on the Barratt Impulsiveness Scale, the NEO-PI-R neuroticism subscale, or the Dissociative Experiences Scale.

In contrast to a previous report (19), healthy comparison subjects showed additional evidence of endogenous opioid system activation (reductions in BP_ND) in the left anterior thalamus (x, y, z=–11, 11, 18; cluster=13; z=5.16; 13% change), the left medial thalamus (x, y, z=–4, –10, 5; cluster=2066; z=5.65; 12% change), and the right hippocampus (x, y, z=29, –11, –24; cluster=632; z=5.16, p=0.013; 20% change). More widespread areas with a different regional distribution of endogenous opioid system activation during sadness were seen in the borderline personality disorder group. These included the left inferior temporal cortex (x, y, z=–24, 13, –33; cluster=64; z=5.43; 20% change), the left posterior thalamus (x, y, z=–15, –25, 17; cluster=113; z=4.87; 12% change), the right ventral pallidum (x, y, z=14, –1, -11; cluster=1481; z=5.98; 11% change), and the left amygdala (x, y, z=–21, 2, –19; cluster=81; z=4.56; 9% change). After correcting for multiple comparisons, no significant correlations between PANAS subscales or total scores and regional endogenous opioid system activation were observed for either group. No other correlations between endogenous opioid activation and other scales survived correction for multiple comparisons.

Borderline personality disorder patients demonstrated greater endogenous opioid system activation relative to comparison subjects during sadness in the pregenual anterior cingulate, left orbitofrontal cortex, left ventral pallidum, left amygdala, and left inferior temporal cortex (Table 2; Figure 3). In the opposite direction, significantly greater regional deactivation of opioid neurotransmission in borderline personality disorder patients relative to comparison subjects occurred in the left nucleus accumbens and the right hippocampus/parahippocampus (Table 2; Figure 4).

We observed greater baseline (neutral state) μ-opioid receptor availability in borderline personality disorder patients relative to comparison subjects in cortical (orbitofrontal cortex) and subcortical (caudate, nucleus accumbens, amygdala) regions. We hypothesized that greater receptor availability may occur because of lower baseline endogenous neurotransmitter tone. Increases in BP_ND may reflect increases in actual receptor protein or increases in the proportion of high-affinity receptors (i.e., coupled with transduction mechanisms) preferentially labeled by agonist radiotracers (37). Frequently these processes occur simultaneously and are interpreted as receptor up-regulation compensatory to lower endogenous opioid system tone. In rodent models, regional μ-opioid receptor protein and mRNA up-regulation have been described in response to social and experimental stress (38) and as a consequence of opioid peptide depletion (39). The opposite effect was observed in the posterior thalamus in humans, with reductions in μ-opioid BP_ND in borderline personality disorder. This coincides in location and directionality with effects found in major depressive disorder, related to poor antidepressant response and hyperactivity of the hypothalamic-pituitary-adrenal axis (19, 20).

Relative to comparison subjects, patients with borderline personality disorder demonstrated greater activation of the endogenous opioid system in response to sustained sadness in the pregenual anterior cingulate, left orbitofrontal cortex, left ventral pallidum, and left amygdala. These highly interconnected brain regions are implicated in evaluation and behavioral responses to salient stimuli and in decision making in healthy volunteers. Orbitofrontal cortex lesions are associated with poor decision making and difficulties in switching cognitive strategies (40). This region has extensive connections with the cingulate gyrus, nucleus accumbens, amygdala, hippocampus, and hypothalamus (41), which together form networks implicated in assessing saliency, intensity, and valence of rewards and stressors and in regulating behavioral responses (42, 43).

The left lateralization of many of the results is interesting. Left lateralization has been described during successful retrieval of emotional context in the amygdala and in frontotemporal networks (44).

Mu-opioid receptors in the ventral pallidum have been implicated in encoding hedonic value of rewards (45), regulation of midbrain dopaminergic inputs, and integration of amygdala and prefrontal cortex connections, affecting motivated behavior (46). Activation of the endogenous opioid system in the orbitofrontal cortex, anterior cingulate, thalamus, nucleus accumbens, ventral pallidum, and amygdala has been shown to suppress both physical and emotional aspects of stressful challenges (19, 22, 47). Consistent with those findings, we observed negative but nonsignificant correlations between endogenous opioid system activation in the left amygdala and Barratt Impulsiveness Scale scores in the borderline personality disorder group. There were also negative but nonsignificant correlations between left inferior temporal cortex activation and increases in negative affect during sadness, again suggesting that in borderline personality disorder the endogenous opioid system is involved in the suppression of emotional responses. This interpretation corresponds to reports of relief from aversive arousal during cutting and self-injury (48) and increased pain thresholds in patients with borderline personality disorder (23).

Patients with borderline personality disorder were also differentiated from comparison subjects by a relative deactivation of μ-opioid neurotransmission in the nucleus accumbens, the hippocampus/parahippocampus, and the hypothalamus. The nucleus accumbens is implicated in the assignment of salience to both positive and negative events (42). The hippocampus and parahippocampus have roles in explicit memory encoding and retrieval and in autonomic nervous system and neuroendocrine regulation through hypothalamic connections (49).

Brain regions where increases in neutral state μ-opioid receptor availability were observed largely overlapped with those in which greater endogenous opioid system activation was found during sadness induction. If increases in baseline receptor availability reflect lower basal levels of dynamic regulatory control of emotional states and stress by the typically suppressive μ-opioid system, the response of these circuits during recall of negative experiences would be consistent with exaggerated stress-like responses to emotional stimuli that were not observed in comparison subjects.

Greater μ-opioid availability and endogenous opioid release in response to painful stimuli appear to be associated to impulsivity traits in healthy volunteers in locations overlapping with our findings here (24). Serotonergic mechanisms, long implicated in borderline personality disorder pathophysiology (50, 51), along with dopaminergic systems, have been associated with various forms of impulsive behavior as well. Our findings are consonant with the concept that both borderline personality disorder and impulsivity are multifactorial, affecting relevant circuits and involving various neurotransmitter systems, including the endogenous opioid system (24). For example, well-described neurotransmitter-neurotransmitter interactions reveal regulation of serotonergic and dopaminergic cell firing by μ-opioid receptors in raphe (52) and ventral tegmental nuclei (53), respectively.

This study was limited by using small numbers of study subjects and including only women. While we think the findings are intriguing, we must be cautious in assuming that they are readily generalizable.

Linehan et al. (7) suggested that borderline personality disorder is characterized by a low threshold to becoming emotionally dysregulated, followed by a rise to high levels of emotional arousal, with a slow intensity decrement over time. Greater emotional lability and dysregulation may occur in patients with borderline personality disorder because they do not attribute the correct saliency to an emotional event or stimulus (greater nucleus accumbens deactivation). Once they overattribute an emotion to an event, they cannot shift away from that emotion or shift their emotional or interpersonal strategy (orbital frontal cortex overactivation), even when the strategy is not interpersonally productive. The stimulus may become encoded with much greater emotional intensity (amygdala-hippocampal effects) than it should have, leading to greater reactivity to future similar emotional events.

Overall, we have described initial evidence of regional alterations in the function of the endogenous opioid system and µ-opioid receptors in brain regions involved in emotion and stress processing, decision making, and pain and neuroendocrine regulation. Further investigation into interindividual variations of the µ-opioid system is warranted.