Ventral Basal Ganglia Research Articles

Updating the striatal-pallidal wiring diagram.

The striatal and pallidal complexes are basal ganglia structures that orchestrate learning and execution of flexible behavior. Models of how the basal ganglia subserve these functions have evolved considerably, and the advent of optogenetic and molecular tools has shed light on the heterogeneity of subcircuits within these pathways. However, a synthesis of how molecularly diverse neurons integrate into existing models of basal ganglia function is lacking. Here, we provide an overview of the neurochemical and molecular diversity of striatal and pallidal neurons and synthesize recent circuit connectivity studies in rodents that takes this diversity into account. We also highlight anatomical organizational principles that distinguish the dorsal and ventral basal ganglia pathways in rodents. Future work integrating the molecular and anatomical properties of striatal and pallidal subpopulations may resolve controversies regarding basal ganglia network function.

Ventral pallidal regulation of motivated behaviors and reinforcement.

The interconnected nuclei of the ventral basal ganglia have long been identified as key regulators of motivated behavior, and dysfunction of this circuit is strongly implicated in mood and substance use disorders. The ventral pallidum (VP) is a central node of the ventral basal ganglia, and recent studies have revealed complex VP cellular heterogeneity and cell- and circuit-specific regulation of reward, aversion, motivation, and drug-seeking behaviors. Although the VP is canonically considered a relay and output structure for this circuit, emerging data indicate that the VP is a central hub in an extensive network for reward processing and the regulation of motivation that extends beyond classically defined basal ganglia borders. VP neurons respond temporally faster and show more advanced reward coding and prediction error processing than neurons in the upstream nucleus accumbens, and regulate the activity of the ventral mesencephalon dopamine system. This review will summarize recent findings in the literature and provide an update on the complex cellular heterogeneity and cell- and circuit-specific regulation of motivated behaviors and reinforcement by the VP with a specific focus on mood and substance use disorders. In addition, we will discuss mechanisms by which stress and drug exposure alter the functioning of the VP and produce susceptibility to neuropsychiatric disorders. Lastly, we will outline unanswered questions and identify future directions for studies necessary to further clarify the central role of VP neurons in the regulation of motivated behaviors. Significance: Research in the last decade has revealed a complex cell- and circuit-specific role for the VP in reward processing and the regulation of motivated behaviors. Novel insights obtained using cell- and circuit-specific interrogation strategies have led to a major shift in our understanding of this region. Here, we provide a comprehensive review of the VP in which we integrate novel findings with the existing literature and highlight the emerging role of the VP as a linchpin of the neural systems that regulate motivation, reward, and aversion. In addition, we discuss the dysfunction of the VP in animal models of neuropsychiatric disorders.

Research Note: Functional Connectivity Between a Corticostriatal Network and the Cerebellum.

Basal ganglia and cerebellum are structurally and functionally connected in animals. In humans, tractography and seed-based functional connectivity have confirmed this cerebellar-striatal relation. Independent component analysis (ICA) showed that both cerebellum and basal ganglia take part in distinct intrinsic networks. Probabilistic ICA analysis was applied to the brain images of 15 healthy volunteers during the resting state and using a 3T MRI. A spatial map corresponding to dorsal and ventral basal ganglia circuits was also found to be in functional coherence with crus 2, especially with its vermal region. It is speculated that such cerebellar-basal ganglionic rsFC could reflect structural interconnections traced in animals and explain reward-based activity detected in the cerebellum.

'Feedback' for feeding.

A new study discovered that ventral pallidal neurons projecting back to the nucleus accumbens promote consumption. The findings call into question the accepted direction of information flow through the ventral basal ganglia and open new avenues for studying how consumption is regulated in proportion to subjective value.

Acute changes in cerebral blood flow after single-infusion ketamine in major depression: A pilot study

BackgroundKetamine provides rapid antidepressant response in those struggling with major depressive disorder (MDD). This study measured acute changes in brain activity over 24 h after a single infusion of ketamine using arterial spin labeled (ASL) functional magnetic resonance imaging (fMRI) in patients with MDD. ASL is a novel technique that provides quantitative values to measure cerebral blood flow (CBF). MethodsA single sub-anesthetic dose (0.5 mg/kg) of ketamine was delivered intravenously. Treatment-refractory patients (n = 11) were assessed at: Baseline (pre-infusion), and approximately 1 h, 6 h, and 24 h post-infusion. Linear mixed-effects models detected changes in CBF with respect to treatment outcome, and results were corrected for false discovery rate (FDR). ResultsAfter ketamine infusion, increased CBF was observed in the thalamus, while decreased CBF was observed in lateral occipital cortex in all patients. Time-by-response interactions were noted in ventral basal ganglia and medial prefrontal cortex, where CBF change differed according to antidepressant response. LimitationsModest sample size is a limitation of this pilot study; strict statistical correction and visualization of single-subject data attempted to ameliorate this issue. ConclusionIn this pilot study, a sub-anesthetic dose of ketamine was associated with acute neurofunctional changes that may be consistent with altered attention, specifically increased thalamus activity coupled with decreased cortical activity. By contrast, antidepressant response to ketamine was associated with changes in reward-system regions, specifically ventral basal ganglia and medial prefrontal cortex. Further work is needed to determine whether these results generalize to larger samples and/or serial ketamine infusions associated with longer-lasting clinical effects.

Complementary Roles for Ventral Pallidum Cell Types and Their Projections in Relapse.

The ventral pallidum (VP) is a key node in the neural circuits controlling relapse to drug seeking. How this role relates to different VP cell types and their projections is poorly understood. Using male rats, we show how different forms of relapse to alcohol-seeking are assembled from VP cell types and their projections to lateral hypothalamus (LH) and ventral tegmental area (VTA). Using RNAScope in situ hybridization to characterize activity of different VP cell types during relapse to alcohol-seeking provoked by renewal (context-induced reinstatement), we found that VP Gad1 and parvalbumin (PV), but not vGlut2, neurons show relapse-associated changes in c-Fos expression. Next, we used retrograde tracing, chemogenetic, and electrophysiological approaches to study the roles of VPGad1 and VPPV neurons in relapse. We show that VPGad1 neurons contribute to contextual control over relapse (renewal), but not to relapse during reacquisition, via projections to LH, where they converge with ventral striatal inputs onto LHGad1 neurons. This convergence of striatopallidal inputs at the level of individual LHGad1 neurons may be critical to balancing propensity for relapse versus abstinence. In contrast, VPPV neurons contribute to relapse during both renewal and reacquisition via projections to VTA. These findings identify a double dissociation in the roles for different VP cell types and their projections in relapse. VPGad1 neurons control relapse during renewal via projections to LH. VPPV neurons control relapse during both renewal and reacquisition via projections to VTA. Targeting these different pathways may provide tailored interventions for different forms of relapse.SIGNIFICANCE STATEMENT Relapse to drug or reward seeking after a period of extinction or abstinence remains a key impediment to successful treatment. The ventral pallidum, located in the ventral basal ganglia, has long been recognized as an obligatory node in a 'final common pathway' for relapse. Yet how this role relates to the considerable VP cellular and circuit heterogeneity is not well understood. We studied the cellular and circuit architecture for VP in relapse control. We show that different forms of relapse have complementary VP cellular and circuit architectures, raising the possibility that targeting these different neural architectures may provide tailored interventions for different forms of relapse.

Ventral pallidum encodes relative reward value earlier and more robustly than nucleus accumbens

The ventral striatopallidal system, a basal ganglia network thought to convert limbic information into behavioral action, includes the nucleus accumbens (NAc) and the ventral pallidum (VP), typically described as a major output of NAc. Here, to investigate how reward-related information is transformed across this circuit, we measure the activity of neurons in NAc and VP when rats receive two highly palatable but differentially preferred rewards, allowing us to track the reward-specific information contained within the neural activity of each region. In VP, we find a prominent preference-related signal that flexibly reports the relative value of reward outcomes across multiple conditions. This reward-specific firing in VP is present in a greater proportion of the population and arises sooner following reward delivery than in NAc. Our findings establish VP as a preeminent value signaler and challenge the existing model of information flow in the ventral basal ganglia.

Songbird Ventral Basal Ganglia Sends Performance Error Signals to Dopaminergic Midbrain

Ventral tegmental area (VTA) dopamine neurons signal prediction error, the difference between actual and predicted outcome, but it remains unclear how error is computed. Here we identify in songbirds a ventral basal ganglia (vBG) region that is required for song learning and that sends prediction error signals to VTA. During singing, vBG neurons heterogeneously encoded song timing, auditory error, predicted error, and the difference between the two (prediction error). Viral tracing revealed inputs to vBG from auditory and vocal motor thalamus, auditory and vocal motor cortex, and VTA. Our findings reveal a classic actor-critic circuit motif in which a ventral critic learns the ‘prediction’ component of a prediction error signal that is relayed by VTA to a dorsal actor (the vocal motor BG nucleus Area X). A circuit motif for computing reward prediction error can compute predicted performance quality during motor sequence learning.

Mapping anhedonia-specific dysfunction in a transdiagnostic approach: an ALE meta-analysis.

Anhedonia is a prominent symptom in neuropsychiatric disorders, most markedly in major depressive disorder (MDD) and schizophrenia (SZ). Emerging evidence indicates an overlap in the neural substrates of anhedonia between MDD and SZ, which supported a transdiagnostic approach. Therefore, we used activation likelihood estimation (ALE) meta-analysis of functional magnetic resonance imaging studies in MDD and SZ to examine the neural bases of three subdomains of anhedonia: consummatory anhedonia, anticipatory anhedonia and emotional processing. ALE analysis focused specifically on MDD or SZ was used later to dissociate specific anhedonia-related neurobiological impairments from potential disease general impairments. ALE results revealed that consummatory anhedonia was associated with decreased activation in ventral basal ganglia areas, while anticipatory anhedonia was associated with more substrates in frontal-striatal networks except the ventral striatum, which included the dorsal anterior cingulate, middle frontal gyrus and medial frontal gyrus. MDD and SZ patients showed similar neurobiological impairments in anticipatory and consummatory anhedonia, but differences in the emotional experience task, which may also involve affective/mood general processing. These results support that anhedonia is characterized by alterations in reward processing and relies on frontal-striatal brain circuitry. The transdiagnostic approach is a promising way to reveal the overall neurobiological framework that contributes to anhedonia and could help to improve targeted treatment strategies.Electronic supplementary materialThe online version of this article (doi:10.1007/s11682-015-9457-6) contains supplementary material, which is available to authorized users.

Default mode network, motor network, dorsal and ventral basal ganglia networks in the rat brain: comparison to human networks using resting state-fMRI.

Rodent models are developed to enhance understanding of the underlying biology of different brain disorders. However, before interpreting findings from animal models in a translational aspect to understand human disease, a fundamental step is to first have knowledge of similarities and differences of the biological systems studied. In this study, we analyzed and verified four known networks termed: default mode network, motor network, dorsal basal ganglia network, and ventral basal ganglia network using resting state functional MRI (rsfMRI) in humans and rats. Our work supports the notion that humans and rats have common robust resting state brain networks and that rsfMRI can be used as a translational tool when validating animal models of brain disorders. In the future, rsfMRI may be used, in addition to short-term interventions, to characterize longitudinal effects on functional brain networks after long-term intervention in humans and rats.

Neuroanatomy of Individual Differences in Language in Adult Males with Autism.

One potential source of heterogeneity within autism spectrum conditions (ASC) is language development and ability. In 80 high-functioning male adults with ASC, we tested if variations in developmental and current structural language are associated with current neuroanatomy. Groups with and without language delay differed behaviorally in early social reciprocity, current language, but not current autistic features. Language delay was associated with larger total gray matter (GM) volume, smaller relative volume at bilateral insula, ventral basal ganglia, and right superior, middle, and polar temporal structures, and larger relative volume at pons and medulla oblongata in adulthood. Despite this heterogeneity, those with and without language delay showed significant commonality in morphometric features when contrasted with matched neurotypical individuals (n = 57). In ASC, better current language was associated with increased GM volume in bilateral temporal pole, superior temporal regions, dorsolateral fronto-parietal and cerebellar structures, and increased white matter volume in distributed frontal and insular regions. Furthermore, current language–neuroanatomy correlation patterns were similar across subgroups with or without language delay. High-functioning adult males with ASC show neuroanatomical variations associated with both developmental and current language characteristics. This underscores the importance of including both developmental and current language as specifiers for ASC, to help clarify heterogeneity.

Haloperidol blocks dorsal striatum activity but not analgesia in a placebo paradigm

Although placebo analgesia has been associated with an engagement of the endogenous opioid system there is growing evidence from neuropharmacological studies for an involvement of additional neurotransmitter systems. An increased dopaminergic neurotransmission in the ventral basal ganglia that has been found during placebo analgesia suggests a role for the dopaminergic system (Scott et al., 2007). It is, however, unclear whether striatal dopaminergic activity is causally involved in this type of analgesia. This study aimed at exploring the functional role of the dopaminergic system in placebo analgesia. To this end, we investigated the effect of the dopamine D2/D3 receptor antagonist haloperidol on behavioral and neural measures of placebo analgesia using functional magnetic resonance imaging (fMRI) in healthy volunteers. We found that 2 mg haloperidol p.o. significantly reduced the correlation between dorsal striatum activity and the individual placebo response, but had no significant effect on placebo analgesia at the behavioral or neural level, as indexed by activity in sensory or pain-modulatory brain regions.Our study therefore suggests that dopaminergic neurotransmission might not be causally involved in placebo analgesia but is related to phenomena associated with placebo analgesia such as reward processing and learning.

Deep brain stimulation of the subthalamic nucleus reestablishes neuronal information transmission in the 6-OHDA rat model of parkinsonism

Pathophysiological activity of basal ganglia neurons accompanies the motor symptoms of Parkinson's disease. High-frequency (>90 Hz) deep brain stimulation (DBS) reduces parkinsonian symptoms, but the mechanisms remain unclear. We hypothesize that parkinsonism-associated electrophysiological changes constitute an increase in neuronal firing pattern disorder and a concomitant decrease in information transmission through the ventral basal ganglia, and that effective DBS alleviates symptoms by decreasing neuronal disorder while simultaneously increasing information transfer through the same regions. We tested these hypotheses in the freely behaving, 6-hydroxydopamine-lesioned rat model of hemiparkinsonism. Following the onset of parkinsonism, mean neuronal firing rates were unchanged, despite a significant increase in firing pattern disorder (i.e., neuronal entropy), in both the globus pallidus and substantia nigra pars reticulata. This increase in neuronal entropy was reversed by symptom-alleviating DBS. Whereas increases in signal entropy are most commonly indicative of similar increases in information transmission, directed information through both regions was substantially reduced (>70%) following the onset of parkinsonism. Again, this decrease in information transmission was partially reversed by DBS. Together, these results suggest that the parkinsonian basal ganglia are rife with entropic activity and incapable of functional information transmission. Furthermore, they indicate that symptom-alleviating DBS works by lowering the entropic noise floor, enabling more information-rich signal propagation. In this view, the symptoms of parkinsonism may be more a default mode, normally overridden by healthy basal ganglia information. When that information is abolished by parkinsonian pathophysiology, hypokinetic symptoms emerge.

Timing and expectation of reward: a neuro-computational model of the afferents to the ventral tegmental area

Neural activity in dopaminergic areas such as the ventral tegmental area is influenced by timing processes, in particular by the temporal expectation of rewards during Pavlovian conditioning. Receipt of a reward at the expected time allows to compute reward-prediction errors which can drive learning in motor or cognitive structures. Reciprocally, dopamine plays an important role in the timing of external events. Several models of the dopaminergic system exist, but the substrate of temporal learning is rather unclear. In this article, we propose a neuro-computational model of the afferent network to the ventral tegmental area, including the lateral hypothalamus, the pedunculopontine nucleus, the amygdala, the ventromedial prefrontal cortex, the ventral basal ganglia (including the nucleus accumbens and the ventral pallidum), as well as the lateral habenula and the rostromedial tegmental nucleus. Based on a plausible connectivity and realistic learning rules, this neuro-computational model reproduces several experimental observations, such as the progressive cancelation of dopaminergic bursts at reward delivery, the appearance of bursts at the onset of reward-predicting cues or the influence of reward magnitude on activity in the amygdala and ventral tegmental area. While associative learning occurs primarily in the amygdala, learning of the temporal relationship between the cue and the associated reward is implemented as a dopamine-modulated coincidence detection mechanism in the nucleus accumbens.

Poor reward sensitivity and apathy after stroke

To examine the relationship between reward sensitivity and self-reported apathy in stroke patients and to investigate the neuroanatomical correlates of both reward sensitivity and apathy. In this prospective study, 55 chronic stroke patients were administered a questionnaire to assess apathy and a laboratory task to examine reward sensitivity by measuring motivationally driven behavior ("reinforcement-related speeding"). Fifteen participants without brain damage served as controls for the laboratory task. Negative mood, working memory, and global cognitive functioning were also measured to determine whether reward insensitivity and apathy were secondary to cognitive impairments or negative mood. Voxel-based lesion-symptom mapping was used to explore the neuroanatomical substrates of reward sensitivity and apathy. Participants showed reinforcement-related speeding in the highly reinforced condition of the laboratory task. However, this effect was significant for the controls only. For patients, poorer reward sensitivity was associated with greater self-reported apathy (p < 0.05) beyond negative mood and after lesion size was controlled for. Neither apathy nor reward sensitivity was related to working memory or global cognitive functioning. Voxel-based lesion-symptom mapping showed that damage to the ventral putamen and globus pallidus, dorsal thalamus, and left insula and prefrontal cortex was associated with poorer reward sensitivity. The putamen and thalamus were also involved in self-reported apathy. Poor reward sensitivity in stroke patients with damage to the ventral basal ganglia, dorsal thalamus, insula, or prefrontal cortex constitutes a core feature of apathy. These results provide valuable insight into the neural mechanisms and brain substrate underlying apathy.

Imaging Social Motivation: Distinct Brain Mechanisms Drive Effort Production during Collaboration versus Competition

Collaborative and competitive interactions have been investigated extensively so as to understand how the brain makes choices in the context of strategic games, yet such interactions are known to influence a more basic dimension of behavior: the energy invested in the task. The cognitive mechanisms that motivate effort production in social situations remain poorly understood, and their neural counterparts have not been explored so far. A dominant idea is that the motivation provided by the social context is reducible to the personal utility of effort production, which decreases in collaboration and increases in competition. Using functional magnetic resonance imaging, we scanned human participants while they produced a physical effort in a collaborative or competitive context. We found that motivation was indeed primarily driven by personal utility, which was reflected in brain regions devoted to reward processing (the ventral basal ganglia). However, subjects who departed from utility maximization, working more in collaborative situations, showed greater functional activation and anatomical volume in a brain region implicated previously in social cognition (the temporoparietal junction). Therefore, this region might mediate a purely pro-social motivation to produce greater effort in the context of collaboration. More generally, our findings suggest that the individual propensity to invest energy in collaborative work might have an identifiable counterpart in the brain functional architecture.

Dissociable cortical and ventral striatal responses to painful somatosensory stimulation measured using functional MRI imaging

INTRODUCTION Investigation of the neural responses of chronic pain have traditionally involved establishing the BOLD fMRI response to acute pain in a nodal network that has been referred to as the ‘pain matrix’ or the ‘pain neuromatrix’ (1). However, Melzack originally used the term ‘matrix’ because the system to which he referred was multimodal in function and lacked specificity. This might explain why, over 20 years after the term was coined, there has been little translational benefit to patients in terms of improved management of chronic pain states despite numerous studies examining the ‘pain matrix response’. The basal ganglia form part of this matrix and are worthy of further investigation. Destruction of nigrostriatal neurones in the ventral basal ganglia are associated with reduced pain thresholds, the inverse effect occurring with nigrostriatal stimulation(2). However, inactivation of the accumbens core in the ventral basal ganglia with local anaesthetic has demonstrated a hyperalgesic response (3). Molecular imaging has been used to examine the differential roles of dorsal and ventral basal ganglia in pain perception (4) . These authors found that whilst nigrostriatal D2-dopamine activity correlates with sensory and affective ratings, in accumbens the dopamine response is positively associated with negative affect and fear ratings during pain, aspects of the pain experience that are thought to better explain interindividual variations in chronic pain (5) and response to analgesia. In establishing a region of interest approach to the investigation of chronic pain through the application of acutely painful stimuli, the ventral striatum may therefore be an important target. The role of the ventral striatum in response to aversive stimuli is receiving increasing attention, in counterpart to studies of its responsivity to rewarding stimuli. Recent work (6) suggests that the differential striatal responses to acute pain may provide a meaningful insight into the neural substrates of chronic pain perception, including idiopathic pain disorders and the functional somatic syndromes, where activation of the ‘pain matrix’ as a whole has proved unable to. We have investigated the brain response to somatosensory pain, specifically examining the response of the ventral striatum in contrast to other components of the ‘pain matrix’.

Individual differences in brain structure underpin empathizing-systemizing cognitive styles in male adults.

Individual differences in cognitive style can be characterized along two dimensions: ‘systemizing’ (S, the drive to analyze or build ‘rule-based’ systems) and ‘empathizing’ (E, the drive to identify another's mental state and respond to this with an appropriate emotion). Discrepancies between these two dimensions in one direction (S > E) or the other (E > S) are associated with sex differences in cognition: on average more males show an S > E cognitive style, while on average more females show an E > S profile. The neurobiological basis of these different profiles remains unknown. Since individuals may be typical or atypical for their sex, it is important to move away from the study of sex differences and towards the study of differences in cognitive style. Using structural magnetic resonance imaging we examined how neuroanatomy varies as a function of the discrepancy between E and S in 88 adult males from the general population. Selecting just males allows us to study discrepant E-S profiles in a pure way, unconfounded by other factors related to sex and gender. An increasing S > E profile was associated with increased gray matter volume in cingulate and dorsal medial prefrontal areas which have been implicated in processes related to cognitive control, monitoring, error detection, and probabilistic inference. An increasing E > S profile was associated with larger hypothalamic and ventral basal ganglia regions which have been implicated in neuroendocrine control, motivation and reward. These results suggest an underlying neuroanatomical basis linked to the discrepancy between these two important dimensions of individual differences in cognitive style.

Neural Mechanisms Underlying Motivation of Mental Versus Physical Effort

Mental and physical efforts, such as paying attention and lifting weights, have been shown to involve different brain systems. These cognitive and motor systems, respectively, include cortical networks (prefronto-parietal and precentral regions) as well as subregions of the dorsal basal ganglia (caudate and putamen). Both systems appeared sensitive to incentive motivation: their activity increases when we work for higher rewards. Another brain system, including the ventral prefrontal cortex and the ventral basal ganglia, has been implicated in encoding expected rewards. How this motivational system drives the cognitive and motor systems remains poorly understood. More specifically, it is unclear whether cognitive and motor systems can be driven by a common motivational center or if they are driven by distinct, dedicated motivational modules. To address this issue, we used functional MRI to scan healthy participants while performing a task in which incentive motivation, cognitive, and motor demands were varied independently. We reasoned that a common motivational node should (1) represent the reward expected from effort exertion, (2) correlate with the performance attained, and (3) switch effective connectivity between cognitive and motor regions depending on task demand. The ventral striatum fulfilled all three criteria and therefore qualified as a common motivational node capable of driving both cognitive and motor regions of the dorsal striatum. Thus, we suggest that the interaction between a common motivational system and the different task-specific systems underpinning behavioral performance might occur within the basal ganglia.

Association of Plasma Interleukin-18 Levels with Emotion Regulation and μ-Opioid Neurotransmitter Function in Major Depression and Healthy Volunteers

Alterations in central neurotransmission and immune function have been documented in major depression (MDD). Central and peripheral endogenous opioids are linked to immune functioning in animal models, stress-activated, and dysregulated in MDD. We examined the relationship between μ-opioid receptor (OR)-mediated neurotransmission and a proinflammatory cytokine (interleukin [IL]-18). We studied 28 female subjects (14 MDDs, 14 control subjects) with positron emission tomography and [(11)C] carfentanil (μ-OR selective) during neutral and sadness states. With a simple regression model in SPM2 (Wellcome Trust, London, England) we identified brain regions where baseline μ-OR availability (nondisplaceable binding potential [BP(ND)]) and sadness-induced changes in μ-OR BP(ND) were associated with baseline IL-18. Baseline IL-18 was greater in MDDs than control subjects [t(25) = 2.13, p = .04]. In control subjects IL-18 was correlated with negative emotional ratings at baseline and during sadness induction. In MDDs, IL-18 was positively correlated with baseline regional μ-OR BP(ND) and with sadness-induced μ-opioid system activation in the subgenual anterior cingulate, ventral basal ganglia, and amygdala. This study links plasma IL-18 with sadness-induced emotional responses in healthy subjects, the diagnosis of MDD, and μ-opioid functioning, itself involved in stress adaptation, emotion regulation, and reward. This suggests that IL-18 represents a marker associated with emotion regulation/dysregulation at least in part through central opioid mechanisms.