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1.  Valence-Specific Effects of BDNF Val66Met Polymorphism on Dopaminergic Stress and Reward Processing in Humans 
The Journal of Neuroscience  2014;34(17):5874-5881.
Brain-derived neurotrophic factor (BDNF) levels in dopaminergic (DA) cells within the ventral tegmental area (VTA)/nucleus accumbens (NAc) circuitry appear to be a candidate mechanism for the neuroadaptive changes that follow stress and reward responses in animal models. However, the role of the BDNF gene variants in responses to salient cues through DA neurotransmission in humans remains unexplored. Here, we studied the effect of the common functional BDNF Val66Met (rs6265) polymorphism on rewarding experiences in the striatum and DA-mediated responses to stress. Seventy-two healthy controls were genotyped for the BDNF Val66Met polymorphism and underwent the monetary incentive delay task during an functional magnetic resonance imaging (fMRI) session. Forty-nine of them also underwent a sustained pain challenge with and without placebo administration with potential analgesic properties during PET measures of DA D2/3-receptor-mediated neurotransmission. Neuroimaging results revealed a significant effect of BDNF (Met66 carriers > Val/Val) on brain responses during the anticipation of monetary losses, baseline D2/3 receptor availability, and pain-stress-induced DA release in the NAc. Conversely, BDNF Met66 carriers showed no activation in response to monetary gains and a blunted DA response to the analgesic placebo in the NAc. These results provide initial human evidence regarding the effect of the BDNF Val66Met polymorphism on DA-mediated responses to stress, its cognitive regulation by positive expectations, and the anticipatory responses to monetary gains and losses in the VTA-NAc pathway. Our results are of relevance to the neurobiology of stress and reward interactions and the pathophysiology of stress-related disorders.
doi:10.1523/JNEUROSCI.2152-13.2014
PMCID: PMC3996214  PMID: 24760847
BDNF Val66Met; dopamine; nucleus accumbens; pain; reward; stress
2.  Role of μ-Opioid System in the Formation of Memory of Placebo Responses 
Molecular psychiatry  2012;18(2):135-137.
The endogenous opioid system is centrally involved in short-term placebo analgesic effects, but its potential regulation of memory and learning circuits, critical for the sustainability of placebo responses, has not been explored. Here we examined the recall of analgesic effects after placebo administration as a function of its initial capacity to activate μ-opioid neurotransmission. Memories of therapeutic/adverse responses 24 hours after placebo administration were associated with differences in μ-opioid neurotransmission in the Papez circuit, VTA, amygdala and septum. These data suggests that μ-opioid neurotransmission is involved in the recall of therapeutic benefit, providing a framework to understand stimulus learning and long-term therapeutic effect associations.
doi:10.1038/mp.2012.16
PMCID: PMC4152848  PMID: 22430673
placebo; analgesia; μ-opioid receptor; recall; memory
3.  Real-Time Sharing and Expression of Migraine Headache Suffering on Twitter: A Cross-Sectional Infodemiology Study 
Background
Although population studies have greatly improved our understanding of migraine, they have relied on retrospective self-reports that are subject to memory error and experimenter-induced bias. Furthermore, these studies also lack specifics from the actual time that attacks were occurring, and how patients express and share their ongoing suffering.
Objective
As technology and language constantly evolve, so does the way we share our suffering. We sought to evaluate the infodemiology of self-reported migraine headache suffering on Twitter.
Methods
Trained observers in an academic setting categorized the meaning of every single “migraine” tweet posted during seven consecutive days. The main outcome measures were prevalence, life-style impact, linguistic, and timeline of actual self-reported migraine headache suffering on Twitter.
Results
From a total of 21,741 migraine tweets collected, only 64.52% (14,028/21,741 collected tweets) were from users reporting their migraine headache attacks in real-time. The remainder of the posts were commercial, re-tweets, general discussion or third person’s migraine, and metaphor. The gender distribution available for the actual migraine posts was 73.47% female (10,306/14,028), 17.40% males (2441/14,028), and 0.01% transgendered (2/14,028). The personal impact of migraine headache was immediate on mood (43.91%, 6159/14,028), productivity at work (3.46%, 486/14,028), social life (3.45%, 484/14,028), and school (2.78%, 390/14,028). The most common migraine descriptor was “Worst” (14.59%, 201/1378) and profanity, the “F-word” (5.3%, 73/1378). The majority of postings occurred in the United States (58.28%, 3413/5856), peaking on weekdays at 10:00h and then gradually again at 22:00h; the weekend had a later morning peak.
Conclusions
Twitter proved to be a powerful source of knowledge for migraine research. The data in this study overlap large-scale epidemiological studies, avoiding memory bias and experimenter-induced error. Furthermore, linguistics of ongoing migraine reports on social media proved to be highly heterogeneous and colloquial in our study, suggesting that current pain questionnaires should undergo constant reformulations to keep up with modernization in the expression of pain suffering in our society. In summary, this study reveals the modern characteristics and broad impact of migraine headache suffering on patients’ lives as it is spontaneously shared via social media.
doi:10.2196/jmir.3265
PMCID: PMC4004155  PMID: 24698747
migraine; headache; epidemiology; social media; Twitter
4.  Alterations in Endogenous Opioid Functional Measures in Chronic Back Pain 
The Journal of Neuroscience  2013;33(37):14729-14737.
The absence of consistent end organ abnormalities in many chronic pain syndromes has led to a search for maladaptive CNS mechanisms that may explain their clinical presentations and course. Here, we addressed the role of brain regional μ-opioid receptor-mediated neurotransmission, one of the best recognized mechanisms of pain regulation, in chronic back pain in human subjects. We compared μ-opioid receptor availability in vivo at baseline, during pain expectation, and with moderate levels of sustained pain in 16 patients with chronic nonspecific back pain (CNBP) and in 16 age- and gender-matched healthy control subjects, using the μ-opioid receptor-selective radioligand [11C]carfentanil and positron emission tomography. We found that CNBP patients showed baseline increases in thalamic μ-opioid receptor availability, contrary to a previously studied sample of patients diagnosed with fibromyalgia. During both pain expectation and sustained pain challenges, CNBP patients showed regional reductions in the capacity to activate this neurotransmitter system compared with their control sample, further associated with clinical pain and affective state ratings. Our results demonstrate heterogeneity in endogenous opioid system functional measures across pain conditions, and alterations in both receptor availability and endogenous opioid function in CNBP that are relevant to the clinical presentation of these patients and the effects of opioid analgesics on μ-opioid receptors.
doi:10.1523/JNEUROSCI.1400-13.2013
PMCID: PMC3771036  PMID: 24027273
5.  DRD2 polymorphisms modulate reward and emotion processing, dopamine neurotransmission and openness to experience 
Dopamine (DA) neurotransmission through D2 receptors (DRD2) has been implicated in the regulation of reward processing, cognition and the effects of drugs of abuse, and also has significant effects in responses to stressors and salient aversive stimuli. An examination of the influence of genetic variation across multiple psychophysical measures therefore appears critical to understand the neurobiology of DA-modulated complex personality traits and psychiatric illnesses. To examine interindividual variation in the function of DRD2 modulated mechanisms in healthy humans, we used a haplotype-based and single nucleotide polymorphism (SNP) investigation. Their effects were interrogated with functional magnetic resonance imaging (fMRI) during reward and emotional processing. We found that a haplotype block composed by two SNPs, rs4274224 and rs4581480, affected the hemodynamic responses of the dorsolateral prefrontal cortex (DLPFC) during reward expectation and the subgenual anterior cingulate cortices (sgACC) during implicit emotional processing. Exploratory analysis within the significant haplotype block revealed the same functional effects only for the SNP rs4274224. Further analysis on rs4274224 using functional connectivity and positron emission tomography (PET) measures of DA D2/3 receptor mediated neurotransmission confirmed a gene effect on the functional connectivity of the DLPFC during reward anticipation and subcortical stress induced dopamine release. At a phenotypic trait level, significant effects of genotype were obtained for the NEO PI-R “Openness to Experience” and further correlated with neuroimaging data. Overall, these results show significant neurobiological effects of genotype variation in DRD2 on multiple functional domains, such as emotional, stress and reward processing. As such, it contributes to normal variation and potentially to vulnerability to psychopathology associated with those functions, such as risk for mood and substance use disorders.
doi:10.1016/j.cortex.2012.01.010
PMCID: PMC3381848  PMID: 22424959
imaging; dopamine; DLPFC; reward; emotion
6.  Variation in the Corticotropin-Releasing Hormone Receptor 1 (CRHR1) Gene influences fMRI Signal Responses during Emotional Stimulus Processing 
The Journal of Neuroscience  2012;32(9):3253-3260.
The corticotropin-releasing hormone (CRH) system coordinates neuroendocrine and behavioral responses to stress and has been implicated in the development of major depressive disorder (MDD). Recent reports suggest that GG-homozygous individuals of a single nucleotide polymorphism (rs110402) in the CRH receptor 1 (CRHR1) gene show behavioral and neuroendocrine evidence of stress vulnerability. The present study explores whether those observations extend to the neuronal processing of emotional stimuli in humans. CRHR1 was genotyped in 83 controls and preliminary sample of 16 unmedicated patients with MDD who completed a functional magnetic resonance imaging scan while viewing blocks of positive, negative, and neutral words. In addition, potential mediating factors such as early life stress, sex, personality traits, and negative memory bias were examined. Robust differences in blood oxygenation-level dependent (BOLD) signal were found in healthy controls (A allele carriers > GG-homozygotes) while viewing negative versus neutral words in the right middle temporal/angular gyrus. Among GG-homozygotes, BOLD signal in the subgenual cingulate was greater in MDD participants (n = 9) compared to controls (n = 33). Conversely, among A-carriers, BOLD signal was smaller in MDD (n = 7) compared to controls (n = 50) in the hypothalamus, bilateral amygdala, and left nucleus accumbens. Early life stress, personality traits, and levels of negative memory bias were associated with brain activity depending on genotype. Results from healthy controls and a preliminary sample of MDD participants show that CRHR1 SNP rs110402 moderates neural responses to emotional stimuli, suggesting a potential mechanism of vulnerability for the development of MDD.
doi:10.1523/JNEUROSCI.5533-11.2012
PMCID: PMC3297975  PMID: 22378896
7.  FMRI BOLD responses to negative stimuli in the prefrontal cortex are dependent on levels of recent negative life stress in major depressive disorder 
Psychiatry research  2010;183(3):202-208.
It is poorly understood how stressors modulate neurobiological mechanisms that may contribute to the heterogeneity of Major Depressive Disorder (MDD). Unmedicated patients diagnosed with MDD (n = 15) and individually matched healthy controls (n = 15) completed stress questionnaires and were studied with functional magnetic resonance imaging while viewing emotional words. Significant effects of recent negative life stressors, but not early life stress/trauma, were observed on regional blood oxygen level dependent activity during presentation of negative words in patients with MDD. No significant effects of stress on brain activation to negative words were found in controls. In MDD patients, positive correlations were found bilaterally in orbitofrontal areas 11l/47/12m, which are involved in representing negatively-valenced stimuli. Negative correlations were also found in the right ventrolateral prefrontal area 45, subgenual cingulate area 25, and nucleus accumbens, all of which are implicated in the pathophysiology of MDD. Negative memory bias was additionally positively associated with recent negative life stress and negatively associated with subgenual cingulate activation, suggesting a mechanism by which stress may contribute to these abnormalities. The severity of recent negative life stressors is an important modifier of neurobiological and cognitive function in MDD and may help explain heterogeneity in the disorder.
doi:10.1016/j.pscychresns.2009.12.002
PMCID: PMC2938037  PMID: 20685091
orbital; subgenual; ventrolateral; accumbens; memory; depression
8.  PET Measures of Endogenous Opioid Neurotransmission Predict Impulsiveness Traits in Humans 
Archives of general psychiatry  2009;66(10):1124-1134.
Objective
The endogenous opioid system and μ-opioid receptors are known to interface environmental events, both positive (e.g., relevant emotional stimuli) and negative (e.g., stressors) with pertinent behavioral responses, regulating motivated behavior. Here we examined the degree to which trait impulsiveness, the tendency to act on cravings and urges rather than delaying gratification, is predicted by either baseline μ-opioid receptor availability or the response of this system to a standardized, experientially-matched stressor.
Method
Nineteen (19) young healthy male volunteers completed a personality questionnaire (NEO PI-R) and positron emission tomography scans with the μ-opioid receptor selective radiotracer [11C]carfentanil. Measures of receptor concentrations were obtained at rest and during the receipt of an experimentally maintained pain stressor of matched intensity between subjects. Baseline receptor levels and stress-induced activation of μ-opioid neurotransmission were compared between subjects scoring above and below the population median of the NEO impulsiveness subscale and the orthogonal dimension, deliberation, expected to interact with it.
Results
High impulsiveness and low deliberation scores were associated with significantly higher regional μ-opioid receptor concentrations and greater stress-induced endogenous opioid system activation. Effects were obtained in regions involved in motivated behavior and the effects of drugs of abuse: prefrontal and orbitofrontal cortex, anterior cingulate, thalamus, nucleus accumbens and basolateral amygdala. Mu-opioid receptor availability, and the magnitude of stress-induced endogenous opioid activation in these regions accounted for 21 to 49% of the variance in these personality traits.
Conclusions
Our data demonstrate that individual differences in the function of the endogenous μ-opioid system predicts personality traits that confer vulnerability or resiliency for risky behaviors, such as the predisposition to develop substance use disorders. These personality traits are also implicated in psychopathological states (e.g., personality disorders), where variations in the function of this neurotransmitter system may play a role as well.
doi:10.1001/archgenpsychiatry.2009.134
PMCID: PMC3085183  PMID: 19805703
9.  Neurobiological Mechanisms of Placebo Responses 
doi:10.1111/j.1749-6632.2009.04424.x
PMCID: PMC3073412  PMID: 19338509
Positron emission tomography; pain; stress; opioid dopamine; placebo; human
10.  Monoamine Oxidase A Genotype Predicts Human Serotonin 1A Receptor Availability In Vivo 
The serotonergic system, including the serotonin 1A (5-HT1A) receptor, has been implicated in the pathophysiology of a number of neuropsychiatric disorders. Current data shows substantial inter-individual variation in the regional concentration of this receptor site, the source of which is unclear. Monoamine oxidase A (MAO-A) is a key regulator of serotonin metabolism, and polymorphic variation in the X-linked MAO-A gene influences its expression. We hypothesized that polymorphism in the MAO-A gene would be associated with sex-specific variation in 5-HT1A receptor expression. We used positron emission tomography and [11C]WAY-100635 to quantify 5-HT1A receptors in a group of 31 healthy and un-medicated depressed individuals. The same individuals were genotyped for an upstream variable number tandem repeat polymorphism in the promoter of the MAO-A gene. Analysis of variance of 5-HT1A receptor availability demonstrated a significant effect of MAO-A genotype in the raphe nuclei, medial and inferior temporal cortex, insula, medial prefrontal cortex, and anterior cingulate (p<0.05). The effect persisted when age, race, body mass index, and diagnosis were included in the model. Genotypes with greater putative MAO-A activity were associated with greater 5-HT1A receptor availability in women, but not in men. Genotype predicted a substantial 42-74% of the variance in receptor availability in women, depending on the brain region (p<0.05). Depression diagnosis was not associated with MAO-A genotype or 5-HT1A receptor availability in these regions. These results demonstrate a sex-specific interaction between two key molecules of the human serotonergic system, and suggest a neurobiological basis for sexual dimorphism in serotonin-modulated phenotypes.
doi:10.1523/JNEUROSCI.2391-08.2008
PMCID: PMC2613649  PMID: 18971477
sex difference; polymorphism; positron emission tomography; serotonin; serotonergic 1A receptor; monoamine oxidase; imaging; genetics; human; depression
11.  Pronociceptive and Antinociceptive Effects of Estradiol through Endogenous Opioid Neurotransmission in Women 
Prominent interindividual and sex-dependent differences have been described in responses to sustained pain and other stressful stimuli. Variations in μ-opioid receptor-mediated endogenous opioid neurotransmission may underlie some of these processes. We examined both baseline μ-opioid receptor levels and the activation of this neurotransmitter system during sustained pain using positron emission tomography in a sample of young healthy men and women. Women were studied twice, during low and high estrogen states. The high-estrogen state was associated with regional increases in baseline μ-opioid receptor availability in vivo and a greater activation of endogenous opioid neurotransmission during the pain stressor. The latter did not differ from that obtained in males. During the low estrogen condition, however, significant reductions in endogenous opioid tone were observed at the level of thalamus, nucleus accumbens, and amygdala, which were associated with hyperalgesic responses. Estrogen-associated variations in the activity of μ-opioid neurotransmission correlated with individual ratings of the sensory and affective perceptions of the pain and the subsequent recall of that experience. These data demonstrate a significant role of estrogen in modulating endogenous opioid neurotransmission and associated psychophysical responses to a pain stressor in humans.
doi:10.1523/JNEUROSCI.5223-05.2006
PMCID: PMC1808228  PMID: 16723535
μ-opioid receptors; pain; stress; sex differences; PET; human
12.  Functional genetic variants in the vesicular monoamine transporter 1 (VMAT1) modulate emotion processing 
Molecular psychiatry  2013;19(1):129-139.
SUMMARY
Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits, and risk for psychopathology.
doi:10.1038/mp.2012.193
PMCID: PMC4311877  PMID: 23337945
13.  Indirect Effect of Corticotropin-Releasing Hormone Receptor 1 Gene Variation on Negative Emotionality and Alcohol Use via Right Ventrolateral Prefrontal Cortex 
The Journal of Neuroscience  2014;34(11):4099-4107.
Variations in the corticotropin-releasing hormone receptor 1 (CRHR1) gene have been found to interact with stress in modulating excessive alcohol consumption. However, the neural mechanisms through which CRHR1 influences this risk in humans is largely unknown. This study examined the influence of an intronic CRHR1 gene variant, rs110402, on brain responses to negative emotional words, negative emotional traits, and alcohol use in adolescents and young adults at high risk for alcoholism. Childhood stress was investigated as a potential moderator. Using functional magnetic resonance imaging, we found that a region in the right ventrolateral prefrontal cortex (rVLPFC) was more engaged during negative emotional word processing in G homozygotes than in A allele carriers (p(FWE corrected) < 0.01, N = 77). Moreover, an indirect effect of genotype on negative emotionality via rVLPFC activation (p < 0.05, N = 69) was observed, which was further moderated by childhood stress (p < 0.05, N = 63). Specifically, with low childhood stress, G homozygotes exhibited lower levels of negative emotionality associated with greater rVLPFC activation, suggesting that the rVLPFC is involved in reappraisal that neutralizes negative emotional responses. In addition, we found that genotype indirectly modulated excessive alcohol consumption (p < 0.05, N = 69). Specifically, G homozygotes showed greater rVLPFC activation and had lower levels of negative emotionality, which were associated with fewer binge-drinking days and fewer alcohol related problems. This work provides support for a model in which CRHR1 gene variation modulates the risk of problem drinking via an internalizing/negative affect pathway involving rVLPFC and reappraisal of negative emotion.
doi:10.1523/JNEUROSCI.3672-13.2014
PMCID: PMC3951705  PMID: 24623788
alcohol consumption; childhood stress; CRHR1; genetics; negative emotionality; prefrontal cortex
14.  Increased Coupling of Intrinsic Networks in Remitted Depressed Youth Predicts Rumination and Cognitive Control 
PLoS ONE  2014;9(8):e104366.
Objective
Functional connectivity MRI (fcMRI) studies of individuals currently diagnosed with major depressive disorder (MDD) document hyperconnectivities within the default mode network (DMN) and between the DMN and salience networks (SN) with regions of the cognitive control network (CCN). Studies of individuals in the remitted state are needed to address whether effects derive from trait, and not state or chronic burden features of MDD.
Method
fcMRI data from two 3.0 Tesla GE scanners were collected from 30 unmedicated (47% medication naïve) youth (aged 18–23, modal depressive episodes = 1, mean age of onset = 16.2, SD = 2.6) with remitted MDD (rMDD; modal years well = 4) and compared with data from 23 healthy controls (HCs) using four bilateral seeds in the DMN and SN (posterior cingulate cortex (PCC), subgenual anterior cingulate (sgACC), and amygdala), followed by voxel-based comparisons of the whole brain.
Results
Compared to HCs, rMDD youth exhibited hyperconnectivities from both PCC and sgACC seeds with lateral, parietal, and frontal regions of the CCN, extending to the dorsal medial wall. A factor analysis reduced extracted data and a PCC factor was inversely correlated with rumination among rMDD youth. Two factors from the sgACC hyperconnectivity clusters were related to performance in cognitive control on a Go/NoGo task, one positively and one inversely.
Conclusions
Findings document hyperconnectivities of the DMN and SN with the CCN (BA 8/10), which were related to rumination and sustained attention. Given these cognitive markers are known predictors of response and relapse, hyperconnectivities may increase relapse risk or represent compensatory mechanisms.
doi:10.1371/journal.pone.0104366
PMCID: PMC4146466  PMID: 25162661
15.  Building up Analgesia in Humans via the Endogenous μ-Opioid System by Combining Placebo and Active tDCS: A Preliminary Report 
PLoS ONE  2014;9(7):e102350.
Transcranial Direct Current Stimulation (tDCS) is a method of non-invasive brain stimulation that has been frequently used in experimental and clinical pain studies. However, the molecular mechanisms underlying tDCS-mediated pain control, and most important its placebo component, are not completely established. In this pilot study, we investigated in vivo the involvement of the endogenous μ-opioid system in the global tDCS-analgesia experience. Nine healthy volunteers went through positron emission tomography (PET) scans with [11C]carfentanil, a selective μ-opioid receptor (MOR) radiotracer, to measure the central MOR activity during tDCS in vivo (non-displaceable binding potential, BPND) - one of the main analgesic mechanisms in the brain. Placebo and real anodal primary motor cortex (M1/2mA) tDCS were delivered sequentially for 20 minutes each during the PET scan. The initial placebo tDCS phase induced a decrease in MOR BPND in the periaqueductal gray matter (PAG), precuneus, and thalamus, indicating activation of endogenous μ-opioid neurotransmission, even before the active tDCS. The subsequent real tDCS also induced MOR activation in the PAG and precuneus, which were positively correlated to the changes observed with placebo tDCS. Nonetheless, real tDCS had an additional MOR activation in the left prefrontal cortex. Although significant changes in the MOR BPND occurred with both placebo and real tDCS, significant analgesic effects, measured by improvements in the heat and cold pain thresholds, were only observed after real tDCS, not the placebo tDCS. This study gives preliminary evidence that the analgesic effects reported with M1-tDCS, can be in part related to the recruitment of the same endogenous MOR mechanisms induced by placebo, and that such effects can be purposely optimized by real tDCS.
doi:10.1371/journal.pone.0102350
PMCID: PMC4100885  PMID: 25029273
16.  Functional neuroimaging of emotional processing in women with polycystic ovary syndrome: a case-control pilot study 
Fertility and sterility  2013;100(1):200-7.e1.
Objective
To evaluate emotional processing in women with insulin-resistant polycystic ovary syndrome (IR-PCOS) and its relationship to glucose regulation and the mu-opioid system.
Design
Case-control pilot.
Setting
Tertiary referring medical center.
Patient(s)
Seven women with IR-PCOS and five non-insulin-resistant controls, aged 21–40 years, recruited from the general population.
Intervention(s)
Sixteen weeks of metformin (1,500 mg/day) in women with IR-PCOS.
Main Outcome Measure(s)
Assessment of mood, metabolic function, and neuronal activation during an emotional task using functional magnetic resonance imaging (fMRI), and mu-opioid receptor availability using positive emission tomography (PET).
Result(s)
We found that insulin-resistant PCOS patients [1] had greater limbic activation during an emotion task than controls (n = 5); [2] trended toward decreased positive affect and increased trait anxiety; [3] after metformin treatment, had limbic activation that no longer differed from controls; and [4] had positive correlations between fMRI limbic activation during emotional processing and mu-opioid binding potential.
Conclusion(s)
Patients with IR-PCOS had greater regional activation during an emotion task than the controls, although this resolved with metformin therapy. Alterations in mu-opioid neurotransmission may underlie limbic system activity and mood disorders in IR-PCOS.
Clinical Trial Registration Number
NCT00670800.
doi:10.1016/j.fertnstert.2013.02.054
PMCID: PMC3900232  PMID: 23557757
Emotion; functional magnetic resonance; insulin resistance; imaging (fMRI); mu-opioid neurotransmission; polycystic ovary syndrome (PCOS)
17.  Emotion regulation through execution, observation, and imagery of emotional movements 
Brain and cognition  2013;82(2):219-227.
According to Damasio’s somatic marker hypothesis, emotions are generated by conveying the current state of the body to the brain through interoceptive and proprioceptive afferent input. The resulting brain activation patterns represent unconscious emotions and correlate with subjective feelings. This proposition implies a corollary that the deliberate control of motor behavior could regulate feelings. We tested this possibility, hypothesizing that engaging in movements associated with a certain emotion would enhance that emotion and/or the corresponding valence. Furthermore, because motor imagery and observation are thought to activate the same mirror-neuron network engaged during motor execution, they might also activate the same emotional processing circuits, leading to similar emotional effects. Therefore, we measured the effects of motor execution, motor imagery and observation of whole-body dynamic expressions of emotions (happiness, sadness, fear) on affective state. All three tasks enhanced the corresponding affective state, indicating their potential to regulate emotions.
doi:10.1016/j.bandc.2013.03.001
PMCID: PMC4067484  PMID: 23561915
Body expression of emotion; Nonverbal behavior; Emotion regulation; Embodiment; Simulation; Motor imagery
18.  3D-Neuronavigation In Vivo Through a Patient's Brain During a Spontaneous Migraine Headache 
A growing body of research, generated primarily from MRI-based studies, shows that migraine appears to occur, and possibly endure, due to the alteration of specific neural processes in the central nervous system. However, information is lacking on the molecular impact of these changes, especially on the endogenous opioid system during migraine headaches, and neuronavigation through these changes has never been done. This study aimed to investigate, using a novel 3D immersive and interactive neuronavigation (3D-IIN) approach, the endogenous µ-opioid transmission in the brain during a migraine headache attack in vivo. This is arguably one of the most central neuromechanisms associated with pain regulation, affecting multiple elements of the pain experience and analgesia. A 36 year-old female, who has been suffering with migraine for 10 years, was scanned in the typical headache (ictal) and nonheadache (interictal) migraine phases using Positron Emission Tomography (PET) with the selective radiotracer [11C]carfentanil, which allowed us to measure µ-opioid receptor availability in the brain (non-displaceable binding potential - µOR BPND). The short-life radiotracer was produced by a cyclotron and chemical synthesis apparatus on campus located in close proximity to the imaging facility. Both PET scans, interictal and ictal, were scheduled during separate mid-late follicular phases of the patient's menstrual cycle. During the ictal PET session her spontaneous headache attack reached severe intensity levels; progressing to nausea and vomiting at the end of the scan session. There were reductions in µOR BPND in the pain-modulatory regions of the endogenous µ-opioid system during the ictal phase, including the cingulate cortex, nucleus accumbens (NAcc), thalamus (Thal), and periaqueductal gray matter (PAG); indicating that µORs were already occupied by endogenous opioids released in response to the ongoing pain. To our knowledge, this is the first time that changes in µOR BPND during a migraine headache attack have been neuronavigated using a novel 3D approach. This method allows for interactive research and educational exploration of a migraine attack in an actual patient's neuroimaging dataset.
doi:10.3791/50682
PMCID: PMC4186390  PMID: 24962460
Medicine; Issue 88; μ-opioid; opiate; migraine; headache; pain; Positron Emission Tomography; molecular neuroimaging; 3D; neuronavigation
19.  μ-Opioid activation in the prefrontal cortex in migraine attacks – brief report I 
We evaluated in vivo the μ-opioid system during spontaneous episodic migraine headaches. Seven patients were scanned at different phases of their migraine using positron emission tomography with the selective μ-opioid receptor (μOR) radiotracer [11C]carfentanil. In the ictal phase, there was μOR activation in the medial prefrontal cortex, which was strongly associated with the μOR availability level during the interictal phase. Furthermore, μ-opioid binding changes showed moderate negative correlation with the combined extension and severity of the attacks. These results indicate for the first time that there is high μOR activation in the migraineurs' brains during headache attacks in response to their pain.
doi:10.1002/acn3.65
PMCID: PMC4110741  PMID: 25072055
20.  μ-Opioid activation in the midbrain during migraine allodynia – brief report II 
We investigated in vivo the allodynic response of the central μ-opioid system during spontaneous migraine headaches, following a sustained pain threshold challenge on the trigeminal ophthalmic region. Six migraineurs were scanned during the ictal and interictal phases using positron emission tomography (PET) with the selective μ-opioid receptor (μOR) radiotracer [11C]carfentanil. Females were scanned during the mid-late follicular phase of two separate cycles. Patients showed ictal trigeminal allodynia during the thermal challenge that was concurrent and positively correlated with μOR activation in the midbrain, extending from red nucleus to ventrolateral periaqueductal gray matter. These findings demonstrate for the first time in vivo the high μOR activation in the migraineurs' brains in response to their allodynic experience.
doi:10.1002/acn3.66
PMCID: PMC4184673  PMID: 25328905
21.  Response of the μ-opioid system to social rejection and acceptance 
Molecular psychiatry  2013;18(11):10.1038/mp.2013.96.
The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n = 18), we used a μ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography (PET) during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus, and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids play a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG, and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula, and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well-being in the social environment.
doi:10.1038/mp.2013.96
PMCID: PMC3814222  PMID: 23958960
opioid; PET; social; rejection; acceptance; depression; mu; stress
22.  Personality Trait Predictors of Placebo Analgesia and Neurobiological Correlates 
Neuropsychopharmacology  2012;38(4):639-646.
Personality traits have been shown to interact with environmental cues to modulate biological responses including treatment responses, and potentially having a role in the formation of placebo effects. Here, we assessed psychological traits in 50 healthy controls as to their capacity to predict placebo analgesic effects, placebo-induced activation of μ-opioid neurotransmission and changes in cortisol plasma levels during a sustained experimental pain challenge (hypertonic saline infused in the masseter muscle) with and without placebo administration. Statistical analyses showed that an aggregate of scores from Ego-Resiliency, NEO Altruism, NEO Straightforwardness (positive predictors) and NEO Angry Hostility (negative predictor) scales accounted for 25% of the variance in placebo analgesic responses. Molecular imaging showed that subjects scoring above the median in a composite of those trait measures also presented greater placebo-induced activation of μ-opioid neurotransmission in the subgenual and dorsal anterior cingulate cortex (ACC), orbitofrontal cortex, insula, nucleus accumbens, amygdala and periaqueductal gray (PAG). Endogenous opioid release in the dorsal ACC and PAG was positively correlated with placebo-induced reductions in pain ratings. Significant reductions in cortisol levels were observed during placebo administration and were positively correlated with decreases in pain ratings, μ-opioid system activation in the dorsal ACC and PAG, and as a trend, negatively with NEO Angry Hostility scores. Our results show that personality traits explain a substantial proportion of the variance in placebo analgesic responses and are further associated with activations in endogenous opioid neurotransmission, and as a trend cortisol plasma levels. This initial data, if replicated in larger sample, suggest that simple trait measures easily deployable in the field could be utilized to reduce variability in clinical trials, but may also point to measures of individual resiliency in the face of aversive stimuli such as persistent pain and potentially other stressors.
doi:10.1038/npp.2012.227
PMCID: PMC3572460  PMID: 23187726
placebo; personality; resilience; stress; opioids; cortisol; cortisol; Imaging; Clinical or Preclinical; Neuroendocrinology; Opioids; Pain; Analgesics; personality; placebo; resilience
23.  Accumbens functional connectivity during reward mediates sensation-seeking and alcohol use in high-risk youth* 
Drug and alcohol dependence  2012;128(1-2):130-139.
BACKGROUND
Differences in fronto-striatal connectivity in problem substance users have suggested reduced influence of cognitive regions on reward-salience regions. Youth with a family history of alcoholism (FH+) have disrupted ventral striatal processing compared with controls with no familial risk (FH−). As sensation-seeking represents an additional vulnerability factor, we hypothesized that functional connectivity during reward anticipation would differ by family history, and would mediate the relationship between sensation-seeking and drinking in high-risk subjects.
METHODS
Seventy 18–22 year olds (49 FH+/21 FH−) performed a monetary incentive delay task during functional magnetic resonance imaging. Group connectivity differences for incentive (reward/loss) vs. neutral conditions were evaluated with psychophysiological interaction (PPI) analysis, seeded in nucleus accumbens (NAcc). Indirect effects of sensation-seeking on drinking volume through accumbens connectivity were tested.
RESULTS
NAcc connectivity with paracentral lobule/precuneus and sensorimotor areas was decreased for FH− versus increased for FH+ during incentive anticipation. In FH+, task-related functional coupling between left NAcc and supplementary sensorimotor area (SSMA) and right precuneus correlated positively with sensation-seeking and drinking volume and mediated their relationship. In FH−, left NAcc-SSMA connectivity correlated negatively with sensation-seeking but was not related to drinking.
CONCLUSIONS
These results suggest preexisting differences in accumbens reward-related functional connectivity in high-risk subjects. NAcc coupling with SSMA, involved in attention and motor networks, and precuneus, a default mode structure, appear to mediate sensation-seeking’s effect on drinking in those most at-risk. Differences in accumbens connectivity with attention/motor/default networks, rather than control systems, may influence the reward system’s role in vulnerability for substance abuse.
doi:10.1016/j.drugalcdep.2012.08.019
PMCID: PMC3546225  PMID: 22958950
Adolescent; alcoholism; functional connectivity; nucleus accumbens; reward; substance use
24.  Personalized Medicine and Opioid Analgesic Prescribing for Chronic Pain: Opportunities and Challenges 
Use of opioid analgesics for pain management has increased dramatically over the past decade, with corresponding increases in negative sequelae including overdose and death. There is currently no well-validated objective means of accurately identifying patients likely to experience good analgesia with low side effects and abuse risk prior to initiating opioid therapy. This paper discusses the concept of data-based personalized prescribing of opioid analgesics as a means to achieve this goal. Strengths, weaknesses, and potential synergism of traditional randomized placebo-controlled trial (RCT) and practice-based evidence (PBE) methodologies as means to acquire the clinical data necessary to develop validated personalized analgesic prescribing algorithms are overviewed. Several predictive factors that might be incorporated into such algorithms are briefly discussed, including genetic factors, differences in brain structure and function, differences in neurotransmitter pathways, and patient phenotypic variables such as negative affect, sex, and pain sensitivity. Currently available research is insufficient to inform development of quantitative analgesic prescribing algorithms. However, responder subtype analyses made practical by the large numbers of chronic pain patients in proposed collaborative PBE pain registries, in conjunction with follow-up validation RCTs, may eventually permit development of clinically useful analgesic prescribing algorithms.
Perspective
Current research is insufficient to base opioid analgesic prescribing on patient characteristics. Collaborative PBE studies in large, diverse pain patient samples in conjunction with follow-up RCTs may permit development of quantitative analgesic prescribing algorithms which could optimize opioid analgesic effectiveness, and mitigate risks of opioid-related abuse and mortality.
doi:10.1016/j.jpain.2012.10.016
PMCID: PMC3564046  PMID: 23374939
Opioid analgesics; chronic pain; personalized medicine; side effects; opioid abuse
25.  Denicotinized Versus Average Nicotine Tobacco Cigarette Smoking Differentially Releases Striatal Dopamine 
Nicotine & Tobacco Research  2012;15(1):11-21.
Introduction:
Nicotine has long been recognized as a necessary but insufficient component of tobacco cigarettes to maintain a psychophysiological need to smoke. This study examined venous plasma concentrations effects of nicotine in cigarette smoking after overnight abstinence to release striatal dopamine (DA).
Methods:
Twenty-two male smokers smoked either denicotinized (denic) or average nicotine (nic) cigarettes under single blind conditions. Each was given [11C]raclopride and scanned in a positron emission tomography (PET) facility.
Results:
Smoking either denic or nic cigarettes released striatal DA. Denic cigarette smoking released DA primarily in the right striatum, whereas nic cigarette smoking released DA in both striata, but especially in the left. Increases in venous plasma nicotine concentrations correlated positively with increased DA release in the left caudate nucleus. Smoking denic cigarettes reduced craving as much as smoking nic cigarettes. Craving reduction after nic tobacco smoking correlated with increases in plasma nicotine.
Conclusions:
Nonnicotine factors in tobacco smoking produce important right brain effects. Nicotine is a pharmacological factor during tobacco smoking that releases bilateral striatal DA, but more in the left brain.
doi:10.1093/ntr/nts029
PMCID: PMC3524055  PMID: 22491891

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