Activity In Nucleus Accumbens Research Articles

Effect of antidepressant drugs on the vmPFC-limbic circuitry

Our recent study indicates that the lesions of the prefrontal cortex in rats result in depressive-like behavior in forced swim test and REM sleep alterations, two well-established biomarkers of depression disorder. We hypothesized that antidepressants may target the PFC to reverse depression. Systemic injections of antidepressants: the tricyclic antidepressant desipramine (DMI), the selective serotonin reuptake inhibitor fluoxetine, and the NMDA-antagonist ketamine selectively increased cFos expression (a marker of neuronal activity) in the deep layers of the ventromedial PFC (vmPFC) in rats. Of the vmPFC's limbic system targets, only the nucleus accumbens (NAc) was also activated by DMI. Using a retrograde tracer and a neuronal toxin, we also found that DMI-activated vmPFC neurons project to the NAc and that NAc activation by DMI was lost following vmPFC lesion. These results suggest that the vmPFC may be an essential target of antidepressant drugs, its projections to the NAc may be a key circuit regulating antidepressant action, and dysfunction of this pathway may contribute to depression.

Oxytocin increases VTA activation to infant and sexual stimuli in nulliparous and postpartum women

After giving birth, women typically experience decreased sexual desire and increased responsiveness to infant stimuli. These postpartum changes may be viewed as a trade-off in reproductive interests, which could be due to alterations in brain activity including areas associated with reward. The goal of this study was to describe the roles of oxytocin and parity on reward area activation in response to reproductive stimuli, specifically infant and sexual images. Because they have been shown to be associated with reward, the ventral tegmental area (VTA) and nucleus accumbens (NAc) were targeted as areas of expected alterations in activity. Oxytocin was chosen as a potential mediator of reproductive trade-offs because of its relationship to both mother–infant interactions, including breastfeeding and bonding, and sexual responses. We predicted that postpartum women would show higher reward area activation to infant stimuli and nulliparous women would show higher activation to sexual stimuli and that oxytocin would increase activation to infant stimuli in nulliparous women. To test this, we measured VTA and NAc activation using fMRI in response to infant photos, sexual photos, and neutral photos in 29 postpartum and 30 nulliparous women. Participants completed the Sexual Inhibition (SIS) and Sexual Excitation (SES) Scales and the Brief Index of Sexual Function for Women (BISF-W), which includes a sexual desire dimension, and received either oxytocin or placebo nasal spray before viewing crying and smiling infant and sexual images in an fMRI scanner. For both groups of women, intranasal oxytocin administration increased VTA activation to both crying infant and sexual images but not to smiling infant images. We found that postpartum women showed lower SES, higher SIS, and lower sexual desire compared to nulliparous women. Across parity groups, SES scores were correlated with VTA activation and subjective arousal ratings to sexual images. In postpartum women, sexual desire was positively correlated with VTA activation to sexual images and with SES. Our findings show that postpartum decreases in sexual desire may in part be mediated by VTA activation, and oxytocin increased activation of the VTA but not NAc in response to sexual and infant stimuli. Oxytocin may contribute to the altered reproductive priorities in postpartum women by increasing VTA activation to salient infant stimuli.

Cocaine addiction: Role for glutamate, glia and chemokine

Aims: The aim of the study is to investigate the effect of novel activators of glutamate transporter (GLT-1), ceftriaxone (CTX) and clavulanic acid (CLAV), on drug taking and seeking behavior. In addition, glial cell activity after cocaine exposure and during short and long-termwithdrawal has been examined. Furthermore, possible involvement of chemokine receptor, CXCR4, in cocaine reward was examined. Methods: The effect of CTX and CLAV was tested in mouse intravenous self-administration model. Acquisition of selfadministration under fixed-ratio (FR) schedule of reinforcement was used as a measure of drug-taking behavior, and progressive ratio (PR) schedule of reinforcement was used to assess drugseeking behavior. In a separate study, rats were injected with cocaine (15mg/kg, i.p.) for 7 consecutive days, and glial cell activitywas investigated using immuno-fluorescencemicroscopy at 2h, 2, 10 and 30 days after last injection. Effect of AMD3100, a CXCR4 antagonist, on development of cocaine conditioned place preference was tested. Results: CTX and CLAV pretreatment decreased cocaine intake in mice maintained under the PR of reinforcement. However only the CTX not CLAV pre-treatment was able to decrease acquisition of self-administration in mice under FR schedule of reinforcement. There was a significant increase of astrocytic activation in nucleus accumbens of rats withdrawn from cocaine for 30 days. AMD3100 attenuated development of cocaine conditioned place preference. Conclusions: GLT-1 activators are able to decrease reinforcing strength of cocaine by increasing the extracellular glutamate reuptake. Astrocyte activity is increased in nucleus accumbens of rats in long-term cocaine withdrawal. Attenuation of cocaine conditioned place preference byAMD3100 suggests a role for chemokine receptor in drug reward. Financial Support: T32 DA 07237 P30 DA013429R21 DA043718.

Nicotine infusion in the wake-promoting basal forebrain enhances alcohol-induced activation of nucleus accumbens.

Nicotine and alcohol co-abuse is highly prevalent. Recently, we have shown that nicotine infusion in the basal forebrain (BF) increases alcohol consumption. As nucleus accumbens (NAc) is the terminal brain region associated with drug addiction, we hypothesize that nicotine infusion in the BF may enhance alcohol-induced activation of NAc. Adult male Sprague-Dawley rats were surgically implanted with bilateral guide cannulas in the BF. Following postoperative recovery, rats were divided into 4 groups: (i) ACSF+W group received artificial cerebrospinal fluid (ACSF; 500nl/side) in the BF and systemic water (intragastric [ig]; 10ml/kg; N=5), (ii) ethanol (EtOH) group received ACSF in the BF (500nl/side) and systemic alcohol (ig; 3g/kg; N=5), (iii) NiC group received nicotine in the BF (75pmole/500nl/side) and systemic water (ig; 10ml/kg; N=5), and (iv) NiC+EtOH group received nicotine in the BF (75pmole/500nl/side) and systemic alcohol (ig; 3g/kg; N=5). Rats were euthanized 2hours after treatment to examine c-Fos expression in the NAc by immunohistochemistry. All injections sites were localized in the BF. Two-way analysis of variance (ig vs. infusion) revealed significant main effects of both treatments (ig and infusion, p<0.001) on c-Fos expression in the NAc shell, but not in the core. Subsequent post hoc test (Bonferroni's) revealed that as compared to ACSF+W group, c-Fos expression was significantly increased in the shell of NAc of rats in all 3 (EtOH, NiC, and NiC+EtOH) groups with maximal increase observed in NiC+EtOH group. The results suggest the following: (i) BF nicotine infusion induced c-Fos in both core and the shell region of NAc at levels comparable to those observed after systemic alcohol administration; (ii) BF nicotine infusion with systemic alcohol induced a significant additive increase in c-Fos expression only in the NAc shell region. These findings implicate the BF in alcohol and nicotine co-use.

BK channels mediate dopamine inhibition of firing in a subpopulation of core nucleus accumbens medium spiny neurons

Dopamine, a key neurotransmitter mediating the rewarding properties of drugs of abuse, is widely believed to exert some of its effects by modulating neuronal activity of nucleus accumbens (NAcc) medium spiny neurons (MSNs). Although its effects on synaptic transmission have been well documented, its regulation of intrinsic neuronal excitability is less understood. In this study, we examined the cellular mechanisms of acute dopamine effects on core accumbens MSNs evoked firing. We found that 0.5µM A-77636 and 10µM quinpirole, dopamine D1 (DR1s) and D2 receptor (D2Rs) agonists, respectively, markedly inhibited MSN evoked action potentials. This effect, observed only in about 25% of all neurons, was associated with spike-timing-dependent (STDP) long-term potentiation (tLTP), but not long-term depression (tLTD). Dopamine inhibits evoked firing by compromising subthreshold depolarization, not by altering action potentials themselves. Recordings in voltage-clamp mode revealed that all MSNs expressed fast (IA), slowly inactivating delayed rectifier (Idr), and large conductance voltage- and calcium-activated potassium (BKs) channels. Although A-77636 and quinpirole enhanced IA, its selective blockade by 0.5µM phrixotoxin-1 had no effect on evoked firing. In contrast, exposing tissue to low TEA concentrations and to 10µM paxilline, a selective BK channel blocker, prevented D1R agonist from inhibiting MSN firing. This result indicates that dopamine inhibits MSN firing through BK channels in a subpopulation of core accumbens MSNs exclusively associated with spike-timing-dependent long-term potentiation.

SY07-4 * DYSFUNCTION OF GABAERGIC SYSTEM IN THE INSULAR CORTEX CONTRIBUTES TO IMPAIRMENTS OF DECISION-MAKING IN METHAMPHETAMINE-DEPENDENT RATS

Introduction. Patients suffering from neuropsychiatric disorders such as substance-related and addictive disorders have impairments in decision-making, which may be associated with their behavioral abnormalities. However, the neuronal mechanisms underlying such impairments are largely unknown. To address this issue, we developed a gambling test for rodents using an 8-arm radial arm maze, and tested the effect of chronic methamphetamine (METH) treatment on decision-making in rats. Method. The c-fos staining was applied to determine the brain areas activated by the gambling test. Depolarization-evoked GABA release was measured by in vivo dialysis. Results. METH-dependent rats choose a high-risk/high-reward option more frequently, and assign higher subjective value to high returns, than control rats, suggesting that decision-making is impaired in the METH-dependent animals. Immunohistochemical analysis of c-fos following the gambling test revealed aberrant activation of the insular cortex (INS) and nucleus accumbens in METH-dependent animals. Pharmacological studies together with in vivo microdialysis showed that GABAergic neurotransmission in INS played a crucial role in decision-making. Conclusion. Our findings suggest that INS is a critical region involved in decision-making, and that insular GABAergic dysfunction in METH-dependent rats results in risk-taking behaviors associated with poor decision-making.

Balancing reward and work: Anticipatory brain activation in NAcc and VTA predict effort differentially

Complex decision-making involves anticipation of future rewards to bias effort for obtaining it. Using fMRI, we investigated 50 participants employing an instrumental-motivation task that cued reinforcement levels before the onset of the motor-response phase. We extracted timecourses from regions of interest (ROI) in the mesocorticolimbic system and used a three-level hierarchical model to separate anticipatory brain responses predicting value and subsequent effort on a trial-by-trial basis. Whereas all ROIs scaled positively with value, higher effort was predicted by higher anticipatory activation in nucleus accumbens (NAcc) but lower activation in ventral tegmental area/substantia nigra (VTA/SN). Moreover, anticipatory activation in the dorsal striatum predicted average effort whereas higher activation in the amygdala predicted above-average effort. Thus, anticipatory activation entails the appetitive drive towards reinforcement that requires effort in order to be obtained. Our results support the role of NAcc as the main hub supported by the salience network operating on a trial-by-trial basis, while the dorsal striatum incorporates habitual responding.

The Emerging Role of Nucleus Accumbens Oxytocin in Social Cognition

The nucleus accumbens (NAc), also known as the ventral striatum, is a key node of the mesocorticolimbic reward system. This circuit has received great attention because of its role in the pathophysiology of addiction and depression. However, it likely evolved to motivate behaviors that were important for survival, reproduction, and fitness. Increasing evidence suggests that adaptive social behaviors in a wide diversity of species are also reinforced by this system. The evolutionary persistence of these behaviors might require this reinforcement, particularly in cases where individual benefit and group benefit are in conflict. A particularly attractive idea is that the neuropeptide oxytocin (OT) functions as a reward signal in the NAc for affiliative interactions. Initially, the strongest experimental evidence in support of this hypothesis derived from classic work showing that oxytocin receptors (OTRs) in the NAc of the prairie vole were critical for its monogamous, highly affiliative behavior (1,2). More recently, we have demonstrated that OT induces plasticity at excitatory synapses in the mouse NAc and that pharmacologic blockade or molecular ablation of OTRs in the NAc impairs social reward processing (3). In this issue of Biological Psychiatry, Loth et al. (4) demonstrate that polymorphisms in the OXTR gene, which encodes the OTR, correlate with changes in the processing of social information and functional magnetic resonance imaging assays of NAc activation patterns. These studies add to the growing body of evidence that OTRs in the NAc play an important role in mediating social cognition and that OXTR polymorphisms interact with life events to have an important influence on how individuals react to social cues. In the lay press, OT is often referred to as the “love hormone.” However, as evidenced by the distinctions drawn between “storge,” “eros,” and “philia,” the Ancient Greeks recognized that “love” takes many forms depending on its social context (e.g., maternal, erotic, communal). To date, it is unknown how OT is able to mediate differentially these distinct types of love. Emerging evidence suggests the possibility that the mode of transmission (paracrine or synaptic) and the brain regions targeted by the regulation of receptor expression dictate this specificity (Figure 1). For example, OT released by the hypothalamus into the systemic circulation via axon terminals in the posterior pituitary binds to OTRs in the uterus and mammary glands to mediate parturition and lactation. The magnocellular hypothalamic neurons responsible for this systemic release are also capable of releasing OT, via a somatodendritic mechanism,

Prefrontal recruitment during social rejection predicts greater subsequent self-regulatory imbalance and impairment: neural and longitudinal evidence

Social rejection impairs self-regulation, yet the neural mechanisms underlying this relationship remain unknown. The right ventrolateral prefrontal cortex (rVLPFC) facilitates self-regulation and plays a robust role in regulating the distress of social rejection. However, recruiting this region’s inhibitory function during social rejection may come at a self-regulatory cost. As supported by prominent theories of self-regulation, we hypothesized that greater rVLPFC recruitment during rejection would predict a subsequent self-regulatory imbalance that favored reflexive impulses (i.e., cravings), which would then impair self-regulation. Supporting our hypotheses, rVLPFC activation during social rejection was associated with greater subsequent nucleus accumbens (NAcc) activation and lesser functional connectivity between the NAcc and rVLPFC to appetitive cues. Over seven days, the effect of daily felt rejection on daily self-regulatory impairment was exacerbated among participants who showed a stronger rVLPFC response to social rejection. This interactive effect was mirrored in the effect of daily felt rejection on heightened daily alcohol cravings. Our findings suggest that social rejection likely impairs self-regulation by recruiting the rVLPFC, which then tips the regulatory balance towards reward-based impulses.

Neural Systems Underlying the Reappraisal of Personally Craved Foods

Craving of unhealthy food is a common target of self-regulation, but the neural systems underlying this process are understudied. In this study, participants used cognitive reappraisal to regulate their desire to consume idiosyncratically craved or not craved energy-dense foods, and neural activity during regulation was compared with each other and with the activity during passive viewing of energy-dense foods. Regulation of both food types elicited activation in classic top-down self-regulation regions including the dorsolateral prefrontal, inferior frontal, and dorsal anterior cingulate cortices. This main effect of regulation was qualified by an interaction, such that activation in these regions was significantly greater during reappraisal of craved (versus not craved) foods and several regions, including the dorsolateral prefrontal, inferior frontal, medial frontal, and dorsal anterior cingulate cortices, were uniquely active during regulation of personally craved foods. Body mass index significantly negatively correlated with regulation-related activation in the right dorsolateral PFC, thalamus, and bilateral dorsal ACC and with activity in nucleus accumbens during passive viewing of craved (vs. neutral, low-energy density) foods. These results suggest that several of the brain regions involved in the self-regulation of food craving are similar to other kinds of affective self-regulation and that others are sensitive to the self-relevance of the regulation target.

Effect of GABRA2 genotype on development of incentive-motivation circuitry in a sample enriched for alcoholism risk.

Heightened reactivity of the incentive-motivation system has been proposed to underlie adolescent-typical risky behaviors, including problem alcohol involvement. However, even in adolescence considerable individual variation in these behaviors exists, which may have genetic underpinnings and be related to variations in risk for later alcohol use disorder (AUD). Variants in GABRA2 have been associated with adult alcohol dependence as well as phenotypic precursors, including impulsiveness and externalizing behaviors. We investigated the impact of GABRA2 on the developmental trajectory of nucleus accumbens (NAcc) activation during anticipation of monetary reward from childhood to young adulthood. Functional MRI during a monetary incentive delay task was collected in 175 participants, with the majority (n = 151) undergoing repeated scanning at 1- to 2-year intervals. One group entered the study at age 8-13 years (n = 76) and another entered at age 18-23 years (n = 99). Most participants were children of alcoholics (79%) and thus at heightened risk for AUD. A total of 473 sessions were completed, covering ages 8-27 years. NAcc activation was heightened during adolescence compared with childhood and young adulthood. GABRA2 genotype (SNP rs279858) was associated with individual differences in NAcc activation specifically during adolescence, with the minor allele (G) associated with greater activation. Furthermore, NAcc activation mediated an effect of genotype on alcohol problems (n = 104). This work demonstrates an impact of GABRA2 genotype on incentive-motivation neurocircuitry in adolescence, with implications for vulnerability to alcoholism. These findings represent an important step toward understanding the genetic and neural basis of individual differences in how risk for addiction unfolds across development.

Dissociating Motivation from Reward in Human Striatal Activity

Neural activity in the striatum has consistently been shown to scale with the value of anticipated rewards. As a result, it is common across a number of neuroscientific subdiscliplines to associate activation in the striatum with anticipation of a rewarding outcome or a positive emotional state. However, most studies have failed to dissociate expected value from the motivation associated with seeking a reward. Although motivation generally scales positively with increases in potential reward, there are circumstances in which this linkage does not apply. The current study dissociates value-related activation from that induced by motivation alone by employing a task in which motivation increased as anticipated reward decreased. This design reverses the typical relationship between motivation and reward, allowing us to differentially investigate fMRI BOLD responses that scale with each. We report that activity scaled differently with value and motivation across the striatum. Specifically, responses in the caudate and putamen increased with motivation, whereas nucleus accumbens activity increased with expected reward. Consistent with this, self-report ratings indicated a positive association between caudate and putamen activity and arousal, whereas activity in the nucleus accumbens was more associated with liking. We conclude that there exist regional limits on inferring reward expectation from striatal activation.

Reward sensitivity modulates connectivity among reward brain areas when processing anticipatory reward cues

Reward sensitivity relates to increased response in reward brain areas during the processing of reward cues. However, it is unknown how this trait modulates brain connectivity. We analyzed the relationship between effective connectivity and personality in response to anticipatory reward cues from the midbrain and nucleus accumbens to the orbitofrontal cortex and the amygdala, respectively. Forty-four males performed an adaptation of the Monetary Incentive Delay Task and completed the Sensitivity to Reward scale. Sensitivity to reward scores related to stronger activation in the nucleus accumbens and midbrain during the processing of reward cues. Psychophysiological interaction analyses revealed that midbrain-medial orbitofrontal cortex connectivity was negatively correlated with sensitivity to reward scores for high compared with low incentive cues. Also, nucleus accumbens-amygdala connectivity correlated negatively with sensitivity to reward scores during reward anticipation. Our results suggest that high reward sensitivity modulates brain connectivity.

Role of nucleus accumbens in neuropathic pain: Linked multi-scale evidence in the rat transitioning to neuropathic pain

Despite recent evidence implicating the nucleus accumbens (NAc) as causally involved in the transition to chronic pain in humans, underlying mechanisms of this involvement remain entirely unknown. Here we elucidate mechanisms of NAc reorganizational properties (longitudinally and cross-sectionally), in an animal model of neuropathic pain (spared nerve injury [SNI]). We observed interrelated changes: (1) In resting-state functional magnetic resonance imaging (fMRI), functional connectivity of the NAc to dorsal striatum and cortex was reduced 28days (but not 5days) after SNI; (2) Contralateral to SNI injury, gene expression of NAc dopamine 1A, 2, and κ-opioid receptors decreased 28days after SNI; (3) In SNI (but not sham), covariance of gene expression was upregulated at 5days and settled to a new state at 28days; and (4) NAc functional connectivity correlated with dopamine receptor gene expression and with tactile allodynia. Moreover, interruption of NAc activity (via lidocaine infusion) reversibly alleviated neuropathic pain in SNI animals. Together, these results demonstrate macroscopic (fMRI) and molecular reorganization of NAc and indicate that NAc neuronal activity is necessary for full expression of neuropathic pain-like behavior.

Differential Contributions of Infralimbic Prefrontal Cortex and Nucleus Accumbens during Reward-Based Learning and Extinction

Using environmental cues for the prediction of future events is essential for survival. Such cue-outcome associations are thought to depend on mesolimbic circuitry involving the nucleus accumbens (NAc) and prefrontal cortex (PFC). Several studies have identified roles for both NAc and PFC in the expression of stable goal-directed behaviors, but much remains unknown about their roles during learning of such behaviors. To further address this question, we used in vivo oxygen amperometry, a proxy for blood oxygen level-dependent (BOLD) signal measurement in human functional magnetic resonance imaging, in rats performing a cued lever-pressing task requiring discrimination between a rewarded and nonrewarded cue. Simultaneous oxygen recordings were obtained from infralimbic PFC (IFC) and NAc throughout both acquisition and extinction of this task. Activation of NAc was specifically observed following rewarded cue onset during the entire acquisition phase and also during the first days of extinction. In contrast, IFC activated only during the earliest periods of acquisition and extinction, more specifically to the nonrewarded cue. Thus, in vivo oxygen amperometry permits a novel, stable form of longitudinal analysis of brain activity in behaving animals, allowing dissociation of the roles of different brain regions over time during learning of reward-driven instrumental action. The present results offer a unique temporal perspective on how NAc may promote actions directed toward anticipated positive outcome throughout learning, while IFC might suppress actions that no longer result in reward, but only during critical periods of learning.

Enhanced synthesis and release of dopamine in transgenic mice with gain‐of‐function α6* nAChRs

α6β2* nicotinic acetylcholine receptors (nAChRs)s in the ventral tegmental area to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function α6β2* nAChRs (α6L9'S mice) that are hypersensitive to nicotine and endogenous acetylcholine. Evoked extracellular dopamine (DA) levels were enhanced in α6L9'S NAc slices compared to control, non-transgenic (non-Tg) slices. Extracellular DA levels in both non-Tg and α6L9'S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing α6β2* nAChR activation by acetylcholine plays a role in enhancing DA levels, as α-conotoxin MII completely abolished evoked DA release in α6L9'S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, α6L9'S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid compared to non-Tg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid, and norepinephrine (NE) were unchanged in α6L9'S compared to non-Tg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in α6L9'S NAc. Overall, these results show that enhanced α6β2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels.

Fluoxetine Epigenetically Alters the CaMKIIα Promoter in Nucleus Accumbens to Regulate ΔFosB Binding and Antidepressant Effects

Chronic social defeat stress in mice produces a susceptible phenotype characterized by several behavioral abnormalities consistent with human depression that are reversed by chronic but not acute exposure to antidepressant medications. Recent work in addiction models demonstrates that the transcription factor ΔFosB and protein kinase calmodulin-dependent protein kinase II (CaMKII) are co-regulated in nucleus accumbens (NAc), a brain reward region implicated in both addiction and depression models including social defeat. Previous work has also demonstrated that ΔFosB is induced in NAc after chronic social defeat stress or after chronic antidepressant treatment, wherein it mediates a pro-resilience or antidepressant-like phenotype. Here, using chromatin immunoprecipitation assays, we found that ΔFosB binds the CaMKIIα gene promoter in NAc and that this binding increases after mice are exposed to chronic social defeat stress. Paradoxically, chronic exposure to the antidepressant fluoxetine reduces binding of ΔFosB to the CaMKIIα promoter and reduces CaMKII expression in NAc, despite the fact that ΔFosB is induced under these conditions. These data suggest a novel epigenetic mechanism of antidepressant action, whereby fluoxetine induces some chromatin change at the CaMKIIα promoter, which blocks the ΔFosB binding. Indeed, chronic fluoxetine reduces acetylation and increases lysine-9 dimethylation of histone H3 at the CaMKIIα promoter in NAc, effects also seen in depressed humans exposed to antidepressants. Overexpression of CaMKII in NAc blocks fluoxetine's antidepressant effects in the chronic social defeat paradigm, whereas inhibition of CaMKII activity in NAc mimics fluoxetine exposure. These findings suggest that epigenetic suppression of CaMKIIα expression in NAc is behaviorally relevant and offer a novel pathway for possible therapeutic intervention in depression and related syndromes.

P.2.b.033 A randomized study of escitalopram and paroxetine controlled-release in the treatment of Japanese patients with major depressive disorder

The extent to which affective reactivity and associated neural underpinnings are altered by depression remains equivocal. This study assessed striatal activation in fifty-one unmedicated female participants meeting DSM-IV criteria for Major Depressive Disorder (MDD) and 61 age-matched healthy females (HC) aged 17–63 years. Participants completed an affective reactivity functional magnetic resonance imaging task. Data were preprocessed using SPM8, and region-of-interest analyses were completed using MarsBaR to extract caudate, putamen, and nucleus accumbens (NAcc) activation. General linear repeated measure ANOVAs were used to assess group differences and correlational analyses were used to measure the association between activation, depression severity, and anhedonia. Main effects of hemisphere, valence, and group status were observed, with MDD participants demonstrating decreased striatal activation compared with HC. Across groups and valence types, the left hemisphere demonstrated greater activation than the right hemisphere in the putamen and nucleus accumbens, whereas the right hemisphere demonstrated greater activation than the left in the caudate. Additionally, unpleasant stimuli elicited greater activation than pleasant and neutral stimuli in the caudate and putamen, and unpleasant stimuli elicited greater activation than neutral stimuli in the NAcc. There were no significant associations between activation, depression severity, and anhedonia. Overall, depression was characterized by reduced affective reactivity in the striatum, regardless of stimuli valence, supporting the emotion context insensitivity model of depression.

Affective traits link to reliable neural markers of incentive anticipation

While theorists have speculated that different affective traits are linked to reliable brain activity during anticipation of gains and losses, few have directly tested this prediction. We examined these associations in a community sample of healthy human adults (n=52) as they played a Monetary Incentive Delay task while undergoing functional magnetic resonance imaging (FMRI). Factor analysis of personality measures revealed that subjects independently varied in trait Positive Arousal and trait Negative Arousal. In a subsample (n=14) retested over 2.5years later, left nucleus accumbens (NAcc) activity during anticipation of large gains (+$5.00) and right anterior insula activity during anticipation of large losses (−$5.00) showed significant test–retest reliability (intraclass correlations>0.50, p's<0.01). In the full sample (n=52), trait Positive Arousal correlated with individual differences in left NAcc activity during anticipation of large gains, while trait Negative Arousal correlated with individual differences in right anterior insula activity during anticipation of large losses. Associations of affective traits with neural activity were not attributable to the influence of other potential confounds (including sex, age, wealth, and motion). Together, these results demonstrate selective links between distinct affective traits and reliably-elicited activity in neural circuits associated with anticipation of gain versus loss. The findings thus reveal neural markers for affective dimensions of healthy personality, and potentially for related psychiatric symptoms.

Disordered reward processing and functional connectivity in trichotillomania: A pilot study

BackgroundThe neurobiology of Trichotillomania is poorly understood, although there is increasing evidence to suggest that TTM may involve alterations of reward processing. The current study represents the first exploration of reward processing in TTM and the first resting state fMRI study in TTM. We incorporate both event-related fMRI using a monetary incentive delay (MID) task, and resting state fMRI, using two complementary resting state analysis methodologies (functional connectivity to the nucleus accumbens and dual regression within a reward network) in a pilot study to investigate differences in reward processing between TTM and healthy controls (HC). Methods21 unmedicated subjects with TTM and 14 HC subjects underwent resting state fMRI scans. A subset (13 TTM and 12 HC) also performed the MID task. ResultsFor the MID task, TTM subjects showed relatively decreased nucleus accumbens (NAcc) activation to reward anticipation, but relative over-activity of the NAcc to both gain and loss outcomes. Resting state functional connectivity analysis showed decreased connectivity of the dorsal anterior cingulate (dACC) to the NAcc in TTM. Dual regression analysis of a reward network identified through independent component analysis (ICA) also showed decreased dACC connectivity and more prominently decreased basolateral amygdala connectivity within the reward network in TTM. ConclusionsDisordered reward processing at the level of NAcc, also involving decreased modulatory input from the dACC and the basolateral amygdala may play a role in the pathophysiology of TTM.