Joshua Woolley

Binge eating is associated with right orbitofrontal-insular-striatal atrophy in frontotemporal dementia

Background: Neurophysiologic studies on human and nonhuman primates implicate an orbitofrontal-insular-striatal circuit in high-level regulation of feeding. However, the role of these areas in determining feeding disturbances in neurologic patients remains uncertain. Objective and Methods: To determine brain structures critical for control of eating behavior, we performed a prospective, laboratory-based, free-feeding study of 18 healthy control subjects and 32 patients with neurodegenerative disease. MR voxel-based morphometry (VBM) was used to identify regions of significant atrophy in patients who overate compared with those who did not. Results: Despite normal taste recognition, 6 of 32 patients compulsively binged, consuming large quantities of food after reporting appropriate satiety. All six patients who overate were clinically diagnosed with frontotemporal dementia (FTD), a disorder previously associated with disordered eating, while the nonovereaters were diagnosed with FTD, semantic dementia, progressive aphasia, progressive supranuclear palsy, and Alzheimer disease. VBM revealed that binge-eating patients had significantly greater atrophy in the right ventral insula, striatum, and orbitofrontal cortex. Conclusion: Binge eating can occur despite reported satiety and is associated with damage to a right-sided orbitofrontal-insular-striatal circuit in humans. These findings support a model in which ventral insular and orbitofrontal cortices serve as higher-order gustatory regions and cooperate with the striatum to guide appropriate feeding responses. Glossary: AD = Alzheimer disease; FTD = frontotemporal dementia; GCRC = General Clinical Research Center; MMSE = Mini-Mental State Examination; OFC = orbitofrontal cortex; PA = progressive aphasia; PSP = progressive supranuclear palsy; ROI = region of interest; SemD = semantic dementia; VBM = voxel-based morphometry.

Nucleus accumbens opioids regulate flavor-based preferences in food consumption

Opioid signaling in the nucleus accumbens (NAcc) regulates feeding behavior, having particularly strong effects on consumption of highly palatable foods. Since macronutrient content may contribute to palatability, it is uncertain whether opioid regulation of food consumption is based primarily on its macronutrient content or its flavor per se. In order to isolate the effect of flavor, we manipulated opioid signaling in the NAcc in rats and quantified consumption of differently flavored but nutritionally identical pellets. When pellets of either flavor were presented alone, microinjection of d-Ala(2),N,Me-Phe(4),Gly-ol(5)-enkephalin (DAMGO (a mu opioid receptor (MOP) agonist)) into the NAcc increased consumption of pellets of both flavors equally. When both flavors of pellets were presented simultaneously, however, DAMGO in the NAcc selectively increased, while naltrexone (a non-selective opioid antagonist) in the NAcc selectively decreased, consumption of the more preferred flavor. Systemic naltrexone injection had no flavor specific effects, decreasing consumption of both flavors equally. Non-selective inactivation of NAcc neurons by local microinjection of muscimol (a GABA(A) agonist) increased consumption of both the more- and less-preferred flavors equally. These results indicate that opioid signaling directly regulates a subset of NAcc neurons that can selectively enhance consumption of preferred palatable foods based exclusively on flavor cues.

Oxytocin administration enhances controlled social cognition in patients with schizophrenia

BACKGROUND Individuals with schizophrenia have functionally significant deficits in automatic and controlled social cognition, but no currently available pharmacologic treatments reduce these deficits. The neuropeptide oxytocin has multiple prosocial effects when administered intranasally in humans and there is growing interest in its therapeutic potential in schizophrenia. METHODS We administered 40 IU of oxytocin and saline placebo intranasally to 29 male subjects with schizophrenia and 31 age-matched, healthy controls in a randomized, double-blind, placebo-controlled, cross-over study. Social cognition was assessed with The Awareness of Social Inference Test (TASIT) and the Reading the Mind in the Eyes Test (RMET). We examined the effects of oxytocin administration on automatic social cognition (the ability to rapidly interpret and understand emotional cues from the voice, face, and body); controlled social cognition (the ability to comprehend indirectly expressed emotions, thoughts, and intentions through complex deliberations over longer time periods); and a control task (the ability to comprehend truthful dialog and perform general task procedures) in individuals with and without schizophrenia using mixed factorial analysis of variance models. RESULTS Patients with schizophrenia showed significant impairments in automatic and controlled social cognition compared to healthy controls, and administration of oxytocin significantly improved their controlled, but not automatic, social cognition, F(1, 58)=8.75; p=0.004. Conversely, oxytocin administration had limited effects on social cognition in healthy participants. Patients and controls performed equally well and there were no effects of oxytocin administration on the control task. DISCUSSION Intact social cognitive abilities are associated with better functional outcomes in individuals with schizophrenia. Our data highlight the potentially complex effects of oxytocin on some but not all aspects of social cognition, and support the exploration of intranasal oxytocin as a potential adjunct treatment to improve controlled social cognition in schizophrenia.

Endogenous dopaminergic modulation of the lamprey spinal locomotor network.

The lamprey spinal cord contains three dopaminergic systems. The most extensive is the ventromedial plexus in which dopamine is co-localized with 5-HT and tachykinins. In this study we have investigated the effects of endogenously released dopamine on NMDA-induced spinal activity, and for comparison applied dopamine exogenously. The dopamine reuptake blocker bupropion increases the levels of extracellular dopamine in the spinal cord. Bath application of bupropion during ongoing NMDA-induced network activity (around 2 Hz) resulted in an initial increase of the burst rate followed by a transitional phase with the fast rhythm superimposed on a much slower ventral root burst activity (below 0.25 Hz). Finally only the slow rhythm was observed. The same response pattern with regard to the fast and slow rhythms was observed when dopamine was slowly perfused over the spinal cord, resulting in a gradual build-up of dopamine concentration. At low constant dopamine concentrations, however, an increased burst frequency was maintained, but at somewhat higher concentrations the fast burst rate instead was decreased. The degree of modulation of fictive locomotion by dopamine was also tested at low and high NMDA concentrations. Dopamine was found to exert stronger effects at low NMDA concentrations. With high NMDA concentrations dopamine did not induce the transition phase or the slow ventral root bursting. The slow alternating ventral root bursts, induced by bupropion, shifted to synchronized activity when glycinergic synaptic transmission was blocked with strychnine, testifying that the alternation depended on a crossed glycinergic action as previously shown for the fast rhythm.

Endogenous opioids encode relative taste preference

Endogenous opioid signaling contributes to the neural control of food intake. Opioid signaling is thought to regulate palatability, the reward value of a food item as determined by orosensory cues such as taste and texture. The reward value of a food reflects not only these sensory properties but also the relative value of competing food choices. In the present experiment, we used a consummatory contrast paradigm to manipulate the relative value of a sucrose solution for two groups of rats. Systemic injection of the nonspecific opioid antagonist naltrexone suppressed sucrose intake; for both groups, however, this suppression was selective, occurring only for the relatively more valuable sucrose solution. Our results indicate that endogenous opioid signaling contributes to the encoding of relative reward value.

Nucleus accumbens opioid signaling conditions short-term flavor preferences

Opioid signaling in the nucleus accumbens (NAcc) strongly modulates flavor-based food choice. To further investigate the role of opioid signaling in taste reward, we used a sensory specific satiety (SSS) paradigm to devalue specific flavors of nutritionally identical food pellets in rats. In the NAcc, infusion of a mu opioid (MOP) receptor selective agonist selectively increased consumption of a pre-fed flavor, thus reversing the SSS effect. Conversely, blockade of endogenous opioid signaling with the opioid antagonist naltrexone selectively decreased consumption of a recently consumed flavor, potentiating the SSS effect. No enhancement of consumption was observed if a delay of 3 h was imposed following the intra-NAcc MOP agonist indicating that there were no long-term changes in flavor preference. If a delay was introduced between the initial flavor exposure and the intra-NAcc MOP agonist infusion, pellet consumption was increased non-selectively (irrespective of flavor) suggesting that close temporal contiguity between flavor experience and NAcc opioid action is critical for the opioid effect on flavor preference. In contrast to opioid effects, inactivating NAcc neurons by local microinjection of muscimol (a GABAA agonist) increased consumption of both the pre-fed and non-pre-fed flavors equally. These results demonstrate that opioids released in the NAcc during consumption of palatable foods produce a selective and transient increase in preference for a recently sampled flavor.

Opposing effects of intra-nucleus accumbens mu and kappa opioid agonists on sensory specific satiety.

Mu opioid (MOP) agonists acting in the nucleus accumbens (NAcc) robustly enhance consumption of palatable foods. In addition, the effect on consumption of palatable foods produced by MOP agonists acting in the NAcc depends on both recent flavor exposure and the availability of a choice between different-flavored foods. In contrast, kappa opioid (KOP) agonists have variable effects on feeding and KOP agonists have MOP opposing behavioral actions when microinjected at several brain sites. We previously demonstrated that NAcc MOP agonists reverse the devaluation (satiety) effect of pre-feeding for a given flavor; in fact, NAcc MOP agonists selectively increase consumption of a recently sampled food. In contrast, in the present study, we found that the selective KOP agonist U50488 injected into the NAcc of rats reduced consumption of a recently sampled flavor while increasing consumption of the flavor that was not pre-fed. Intra-NAcc U50488 did not affect overall consumption or flavor preference in the absence of pre-feeding. The present data, in conjunction with our previous findings, highlight the robust and opposing role of NAcc MOP and KOP opioid receptors in palatability-based food choice and consumption and raise the possibility that an endogenous KOP agonist acting in the NAcc contributes to the phenomenon of sensory specific satiety.

Oxytocin effects in schizophrenia: Reconciling mixed findings and moving forward

HIGHLIGHTSStudies of oxytocin in schizophrenia have yielded mixed results.Study design and individual differences may account for this heterogeneity.Oxytocin may improve specific deficits not captured in many studies.Future studies should employ precise, objective outcomes to capture oxytocin effects. ABSTRACT Schizophrenia is a severe mental illness that causes major functional impairment. Current pharmacologic treatments are inadequate, particularly for addressing negative and cognitive symptoms of the disorder. Oxytocin, a neuropeptide known to moderate social behaviors, has been investigated as a potential therapeutic for schizophrenia in recent years. Results have been decidedly mixed, leading to controversy regarding oxytocins utility. In this review, we outline several considerations for interpreting the extant literature and propose a focused agenda for future work that builds on the most compelling findings regarding oxytocin effects in schizophrenia to date. Specifically, we examine underlying causes of heterogeneity in randomized clinical trials (RCTs) conducted thus far and highlight the complexity of the human oxytocin system. We then review evidence of oxytocins effects on specific deficits in schizophrenia, arguing for further study using objective, precise outcome measures in order to determine whether oxytocin has the potential to improve functional impairment in schizophrenia.

A two-week pilot study of intranasal oxytocin for cocaine-dependent individuals receiving methadone maintenance treatment for opioid use disorder

Abstract About 30–60% of the patients receiving methadone for opioid use disorder (OUD) actively use cocaine. Cocaine use disorder (CUD) has no FDA-approved pharmacological treatment; existing psychosocial treatments are inadequate. Oxytocin (OT), a social neuropeptide, has preclinical promise as an adjunctive treatment for both OUD and CUD. Twenty-two individuals receiving methadone for OUD with co-occurring CUD were randomized to receive OT or placebo intranasally 40 IU twice daily for two weeks. A priori aims were feasibility and safety. Exploratory effectiveness aims included laboratory-based measures of drug craving, drug-related implicit cognition, and drug use. High retention rates (93.5%), the absence of study-related adverse events, and the fact that OT was well tolerated in this population support the feasibility of larger trials. Two weeks of OT (but not placebo) significantly reduced cocaine craving at day 15 compared to baseline (mean change ± SD: OT = −0.23 ± 0.19, p = 0.004; PL = −0.16 ± 0.29, p = 0.114). For heroin craving, the placebo group reported a trend-level increase over time while the OT group remained unchanged – with medium to large effect sizes between the groups (Cohen’s d = 0.71–0.90). OT led to a significant switch from implicit self-association with drugs to implicitly associating drugs with others (mean change ± SD: 0.25 ± 0.35, p = 0.037) and a trend-level reduction in self-reported cocaine use over time (Z = −1.78, p = 0.075). Furthermore, OT significantly increased the accuracy of self-reported cocaine use when correlated with quantitative urine levels of cocaine metabolite. This proof-of-concept study provides promising early evidence that OT may be an effective adjunct to the treatment of co-occurring CUD and OUD. Further investigation with larger trials is warranted.

The autonomic and behavioral profile of emotional dysregulation

The authors describe a patient with focal brain atrophy and emotional lability characterized by episodes of excessive crying and laughing. The patient was selectively impaired in the production of voluntary complex facial movements and was unable to regulate her emotional behavior and autonomic reactivity. She also displayed increased behavioral and autonomic changes when explicitly trying to suppress her responses to emotional stimuli (compared with when not trying to regulate her responses). This pattern of deficits supports a selective deficit in voluntary emotional control.