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.

Longer depressive episodes and medication failure at baseline are robust predictors of poor response to ECT, with effect sizes that are modest but clinically relevant. Patient characteristics used traditionally such as age, psychosis, and melancholic features are less likely to be clinically useful. More robust clinical and biological predictors are needed for management of depressed patients considering ECT.

The μ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen “social pain.” We used positron emission tomography scanning with the selective MOR radioligand [11C]carfentanil to test the hypothesis that MOR system activation in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n = 17) compared to healthy controls (HCs, n = 18). During rejection, MDD patients showed reduced MOR activation (e.g., reduced endogenous opioid release) in brain regions regulating stress, mood, and motivation, and slower emotional recovery compared to HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with MOR activation in the nucleus accumbens, a reward structure. Abnormal MOR function in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse, and contribute to poor treatment outcomes.

We compared the spatial tuning properties of neurons in two fields [primary auditory cortex (A1) and posterior auditory field (PAF)] of cat auditory cortex. Broadband noise bursts of 80-ms duration were presented from loudspeakers throughout 360 degrees in the horizontal plane (azimuth) or 260 degrees in the vertical median plane (elevation). Sound levels varied from 20 to 40 dB above units' thresholds. We recorded neural spike activity simultaneously from 16 sites in field PAF and/or A1 of alpha-chloralose-anesthetized cats. We assessed spatial sensitivity by examining the dependence of spike count and response latency on stimulus location. In addition, we used an artificial neural network (ANN) to assess the information about stimulus location carried by spike patterns of single units and of ensembles of 2-32 units. The results indicate increased spatial sensitivity, more uniform distributions of preferred locations, and greater tolerance to changes in stimulus intensity among PAF units relative to A1 units. Compared to A1 units, PAF units responded at significantly longer latencies, and latencies varied more strongly with stimulus location. ANN analysis revealed significantly greater information transmission by spike patterns of PAF than A1 units, primarily reflecting the information transmitted by latency variation in PAF. Finally, information rates grew more rapidly with the number of units included in neural ensembles for PAF than A1. The latter finding suggests more accurate population coding of space in PAF, made possible by a more diverse population of neural response types.

IMPORTANCE High placebo responses have been observed across a wide range of pathologies, severely impacting drug development.OBJECTIVE To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD). DESIGN, SETTING, AND PARTICIPANTSIn this study involving 2 placebo lead-in phases followed by an open antidepressant administration, we performed a single-blinded 2-week crossover randomized clinical trial of 2 identical oral placebos (described as having either active or inactive fast-acting antidepressant-like effects) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or, in some cases, another agent as clinically indicated. The volunteers (35 medication-free patients with MDD at a university health system) were studied with positron emission tomography and the μ-opioid receptor-selective radiotracer [ 11 C]carfentanil after each 1-week inactive and active oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect. MAIN OUTCOMES AND MEASURESChanges in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of μ-opioid receptor binding. RESULTSHigher baseline μ-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment (r = 0.48; P = .02). Reductions in depressive symptoms after 1 week of active placebo treatment, compared with the inactive, were associated with increased placebo-induced μ-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala (nucleus accumbens: r = 0.6; P < .001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial.CONCLUSIONS AND RELEVANCE These data demonstrate that placebo-induced activation of the μ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02178696

Context Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proved particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD). Objective To determine whether low-expression NPY genotypes are associated with negative emotional processing at three levels of analysis. Design Cross-sectional, case-control. Setting Academic medical center. Participants Forty-four individuals with MDD and 137 healthy controls; 152 (84%) were classified by NPY genotype as low, intermediate, or high, according to previously established haplotype-based expression data. Main Outcome Measures Healthy subjects participated in functional magnetic resonance imaging while viewing negative (versus neutral) words (n=58), and rated positive and negative affect during a pain-stress challenge (n=78). Genotype distribution was compared between 113 control and 39 MDD subjects. Results Among healthy individuals, negatively valenced words activated medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (p=0.029). Whole-brain regression of responses to negative words showed that rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (p<0.05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (p=0.002). Low-expression NPY genotypes were over-represented in MDD after controlling for age and sex (p=0.004). Population stratification did not account for the results. Conclusions These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD.

We evaluated the spatial selectivity of auditory cortical neurons in awake cats. Single- and multiunit activity was recorded in primary auditory cortex as the animals performed a nonspatial auditory discrimination or sat idly. Their heads were unrestrained, and head position was tracked. Broadband sounds were delivered from locations throughout 360 degrees on the horizontal plane, and source locations were expressed in head-centered coordinates. As in anesthetized animals, the firing rates of most units were modulated by sound location, and most units responded best to sounds in the contralateral hemifield. Tuning was sharper than in anesthetized cats, in part because of suppression at nonoptimal locations. Nonetheless, spatial receptive fields typically spanned 150-180 degrees. Units exhibited diverse temporal response patterns that often depended on sound location. An information-theoretic analysis showed that information transmission was reduced by approximately 10% when the precision of spike timing was disrupted by 16-32 msec, and by approximately 50% when all location-related variation of spike timing was removed. Spikes occurring within 60 msec of stimulus onset transmitted the most location-related information, but later spikes also carried information. The amount of information transmitted by ensembles of units increased with the number of units, indicating some degree of mutual independence in the spatial information transmitted by various units. Spatial tuning and information transmission were changed little by an increase in sound level of 20-30 dB. For the vast majority of units, receptive fields showed no significant change with the cat's head position or level of participation in the auditory task.

Background Recent neuroimaging studies have demonstrated resting-state functional connectivity (rsFC) abnormalities among intrinsic brain networks in Major Depressive Disorder (MDD); however, their role as predictors of treatment response has not yet been explored. Here, we investigate whether network-based rsFC predicts antidepressant and placebo effects in MDD. Methods We performed a randomized controlled trial of two weeklong, identical placebos (described as having either “active” fast-acting, antidepressant effects or as “inactive”) followed by a ten-week open-label antidepressant medication treatment. Twenty-nine participants underwent a rsFC fMRI scan at the completion of each placebo condition. Networks were isolated from resting-state blood-oxygen-level-dependent signal fluctuations using independent component analysis. Baseline and placebo-induced changes in rsFC within the default-mode, salience, and executive networks were examined for associations with placebo and antidepressant treatment response. Results Increased baseline rsFC in the rostral anterior cingulate (rACC) within the salience network, a region classically implicated in the formation of placebo analgesia and the prediction of treatment response in MDD, was associated with greater response to one week of active placebo and ten weeks of antidepressant treatment. Machine learning further demonstrated that increased salience network rsFC, mainly within the rACC, significantly predicts individual responses to placebo administration. Conclusions These data demonstrate that baseline rsFC within the salience network is linked to clinical placebo responses. This information could be employed to identify patients who would benefit from lower doses of antidepressant medication or non-pharmacological approaches, or to develop biomarkers of placebo effects in clinical trials.