Generalized Encoding of the Relative Subjective Value of Cognitive Effort in the Dorsal ACC.

Making choices about whether and when to engage cognitive effort are a common feature of everyday experience, with important consequences for academic, career, and health outcomes. Yet, despite their hypothesized importance, very little is understood about the underlying mechanisms that support this form of human cost-benefit decision-making. To investigate these mechanisms, we used the Cognitive Effort Discounting Paradigm (Cog-ED) during fMRI scanning to precisely quantify the neural encoding of varying cognitive effort demands relative to reward outcomes, within two distinct cognitive domains (working memory, speech comprehension). The findings provide strong evidence that the dorsal anterior cingulate cortex (dACC) plays a central and selective role in this decision-making process. Trial-by-trial modulations in dACC activation tracked the relative subjective value of the low-effort, low-reward option, with the strongest activity occurring when this was of greater value than the high-effort, high-reward option. In contrast, dACC activity was not modulated by decision difficulty, though such effects were found in other frontoparietal regions. Critically, dACC activity was also strongly correlated across the two decision-making task domains and further predicted subsequent choice behavior in both. Together, the results suggest that dACC activity modulation reflects a domain-general valuation comparison mechanism, which acts to bias participants away from decisions to engage in cognitive effort, when the perceived subjective costs of such engagement outweigh the reward-related benefits. These findings complement work in other cost domains and species by pointing to a clear role of the dACC in representing subjective value differences between choice options during cost-benefit decision-making.

Neuroinflammation: A Modifiable Pathway Linking Obesity, Alzheimer's disease, and Depression.

Obesity, depression and Alzheimer's disease (AD) are three major interrelated modern health conditions with complex relationships. Early-life depression may serve as a risk factor for AD, while late-life depression may be a prodrome of AD. Depression affects approximately 23% of obese individuals, and depression itself raises the risk of obesity by 37%. Mid-life obesity independently increases AD risk, while late-life obesity, particularly metabolically healthy obesity, may offer protection against AD pathology. Chronic inflammation serves as a key mechanism linking obesity, AD, and depression, encompassing systemic inflammation from metabolic disturbances, immune dysregulation through the gut microbiome, and direct interactions with amyloid pathology and neuroinflammation. In this review, we explore the biological mechanisms of neuroinflammation in relation to obesity, AD, and depression. We assess the efficacy of therapeutic interventions targeting neuroinflammation and discuss current and future radiological imaging initiatives for studying neuroinflammation. By comprehending the intricate interplay among depression, obesity, and AD, especially the role of neuroinflammation, we can advance our understanding and develop innovative strategies for prevention and treatment.

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status.

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states.

Functional anatomy of subthalamic nucleus stimulation in Parkinson disease.

OBJECTIVE: We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3-dimensional brain region and to assign statistical significance after stringent type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS. METHODS: Fifty-one PD participants with STN DBS were evaluated off medication, with DBS off and during unilateral STN DBS with clinically optimized settings. Dependent variables included DBS-induced changes in Unified Parkinson Disease Rating Scale (UPDRS) subscores, kinematic measures of bradykinesia and rigidity, working memory, response inhibition, mood, anxiety, and akathisia. Weighted t tests at each voxel produced p images showing where DBS most significantly affected each dependent variable based on outcomes of participants with nearby DBS. Finally, a permutation test computed the probability that this p image indicated significantly different responses based on stimulation site. RESULTS: Most motor variables improved with DBS anywhere in the STN region, but several motor, cognitive, and affective responses significantly depended on precise location stimulated, with peak p values in superior STN/zona incerta (quantified bradykinesia), dorsal STN (mood, anxiety), and inferior STN/substantia nigra (UPDRS tremor, working memory). INTERPRETATION: Our method identified DBS-induced behavioral changes that depended significantly on DBS site. These results do not support complete functional segregation within STN, because movement improved with DBS throughout, and mood improved with dorsal STN DBS. Rather, findings support functional convergence of motor, cognitive, and limbic information in STN.

A single brain-derived neurotrophic factor infusion into the dorsomedial prefrontal cortex attenuates cocaine self-administration-induced phosphorylation of synapsin in the nucleus accumbens during early withdrawal.

BACKGROUND: Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. METHODS: In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. RESULTS: Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. CONCLUSIONS: Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration-induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal.

A comparison of D2 receptor specific binding in obese and normal-weight individuals using PET with (N-[(11)C]methyl)benperidol.

Previous PET imaging studies have demonstrated mixed findings regarding dopamine D2/D3 receptor availability in obese relative to nonobese humans. Nonspecific D2/D3 radioligands do not allow for separate estimation of D2 receptor (D2R) and D3 receptor (D3R) subtypes of the D2 receptor family, which may play different roles in behavior and are distributed differently throughout the brain. These radioligands are also displaceable by endogenous dopamine, confounding interpretation of differences in receptor availability with differing levels of dopamine release. The present study used PET imaging with the D2R-selective radioligand (N-[(11)C] methyl)benperidol ([(11)C]NMB), which is nondisplaceable by endogenous dopamine, to estimate D2R specific binding (BPND) and its relationship to body mass index (BMI) and age in 15 normal-weight (mean BMI = 22.6 kg/m(2)) and 15 obese (mean BMI = 40.3 kg/m(2)) men and women. Subjects with illnesses or taking medications that interfere with dopamine signaling were excluded. Striatal D2R BPND was calculated using the Logan graphical method with cerebellum as a reference region. D2R BPND estimates were higher in putamen and caudate relative to nucleus accumbens, but did not differ between normal-weight and obese groups. BMI values did not correlate with D2R BPND . Age was negatively correlated with putamen D2R BPND in both groups. These results suggest that altered D2R specific binding is not involved in the pathogenesis of obesity per se and underscore the need for additional studies evaluating the relationship between D3R, dopamine reuptake, or endogenous dopamine release and human obesity.

Associations Between Socioeconomic Status, Obesity, Cognition, and White Matter Microstructure in Children.

Importance: Lower neighborhood and household socioeconomic status (SES) are associated with negative health outcomes and altered brain structure in children. It is unclear whether such findings extend to white matter and via what mechanisms. Objective: To assess whether and how neighborhood and household SES are independently associated with children's white matter microstructure and examine whether obesity and cognitive performance (reflecting environmental cognitive and sensory stimulation) are plausible mediators. Design, Setting, and Participants: This cross-sectional study used baseline data from participants in the Adolescent Brain Cognitive Development (ABCD) study. Data were collected at 21 US sites, and school-based recruitment was used to represent the US population. Children aged 9 to 11 years and their parents or caregivers completed assessments between October 1, 2016, and October 31, 2018. After exclusions, 8842 of 11 875 children in the ABCD study were included in the analyses. Data analysis was conducted from July 11 to December 19, 2022. Exposures: Neighborhood disadvantage was derived from area deprivation indices at participants' primary residence. Household SES factors were total income and highest parental educational attainment. Main Outcomes and Measures: A restriction spectrum imaging (RSI) model was used to quantify restricted normalized directional (RND; reflecting oriented myelin organization) and restricted normalized isotropic (RNI; reflecting glial and neuronal cell bodies) diffusion in 31 major white matter tracts. The RSI measurements were scanner harmonized. Obesity was assessed through body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), age- and sex-adjusted BMI z scores, and waist circumference, and cognition was assessed through the National Institutes of Health Toolbox Cognition Battery. Analyses were adjusted for age, sex, pubertal development stage, intracranial volume, mean head motion, and twin or siblingship. Results: Among 8842 children, 4543 (51.4%) were boys, and the mean (SD) age was 9.9 (0.7) years. Linear mixed-effects models revealed that greater neighborhood disadvantage was associated with lower RSI-RND in the left superior longitudinal fasciculus (ß = -0.055; 95% CI, -0.081 to -0.028) and forceps major (ß = -0.040; 95% CI, -0.067 to -0.013). Lower parental educational attainment was associated with lower RSI-RND in the bilateral superior longitudinal fasciculus (eg, right hemisphere: ß = 0.053; 95% CI, 0.025-0.080) and bilateral corticospinal or pyramidal tract (eg, right hemisphere: ß = 0.042; 95% CI, 0.015-0.069). Structural equation models revealed that lower cognitive performance (eg, lower total cognition score and higher neighborhood disadvantage: ß = -0.012; 95% CI, -0.016 to -0.009) and greater obesity (eg, higher BMI and higher neighborhood disadvantage: ß = -0.004; 95% CI, -0.006 to -0.001) partially accounted for the associations between SES and RSI-RND. Lower household income was associated with higher RSI-RNI in most tracts (eg, right inferior longitudinal fasciculus: ß = -0.042 [95% CI, -0.073 to -0.012]; right anterior thalamic radiations: ß = -0.045 [95% CI, -0.075 to -0.014]), and greater neighborhood disadvantage had similar associations in primarily frontolimbic tracts (eg, right fornix: ß = 0.046 [95% CI, 0.019-0.074]; right anterior thalamic radiations: ß = 0.045 [95% CI, 0.018-0.072]). Lower parental educational attainment was associated with higher RSI-RNI in the forceps major (ß = -0.048; 95% CI, -0.077 to -0.020). Greater obesity partially accounted for these SES associations with RSI-RNI (eg, higher BMI and higher neighborhood disadvantage: ß = 0.015; 95% CI, 0.011-0.020). Findings were robust in sensitivity analyses and were corroborated using diffusion tensor imaging. Conclusions and Relevance: In this cross-sectional study, both neighborhood and household contexts were associated with white matter development in children, and findings suggested that obesity and cognitive performance were possible mediators in these associations. Future research on children's brain health may benefit from considering these factors from multiple socioeconomic perspectives.

Neuroinflammation in the Amygdala Is Associated With Recent Depressive Symptoms.

BACKGROUND: Converging evidence suggests that elevated inflammation may contribute to depression. Yet, the link between peripheral inflammation and neuroinflammation in depression is unclear. Here, using data from the UK Biobank, we estimated associations among depression, C-reactive protein (CRP) as a measure of peripheral inflammation, and neuroinflammation as indexed by diffusion basis spectral imaging-based restricted fraction (DBSI-RF). METHODS: DBSI-RF was derived from diffusion-weighted imaging data (N = 11,512) for whole-brain gray matter (global-RF), and regions of interest in the bilateral amygdala (amygdala-RF) and hippocampus (hippocampus-RF), and CRP was estimated from blood (serum) samples. Self-reported recent depression symptoms were measured using a 4-item assessment. Linear regressions were used to estimate associations between CRP and DBSI-RFs with depression while adjusting for the following covariates: age, sex, body mass index, smoking, drinking, and medical conditions. RESULTS: Elevated CRP was associated with higher depression symptoms (ß = 0.04, false discovery rate-corrected p < .005) and reduced global-RF (ß = -0.03, false discovery rate-corrected p < .001). Higher amygdala-RF was associated with elevated depression-an effect resilient to added covariates and CRP (ß = 0.02, false discovery rate-corrected p < .05). Interestingly, this association was stronger in individuals with a lifetime history of depression (ß = 0.07, p < .005) than in those without (ß = 0.03, p < .05). Associations between global-RF or hippocampus-RF with depression were not significant, and no DBSI-RF indices indirectly linked CRP with depression (i.e., mediation effect). CONCLUSIONS: Peripheral inflammation and DBSI-RF neuroinflammation in the amygdala are independently associated with depression, consistent with animal studies suggesting distinct pathways of peripheral inflammation and neuroinflammation in the pathophysiology of depression and with investigations highlighting the role of the amygdala in stress-induced inflammation and depression.

Associations between socioeconomic status and white matter microstructure in children: indirect effects via obesity and cognition.

Importance: Both neighborhood and household socioeconomic disadvantage relate to negative health outcomes and altered brain structure in children. It is unclear whether such findings extend to white matter development, and via what mechanisms socioeconomic status (SES) influences the brain. Objective: To test independent associations between neighborhood and household SES indicators and white matter microstructure in children, and examine whether body mass index and cognitive function (a proxy of environmental cognitive/sensory stimulation) may plausibly mediate these associations. Design: This cross-sectional study used baseline data from the Adolescent Brain Cognitive Development (ABCD) Study, an ongoing 10-year cohort study tracking child health. Setting: School-based recruitment at 21 U.S. sites. Participants: Children aged 9 to 11 years and their parents/caregivers completed baseline assessments between October 1 st , 2016 and October 31 st , 2018. Data analysis was conducted from July to December 2022. Exposures: Neighborhood disadvantage was derived from area deprivation indices at primary residence. Household SES indicators were total income and the highest parental education attainment. Main Outcomes and Measures: Thirty-one major white matter tracts were segmented from diffusion-weighted images. The Restriction Spectrum Imaging (RSI) model was implemented to measure restricted normalized directional (RND; reflecting oriented myelin organization) and isotropic (RNI; reflecting glial/neuronal cell bodies) diffusion in each tract. Obesity-related measures were body mass index (BMI), BMI z -scores, and waist circumference, and cognitive performance was assessed using the NIH Toolbox Cognition Battery. Linear mixed-effects models tested the associations between SES indicators and scanner-harmonized RSI metrics. Structural equation models examined indirect effects of obesity and cognitive performance in the significant associations between SES and white mater microstructure summary principal components. Analyses were adjusted for age, sex, pubertal development stage, intracranial volume, and head motion. Results: The analytical sample included 8842 children (4299 [48.6%] girls; mean age [SD], 9.9 [0.7] years). Greater neighborhood disadvantage and lower parental education were independently associated with lower RSI-RND in forceps major and corticospinal/pyramidal tracts, and had overlapping associations in the superior longitudinal fasciculus. Lower cognition scores and greater obesity-related measures partially accounted for these SES associations with RSI-RND. Lower household income was related to higher RSI-RNI in almost every tract, and greater neighborhood disadvantage had similar effects in primarily frontolimbic tracts. Lower parental education was uniquely linked to higher RSI-RNI in forceps major. Greater obesity-related measures partially accounted for these SES associations with RSI-RNI. Findings were robust in sensitivity analyses and mostly corroborated using traditional diffusion tensor imaging (DTI). Conclusions and Relevance: These cross-sectional results demonstrate that both neighborhood and household contexts are relevant to white matter development in children, and suggest cognitive performance and obesity as possible pathways of influence. Interventions targeting obesity reduction and improving cognition from multiple socioeconomic angles may ameliorate brain health in low-SES children. Key Points: Question: Are neighborhood and household socioeconomic levels associated with children’s brain white matter microstructure, and if so, do obesity and cognitive performance (reflecting environmental stimulation) mediate the associations?Findings: In a cohort of 8842 children, higher neighborhood disadvantage, lower household income, and lower parental education had independent and overlapping associations with lower restricted directional diffusion and greater restricted isotropic diffusion in white matter. Greater body mass index and poorer cognitive performance partially mediated these associations.Meaning: Both neighborhood and household poverty may contribute to altered white matter development in children. These effects may be partially explained by obesity incidence and poorer cognitive performance.

Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum.

Neuroinflammation is both a consequence and driver of overfeeding and weight gain in rodent obesity models. Advances in magnetic resonance imaging (MRI) enable investigations of brain microstructure that suggests neuroinflammation in human obesity. To assess the convergent validity across MRI techniques and extend previous findings, we used diffusion basis spectrum imaging (DBSI) to characterize obesity-associated alterations in brain microstructure in 601 children (age 9-11 years) from the Adolescent Brain Cognitive DevelopmentSM Study. Compared with children with normal-weight, greater DBSI restricted fraction (RF), reflecting neuroinflammation-related cellularity, was seen in widespread white matter in children with overweight and obesity. Greater DBSI-RF in hypothalamus, caudate nucleus, putamen, and, in particular, nucleus accumbens, correlated with higher baseline body mass index and related anthropometrics. Comparable findings were seen in the striatum with a previously reported restriction spectrum imaging (RSI) model. Gain in waist circumference over 1 and 2 years related, at nominal significance, to greater baseline RSI-assessed restricted diffusion in nucleus accumbens and caudate nucleus, and DBSI-RF in hypothalamus, respectively. Here we demonstrate that childhood obesity is associated with microstructural alterations in white matter, hypothalamus, and striatum. Our results also support the reproducibility, across MRI methods, of findings of obesity-related putative neuroinflammation in children.

Characterization of extrastriatal D2 in vivo specific binding of [¹8F](N-methyl)benperidol using PET.

PET imaging studies of the role of the dopamine D2 receptor family in movement and neuropsychiatric disorders are limited by the use of radioligands that have near-equal affinities for D2 and D3 receptor subtypes and are susceptible to competition with endogenous dopamine. By contrast, the radioligand [¹8F]N-methylbenperidol ([¹8F]NMB) has high selectivity and affinity for the D2 receptor subtype (D2R) and is not sensitive to endogenous dopamine. Although [¹8F]NMB has high binding levels in striatum, its utility for measuring D2R in extrastriatal regions is unknown. A composite MR-PET image was constructed across 14 healthy adult participants representing average NMB uptake 60 to 120 min after [¹8F]NMB injection. Regional peak radioactivity was identified using a peak-finding algorithm. FreeSurfer and manual tracing identified a priori regions of interest (ROI) on each individual's MR image and tissue activity curves were extracted from coregistered PET images. [¹8F]NMB binding potentials (BP(ND) s) were calculated using the Logan graphical method with cerebellum as reference region. In eight unique participants, extrastriatal BP(ND) estimates were compared between Logan graphical methods and a three-compartment kinetic tracer model. Radioactivity and BP(ND) levels were highest in striatum, lower in extrastriatal subcortical regions, and lowest in cortical regions relative to cerebellum. Age negatively correlated with striatal BP(ND) s. BP(ND) estimates for extrastriatal ROIs were highly correlated across kinetic and graphical methods. Our findings indicate that PET with [¹8F]NMB measures specific binding in extrastriatal regions, making it a viable radioligand to study extrastriatal D2R levels in healthy and diseased states.

Domain-general cognitive motivation: Evidence from economic decision-making - Final Registered Report.

Stable individual differences in cognitive motivation (i.e., the tendency to engage in and enjoy effortful cognitive activities) have been documented with self-report measures, yet convergent support for a trait-level construct is still lacking. In the present study, we used an innovative decision-making paradigm (COG-ED) to quantify the costs of cognitive effort, a metric of cognitive motivation, across two distinct cognitive domains: working memory (an N-back task) and speech comprehension (understanding spoken sentences in background noise). We hypothesized that cognitive motivation operates similarly within individuals, regardless of domain. Specifically, in 104 adults aged 18-40 years, we tested whether individual differences in effort costs are stable across domains, even after controlling for other potential sources of shared individual variation. Conversely, we evaluated whether the costs of cognitive effort across domains may be better explained in terms of other relevant cognitive and personality-related constructs, such as working memory capacity or reward sensitivity. We confirmed a reliable association among effort costs in both domains, even when these other sources of individual variation, as well as task load, are statistically controlled. Taken together, these results add support for trait-level variation in cognitive motivation impacting effort-based decision making across multiple domains.

Plasma Neurofilament Light Chain Levels Are Elevated in Children and Young Adults With Wolfram Syndrome.

Wolfram syndrome is a rare disease caused by pathogenic variants in the WFS1 gene with progressive neurodegeneration. As an easily accessible biomarker of progression of neurodegeneration has not yet been found, accurate tracking of the neurodegenerative process over time requires assessment by costly and time-consuming clinical measures and brain magnetic resonance imaging (MRI). A blood-based measure of neurodegeneration, neurofilament light chain (NfL), is relatively inexpensive and can be repeatedly measured at remote sites, standardized, and measured in individuals with MRI contraindications. To determine whether NfL levels may be of use in disease monitoring and reflect disease activity in Wolfram syndrome, plasma NfL levels were compared between children and young adults with Wolfram syndrome (n = 38) and controls composed of their siblings and parents (n = 35) and related to clinical severity and selected brain region volumes within the Wolfram group. NfL levels were higher in the Wolfram group [median (interquartile range) NfL = 11.3 (7.8-13.9) pg/mL] relative to controls [5.6 (4.5-7.4) pg/mL]. Within the Wolfram group, higher NfL levels related to worse visual acuity, color vision and smell identification, smaller brainstem and thalamic volumes, and faster annual rate of decrease in thalamic volume over time. Our findings suggest that plasma NfL levels can be a powerful tool to non-invasively assess underlying neurodegenerative processes in children, adolescents and young adults with Wolfram syndrome.

Low-Dose Augmentation With Buprenorphine for Treatment-Resistant Depression: A Multisite Randomized Controlled Trial With Multimodal Assessment of Target Engagement.

Background: The experimental therapeutics approach that combines a placebo-controlled clinical trial with translational neuroscience methods can provide a better understanding of both the clinical and physiological effects of pharmacotherapy. We aimed to test the efficacy and tolerability of low-dose augmentation with buprenorphine (BPN) for treatment-resistant depression, combined with multimodal assessment of target engagement. Methods: In this multisite randomized clinical trial, 85 participants ≥50 years of age with a major depressive episode that had not responded to venlafaxine extended release were randomized to augmentation with BPN or placebo for 8 weeks. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale. In addition, three linked experiments were conducted to test target engagement: 1) functional magnetic resonance imaging using the monetary incentive delay task, 2) brain positron emission tomography of healthy participants using a novel kappa opioid receptor antagonist tracer [11C]LY2795050, and 3) transcranial magnetic stimulation measure of cortical transmission after daily BPN administration. Results: The mean ± SD dosage of BPN was 0.59 ± 0.33 mg/day. There were no significant differences between the BPN and placebo groups in Montgomery-Åsberg Depression Rating Scale changes over time or adverse effects. BPN administration had minimal effects on functional magnetic resonance imaging blood oxygen level-dependent responses in regions involved in reward anticipation and response, no significant displacement of kappa opioid receptor radioligand in positron emission tomography imaging, and no significant changes in transcranial magnetic stimulation measures of inhibitory and excitatory cortical transmission. Conclusions: Our findings suggest a lack of clinical effect of low-dose BPN augmentation and lack of target engagement with this dosage and physiological probes.

Domain-general cognitive motivation: evidence from economic decision-making.

Stable individual differences in cognitive motivation (i.e., the tendency to engage in and enjoy effortful cognitive activities) have been documented with self-report measures, yet convergent support for a trait-level construct is still lacking. In the present study, we use an innovative decision-making paradigm (COG-ED) to quantify the costs of cognitive effort, a metric of cognitive motivation, across two distinct cognitive domains (working memory and speech comprehension). We hypothesize that cognitive motivation operates similarly within individuals, regardless of domain. Specifically, we test whether individual differences in effort costs are stable across domains, even after controlling for other potential sources of shared individual variation. Conversely, we evaluate whether the costs of cognitive effort across domains may be better explained in terms of other relevant cognitive and personality-related constructs, such as working memory capacity or reward sensitivity.

Nucleus accumbens microstructure mediates the relationship between obesity and eating behavior in adults.

OBJECTIVE: Basal ganglia regions are part of the brain's reward-processing networks and are implicated in the neurobiology of obesity and eating disorders. This study examines basal ganglia microstructural properties in adults with and without obesity. METHODS: Diffusion basis spectrum imaging (DBSI) images were analyzed to obtain putative imaging markers of neuroinflammation. Relationships between basal ganglia DBSI metrics and reward sensitivity and eating behaviors were also explored. RESULTS: A total of 46 participants (25 people with obesity; aged 20-40 years; 37 women) were included. Relative to the people in the normal-weight group, people with obesity had smaller caudate and larger nucleus accumbens (NAcc) volumes (p < 0.05) and lower DBSI fiber fraction (reflecting apparent axonal/dendrite density) in NAcc and putamen, higher DBSI nonrestricted fraction (reflecting tissue edema) in NAcc and caudate, and higher DBSI restricted fraction (reflecting tissue cellularity) in putamen (p ≤ 0.01, all). Increased emotional and reward eating behaviors were related to lower NAcc axonal/dendrite density and greater tissue edema (p ≤ 0.002). The relationships between emotional eating and adiposity measures were mediated by NAcc microstructure. CONCLUSIONS: These findings provide evidence that microstructural alterations in basal ganglia relate to obesity and insights linking NAcc microstructure and eating behavior in adults.

Obesity and White Matter Neuroinflammation Related Edema in Alzheimer's Disease Dementia Biomarker Negative Cognitively Normal Individuals.

BACKGROUND: Obesity is related to quantitative neuroimaging abnormalities including reduced gray matter volumes and impaired white matter microstructural integrity, although the underlying mechanisms are not well understood. OBJECTIVE: We assessed influence of obesity on neuroinflammation imaging that may mediate brain morphometric changes. Establishing the role of neuroinflammation in obesity will enhance understanding of this modifiable disorder as a risk factor for Alzheimer's disease (AD) dementia. METHODS: We analyzed brain MRIs from 104 cognitively normal participants (CDR = 0) and biomarker negativity for CSF amyloid or tau. We classified body mass index (BMI) as normal (BMI <25, N = 62) or overweight and obese (BMI ≥25, N = 42). Blood pressure was measured. BMI and blood pressure classifications were related to neuroinflammation imaging (NII) derived edema fraction in 17 white matter tracts. This metric was also correlated to hippocampal volumes and CSF biomarkers of inflammation and neurodegeneration: YKL-40, SNAP25, VILIP, tau, and NFL. RESULTS: Participants with BMI <25 had lower NII-derived edema fraction, with protective effects of normal blood pressure. Statistically significant white matter tracts included the internal capsule, external capsule, and corona radiata, FDR correc-ted for multiple comparisons to alpha = 0.05. Higher NII-derived edema fractions in the internal capsule, corpus callosum, gyrus, and superior fronto-occipital fasciculus were related with smaller hippocampal volumes only in individuals with BMI ≥25. There were no statistically significant correlations between NII-derived edema fraction and CSF biomarkers. CONCLUSION: We demonstrate statistically significant relationships between neuroinflammation, elevated BMI, and hippocampal volume, raising implications for neuroinflammation mechanisms of obesity-related brain dysfunction in cognitively normal elderly.

A role for 2-arachidonoylglycerol and endocannabinoid signaling in the locomotor response to novelty induced by olfactory bulbectomy.

Bilateral olfactory bulbectomy (OBX) in rodents produces behavioral and neurochemical changes associated clinically with depression and schizophrenia. Most notably, OBX induces hyperlocomotion in response to the stress of exposure to a novel environment. We examined the role of the endocannabinoid system in regulating this locomotor response in OBX and sham-operated rats. In our study, OBX-induced hyperactivity was restricted to the first 3 min of the open field test, demonstrating the presence of novelty (0-3 min) and habituation (3-30 min) phases of the open field locomotor response. Levels of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide were decreased in the ventral striatum, a brain region deafferented by OBX, whereas cannabinoid receptor densities were unaltered. In sham-operated rats, 2-AG levels in the ventral striatum were negatively correlated with distance traveled during the novelty phase. Thus, low levels of 2-AG are reflected in a hyperactive open field response. This correlation was not observed in OBX rats. Conversely, 2-AG levels in endocannabinoid-compromised OBX rats correlated with distance traveled during the habituation phase. In OBX rats, pharmacological blockade of cannabinoid CB(1) receptors with either AM251 (1 mg kg(-1) i.p.) or rimonabant (1 mg kg(-1) i.p.) increased distance traveled during the habituation phase. Thus, blockade of endocannabinoid signaling impairs habituation of the hyperlocomotor response in OBX, but not sham-operated, rats. By contrast, in sham-operated rats, effects of CB(1) antagonism were restricted to the novelty phase. These findings suggest that dysregulation in the endocannabinoid system, and 2-AG in particular, is implicated in the hyperactive locomotor response induced by OBX. Our studies suggest that drugs that enhance 2-AG signaling, such as 2-AG degradation inhibitors, might be useful in human brain disorders modeled by OBX.

Striatal Dopamine Responses to Feeding are Altered in People with Obesity.

OBJECTIVE: This study determined whether striatal dopamine (DA) release is affected by food ingestion and whether the DA response to high-calorie food images is greater in the fasted than in the fed state in people with obesity. METHODS: Striatal DA release was evaluated in 10 people with obesity and prediabetes after consuming a meal to satiation and after fasting overnight as well as in response to viewing images of high-calorie compared with low-calorie foods after consuming a meal to satiation or fasting overnight by using positron emission tomography with [11 C]raclopride injection. RESULTS: Striatal DA D2/D3 receptor availability was not different during fasted and fed conditions. Viewing images of high-calorie foods induced striatal DA release relative to viewing images of low-calorie foods (P < 0.05), but there was no difference in the magnitude of the response between fasting and fed conditions. CONCLUSIONS: People with obesity and prediabetes do not increase striatal DA release after eating a meal to satiation compared with fasting overnight and fail to inhibit DA release in response to high-calorie food stimuli after eating a meal to satiation. These data suggest that impaired DA signaling contributes to greater energy intake during meals in this population.

Endocannabinoid modulation of amphetamine sensitization is disrupted in a rodent model of lesion-induced dopamine dysregulation.

We tested the hypothesis that increased dopaminergic sensitivity induced by olfactory bulbectomy is mediated by dysregulation of endocannabinoid signaling. Bilateral olfactory bulbectomy induces behavioral and neurobiological symptomatology related to increased dopaminergic sensitivity. Rats underwent olfactory bulbectomy or sham operations and were assessed 2 weeks later in two tests of hyperdopaminergic responsivity: locomotor response to novelty and locomotor sensitization to amphetamine. Amphetamine (1 mg/kg i.p.) was administered to rats once daily for 8 consecutive days to induce locomotor sensitization. URB597, an inhibitor of the anandamide hydrolyzing enzyme fatty-acid amide hydrolase (FAAH), was administered daily (0.3 mg/kg i.p.) to sham and olfactory bulbectomized (OBX) rats to investigate the impact of FAAH inhibition on locomotor sensitization to amphetamine. Pharmacological specificity was evaluated with the CB(1) antagonist/inverse agonist rimonabant (1 mg/kg i.p). OBX rats exhibited heightened locomotor activity in response to exposure either to a novel open field or to amphetamine administration relative to sham-operated rats. URB597 produced a CB(1)-mediated attenuation of amphetamine-induced locomotor sensitization in sham-operated rats. By contrast, URB597 failed to inhibit amphetamine sensitization in OBX rats. The present results demonstrate that enhanced endocannabinoid transmission attenuates development of amphetamine sensitization in intact animals but not in animals with OBX-induced dopaminergic dysfunction. Our data collectively suggest that the endocannabinoid system is compromised in olfactory bulbectomized rats.