DRD2 methylation is associated with executive control network connectivity and severity of alcohol problems among a sample of polysubstance users.

Chronic exposure to alcohol and other drugs of abuse has been associated with deleterious consequences, including functional connectivity deficits within neural networks associated with executive control. Altered functional connectivity within the executive control network (ECN) might underlie the progressive inability to control consumption of alcohol and other drugs as substance use disorders progress. Genetic and epigenetic factors have been associated with substance use disorders (SUDs). For example, dopamine receptor 2 (DRD2) functioning has been associated with alcohol use disorder (AUD) and related phenotypes, including correlates of executive functioning. The present study aims to explore the relationship between a continuous measure of alcohol-related problems, epigenetic markers (methylation) within the DRD2 gene, and functional connectivity within the ECN among a sample of polysubstance users. A community sample of 658 subjects, whose consumption of alcohol, nicotine, and cannabis span across a spectrum of quantity and frequency of use, were obtained across previous studies in polysubstance using populations. Resting state functional magnetic resonance imaging was analyzed to identify intrinsic connectivity networks using a priori regions of interest. Methylation measurement of functionally relevant sites within the DRD2 gene was achieved via pyrosequencing. Regression-based models, including mediation and moderation models, tested the association between DRD2 methylation, functional connectivity within intrinsic neural networks (including the ECN), and severity of alcohol problems. Results suggest that average DRD2 methylation was negatively associated with right ECN (RECN) and left ECN (LECN) connectivity, but not associated with other networks tested, and DRD2 methylation was significantly associated with alcohol problems severity. Mediation models were not supported, although moderation models suggested that connectivity between edges within the RECN moderated the relationship between DRD2 methylation and AUD severity. Results support a theoretical model in which epigenetic factors are associated with neurobiological correlates of alcohol consumption among a sample of polysubstance users.

DRD2 promoter methylation and measures of alcohol reward: functional activation of reward circuits and clinical severity.

Studies have identified strong associations between D2 receptor binding potential and neural responses to rewarding stimuli and substance use. Thus, D2 receptor perturbations are central to theoretical models of the pathophysiology of substance dependence, and epigenetic changes may represent one of the fundamental molecular mechanisms impacting the effects of alcohol exposure on the brain. We hypothesized that epigenetic alterations in the promoter region of the dopamine D2 receptor (DRD2) gene would be associated with cue-elicited activation of neural reward regions, as well as severity of alcohol use behavior. The current study leveraged functional neuroimaging (fMRI) during an alcohol reward paradigm (n = 383) to test associations among DRD2 promoter methylation in peripheral tissue, signal change in the striatum during the presentation of alcohol cues, and severity of alcohol use disorder (AUD). Controlling for age, DRD2 promoter methylation was positively associated with responses to alcohol cues in the right accumbens (partial r = 0.144, P = 0.005), left putamen (partial r = 0.133, P = 0.009), right putamen (partial r = 0.106, P = 0.039), left caudate (partial r = 0.117, P = 0.022), and right caudate (partial r = 0.133, P = 0.009), suggesting that DRD2 methylation was positively associated with robust activation in the striatum in response to reward cues. DRD2 methylation was also positively associated with clinical metrics of AUD severity. Specifically, controlling for age, DRD2 methylation was associated with Alcohol Use Disorders Identification Test total (partial r = 0.140, P = 0.002); Impaired Control Scale total (partial r = 0.097, P = 0.044) and Alcohol Dependence Scale total (partial r = 0.152, P = 0.001). Thus, DRD2 methylation may be a critical mechanism linking D2 receptors with functional striatal brain changes and clinical severity among alcohol users.

Compensatory neural mechanisms in cognitively unimpaired Parkinson disease.

OBJECTIVE: Cognitive impairments in Parkinson disease (PD) are thought to be caused in part by dopamine dysregulation. However, even when nigrostriatal dopamine neuron loss is severe enough to cause motor symptoms, many patients remain cognitively unimpaired. It is unclear what brain mechanisms allow these patients to remain cognitively unimpaired despite substantial dopamine dysregulation. METHODS: Thirty-one cognitively unimpaired PD participants off dopaminergic medications were scanned using functional magnetic resonance imaging while they performed a working memory task, along with 23 controls. We first compared the PD off medication (PD_OFF) group with controls to determine whether PD participants engage compensatory frontostriatal mechanisms during working memory. We then studied the same PD participants on dopaminergic medications to determine whether these compensatory brain changes are altered with dopamine. RESULTS: Controls and PD showed working memory load-dependent activation in the bilateral putamen, anterior-dorsal insula, supplementary motor area, and anterior cingulate cortex. Compared to controls, PD_OFF showed compensatory hyperactivation of bilateral putamen and posterior insula, and machine learning algorithms identified robust differences in putamen activation patterns. Compared to PD_OFF, the PD on medication group showed reduced compensatory activation in the putamen. Loss of compensatory hyperactivation on dopaminergic medication correlated with slower performance on the working memory task and slower cognitive speed on the Symbol Digit Modality Test. INTERPRETATION: Our results provide novel evidence that PD patients maintain normal cognitive performance through compensatory hyperactivation of the putamen. Dopaminergic medication downregulates this hyperactivation, and the degree of downregulation predicts behavior. Identifying cognitive compensatory mechanisms in PD is important for understanding how some patients maintain intact cognitive performance despite nigrostriatal dopamine loss.

Clinical neuroscience of addiction: similarities and differences between alcohol and other drugs.

BACKGROUND: Existing pharmacological treatments for alcohol use disorder (AUD) and other substance use disorders (SUDs) have demonstrated only modest efficacy. Although the field has recently emphasized testing and developing new compounds to treat SUDs, there are numerous challenges inherent to the development of novel medications, and this is particularly true for SUDs. Thus, research to date has tended toward the "repurposing" approach, in which medications developed to treat other mental or physical conditions are tested as SUD treatments. Often, potential treatments are examined across numerous drugs of abuse. Several repurposed medications have shown promise in treating a specific SUD, but few have shown efficacy across multiple SUDs. Examining similarities and differences between AUD and other SUDs may shed light on these findings and offer directions for future research. METHODS: This qualitative review discusses similarities and differences in neural circuitry and molecular mechanism(s) across alcohol and other substances of abuse, and examines studies of pharmacotherapies for AUD and other SUDs. RESULTS: Substances of abuse share numerous molecular targets and involve much of the same neural circuitry, yet compounds tested because they putatively target common mechanisms have rarely indicated therapeutic promise for multiple SUDs. CONCLUSIONS: The lack of treatment efficacy across SUDs may be partially explained by limitations inherent in studying substance users, who comprise a highly heterogeneous population. Alternatively, medications may fail to show efficacy across multiple SUDs due to the fact that the differences between drug mechanisms are more important than their commonalities in terms of influencing treatment response. We suggest that exploring these differences could support novel treatment development, aid in identifying existing medications that may hold promise as treatments for specific SUDs, and ultimately advance translational research efforts.

A Pilot Multisensory Approach for Emotional Eating: Pivoting from Virtual Reality to a 2-D Telemedicine Intervention during the COVID-19 Pandemic.

BACKGROUND AND OBJECTIVES: Emotional eating (EE), or eating in response to negative emotions or stress, can be understood as a manifestation of difficulties regulating emotions among individuals with eating disorders. To date, many virtual reality treatments for eating disorders have focused on body image or exposure methods and have not exclusively targeted EE. There has been a call made by experts in the field for a "new generation" of virtual reality interventions, capable of utilizing virtual reality's potential more fully. We developed a novel emotion regulation (ER) intervention based upon virtual reality to improve EE among adults with an eating disorder diagnosis. The study hypothesized that a novel ER protocol utilizing evidence-based strategies, as well as innovative techniques, would be feasible and acceptable and show preliminary signals of effectiveness for EE. MATERIALS AND METHODS: Due to COVID-19, the study pivoted from the original completely immersive intervention to a 2-D intervention deliverable over telehealth. Twenty-one patients were recruited from the Adult Eating Disorders Program within Stanford University to receive seven weekly one-hour virtual experiences (VEs) focusing on ER. Participants were not randomized but, as part of a pragmatic study design, chose between the novel VE-Emotion Regulation (VE-ER) intervention or continuing their treatment as usual. Before and after the seven sessions, participants completed an assessment by filling out online questionnaires. RESULTS: Overall, VE-ER treatment was feasible, and the participant and therapist acceptability of VE-ER treatment was fairly high. In terms of preliminary effectiveness, the results showed a significant reduction in the frequencies of disordered eating behaviors in both groups, but a greater improvement in EE in the VE-ER group and a significant reduction in emotion dysregulation after the treatment. CONCLUSIONS: This novel pilot study makes a valuable contribution to the scant literature by demonstrating the feasibility, acceptability, and preliminary effectiveness of combining somatic, multisensory, and cognitive manipulations delivered via telemedicine to help patients with EE to manage their emotions. The findings can serve as the basis for larger, controlled studies evaluating the translation of the somatic marker theory from the research literature into real-world U.S. clinic settings.

A Pilot Randomized Controlled Trial of the Insomnia Coach Mobile App to Assess Its Feasibility, Acceptability, and Potential Efficacy.

Insomnia is highly prevalent among military veterans but access to cognitive-behavioral therapy for insomnia (CBT-I) is limited. Thus, this study examined the feasibility, acceptability, and potential efficacy of Insomnia Coach, a CBT-I-based, free, self-management mobile app. Fifty U.S. veterans, who were mostly male (58%) and mean age 44.5 (range = 28-55) years with moderate insomnia symptoms were randomized to Insomnia Coach (n = 25) or a wait-list control condition (n = 25) for 6 weeks. Participants completed self-report measures and sleep diaries at baseline, posttreatment, and follow-up (12 weeks postrandomization), and app participants (n = 15) completed a qualitative interview at posttreatment. Findings suggest that Insomnia Coach is feasible to use, with three quarters of participants using the app through 6 weeks and engaging with active elements. For acceptability, perceptions of Insomnia Coach were very favorable based on both self-report and qualitative interview responses. Finally, for potential efficacy, at posttreatment, a larger proportion of Insomnia Coach (28%) than wait-list control participants (4%) achieved clinically significant improvement (p = .049) and there was a significant treatment effect on daytime sleep-related impairment (d = -0.6, p = .044). Additional treatment effects emerged at follow-up for insomnia severity (d = -1.1, p = .001), sleep onset latency (d = -0.6, p = .021), global sleep quality (d = -0.9, p = .002), and depression symptoms (d = -0.8, p = .012). These findings provide preliminary evidence that among veterans with moderate insomnia symptoms, a CBT-I-based self-management app is feasible, acceptable, and promising for improving insomnia severity and other sleep-related outcomes. Given the vast unmet need for insomnia treatment in the population, Insomnia Coach may provide an easily accessible, convenient public health intervention for individuals not receiving care.

Cognitive impairment in Parkinson's disease is associated with Default Mode Network subsystem connectivity and cerebrospinal fluid Aß.

INTRODUCTION: To identify clinically implementable biomarkers of cognitive impairment in Parkinson's Disease (PD) derived from resting state-functional MRI (rs-fMRI) and CSF protein analysis. METHODS: In this single-center longitudinal cohort study, we analyzed rs-fMRI and CSF biomarkers from 50 PD patients (23 cognitively normal, 18 mild cognitive impairment, 9 dementia) and 19 controls, who completed comprehensive neuropsychological testing. A subgroup of participants returned for follow-up cognitive assessments three years later. From rs-fMRI, we studied the connectivity within two distinct Default Mode Network subsystems: left-to-right hippocampus (LHC-RHC) and medial prefrontal cortex-to-posterior cingulate cortex (mPFC-PCC). We used regression analyses to determine whether imaging (LHC-RHC, mPFC-PCC), clinical (CSF Aß-42:40, disease duration), and demographic (age, sex, education) variables were associated with global and domain-specific cognitive impairments. RESULTS: LHC-RHC (F3,67 = 3.41,p=0.023) and CSF Aß-42:40 (χ2(3) = 8.77,p = 0.033) were reduced across more cognitively impaired PD groups. Notably, LHC-RHC connectivity was significantly associated with all global and domain-specific cognitive impairments (attention/executive, episodic memory, visuospatial, and language) at the baseline visit. In an exploratory longitudinal analysis, mPFC-PCC was associated with future global and episodic memory impairment. CONCLUSION: We used biomarker techniques that are readily available in clinical and research facilities to shed light on the pathophysiologic basis of cognitive impairment in PD. Our findings suggest that there is a functionally distinct role of the hippocampal subsystem within the DMN resting state network, and that intrinsic connectivity between the hippocampi is critically related to a broad range of cognitive functions in PD.

Investigating sex differences in acute intoxication and verbal memory errors after ad libitum cannabis concentrate use.

BACKGROUND: An innovative naturalistic at-home administration procedure was used to investigate sex differences in subjective drug effects and verbal memory errors after ad libitum use of high potency state legal market Δ9-tetrahydrocannabinol (THC) concentrate. METHODS: Regular concentrate users were randomly assigned to ad libitum administration of one of two cannabis concentrate products (70 % or 90 % THC) that they purchased from a dispensary. 65 participants (N = 34 men, N = 31 women) were assessed in a mobile pharmacology lab before, immediately after, and 1 -h after ad libitum concentrate use. Plasma cannabinoids (THC, 11-OH-THC, CBD), subjective drug effects, and verbal memory errors were assessed at all three time points. RESULTS: Although men and women exhibited similar plasma 11-OH-THC levels across time (p = .10), sex differences were found in plasma THC and CBD after legal market concentrate use, with men displaying significantly higher levels of plasma THC and CBD immediately after cannabis concentrate use (plasma THC [ng/mL]: Mmen = 489.88, Mwomen = 135.08, p < .001; plasma CBD [ng/mL]: Mmen = 1.14, Mwomen = 0.53, p = .04). Despite this, sex differences in subjective effects and verbal memory errors did not emerge, although women reported a steeper decrease in drug liking after use (p = .04). CONCLUSION: These data provide the first look at sex differences after acute naturalistic cannabis concentrate use, and suggest much higher THC exposure in men versus women, but similar acute drug and impairment effects across the sexes. Further studies are needed to determine the mechanisms (e.g. tolerance, cannabinoid metabolism, smoking topography) behind these findings.

Acute effects of naturalistic THC vs. CBD use on recognition memory: a preliminary study.

The ratio of ∆9-tetrahydrocannabinol (THC) to cannabidiol (CBD) varies widely across cannabis strains. CBD has opposite effects to THC on a variety of cognitive functions, including acute THC-induced memory impairments. However, additional data are needed, especially under naturalistic conditions with higher potency forms of cannabis, commonly available in legal markets. The goal of this study was to collect preliminary data on the acute effects of different THC:CBD ratios on memory testing in a brief verbal recognition task under naturalistic conditions, using legal-market Colorado dispensary products. Thirty-two regular cannabis users consumed cannabis of differing THC and CBD levels purchased from a dispensary and were assessed via blood draw and a verbal recognition memory test both before (pretest) and after (posttest) ad libitum home administration in a mobile laboratory. Memory accuracy decreased as post-use THC blood levels increased (n = 29), whereas performance showed no relationship to CBD blood levels. When controlling for post-use THC blood levels as a covariate, participants using primarily THC-based strains showed significantly worse memory accuracy post-use, whereas subjects using strains containing both THC and CBD showed no differences between pre- and post-use memory performance. Using a brief and sensitive verbal recognition task, our study demonstrated that naturalistic, acute THC use impairs memory in a dose dependent manner, whereas the combination of CBD and THC was not associated with impairment.

Exercise Intervention Outcomes with Cannabis Users and Nonusers Aged 60 and Older.

Objectives: Cannabis use is increasing among older adults. We examined whether cannabis use impacted results of an intervention to increase physical activity in sedentary adults aged 60 and over. Methods: We measured differences in body mass index (BMI), exercise behavior, and cardiovascular fitness between older adult cannabis users (N = 28) and nonusers (N = 136) participating in an exercise intervention trial. Results: BMI of cannabis users was significantly lower than non-users (p = .007). Cannabis users reported .70 more days of exercise on the Stanford 7-Day Physical Activity Recall than non-users at the 8-week timepoint (p = .068) and were 4.1 points higher on the exercise subscale of the Community Healthy Activities Model Program for Seniors at 16-weeks (p = .045). Neither baseline nor post-intervention fitness differed by cannabis use status, and cardiovascular fitness improved after intervention in the full sample. Conclusion: These preliminary data suggest that current cannabis use status is not associated with a negative impact on fitness and efforts to increase exercise in sedentary older adults. Future studies should collect more detailed information on patterns and forms of cannabis use to understand their potential health effects for older adults.

Association of Naturalistic Administration of Cannabis Flower and Concentrates With Intoxication and Impairment.

Importance: The rapidly growing legal cannabis market includes new and highly potent products, the effects of which, to our knowledge, have not previously been examined in biobehavioral research studies because of federal restrictions on cannabis research. Objective: To use federally compatible, observational methods to study high-∆9-tetrahydrocannabinol (THC) legal market forms of cannabis. Design, Setting, and Participants: In this cohort study with a between-groups design that was conducted in a community and university setting, cannabis flower users and concentrate users were randomly assigned to higher- vs lower-THC products within user groups. Participants completed a baseline and an experimental mobile laboratory assessment that included 3 points: before, immediately after, and 1 hour after ad libitum legal market flower and concentrate use. Of the 133 individuals enrolled and assessed, 55 regular flower cannabis users (41.4%) and 66 regular concentrate cannabis users (49.6%) complied with the study's cannabis use instructions and had complete data across primary outcomes. Exposures: Flower users were randomly assigned to use either 16% or 24% THC flower and concentrate users were randomly assigned to use either 70% or 90% THC concentrate that they purchased from a dispensary. Main Outcomes and Measures: Primary outcome measures included plasma cannabinoids, subjective drug intoxication, and neurobehavioral tasks testing attention, memory, inhibitory control, and balance. Results: A total of 121 participants completed the study for analysis: 55 flower users (mean [SD] age, 28.8 [8.1] years; 25 women [46%]) and 66 concentrate users (mean [SD] age, 28.3 [10.4] years; 30 women [45%]). Concentrate users compared with flower users exhibited higher plasma THC levels and 11-hydroxyΔ9-THC (THC's active metabolite) across all points. After ad libitum cannabis administration, mean plasma THC levels were 0.32 (SE = 0.43) µg/mL in concentrate users (to convert to millimoles per liter, multiply by 3.18) and 0.14 (SE = 0.16) µg/mL in flower users. Most neurobehavioral measures were not altered by short-term cannabis consumption. However, delayed verbal memory (F1,203 = 32.31; P < .001) and balance function (F1,203 = 18.88; P < .001) were impaired after use. Differing outcomes for the type of product (flower vs concentrate) or potency within products were not observed. Conclusions and Relevance: This study provides information about the association of pharmacological and neurobehavioral outcomes with legal market cannabis. Short-term use of concentrates was associated with higher levels of THC exposure. Across forms of cannabis and potencies, users' domains of verbal memory and proprioception-focused postural stability were primarily associated with THC administration.

Preliminary results from a pilot study examining brain structure in older adult cannabis users and nonusers.

Exploring associations among cannabis use, brain structure, and cognitive function in older adults offers an opportunity to observe potential harm or benefit of cannabis. This pilot study assessed structural magnetic resonance imaging in older adults who were either current cannabis users (n = 28; mean age 69.8 years, 36% female) or nonusers (n = 28; mean age 66.8 years, 61% female). Recruitment targeted users who reported at least weekly use for at least the last year, although users had 23.55 years of regular cannabis use on average (SD=19.89, range 1.5-50 years). Groups were not significantly different in terms of sex, years of education, alcohol use, or anxiety symptoms, but were significantly different in age and depression symptoms. Users and nonusers did not differ in terms of total gray or white matter volumes controlling for age and depression symptoms, but users showed greater regional volume of left putamen, lingual cortex, and rostral middle frontal cortex. No significant differences between groups were observed in performance on a brief computerized cognitive battery. These results suggest that cannabis use likely does not have a widespread impact on overall cortical volume while controlling for age.

The New Runner's High? Examining Relationships Between Cannabis Use and Exercise Behavior in States With Legalized Cannabis.

Scientific literature examining cannabis use in the context of health behaviors, such as exercise engagement, is extremely sparse and has yielded inconsistent findings. This issue is becoming increasingly relevant as cannabis legalization continues, a situation that has been associated with increased initiation of use among adults, and increased potency of available products in legalized states. Physical activity is among the most important health behaviors, but many Americans do not meet minimum exercise recommendations for healthy living. Common issues surrounding low exercise rates include inadequate enjoyment of and motivation to exercise, and poor recovery from exercise. It is unclear whether cannabis use shortly before and/or after exercise impacts these issues, and whether this co-use affects exercise performance. The present online survey study examines attitudes and behaviors regarding cannabis use with exercise among adult cannabis users living in states with full legal access (N = 605). Results indicated that the majority (81.7%) of participants endorsed using cannabis concurrently with exercise, and those who did tended to be younger and more likely to be males (p < 0.0005 for both). Even after controlling for these differences, co-users reported engaging in more minutes of aerobic and anaerobic exercise per week (p < 0.01 and p < 0.05, respectively). In addition, the majority of participants who endorsed using cannabis shortly before/after exercise reported that doing so enhances their enjoyment of and recovery from exercise, and approximately half reported that it increases their motivation to exercise. This study represents an important step in clarifying cannabis use with exercise among adult users in states with legal cannabis markets, and provides guidance for future research directions.

A Novel Observational Method for Assessing Acute Responses to Cannabis: Preliminary Validation Using Legal Market Strains.

Background: The development of novel cannabis research methods that are compatible with current federal regulations is imperative to conduct studies of the effects of legal market cannabis. There is very little research on higher strength, higher Δ9-tetrahydrocannabinol (THC), which has become increasingly available since legalization. Research on strains containing cannabidiol (CBD), a second primary, but nonpsychotomimetic, cannabinoid, is very limited. Materials and Methods: Using a novel observational methodology, regular cannabis users were asked to use one of two legal market cannabis strains that they purchased from a local dispensary (one strain containing 8% THC and 16% CBD (THC+CBD) and one containing a 17% THC concentration, but no CBD (THC). After using their suggested cannabis strain as they typically would for a 3-day period, participants returned to the laboratory immediately after their final use. Measures included a blood draw to measure cannabinoid blood levels and circulating cytokines, self-reported subjective drug effects, and verbal recall memory. Results: Analysis of CBD/THC concentration levels in the blood following the 3-day strain manipulation suggests that all, but one participant (n=23/24) followed instructions and used their assigned strain. Individuals in the THC group (n=11) smoked no more than their usual amount, and participants who used the THC+CBD (n=12) strain smoked more than their reported usual amount, but did not have significantly different THC+metabolite blood levels from the THC group. The THC+CBD strain was also associated with less desire to smoke, lower levels of subjective drug effects, and lower levels of circulating cytokines (TNF-α, IL-6, and IL-1ß) immediately after use. Conclusions: Initial results support the feasibility of this novel observational methodology involving brief manipulation of strain use. Preliminary findings indicate that participants may self-titrate cannabis use based on cannabinoid concentration and the THC+CBD strain was associated with lower levels of cannabis craving, subjective intoxication, and circulating cytokines.

Exploring cannabis concentrates on the legal market: User profiles, product strength, and health-related outcomes.

BACKGROUND: Concentrated cannabis products are increasingly available and used, particularly in states with legal cannabis, but little is known about the profiles and characteristics of concentrate users. We aimed to characterize user profiles of cannabis users living in states with legal medical or recreational cannabis who reported using concentrates to those who do not use concentrates. METHODS: An anonymous online survey was advertised in California, Colorado, Nevada, Oregon, and Washington. We compared respondents who endorsed frequent concentrate use (FC; N = 67) (i.e. 4 days/week) with cannabis users who never use concentrates (NC; N = 64), and with those who smoke/vaporize cannabis flower frequently but never or very rarely use concentrates (FF; N = 60), on measures related to cannabis use patterns and cannabinoid product strength, other substance use, and occupational functioning and health. RESULTS: FC endorsed more symptoms of cannabis use disorder as compared to non-concentrate users (p < 0.05), but were similar to FF and NC on other health and occupational outcomes. FC also differed from FF and NC in that they tended to use cannabis that was higher in THC (p < 0.0005), even when using non-concentrated forms of cannabis (p < 0.005). Over half of FC users reported typically using concentrates of at least 80% THC, and 21% endorsed use of (non-concentrated) dry cannabis flower containing at least 30% THC. CONCLUSIONS: Concentrate users endorsed higher symptoms of cannabis use disorder and use higher strength cannabis even when using non-concentrated forms. Frequent use of concentrates may be associated with additional risks over and above frequent use of flower forms.

Dopamine-related dissociation of cortical and subcortical brain activations in cognitively unimpaired Parkinson's disease patients OFF and ON medications.

BACKGROUND: Despite dopaminergic depletion that is severe enough to cause the motor symptoms of Parkinson's disease (PD), many patients remain cognitively unimpaired. Little is known about brain mechanisms underlying such preserved cognitive abilities and their alteration by dopaminergic medications. OBJECTIVES: We investigated brain activations underlying dopamine-related differences in cognitive function using a unique experimental design with PD patients off and on dopaminergic medications. We tested the dopamine overdose hypothesis, which posits that the excess of exogenous dopamine in the frontal cortical regions can impair cognition. METHODS: We used a two-choice forced response Choice Reaction Time (CRT) task to probe cognitive processes underlying response selection and execution. Functional magnetic resonance imaging data were acquired from 16 cognitively unimpaired (Level-II) PD participants and 15 well-matched healthy controls (HC). We compared task performance (i.e. reaction time and accuracy) and brain activation of PD participants off dopaminergic medications (PD_OFF) in comparison with HC, and PD_OFF participants with those on dopaminergic medications (PD_ON). RESULTS: PD_OFF and PD_ON groups did not differ from each other, or from the HC group, in reaction time or accuracy. Compared to HC, PD_OFF activated the bilateral putamen less, and this was compensated by higher activation of the anterior insula. No such differences were observed in the PD_ON group, compared to HC. Compared to both HC and PD_OFF, PD_ON participants showed dopamine-related hyperactivation in the frontal cortical regions and hypoactivation in the amygdala. CONCLUSION: Our data provide further evidence that PD_OFF and PD_ON participants engage different cortical and subcortical systems to achieve similar levels of cognitive performance as HC. Crucially, our findings demonstrate dopamine-related dissociation in brain activation between cortical and subcortical regions, and provide novel support for the dopamine overdose hypothesis.

Body mass is positively associated with neural response to sweet taste, but not alcohol, among drinkers.

Obesity is a large and growing public health concern, presenting enormous economic and health costs to individuals and society. A burgeoning literature demonstrates that overweight and obese individuals display different neural processing of rewarding stimuli, including caloric substances, as compared to healthy weight individuals. However, much extant research on the neurobiology of obesity has focused on addiction models, without highlighting potentially separable neural underpinnings of caloric intake versus substance use. The present research explores these differences by examining neural response to alcoholic beverages and a sweet non-alcoholic beverage, among a sample of individuals with varying weight status and patterns of alcohol use and misuse. Participants received tastes of a sweet beverage (litchi juice) and alcoholic beverages during fMRI scanning. When controlling for alcohol use, elevated weight status was associated with increased activation in response to sweet taste in regions including the cingulate cortex, hippocampus, precuneus, and fusiform gyrus. However, weight status was not associated with neural response to alcoholic beverages.

Structural neuroimaging correlates of alcohol and cannabis use in adolescents and adults.

BACKGROUND AND AIMS: Chronic alcohol use is associated with lower gray matter volume, and we reported recently that alcohol use showed negative associations with widespread gray matter (GM) volume even among young adults. The current study aimed to test the strength of association between (1) alcohol use and GM volume; (2) alcohol use and white matter (WM) integrity; (3) cannabis use and GM volume; and (4) cannabis use and WM integrity among adults and adolescents. DESIGN AND SETTING: General linear models within large pooled cross-sectional samples of adolescents and adults who had participated in studies collecting substance use and neuroimaging data in the southwestern United States. PARTICIPANTS: The current analysis included adults aged 18-55 years (n = 853) and adolescents aged 14-18 years (n = 439) with a range of alcohol and cannabis use. MEASUREMENTS: The dependent variable was GM volume or WM integrity, with key predictors of alcohol use [Alcohol Use Disorders Identification Test (AUDIT) score] and cannabis use (past 30-day use). FINDINGS: Alcohol use showed large clusters of negative associations (ηp2  = 0.028-0.145, P < 0.001) with GM volume among adults and to a lesser extent (one cluster; ηp2  = 0.070, P < 0.05) among adolescents. Large clusters showed significant associations (ηp2  = 0.050-0.124, P < 0.001) of higher alcohol use with poorer WM integrity, whereas adolescents showed no significant associations between alcohol use and WM. No associations were observed between structural measures and past 30-day cannabis use in adults or adolescents. CONCLUSIONS: Alcohol use severity is associated with widespread lower gray matter volume and white matter integrity in adults, and with lower gray matter volume in adolescents.

What light have resting state fMRI studies shed on cognition and mood in Parkinson's disease?

Much remains unknown about non-motor symptoms of Parkinson's disease (PD), which have variable occurrence, progression, and severity among patients. The existing suite of neuroimaging tools has yielded insight that cannot be garnered by traditional methods such as behavioral and post-mortem assessment. They provide information on brain activity and structure that is invaluable to understanding abnormalities associated with neurodegeneration in PD. Among these tools, functional magnetic resonance imaging (fMRI) is often favored for its safety and spatial resolution. Resting state fMRI research capitalizes on the wealth of information that the brain offers when a person is not performing a motor or cognitive task. It is also a good means to study impaired and heterogeneous populations, such as people with PD. The present article reviews research that applies resting state fMRI to the ongoing hunt for biomarkers of PD non-motor symptoms. Thus far, research in this subfield has focused on two of the most common and significant non-motor symptoms: cognitive impairment and depression. These studies support resting state fMRI as a valid and practical tool for the study of these symptoms, but discrepancies among findings highlight the importance of further research with standardized procedures.