Image-Derived Input Function for Human Brain Using High Resolution PET Imaging with [11C](R)-rolipram and [11C]PBR28

The aim of this study was to test seven previously published image-input methods in state-of-the-art high resolution PET brain images. Images were obtained with a High Resolution Research Tomograph plus a resolution-recovery reconstruction algorithm using two different radioligands with different radiometabolite fractions. Three of the methods required arterial blood samples to scale the image-input, and four were blood-free methods. values was quantified using a scoring system. Using the image input methods that gave the most accurate results with Logan analysis, we also performed kinetic modelling with a two-tissue compartment model.)-rolipram, which has a lower metabolite fraction. Compartment modeling gave less reliable results, especially for the estimation of individual rate constants.C]PBR28), the more difficult it is to obtain a reliable image-derived input function; and 4) in association with image inputs, graphical analyses should be preferred over compartmental modelling

Intrinsic Frontolimbic Connectivity and Mood Symptoms in Young Adult Cannabis Users.

Objective: The endocannbinoid system and cannabis exposure has been implicated in emotional processing. The current study examined whether regular cannabis users demonstrated abnormal intrinsic (a.k.a. resting state) frontolimbic connectivity compared to non-users. A secondary aim examined the relationship between cannabis group connectivity differences and self-reported mood and affect symptoms. Method: Participants included 79 cannabis-using and 80 non-using control emerging adults (ages of 18-30), balanced for gender, reading ability, and age. Standard multiple regressions were used to predict if cannabis group status was associated with frontolimbic connectivity after controlling for site, past month alcohol and nicotine use, and days of abstinence from cannabis. Results: After controlling for research site, past month alcohol and nicotine use, and days of abstinence from cannabis, cannabis users demonstrated significantly greater connectivity between left rACC and the following: right rACC (p = 0.001; corrected p = 0.05; f 2 = 0.55), left amygdala (p = 0.03; corrected p = 0.47; f 2 = 0.17), and left insula (p = 0.03; corrected p = 0.47; f 2 = 0.16). Among cannabis users, greater bilateral rACC connectivity was significantly associated with greater subthreshold depressive symptoms (p = 0.02). Conclusions: Cannabis using young adults demonstrated greater connectivity within frontolimbic regions compared to controls. In cannabis users, greater bilateral rACC intrinsic connectivity was associated with greater levels of subthreshold depression symptoms. Current findings suggest that regular cannabis use during adolescence is associated with abnormal frontolimbic connectivity, especially in cognitive control and emotion regulation regions

Molecular imaging markers to track Huntington’s disease pathology

Huntington’s disease (HD) is a progressive, monogenic dominant neurodegenerative disorder caused by repeat expansion mutation in the huntingtin gene. The accumulation of mutant huntingtin protein, forming intranuclear inclusions, subsequently leads to degeneration of medium spiny neurons in the striatum and cortical areas. Genetic testing can identify HD gene carriers before individuals develop overt cognitive, psychiatric, and chorea symptoms. Thus, HD gene carriers can be studied in premanifest stages to understand and track the evolution of HD pathology. While advances have been made, the precise pathophysiological mechanisms underlying HD are unclear. Magnetic resonance imaging (MRI) and positron emission tomography (PET) have been employed to understand HD pathology in presymptomatic and symptomatic disease stages. PET imaging uses radioactive tracers to detect specific changes, at a molecular level, which could be used as markers of HD progression and to monitor response to therapeutic treatments for HD gene expansion carriers (HDGECs). This review focuses on available PET techniques, employed in cross-sectional and longitudinal human studies, as biomarkers for HD, and highlights future potential PET targets. PET studies have assessed changes in postsynaptic dopaminergic receptors, brain metabolism, microglial activation, and recently phosphodiesterase 10A (PDE10A) as markers to track HD progression. Alterations in PDE10A expression are the earliest biochemical change identified in HD gene carriers up to 43 years before predicted symptomatic onset. Thus, PDE10A expression could be a promising marker to track HD progression from early premanifest disease stages. Other PET targets which have been less well investigated as biomarkers include cannabinoid, adenosine, and GABA receptors. Future longitudinal studies are required to fully validate these PET biomarkers for use to track disease progression from far-onset premanifest to manifest HD stages. PET imaging is a crucial neuroimaging tool, with the potential to detect early changes and validate sensitivity of biomarkers for tracking HD pathology. Moreover, continued development of novel PET tracers provides exciting opportunities to investigate new molecular targets, such as histamine and serotonin receptors, to further understand the mechanisms underlying HD pathology

The Endocannabinoid System and Cannabidiol's Promise for the Treatment of Substance Use Disorder

Substance use disorder is characterized by repeated use of a substance, leading to clinically significant distress, making it a serious public health concern. The endocannabinoid system plays an important role in common neurobiological processes underlying substance use disorder, in particular by mediating the rewarding and motivational effects of substances and substance-related cues. In turn, a number of cannabinoid drugs (e.g., rimonabant, nabiximols) have been suggested for potential pharmacological treatment for substance dependence. Recently, cannabidiol (CBD), a non-psychoactive phytocannabinoid found in the cannabis plant, has also been proposed as a potentially effective treatment for the management of substance use disorder. Animal and human studies suggest that these cannabinoids have the potential to reduce craving and relapse in abstinent substance users, by impairing reconsolidation of drug-reward memory, salience of drug cues, and inhibiting the reward-facilitating effect of drugs. Such functions likely arise through the targeting of the endocannabinoid and serotonergic systems, although the exact mechanism is yet to be elucidated. This article seeks to review the role of the endocannabinoid system in substance use disorder and the proposed pharmacological action supporting cannabinoid drugs' therapeutic potential in addictions, with a focus on CBD. Subsequently, this article will evaluate the underlying evidence for CBD as a potential treatment for substance use disorder, across a range of substances including nicotine, alcohol, psychostimulants, opioids, and cannabis. While early research supports CBD's promise, further investigation and validation of CBD's efficacy, across preclinical and clinical trials will be necessary

PET-kannabinoidimerkkiaineet

Kannabinoidireseptorit ovat osa endokannabinoidijärjestelmää, joka muodostaa lipidipohjaisen signaalijärjestelmän ihmisen keskushermostossa. Erityisesti aivoissa esiintyvien CB1-reseptorien on todettu olevan osallisia erilaisissa fysiologisissa ja patologisissa toiminnoissa. CB1-reseptorit liittyvät myös neuropsykiatrisiin sairauksiin ja aivojen rappeumaan. Positroniemissiotomografia on ei-invasiivinen ja erittäin herkkä menetelmä, jota on hyödynnetty CB1-reseptorien tutkimuksessa. Positroniemissiotomografia perustuu positroniemittoiviin radionuklideihin. PET-kannabinoidimerkkiaineissa on käytetty positroniemittoivina radionuklideina hiili-11:tä ja fluori-18:aa. CB1-reseptorille on kehitetty useita PET-merkkiaineita, joista osaa on käytetty prekliinisissä ja kliinisissä tutkimuksissa. PET-kannabinoidimerkkiaineiden kehityksessä haasteena on useat niille asetetut vaatimukset, jotka ovat olennaisia onnistuneen kuvantamisen kannalta. Radioleimauksiin on käytetty useita menetelmiä, mutta siirtymämetallivälitteinen 18F-fluoraus on tarjonnut mahdollisuuden suoraviivaiseen ja tehokkaaseen merkkiaineiden radioleimaamiseen. Tässä tutkimuksessa valmistettiin kuparivälitteistä 18F-fluorausta varten trimetyylitinattu lähtöaine (3R,5R)-5-(3-trimetyylistannyylifenyyli)-3-[(R)-1-fenyylietyyliamino]-1-(4-trifluorimetyylifenyyli)-pyrrolidiini-2-oni. [18F]Fluoridin aktivointiin käytettiin atseotrooppista tislausta ja kiinteäfaasiuuttoa ja verrattiin näiden [18F]fluoridin aktivointimenetelmien vaikutusta 18F-fluorauksen onnistumiseen. CB1-reseptoreille spesifinen radioligandi [18F]FPATPP, (3R,5R)-5-(3-[18F]fluorifenyyli)-3-[(R)-1-fenyylietyyliamino]-1-(4-trifluori-metyylife-nyyli)pyrrolidiini-2-oni valmistettiin onnistuneesti kuparivälitteisellä 18F-fluorauksella käyttäen trimetyylitinattua lähtöainetta. Kuparivälitteinen 18F-fluoraus on potentiaalinen vaihtoehto [18F]FPATPP:n valmistamiseksi, mutta tutkimus jätti tilaa synteesin jatkokehitykselle

Impact of FAAH Genotype and Marijuana Use on Brain Structure and Neuropsychological Performance in Emerging Adults

Introduction: Chronic MJ use may be associated with higher cognitive ability impairments (see Lisdahl et al., 2013). Regions undergoing later maturation (Gogtay 2004), may be at increased risk for MJ-induced alterations. Endogenous cannabinoid signaling (ECS) is modulated by the function the enzyme Fatty Acid Amide Hydrolase (see Ho & Hilard, 2005), thus the gene encoding for this enzyme (FAAH) impacts ECS (Sipe et al., 2002). Here, we examine the impact of MJ use and FAAH genotype on PFC complexity and underlying frontal white matter (WM) integrity in young adults. Methods: Participants included 37 MJ users and 37 non-using young adults (ages 18-25). Of those, 27 were FAAH A carriers and 47 were homozygous (C/C) carriers. Exclusion criteria included co-morbid psychiatric and neurologic disorders and excessive other drug use. Brain complexity and WM integrity was measured using local gyrification index and Tracula programs. The Letter Number Sequencing, PASAT and D-Kefs c/w interference measured complex attention and inhibition. Multiple regressions and Pearson r correlations were used to predict LGI, WM integrity and cognitive performance indices from MJ use status, FAAH status, and MJ*FAAH interactions controlling for demographic variables and comorbid drug use. Results: MJ users demonstrated decreased LGI in bilateral vmPFC (RH: [beta=-.54, p\u3c.001] and LH: [beta=-.55, p\u3c.001]); bilateral mPFC (RH: [beta=-.48, p=.001] and LH: [beta=-.51, p\u3c.001]); and bilateral frontal poles (RH: [beta=-.31, p=.02]; LH: [beta=-.43, p=.004]), with increased LGI in LH DLPFC [beta=.40, p=.004]. Controlling for the same variables, reduced WM integrity was found in bilateral UCF (RH: [beta=.32, p=.03] and LH: [beta=.31, p=.03]) and fMinor [beta=.27, p=.05] tracts of MJ users. Significant interactions between MJ*FAAH were seen predicting LGI in LH OFC [beta=-.24, p=.04] and WM integrity in fMinor [beta=.26, p=.04] and LH ATR [beta=.36, p=.003]. In MJ users, increased gyrification was associated with better LNS performance in RH mPFC [r=.51, p=.001], RH vmPFC [r=.41, p=.01], and RH frontal pole [r=.45, p=.005] and a negative correlation with gyrification and color-word completion time in LH vmPFC [r=-.32, p=.05]. In MJ users, decreased WM integrity was associated with greater PASAT performance in the RH UNC [r=.38, p=.02]. Discussion: MJ use was associated with reduced LGI in several PFC regions with one region showing an opposite relationship. These results are consistent with Mata and colleagues (2010). We also found reduced WM integrity in fronto-temporal tracts, which may have important emotion regulation implications. These brain characteristics were also moderated by FAAH genotype. Additional implications of ECS and brain health will be discussed

Baked and Buzzed: Investigating the Influence of Co-Use of Cannabis and Alcohol on White Matter Integrity in Emerging Adults

Objective: Growing evidence suggests alcohol and cannabis use independently alter neural structure and functioning, particularly during sensitive developmental time periods such as adolescence and emerging adulthood. However, there has been minimal investigation into the effects co-occurring use of these two substances, despite preliminary evidence of unique acute and psychopharmacological changes due to using alcohol and cannabis together. Method: Data drawn from the IDEAA Consortium was utilized to assess white matter integrity as measured by FreeSurfer’s TRACULA in emerging adults (n=192; 16-27 years old). Timeline Follow-Back was used to calculate past month cannabis use, alcohol use, co-use days, binge alcohol episode, and co-use-binge days. The Stroop task was administered and normed scores were used. Multiple regressions investigated white matter integrity by past month cannabis, alcohol, and co-use days, controlling for appropriate covariates (e.g., site, gender, education, length of abstinence). Analyses were run twice, once with alcohol as measured in standard units and once with binge episodes. Follow-up brain-behavior analyses assessed whether substance use or tracts that differed significantly by substance use then related to Stroop performance. Correction for multiple comparisons was conducted using Benjamini and Hochberg’s (1995) False Discovery Rate correction method. Results: Corrected for multiple comparisons, cannabis use was significantly related to increased mean diffusivity in 12 fronto-limbic and fronto-parietal tracts. Cannabis use also associated with poorer performance on Stroop word reading. Within the MJ+ALC group, increased mean diffusivity associated with better Stroop interference performance. Discussion: The present study found cannabis use was associated with decreased white matter integrity, as measured by mean diffusivity, across fronto-parietal and fronto-limbic tracts. These results suggest a robust relationship between cannabis use and white matter integrity in this neurodevelopmentally sensitive time period. Despite our hypotheses, co-use, alcohol use, and binge drinking did not significantly predict any measures. Future research should further investigate the potential independent and interactive affects of these substances on preclinical and clinical levels. Efforts should be made to inform the public of the likely negative impact of cannabis on white matter quality

Intrinsic Frontolimbic Connectivity and Associated Patterns on Reported Mood Symptoms in Young Adult Cannabis Users

Introduction: Recent legislation changes regarding cannabis in the United States highlights the importance of investigating the impact of regular cannabis use on populations, such as emerging adults, that will likely drive the market given their greater daily use (see Johnston et al., 2014). The endocannbinoid system plays a role in neurodevelopment (see Bossong & Niesink, 2010) and has been implicated in behavioral and emotional processing (see Moreira & Lutz, 2008; see Solinas et al., 2008; see Covey et al., 2014). The current study utilized a multisite functional magnetic resonance imaging (fMRI) dataset of intrinsic (a.k.a. no task/resting state) frontolimbic connectivity among healthy emerging adults. A secondary aim examined the relationship between cannabis group connectivity differences and self-reported mood and affect symptoms. Methods: Participants included consortium data totaling 79 cannabis users (average of 58 past month joints) and 80 controls (0 past month joints & no history of regular use) emerging adults (ages of 18-30), balanced for gender, reading ability, and age. Exclusion criteria included history of medical/neurological illness or injury, independent DSM-IV-TR axis I disorders, and inability to maintain monitored abstinence. Structural and functional neuroimages were preprocessed and analyzed using CPAC software. Regions of interest included: anterior cingulate (rostral and caudal subdivisions), amygdala, insula, and ventral medial prefrontal cortex. Behavioral measurements included the Beck Depression Inventory-II, Beck Anxiety Scale, and the State Trait Anxiety Inventory-Y1. Standard multiple regressions were used to predict if cannabis group status was associated with frontolimbic connectivity after controlling for site, past month alcohol and nicotine use, and days of abstinence from cannabis. Pearson r correlations were run to examine the relationship between group differences in connectivity and self-reported depression and anxiety total scores. Results: On self-reported measures, cannabis users reported significantly more total depression (p=.02) and anxiety (p=.04) symptoms. After controlling for site, past month alcohol and nicotine use, and days of abstinence from cannabis, cannabis users demonstrated significantly greater connectivity between left rACC and the following: left amygdala (p=.03; corrected p=.47; ƒ2 = .17), left insula (p=.03; corrected p=.47; ƒ2 = .16), and right rACC (p=.001; corrected p=.05; ƒ2 =.55). Among cannabis users, greater bilateral rACC connectivity was associated with significantly greater total depressive scores (p=.02). Discussion: Cannabis using young adults demonstrated greater connectivity within frontolimbic regions compared to controls with no recent or regular cannabis use. In cannabis users, greater bilateral rACC intrinsic connectivity was associated with higher levels of depression symptoms. Current findings suggest that regular cannabis use during neurodevelopmental periods may alter intrinsic brain characteristics involved in cognitive control and emotion regulation, and this finding should be considered when designing clinical interventions for this population. Future research may investigate the mechanisms underlying altered rACC connectivity, such as GABA and GLUT signaling, and the impact on mood in young cannabis users