However, to date very few studies have examined intrinsic functional connectivity in adolescents and emerging adults.Studies to date in adolescent and young adult cannabis users have demonstrated increased intrinsic connectivity in frontal -temporal gyrus-cerebellar regions , frontal-parietalcerebellar network , increased middle-frontal and cingulate gyrus connectivity , and increased frontal gyrus activity along with reduced middle temporal activity.Increased connectivity patterns were linked with increased symptoms of cannabis dependence and recent cannabis use frequency.In young adult males, cannabis use was linked with increased connectivity in insula and decreased connectivity in the anterior cingulate and midbrain, even after a month of abstinence.Thus, overall, young cannabis users appear to demonstrate increased intrinsic connectivity patterns, especially in frontal-limbic regions.Still, these studies were primarily in men , thus findings may not generalize to female users.Further, two studies did not control for comorbid alcohol use and despite the aforementioned link between cannabis use and affective processing, no studies to date have specifically examined affective processing networks in cannabis users.Therefore, additional research is needed to examine intrinsic connectivity in affective processing networks in larger samples that include both males and females, controlling for comorbid alcohol use.The purpose of the current study was to explore whether regular cannabis use in adolescents and young adults was associated with aberrant ifcMRI frontolimbic connectivity at rest.We employed a priori region of interest analysis focusing on regions with reported cortical differences between young cannabis users and controls, including: vmPFC , ACC , insula , and amygdala.This project utilized ifcMRI data from three collection sites from the Imaging Data in Emerging Adults with Addiction Consortium.The strength of utilizing multi-site data sets include excellent reliability and validity when combining multi-site ifcMRI data , increased generalizability of more heterogenous groups , and larger sample sizes.It was hypothesized that cannabis users would demonstrate increased intrinsic connectivity patterns in regions subserving emotional expression.Lastly, in order to interpret the findings, a secondary aim examined if group differences in connectivity were associated with cannabis grow racks users’ self-reported anxiety and depressive symptoms.
The current study examined whether cannabis use was associated with frontolimbic intrinsic connectivity using a cross-sectional design in a sample devoid of independent Axis I anxiety FIGURE 2 | Scatter plot between total depression symptoms and bilateral rAcc connectivity in cannabis users.or mood disorders.After controlling for MRI collection site, recent alcohol, and nicotine use, and abstinence from cannabis use, cannabis users demonstrated increased intrinsic connectivity between the left rACC and the following: left insula, left amygdala, and right rACC in comparison to controls, though only group differences between bilateral rACC survived after correcting for multiple comparisons.Further, we found that increased bilateral rACC connectivity was associated with greater sub-clinical depressive symptoms in cannabis users.Current findings parallel previous intrinsic functional studies indicating frequent cannabis use among youth is associated with greater connectivity between frontal and temporal regions , and increased ACC connectivity in males.Resting state connectivity increases in comparison to controls was also reported within the medial frontal gyrus among a high-risk mostly male adolescent group.The present study adds to existing literature by including more females, controlling for other substance use and cannabis abstinence period, and relating the observed connectivity differences to mood-related symptoms.Task-based studies also report altered medial PFC activity associated with cannabis use among emerging adults , suggesting chronic cannabis use is associated with region-specific changes in brain activity and connectivity among regions implicated in emotion regulation, identification, and modulation.The current findings of abnormal functional connectivity in the rACC and limbic regions, which is consistent with our previous structural findings.Our team recently reported that greater cannabis use was related to reduced left rACC volume among young cannabis users, and smaller rACC volumes were also significantly associated with lower performance in an emotional discrimination task.Further, we also found reduced right ACC cortical thickness in a sample of young cannabis users, including a subset of cannabis users with a history of childhood attention deficit hyperactivity disorder, compared to non-using controls.The ACC undergoes significant developmental shifts in functional connectivity during young adulthood , has been implicated in ones’ ability to detect and monitor self-produced errors whether one is conscious/aware of the error or not.
The ACC may be less engaged in cannabis users compared to controls during tasks requiring inhibitory control and error monitoring.The rostral subdivision of the ACC is functionally connected with the amygdala , forming a network for processing affective facets of behavior.In concert with the insula, the ACC also serves to incorporate perceptual information with autonomic and emotional information.More specifically, the rACC has been posited to have top down control influence, serving as a gatekeeper, between regions processing negative affective information and those integrating environmental stimuli, and demonstrates protracted development during young adulthood.Indeed, lesions in the rACC are posited to impair ones’ sensitivity to adjustments in personal performance during a cognitive control task.For example, cannabis users have demonstrated reduced P300 during implicit and empathic emotional processing paradigms, particularly for the highest using cannabis users that also demonstrated deficits in explicit processing of negative emotions.Thus, abnormalities in rACC structure and function may impact various behavioral aspects, including cognitive control and emotional regulation.The current study suggests that chronic cannabis use may increase intrinsic connectivity between emotion regulation regions, which was opposite of our original hypothesis.A potential interpretation may include the inefficiency of prefrontal top-down regulation, as hypothesized by Behan et al., suggesting reduced intrinsic amygdala responsiveness.Further, Pujol et al.found reduced ACC and insula connectivity; however, the study did not examine sub-components of the ACC and used seed-based rather than region of interest approaches.Thus, disruptions in rACC function may lead to challenges in modulating ones’ mood, consistent with the current study findings, or adjusting to emotionally salient internal and external information.Indeed, we also found that increased depressive symptoms among cannabis users were associated with greater connectivity between the bilateral rACC.Alterations in rACC structure and function [see ] have been previously linked with depressive and affective symptoms and antidepressant response.Though the current sample did not meet criteria for an Axis I mood or anxiety disorder, cannabis use may impact regions implicated in symptom manifestation.Although cannabis users reported significantly greater sub-clinical levels of depression, we are unable to determine whether the endorsed symptoms predated the initiation of cannabis use or whether the endorsed symptoms occurred during the course of regular cannabis use among users.Indeed, cross-sectional and longitudinal studies among cannabis using youth have found increased risk of mood and affective symptoms.
Even casual cannabis using young adults report greater depressive symptomatology.Thus, structural and functional abnormalities within the rACC observed in cannabis users may result in mood dysregulation.Alternatively, subtle mood dysregulation may be a risk-factor for riskier cannabis use consumption.Proposed theories accounting for these functional and behavioral differences in cannabis users may have multiple underlying etiologies.Chronic young adult cannabis users demonstrate abnormal CB1 receptor density in the ACC ; thus, frequent cannabis use may influence continued white matter myelination and gray matter pruning within this region, impacting structural integrity.Further, altering CB1 availability and eCB signaling may impact GABA and GLUT signaling, which is observed in the ACC of adolescents with chronic cannabis use , suggesting continued cannabis use may impact healthy ACC functioning.Indeed, rACC glutamate levels have been associated with interactions between task-positive and task-negative sub-regions , suggesting excitatory activity at rest may alter one’s ability to engage networks involved in environmental interaction.Thus, altered inhibitory eCB activity may account for changes in intrinsic ACC connectivity among users.It is also possible that abnormalities in rACC and increased symptoms of depression place adolescents and young adults at increased risk for regular cannabis use.Prospective longitudinal studies are needed to address causality.In terms of youth treatment, there are potential interventions that may target ACC functioning to improve emotional regulation and mood in cannabis users.For example, activation within the ACC was associated with positive treatment outcomes following change talk among a diverse group of cannabis-using youth.Mindfulness-based mediation and a combination of mindfulness with aerobic exercise have also been associated with ACC specific changes.Findings from the current study should be considered in light of potential limitations.Although comorbid use of nicotine products was measured, some participants may have smoked cannabis with nicotine mixed in ; this was not measured in the current study.Given the cross-sectional nature of the current study, potential differences in frontolimbic connectivity and sub-clinical mood symptoms may exist prior to the onset of frequent cannabis grow system use and serve as a risk factor for regular cannabis use during adolescence.The relationships between such factors and substance use patterns among youth have previously been investigated [see ].Therefore, prospective, longitudinal studies are necessary to determine timing and causality.In conclusion, the present multisite imaging study found that among otherwise healthy young adults devoid of independent mood or affective disorders, regular cannabis users had greater intrinsic connectivity between left and right rACC.The current study also found that greater intrinsic bilateral rACC connectivity was associated with greater sub-threshold depressive symptoms among cannabis users.Results coincide and expand uponprior intrinsic and task-based imaging projects among young adults with chronic cannabis use, suggesting altered connectivity between regions with high cannabinoid receptor density that are imperative for emotional inhibition, recognition, and regulation.As THC content continues to rise , today’s users may be at increased risk for elevated mood or anxiety symptoms.Considering these findings, it is recommended that youth delay regular use of cannabis until after peak brain maturation is achieved [see ].In light of the current paper, cannabis interventions for youth may target improving anterior cingulate functioning, including aerobic exercise and mindfulness-based approaches.Pain in Sickle Cell Disease is a major comorbidity and unique.
It can arise from acute, unpredictable episodes of vaso-occlusive crises that may begin in infancy and continue throughout life.Additionally, chronic pain, with or without acute pain crises, occurs in a large proportion of SCD patients.In a study spanning just over 31,000 patient days, 232 adult SCD patients experienced chronic pain on more than 54% of total days.Acute, painful VOCs are a characteristic feature of SCD that require hospitalization, impair quality of life, and impact patient survival.Both acute as well as chronic pain are life disabling.Opioids are the mainstay for pain management in SCD, but high doses of opioids are required and are associated with adverse effects including pruritus, tolerance and opioid-induced hyperalgesia.Rates of opioid overdose are low in patients with SCD and have not shifted with the opioid epidemic.Cannabinoids have been widely considered for treating pain to meet the demand for alternative pain management therapies.Evidence of human use of the Cannabis sativa L.plant in rituals and medicine dates back millennia.In 1970, cannabis was classified as a Schedule 1 drug in the United States , and it was deemed to have no known medical use and a high potential for abuse.Despite the prohibition of cannabis in the U.S.and many European countries, there has been steady progress in studying its constituents for their beneficial effects in many conditions.An analysis of cannabis use among people using opioids for chronic pain management reported greater pain relief with cannabis than with opioids used alone in a national survey of adults in the U.S..In addition, emerging evidence suggests that prescriptions for opioids and deaths attributed to opioid use have declined in states that have made medicinal cannabis legal.Sickle patients often report use of cannabis to manage pain.It will be an understatement to say that the opioid epidemic and Centres for Disease Control guidelines on opioid use in 2016 have added another hurdle to pain management in SCD because pain treatment for both persistent chronic and acute VOC pain is reliant on opioids.Surveys conducted on residents involved in pain management of SCD suggest that potential for opioid tolerance and dependence pose a major hurdle in prescribing opioids.Similarly, adults with SCD reported using cannabis due to increased stigmatization for seeking opioids for pain, recent inadequate opioid dosing by the prescribers, and lack of alternatives through healthcare providers.Similar challenges in opioid prescribing for pain management among providers and patients have been disruptive to lives of patients living with chronic pain in other conditions as well.Thus, inadequate pain management due to fear of opioid prescribing and dosing and stigmatization for continued requirement of opioids in SCD contribute to use of cannabis and related easily available products by the patients to find pain relief.On the other hand, it provides a compelling reason to evaluate the potential of cannabis and its many non-toxic products for the potential to treat sickle pain.