Hemp Growing

Notably, findings from this report appear to be driven specifically by our binge drinking variable, as total 30-day alcohol consumption did not significantly predict any neurocognitive outcome above and beyond binge drinking. Although there are a dearth of studies examining the specific impact of binge drinking on neuropsychological outcomes compared to that of chronic drinking over a longer span of time, some evidence suggests that the repeated periods of high level of intoxication and withdrawal from binge drinking exacerbates the detrimental neurobiological effects of alcohol . Future research is needed to examine chronicity of binge drinking and whether there may be a specific threshold associated with the greatest level of CNS risk. Still, given evidence that binge drinking may be at least as detrimental to the central nervous system as alcohol dependence, public safety measures that aim to reduce binge drinking behavior may have widespread benefits, especially among older PWH. While this study has strengths in novelty, use of a comprehensive neuropsychological battery, and clinical relevance, it also has several limitations. First, the HIV/Binge group-specific sample sizes were relatively small, particularly in Binge+ groups. Although this limited our ability to examine a full factorial three-way interaction between age, HIV status, and binge drinking status, we were still able to examine the novel age by HIV/Binge group interaction with adequate statistical power. Next, our assessment of binge drinking is based solely on self-report and may be subject to error by recall bias, memory difficulties, and/or social desirability bias; however, the majority of alcohol and substance use research relies on self-report of use. In addition, while binge drinking data specifically pertained to use within the last 30 days, we do not know exact amounts of time between participants’ last binge episode and their participation in the study,rolling grow tables limiting our ability to comment on how recency relates to cognitive performance.

Future research may benefit from the use of more objective measures of alcohol use in daily life to more accurately characterize alcohol use patterns . Finally, our exclusion of participants with current non-alcohol substance use disorders limits generalizability to others with binge drinking behavior and/or alcohol use disorder among whom polysubstance use is common. In summary, the current study demonstrated detrimental additive effects of HIV and binge drinking on neurocognitive functioning, and that older adults appear to be most vulnerable to these adverse effects particularly in the neurocognitive domains of learning, delayed recall, and motor skills. Our findings support the need for clinical screening for binge drinking behavior given that many adults who engage in binge drinking behavior do not meet criteria for an AUD, as well as psychoeducation and psychosocial interventions targeting the reduction of binge drinking among older PWH. Additionally, given evidence that improvements in neurocognitive functioning may be possible after sustained sobriety following AUD recovery among HIV- populations , future work is needed to understand whether this may also be true among PWH who reduce or cease binge drinking behavior.There are significant barriers to recruiting and retaining individuals with overlapping vulnerabilities in the pregnancy or postpartum period Wetherington & Roman, 1998. This may result in challenges for generalizability and therein create a relatively sparse knowledge base about the long-term out comes for these women and their children including the environmental, mental health, physiological, and neurological factors. Filling these knowledge deficits and gaps requires ongoing assessment because research tools including those for recruitment and retention change; in addition, substance exposures in pregnancy change , thereby shifting methods to reach target populations of interest and methods to measure outcomes of inter est. It is imperative for the field to identify and address engagement in research, to ensure representation of pregnant and postpartum women that use substances.

Engagement in longitudinal studies will allow a more complete understanding of maternal and child health outcomes as a result of new and emerging trends in prenatal substance exposure. Enhanced understanding of participants’ perspectives on engagement and study participation will allow researchers to more fully address this pressing research and public health need. Prenatal exposure studies began in earnest in the 1970s, after the identification and diagnosis of fetal alcohol syndrome . Careful participant selection and comparison selection were and are necessary to classify effects of prenatal exposures. Protectionist and paternalistic regulations excluded women from health research and limited the field’s understanding about how sex and gender shape substance use and SUD . Research studies on substance exposures during pregnancy expanded rapidly in the past 30 years, in recognition of the cocaine epidemics of the 90s, and the current increases in prenatal opioid and methamphetamine exposures . Indeed, research that focused specifically on prenatal exposures and other women’s health issues has been encouraged by journal editors, policymakers, and funding agencies including the NIH Helping End Addiction Long term initiative. Despite bio-ethical, legal, and social concerns regarding the risks and benefits of research participation for pregnant and postpartum women who use alcohol and drugs , the inclusion of vulnerable populations who are marginalized or stigmatized in research on sensitive topics has not demonstrated undue harm or exposure to unacceptable risk, and in fact, has been associated with potential benefits, such as altruism, catharsis, and gained knowledge . Of course, it is important for researchers to adopt careful experimental design and safeguards that will uphold the principal of non-maleficence and protect vulnerable participants from harm . Exclusion of substance using populations may violate important bio-ethical principles of human subjects research, particularly the principles of autonomy, beneficence, and justice . Exclusion from research not only strips individuals from making decisions about their own autonomy and denies them potential benefits of participating, but also exposes them to great er societal marginalization and may ultimately place them at increased risk of harm due to deficits in critical health knowledge and exposure to inappropriate or ineffective treatments .

Unfortunately, prenatal exposures to alcohol, tobacco, and other drugs are rising , with 1 in 4 pregnancies ex posed to tobacco , alcohol consumption , or illicit drug use . Specifically, opioid exposed pregnancies have increased from 1.5 to 6.5 per 1000 pregnancies . Yet, cannabis exposures are the most prevalent drug exposure, with nearly 7–8% reported exposure in the first trimester . Rising rates of sub stance exposure correspond to increasing health risks and ad verse outcomes at great societal cost and burden to systems of health care and social services, as well as criminal justice. Notably, researchers involved in the NIDA-funded Perinatal-20 Treatment Research Demonstration Program that focused on SUD treatment for pregnant and postpartum women identified seven clinical factors that contributed to significant difficulty and complexity in the recruitment and retention of women in substance use treatment research, including as follows: severity of SUD, legal system involvement, housing instability, interpersonal relationship challenges, parenting responsibilities, employment challenges, and need for more intensive services. These difficulties with recruitment and retention contribute to additional complications for research, including biased samples of convenience recruited through referrals from social and health agencies, limited sample diversity, deviations from there search design, and ethical issues associated with risk and benefits of participation and involvement with the criminal justice or child welfare system. In particular,growing rack when research designs do not involve the possibility of direct benefit due to participation , it is important to understand the unique reasons and motivations that drive decision-making about research participation . Due to all of the aforementioned factors that potentially inhibit the inclusion and engagement of high-risk participants , it is imperative to understand the motivations for engagement in research among high-risk participants, focusing specifically on understanding motivation for research participation, factors that influence decision-making about participation, and barriers to participation.The current study reports results from a qualitative research study conducted as part of an 18-month, multi-site pilot study aimed to develop and demonstrate feasibility of an experimental design for a 10-year, prospective, longitudinal investigation of normative childhood brain development, beginning in pregnancy. A major aim of the 10-year study will be to determine factors that alter brain development including prenatal exposure to opioids and other psychoactive substances, as well as other prenatal and childhood environmental exposures. This goal necessitates recruiting pregnant women previously or currently using substances, as well as a large group of pregnant women who are at low risk of prenatal substance use. Two of the primary aims of the pilot are developing and testing recruitment and retention strategies and addressing ethical and legal challenges of conducting research with a stigmatized and vulnerable population.Individual interviews and one focus group were conducted with a total of 41 women . Women were at high-risk of prenatal or postnatal substance use and were identified through medical clinics, other research study involvement, or SUD treatment programs.

Recruitment took place across five sites in the USA located in California, Georgia, New Mexico, Ohio, and Oklahoma . High-risk pregnant and postpartum women were defined in the current study as a parenting or pregnant woman who had used alcohol and tobacco and/or had a current or past history of SUD. Some participants were currently receiving SUD treatment. Contact was made through trained research personnel located at each specific site with 41 total participants taking part in the current study. Only one focus group that included five women was combined with the individual interviews. The one focus group was conducted in New Mexico prior to group restrictions imposed due to COVID-19.Qualitative methods for the research team, study design, and analysis followed the guidelines recommended by Tong, Sainsbury, and Craig . Qualitative study recruitment began with sites contacting participants in person or by phone and describing the current study and qualitative interview process. All women who expressed interest in participating were scheduled for either a focus group or individual interview depending on whether the interview took place prior to or following COVID-19 restrictions regarding in-person gatherings. Interviews conducted during the COVID-19 restrictions were conducted individually by phone. All participants gave oral informed consent. During the consent process, a brief overview of the qualitative study and all safety measures taken to ensure confidentiality were discussed. Trained qualitative research assistants collected all qualitative data from March 2020 through June 2020. Before engaging in focus groups/individual phone interviews, all participants completed an in-person or online survey that included a demographic questionnaire and watched a short video describing the protocols planned for the larger, longitudinal study including neuroimaging , neuro developmental, and bio-specimen collection. For the focus group, snacks were provided. Participants received a $50–75 incentive for their participation, and this varied based on site. All focus groups and individual interviews were audio-recorded and lasted approximately 45–60 min. Transcription work was conducted by qualitative team members or a transcription company, with team members crosschecking all transcripts to verify accuracy. During the transcription process, all identifying information was removed to ensure privacy. All procedures were approved by the sIRB for the 5-site consortium.Focus group and individual interview guides for the current project were developed by the first author, in conjunction with the evaluation team and other sites within the research consortium reviewing and revising the guide as needed. Focus group and individual interviews were coded individually and combined for data analysis. All coding and data analysis was conducted at one site. Recordings were transferred securely ac cording to IRB-approved methods. It is important to note that focus group and individual data themes were examined a priori and themes were congruent and therefore data were merged.Qualitative data was analyzed using the NVivo© 11 software. Five qualitative researchers worked together to develop a code book focused on broad themes influenced by the semi structured interview guide.The code book was developed using an agreed upon coding scheme with themes not being predetermined but rather emerging from the data. Upon completion of the code book, two teams consisting of two qualitative researchers coded all transcriptions using developed coding templates. Cleaning of data took place as needed . Once coded, inter-coder re liability was established using simple percent agreement, which is a commonly used method for assessing reliability in qualitative studies . Average inter-coder reliability was over 85%. In the “Results” section, themes are described in more detail. The validity of the current research findings are enhanced by several design factors such as the calculation of salient factors using percentage of comments and the team-based approach used for coding.

A sample item includes “In the last 12 months, have you driven a snowmobile, motor boat, Sea-doo, or all-terrain vehicle within an hour of drinking 1 or more drinks of alcohol?” Responses to this item include “Did not drive a snowmobile, motor boat, Sea-doo, or ATV in the last 12 month; Yes; No.” Participants answered 131 questions from this measure approved by the University IRB prior to completing questions from the DUSI-R. Items from the DUSI-R asked participants to indicate their frequency and behaviors, as well as their peer’s behaviors, pertaining to substance use. Sample items include “In the past year, did you drink large quantities of alcohol when you went to parties?”; “In the past year, did any of your friends regularly use alcohol or drugs?” Participants responded by indicating “yes” or “no” to all items. Participants responded to 142 IRB approved items from the questionnaire.These questions were interspersed with the OSDUHS and DUSI-R .Data were analyzed using SPSS 23.0. Adolescents reported their lifetime, past year, and regular usage of tobacco, alcohol, cannabis, pain killers , spice, heroin, Attention-Deficit/Hyperactivity Disorder medication , cocaine, methamphetamine , psilocybin, methylenedioxy-methamphetamine , and Lysergic acid diethylamide . Due to potential individual variation within our sample size, we grouped drugs into categories based on reported usage and perceived consequences among this age group as follows: Group I ; Group II ; Group III ; Group IV . We also categorized time points of usage by lifetime use, use in the past 12 months, and using frequently, as listed in the OSDUHS questionnaire . Using “frequently” was measured as 11-15 times a day for tobacco, 2-3 times a month for alcohol,vertical farming equipment and 6-9 times a year for all other substances. Endorsement of use was weighted based on the Group, whereby Group I drugs were assigned a weight of 1, Group II, a weight of 2, etc.

Each endorsement of a drug in the group was multiplied by the weight and added to the totals of the other Groups to create a Drug Use composite score. Additionally, we created composite scores based on time points by adding the scores generated from the grouped drugs across each respective time point. The goal of this study was to determine whether adolescent neural responses to social violations of expectations were associated with substance use behaviors. Our results indicate that adolescents who demonstrated increased ventral striatal response when expectations were violated used more Group I substances compared to adolescents who demonstrated a decreased VS response when expectations were violated. Older adolescents used more illicit substances, and used substances more frequently than younger adolescents. Most adolescents endorsed using Group I substances compared to other substances. Adolescents who had greater Rejection Sensitivity Questionnaire scores used substances with greater consequences. Ventral striatal activation to violations was greatest in adolescents who endorsed using the most Group I substances compared to adolescents who endorsed using the fewest Group I substances. Researchers have proposed that individuals who use substances may require greater prediction errors to elicit the level of reward exhibited in individuals who use fewer substances by comparison . Additionally, previous research has supported this difference, whereby adolescents who demonstrate a greater ventral striatal response to non-social violations of expectations were more likely to engage in risky behaviors . Perhaps, then, it is unsurprising that adolescents who demonstrate increased ventral striatum response when social expectations were met reported engagement in fewer risky activities by comparison—as these adolescents may require a diminished PE to elicit a dopaminergic or rewarding response. Self-reported happiness to violations of expectations from Study 1 mirrored the aforementioned neural responses; such that participants who reported using a minimum amount of Group I substances were less happy upon experiencing a violation of expectations compared to when expectations were met.

While this effect is not statistically significant, it does suggest that the ventral striatum activation from Study 1 is reflective of a reward prediction error, as adolescents’ self-reported responses were in accordance with their ventral striatum response to violations. Separating the data in this way allowed us to account for individual variation that may have otherwise been lost in analyses, and elucidates important differences in ventral striatal activation with respect to reported substance use. The current study’s novel contribution to the literature is in showing that ventral striatum activation to social feedback is associated with real-world behaviors. We hypothesized that adolescents who demonstrated increased ventral striatal recruitment to positive social violations of expectations would use more types of substances more frequently than adolescents who demonstrated decreased recruitment by comparison. We did not find this association to be significant in our analyses. Instead, we found that for socialtrials, adolescents who recruited the ventral striatum used Group I substances more frequently, and adolescents who recruited the VS when their social expectations were met used fewer Group I substances in the past 12 months and in their lifetime. While we expected an association between ventral striatal response to positive social violations of expectations to predict behavior, as previously mentioned in Chapter 2, it’s likely adolescents were happier/more rewarded when their social expectations were met. Thus, it is unsurprising that a neural region implicated in reward demonstrates greatest response to reinforcing social feedback, which in turn is most associated with real-world social behaviors in adolescents. We suggest that in line with the results on self-reported happiness, adolescents who recruit the ventral striatum when their social expectations are met would be more inclined to act in a way that supports meeting their peers’ expectations—such as avoiding engaging in risky substance use behaviors. Because many adolescents nationwide and in our sample endorse using Group I substances , it is then likely that adolescents who recruited the ventral striatum for social trials were attuned to social norms, and were more likely to engage in social behaviors that were greatly endorsed by their peers.

Consistent with national and regional reports on adolescent drug use ,4×4 grow tray we found that older adolescents in our sample used more substances more frequently than younger adolescents. Research has indicated that older adolescents have greater access to more substances than younger adolescents and are eager to model their older peers’ behavior . We also found that adolescents who reported feeling more sensitive to rejection used more Group IV substances . This is in accordance with literature suggesting adolescents who are more sensitive to rejection take more dangerous risks—including using dangerous substances and engaging in health-compromising activities with their peers . We propose these teenagers engage in such activities because they are concerned about being rejected by their peers if they choose not to. It is likely that factors that contribute to rejection sensitivity may be better predictors of this type of substance use. We suggest adolescents who are not sensitive to rejection do not feel the same pressure to make such risky decisions with such serious consequences—and for them, the potential consequences outweigh the potential rewards of engaging in those behaviors. While our study has notable strengths, we acknowledge its weaknesses—namely, our sample size. Admittedly, our sample is not large enough to generalize to a greater population of adolescents to suggest novel information about adolescent substance use. Instead, we relied upon existing published reports, and found substance use endorsement within our sample was relatively comparable to the national population. We found age was associated with self-reported substance use, and suggest it may function as a moderator between ventral striatal activation and self-reported substance use, as older adolescents have greater access to substances and likely have older friends who use substances . Additionally, we note that it would have been beneficial to collect substance use information at the first time point when they received a scan to 1) draw a more direct correlation to task behavior; and 2) determine how substance use behavior changes over the course of two years in adolescence. Future studies should consider data collection in this way to increase internal validity and shed light on differences in adolescent behavior over time. Our study makes a novel contribution to the prediction error literature in that it differentiates adolescent ventral striatum response to social expectations with their real-world behaviors. These differences suggest future research should consider whether neural responses to social violations of expectations could be predictive of behaviors in adolescence. We propose that adolescents who use socially acceptable substances recruit the ventral striatum and are happier in response to experiencing a violation of expectations, as they require a large violation of their expectation to achieve a rewarding sensation and are attuned to and prefer to learn new social information. We conclude that adolescents who feel rewarded when they receive new social information about their friendship are socially more likely to act in ways to reinforce a rewarding sensation when they are with their friends, including engaging in socially acceptable substance use.Adolescents are often faced with complex social decisions. Deciding how to behave in “the heat of the moment” can be challenging for an adolescent—in part because cognitively, they are capable of making an informed and rational decision, but also their decisions tend to be emotional in nature, which can override rational thought . This is supported by neurobiological research on adolescents, which suggests the limbic system is more responsive during adolescence, while the prefrontal cortex is less so by comparison .

Additionally, researchers have considered adolescence as a sensitive period for socioemotional development , where compared to other age groups , and other people teenagers are more attuned to peer feedback. Considering the developmental changes evinced in neurobiological processes, psychological processes, and social salience during adolescence, it is no wonder making well-informed decisions in an emotional context can be particularly challenging. Behavioral research has indicated that compared to other age groups and compared to when they are alone, adolescents make riskier decisions when they are in the presence of their peers . They also report being more susceptible to peer influence compared to other age groups . A neurobiological study assessing peer influence found that not only do adolescents take more risks compared to young adults or adults, they also recruit regions implicated in reward—including the ventral striatum more than young adults or adults . While these studies and others have assessed adolescent response to peer influence in a laboratory setting , very few have manipulated peer influence to assess real-world behaviors. In their study, Allen and colleagues presented adolescents with a hypothetical scenario and asked them to decide on their own whom to save from a planet before meeting with others to decide collectively. They found that after meeting with other peers, adolescents changed their original choices to be more aligned with the group’s decision. While some adolescents make decisions reflective of a hyperactive reward system coupled with a diminished cognitive control system , most adolescents report engaging in moderate amounts of risky behaviors , suggesting that adolescents are capable of making safer, albeit risky decisions in emotional contexts. However, individual differences may lead adolescents to partake in some risky behaviors but not others , and some peers may be more influential than others . Notably, not all forms of peer influence are implicit or subtle—some are more explicit and are typically considered “peer pressure” . Adolescents reporting on their own susceptibility to peer influence indicate that they are not often coerced, but instead go along with their peers in an effort to be accepted or more liked by them . Additionally, these adolescents are also more likely to partake in risky social activities when a best friend or a higher status/more popular peer is partaking . Taken together, it is likely that adolescents recognize the risk in using substances, but find the risk is outweighed by the reward of peer acceptance.To our knowledge, studies on peer influence in adolescents have primarily focused on the effect of the presence of a same-sex peer, though notably, adolescents are eager to impress members of the opposite sex . Because adolescence marks a time of sexual maturation and increased desire to find a romantic other , we were interested in understanding whether an opposite-sex peer would influence adolescent self-report. The first goal of this study was to attempt to experimentally manipulate peer influence in an adolescent sample to determine whether adolescent self-reported susceptibility to peer influence was associated with experimentally manipulated peer influence.

Alcohol use disorder rates were highest among Native Americans , the Pacific region , payer status of no charge , Medicaid or self-pay , and the lowest income quartile. Heart failure hospitalizations with drug use disorder were the youngest cohort and 29.1% female . Racial/ethnic minorities had higher representation among drug use disorder hospitalizations, as 44.9% of drug use disorder hospitalizations were for black race/ethnicity. Medicaid insurance and lowest quartile income was more prevalent among heart failure hospitalizations with drug use disorder compared to no use, tobacco, or alcohol use disorder . Cocaine was the most frequent substance-specific drug use , followed by other unspecified drugs , cannabis , opioids and amphetamines . Drug use disorder was generally most common for both sexes age <45 years. For males, highest rates of drug use disorder were for Asian/PI hospitalizations , while for females, highest rates were for black hospitalizations . Asian/PI males and females had highest rates of amphetamine use .The Pacific region had highest rates of drug use disorder . Medicaid hospitalizations had highest rates of drug use disorder overall and for cocaine, opioid, and amphetamine use disorders for both sexes. Those in the lowest income quartile had highest rates of drug use disorder overall and for most subcategories. Among national heart failure hospitalizations, 15.5% had comorbid tobacco or substance use disorders. Tobacco use disorder was most common at 12.1% overall, a rate similar to prior studies . For certain male heart failure subgroups, including those age 45 to 55 years, Native American race/ethnicity,trimming marijuana plants and payer status of Medicaid, self pay, or no charge, our results show that approximately one-third of hospitalizations had tobacco use disorder. Tobacco use in OPTIMIZE-HF patients contributed to earlier age of decompensation requiring hospital admission.

Quitting smoking may be as effective a treatment as prescribing ACE inhibitors, beta-blockers, and aldosterone inhibitors in improving survival.Drug use disorder was uncommon among older heart failure patients. The etiology of heart failure in advanced age is well established, largely due to coronary artery disease and poorly controlled hypertension. However, the pathogenesis of heart failure in patients under 40 years is less clear, with many patients diagnosed with idiopathic cardiomyopathy.Untreated drug use disorder may be responsible for heart failure in these young patients where the etiology remains unclassified, as we found high rates of drug use disorder in this population. Because high rates of cocaine and methamphetamine use have been noted among younger heart failure patients and heart failure due to stimulant use may have a reversible component,targeted preventive and treatment efforts for young patients with drug use disorder may reduce the burden of heart failure. There is a paucity of literature investigating tobacco and substance use disorders in heart failure patients especially amongst racial/ethnic subgroups. While Native American race was associated with increased risk of alcohol use disorder, these patients also had high rates of tobacco and drug use disorders. Recent data from the National Survey on Drug Use and Health shows that American Indians or Alaska Natives have higher prevalence of tobacco use and cigarette smoking than all other racial/ethnic groups.38 Black race was associated with substance, alcohol, and drug use disorder. Cocaine use disorder was highest among black heart failure hospitalizations, while amphetamine use disorder was highest for Asian/PI heart failure hospitalizations. A prior study of 11,258 heart failure patients from the ADHERE-EM database found that self-reported illicit drug use with cocaine or methamphetamines was associated with black race compared to Caucasian.Black men and women present with heart failure at a younger age and have the highest age-standardized hospitalization rates compared to other race/ethnicities in the US.34 Addressing underlying substance use disorders in black patients may reduce the burden of heart failure attributed to substances and reduce hospitalizations. Conversely, Asian/PI males and females have the lowest hospitalization rates for heart failure compared to other races in the US. However, the Asian/PI population in the US is rapidly growing with high rates of amphetamine use,which may contribute to future heart failure hospitalizations.

Geographically, the Pacific region stands out for high rates of substance use disorder, especially drug use disorder. Data from NSDUH reports high prevalence of past-month illicit drug use by individuals 18 years or older within Pacific states.Patterns of use in heart failure patients may mirror those of the general population. Providers should be aware of types of substance use prevalent in their region. Rates of tobacco and substance use disorders were higher for patients of lower socioeconomic status as represented by payer status and median household income quartiles. Socioeconomic factors mediate differences in tobacco and substance use disorders based on race/ethnicity. While we cannot adjust for complex community stressors predisposing to tobacco or substance use disorders, evaluating community risk factors for tobacco and substance use disorders, such as density of tobacco stores,16 and identifying vulnerable groups may help develop preventive and treatment strategies, reducing observed disparities. Tobacco and substance use disorders in heart failure patients have implications for the broader health system. Substance use leads to increased costs from decreased productivity, healthcare costs, and crime.Tobacco,alcohol,and cocaine use are associated with increased readmission risk in heart failure patients. Screening for tobacco and substance use disorders has historically been deficient in primary care, emergency room, and hospital settings;despite efforts to improve screening, rates are likely under-appreciated. Heart failure patients who actively smoke but are attempting to quit may be coded with a different ICD-9-CM code than tobacco use disorder, further underestimating numbers.Tobacco and substance use disorders may have even larger negative effects on the healthcare system than currently reported. A violation of expectations produces a prediction error, a learning signal by which organisms update current understanding and knowledge of expectations. The primary neural locus implicated in violations of expectations is the ventral striatum , which undergoes significant development during adolescence, a period marked by sensitivity and responsivity to social feedback and reward.

The VS demonstrates increased activation for reward and reward prediction errors in this age group compared to other age groups. Importantly, the VS is also recruited when adolescents take risks and are in the presence of their peers. While a few studies have examined social violations of expectations in adults, to our knowledge, none have examined social violations of expectations in adolescents. The goal of this dissertation was to implement novel, ecologically valid designs to determine whether neural responses to realistic social feedback from a friend was associated with a common risky behavior, substance use, in adolescents. We found that adolescents recruited the VS for positive social violations of expectations compared to negative violations of expectations, and were happiest when their social expectations were met . We found that adolescents who recruited the VS more for violations of expectations reported greater substance use,vertical farming units while adolescents who recruited the VS less for violations of expectations reported lesser substance use, increased susceptibility to peer influence, and were more susceptible to peer influence in an experimental manipulation. Taken together, this body of work suggests adolescents who are more attuned to social cues from peers require smaller expectancy violations to experience reward; while those who engage in increased social risk taking require greater expectancy violations by comparison to experience reward. Implications of this work are discussed with regard to determining which adolescents are most likely to take greater social risks, based on their VS response to social violations of expectations. The ability to predict daily occurrences is beneficial and adaptive . For example, when deciding whom to ask to prom, a teenager might consider his current relationship status and prior interactions with a girl so he can expect with greater certainty that she will accept his offer. A violation of expectations is an unprecedented experience, and one that changes future behaviors and the expectations of future occurrences. If the girl unexpectedly rejects the teenager, he may be more hesitant to approach her again in the future. The experience of this violation of expectations might change his future behavior to include considering whether another potential prom date already has a date prior to asking her. Prediction Error A violation of expectations leads to a prediction error—a learning signal that is the calculated difference of an event’s outcome minus its expectation. Prediction errors have been examined extensively in behavioral reinforcement studies. This is evinced in a classic example: once a repeated presentation of a stimulus is conditioned to elicit a response for the receipt of a reward, a pigeon learns to peck each time the stimulus is presented to continue to receive the reward. This behavior continues even after the reward is no longer presented, producing a prediction error in the pigeon, whereby the presentation of the stimulus yields pecking, but no receipt of reward . Subsequently, the pigeon demonstrates a changed timing and increased effort of its pecking, suggesting it has learned that by pecking it will receive a reward. To characterize neural responses to prediction error, researchers have examined changes in the signaling of dopamine , a neuromodulator critical in reward receipt and reinforcement learning . Research by Schultz and colleagues assessing variability in prediction error revealed that when monkeys expected juice but did not receive it on schedule, there was decreased DA signaling, suggesting a negative prediction error. When monkeys were not expecting juice and received it, there was increased DA signaling, suggesting a positive prediction error. When the monkeys expected juice and received it, there was little change in the DA neurons, suggesting expectations were met . This seminal body of work suggests variability in reward modulation in dopaminergic regions is dependent on the valence of prediction error. Similar research assessing whether DA neurons encode prediction error found increases in midbrain DA firing when monkeys accurately predicted receipt of a reward compared to inaccurate predictions .

By using an interval-based reward saccade task, Bayer and Glimcher concluded that reward prediction errors could be tracked by measuring the increased firing rate of DA neurons—an occurrence that is indicative of reinforcement learning. The neural basis of prediction error with primary reward in humans supports research in non-human primates, such that humans also demonstrate increased activation in dopaminergic brain regions in response to positive prediction errors, and decreased activation in response to negative prediction errors. The valence of a violation of expectations has been examined neurobiologically in humans. When the violation is positive, researchers find greater activation of the ventral striatum , while a negative violation of expectations is associated with activation in the amygdala , and the insula. Classic studies assessing the magnitude of prediction error in animals have demonstrated that when aviolation of an expectation is large , there is greater dopaminergic activation compared to when it is small . Research in humans has also demonstrated differential activation in error detection and reward circuitry by violation magnitude. The distinct responses in dopaminergic activation to violations of expectations demonstrate how sensitive humans and non-human animals are to this learning signal. It is perhaps unsurprising then, that prediction error is implicated in reward and learning-motivated behaviors, such as substance use and addiction. Substance Use Research on reward prediction errors has indicated that while receipt of primary rewards elicit a dopaminergic response, the chemical compounds associated in drugs of abuse and the drug receptors they act on can produce an even greater response by comparison . Addiction research has indicated that dopaminergic activation in response to receiving rewards produces prediction errors that override decision-making systems . In this case, using an addictive substance produces a surge in dopamine and a large reward prediction error, leaving the user with an increased desire to reuse the substance to obtain the same rewarding sensation . Further examination of reward prediction errors in response to using a drug of abuse suggests that understanding how reward is processed can aid in identifying who may be more at risk for addiction. A review by Hyman and colleagues suggests that individuals who have more associations to the cue of the reward are at a greater risk for reusing and relapsing , as the associations cross multiple fields of dopaminergic innervations. Across multiple studies, researchers find that individuals who demonstrate increased ventral striatum response in association with receiving a reward are more likely to engage in risky behaviors.

Despite these limitations, findings from this study may have implications for the development and implementation of compensatory strategies to improve cART adherence. Given that non-adherers and adherers exhibited comparable recognition abilities, compensatory adherence strategies associated with simple recognition, such as placing a pillbox by a commonly used area, may help to improve adherence in individuals with retrieval difficulties. Moreover, strategies to improve encoding may be of benefit to persons living with HIV-associated memory deficits; for example, requiring self-generation of stimulus pairing has shown to greatly improve immediate and delayed verbal recall in HIV disease . Translated to a clinical setting, asking a patient to generate their own plan for remembering their medications may deepen encoding processes and facilitate later recall thereby improving adherence. Other neurorehabilitation techniques that target encoding and retrieval processes in order to deepen the memory trace may be additionally fruitful in enhancing adherence, such as visual imagery , spaced-learning , and/or pairing medication behaviors with other daily habits that might trigger recall . Additionally, the prominence of a primary retrieval deficit profile strengthens the subcortical dementia explanation of HAND. Because subcortical dementias are often coupled with slowed mental processes and apathy additional techniques, such as providing information at a slower rate or enhancing patient buy-in and decreasing apathy by focusing on the rationale of proper adherence, could prove helpful. Moving forward,drying weed future studies that begin to examine the utility of these techniques to improve antiretroviral adherence are certainly warranted and long overdue as the field begins to translate observations into interventions.

While diagnosis of the schizophrenia prodrome has been a target of the psychiatry field for over a century, it is only in the last decade or so that reliable clinical assessment instruments were developed to identify these “psychosis risk syndromes”. A flurry of research ensued, with an increasing number of specialty clinics worldwide using a variety of assessment and screening tools, and a growing awareness of psychosis risk syndromes in community mental health settings. Most recently, this area of work resulted in an ongoing debate over the inclusion of an attenuated psychosis syndrome diagnosis in the upcoming 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders. Despite the strong reliability of instruments, data only partially support their validity in identifying true “prodromal” cases; therefore, these instruments identify “risk syndromes,” often focused on the presence of attenuated positive psychotic symptoms that are not expected to confer 100% risk for later developing a formal psychotic disorder. The assessment of prodromal psychosis can be complicated by the often non-specific nature of symptoms, and because symptoms typically present in adolescence or young adulthood, when changes in functioning and emotional well-being are common. Furthermore, the assessment process does not end with diagnosis; once the presence of attenuated psychotic symptoms is established, educating clients and their families and addressing anxiety surrounding symptoms and their implications can be challenging. In this paper, we will review psychosis risk syndrome assessment and screening instruments, describe the assessment and feedback process with youth and families and use a case example to illustrate some common issues that arise during psychosis risk assessment. We will primarily focus on the most common risk syndrome based on the presence of attenuated psychotic symptoms but will briefly discuss other syndromes and assessment approaches. Within the last two decades, three well-validated semi-structured interviews sensitive to subthreshold psychotic symptoms were developed to assess the putative prodromal or clinical high risk syndrome for psychosis.

These instruments fall into two categories: instruments aimed at diagnosing CHR syndromes through the presence of attenuated psychotic symptoms , the presence of psychotic symptoms transient in nature, or a combination of trait and state vulnerability markers and instruments aimed at detecting psychosis risk through the presence of subjective neuropsychological and cognitive deficits, or basic symptoms . Mean transition time to psychosis was longer when BS were used to assess psychosis risk than when CHR criteria were used , therefore BS could possibly allow for an earlier assessment of psychosis risk than APS. However, there is a lack of prospective studies investigating the sequence with which symptoms emerge in the course of the prodromal period of psychosis, and therefore this needs further exploration. The set of at-risk criteria based on attenuated psychotic symptoms was initially developed by Yung and colleagues through literature reviews and retrospective assessment of first episode psychosis cases. They first used DSM-III criteria, later turning to a combination of the Brief Psychiatric Rating Scale and the Comprehensive Assessment of Symptoms and History . Attenuated psychotic symptoms were defined by the presence of BPRS symptoms of attenuated level intensity held with a reasonable degree of conviction, as assessed by the CASH . The Comprehensive Assessment of at Risk Mental States was then developed to allow for more sensitivity and breadth in assessing attenuated level psychotic symptoms by defining subthreshold symptoms across a wider range of scores, with concrete anchors. The Structured Interview for Prodromal Syndromes was based on the criteria outlined by Yung and colleagues and modeled after the Positive and Negative Syndrome Scale . Both instruments assess the presence/absence of CHR syndromes and allow for longitudinal assessment of attenuated psychotic symptom severity. Symptoms ratings are based on onset, frequency, impairment, distress, and degree of conviction. The SIPS includes the Scale of Prodromal Syndromes , a 19 item scale which allows clinicians to rate symptoms on four sub-scales that assess: positive symptoms , negative symptoms , disorganized symptoms and general symptoms . Symptoms are rated from 0 to 6 , with considerations of frequency and intensity/degree of conviction included in the individual symptom rating. A rating from 0-2 is considered subthreshold and a rating from 3-5 is in the attenuated range, whereas a rating of 6 is considered fully psychotic. All symptoms are rated on the SOPS based on the last month.

In addition to the SOPS, the SIPS contains the Criteria of Psychotic Syndromes , a modified version of the Global Assessment of Functioning Scale , a schizotypal personality disorder criteria checklist, and an assessment of family history of mental illness. Similar to the CAARMS, the SIPS identifies 3 CHR syndromes and 1 psychotic syndrome; see Table 1 for a detailed overview of syndrome definitions. The SIPS shows good predictive validity, with 40% of CHR patients converting to full psychosis at 2.5 year follow-up . The inter-rater reliability is excellent, with interclass correlation coefficients above 0.75 on all sub-scales , based on ratings of four videotapes by trained clinician . Basic symptoms are subtle subjective neuropsychological and cognitive deficits believed to indicate risk for future psychosis. The Bonn Scale for the Assessment of Basic Symptoms is a clinician-led semi-structured interview that assesses BS,vertical grow systems developed in Germany based on the work of Huber . The original interview has 92 items , although shorter versions of the BSABS are commonly used. The version used by Klosterkotter and colleagues in the Cologne Early Recognition Project assesses for the presence of 66 Basic symptoms, divided into 5 clusters; thought, language, perception, and motor disturbances, impaired body sensations, impaired tolerance to stress, disorders of emotion and affect, and increased emotional reactivity, impaired ability to maintain or initiate social contacts and disturbances of normal nonverbal expression . Each symptom is rated as present, questionably present, or absent. The BSABS shows good diagnostic validity, with the presence of at least one basic symptom predicting schizophrenia with a probability of 70% over an average follow up period of 9.6 years . Inter-rater reliability of the BSABS items ranged from fair to very good based on ratings gathered during 18 joint interviews by a trained clinician pair . There is growing consensus that the SIPS/CAARMS and BSABS approaches can be complementary in the detection of psychosis risk, and can be used to guide treatment specific to each type of syndrome . The European Prediction of Psychosis study in Germany combines the SIPS and BSABS to determine psychosis risk, and found transition rates to psychosis of 19% at 18 month follow up, with the combined approach achieving the highest sensitivity . Given the intensive time and staff training required to use the structured psychosis risk interviews, several self-report -screening measures have been developed to identify those individuals who are most likely to benefit from the interviews. All measures were developed for use in a two-stage screening process with clinical interview and not to be used alone for diagnosis . The Prodromal Questionnaire has long and short versions, with the latter focused on positive symptoms only, along with related distress and impairment. The PQ showed moderate agreement with SIPS diagnoses in an early psychosis clinic-referred sample with 90% sensitivity and 49% specificity, while the PQ-B showed stronger specificity in a similar sample, with 89% sensitivity and 68% specificity . The PROD-SCREEN has 29 items and showed moderate agreement with SIPS diagnoses in a sample of first-degree relatives of schizophrenia patients, and in a general population sample, with less accurate performance among psychiatric outpatients . Preliminary data for the PRIME SCREEN, developed by the authors of the SIPS, was promising , and a revised 12-item Japanese version showed perfect sensitivity and good specificity against SIPS diagnoses in an outpatient psychiatric sample, with predictive validity at 6-month follow-up of 11% . Three other self-report screens with published data include the Self-Screen –Prodrome , the Youth Psychosis At Risk Questionnaire , and the Adolescent Psychotic-Like Symptom Screener , although all calculated concordant validity using full psychosis/schizophrenia interviews or rating scales that were not psychosis risk measures per se.

In sum, screening measures have shown moderate to good concordant validity against risk syndrome diagnosis, with less data available on validity of predicting conversion to full psychosis. They may be most useful in screening mental health patients, with less evidence at this point for use with the general public, which carries a high false positive rate. The percentages of CHR individuals who develop full psychosis range from 16% by 24 month follow-up to 70% by 9.6 years , with average transition rates across studies of 36.7% . Transition to psychosis was more likely in individuals with impaired role and social functioning, prodromal psychotic symptoms of longer duration, a family history of psychosis and more severe levels of prodromal symptoms at baseline . Transition rates are highest in the 6-month period after CHR diagnosis, with decreasing rates over time . Similar to risk assessment across all areas of medicine, transition rates also depend upon the selection process for the sample, with higher rates in “enriched” samples such as those seeking help specifically for potential CHR syndromes . Of note, transition rates to psychosis have declined over time in the published literature , indicating an increased proportion of people falsely identified as being “at-risk” for developing psychosis. Yung and colleagues suggest that individuals are being identified earlier in the course of their illness, pointing out that the duration of untreated attenuated psychotic symptoms in research samples has progressively decreased over time. As mentioned earlier, a longer period of untreated symptoms is associated with increased risk of transition to psychosis. Alternatively, previously employed follow-up times might not be sufficient in length to see these individuals ultimately transition to full psychosis.Finally, widely available interventions may further contribute to a decrease in transition rates, as treatment is never withheld from patients in “naturalistic” longitudinal studies. In addition to tracking psychotic transition rates, two recent studies attempted to characterize the functional and symptomatic outcomes of CHR “false-positives”. A significant percentage of “false-positives” continued to experience attenuated level psychotic symptoms, functional impairment, or both at follow up . Similarly, ongoing longitudinal studies are focusing on functional outcomes independent of conversion status, with a recent study showing that poor verbal learning and memory at baseline predicted worse functional outcome up to 13 years later . It is still unclear how to best conceptualize the symptoms and impairment seen in this group; although Schlosser and colleagues speculate that the stable attenuated level psychotic symptoms and functional impairment seen in these individuals might align more closely with a diagnosis of Schizotypal Personality Disorder than a CHR syndrome. The following vignette illustrates the assessment of attenuated positive symptoms in an adolescent, using the SIPS.

Due to each follow-up visit occurring approximately 4-weeks apart, we potentially captured women around the same phase of the menstrual cycle, and thereby similar P4/E2 ratios, at each assessment. This was to some degree reflected in the average values of P4, E2, and the P4/E2 ratio of our sample. However, the CV estimates for our sample indicated moderate within-person variability across the active medication phase, which was also supported by the larger standard deviations when examining raw P4/E2 values, suggesting some degree of variation in P4/E2 between repeated measures during the active medication phase of this study. Future studies are needed to examine these effects in a larger sample with equal proportions of women in the luteal and follicular phase throughout the trial. Further, gathering assessments every 2 weeks to observe within person changes in response to the combination of varenicline plus naltrexone on smoking and drinking outcomes would be important to further understand the preliminary findings reported herein. The present study must be interpreted in light of strengths and weaknesses. Strengths include hormonal assays of both P4 and E2 at each follow-up appointment, comprising six hormonal assays per participant across the 12 weeks. Limitations include a small sample size and the assessment period of 4 weeks, which potentially limited within-person assessment across distinct phases of the menstrual cycle. While studies have found a relationship between sex hormones and smoking behavior , when summarized across a 4-week period,cannabis drying racks some of those nuanced effects may be less detectable. Another limitation includes the lack of objective measurements of alcohol consumption, such as EtG or CDT. The addition of these objective alcohol consumption measurements may have provided additional validation to self-report alcohol consumption.

In conclusion, this study provides preliminary evidence on the potential role of the effect of biomarkers of sex differences, namely P4/E2 ratio, among female heavy drinking smokers undergoing treatment. While a majority of analyses were null, there was an intriguing medication by hormone level interaction such that varenicline plus naltrexone increased percent days abstinent among women with greater P4/E2 ratio compared to the varenicline plus placebo condition. Additional studies of these effects in larger samples are warranted and sex hormones offer important information above and beyond comparing groups on the bases of sex.It is now widely recognized that cigarette smoking and drinking are behaviorally and clinically intertwined. Epidemiological data from the 2019 National Survey on Drug Use and Health found that 21.7% of adults reported using cigarettes over the last year . The same survey found 10.7% reported daily cigarette use and 6.3% reported heavy alcohol use over the past month . Individuals with a mild or moderate alcohol use disorder have exhibited a smoking prevalence 2 times higher than those without an AUD . The trend continues with those with a severe AUD having a smoking prevalence 3 times higher than those without an AUD . Conversely, nicotine use has also been shown to impact alcohol use. Individuals with any nicotine use disorder are 2.5 times more likely to meet criteria for a 12- month AUD diagnosis, and 3.2 times more likely to meet criteria for a lifetime AUD diagnosis . The effect of nicotine on alcohol use is so robust that even low levels of nicotine have been shown to increase quantity of alcohol consumption. In comparison to nonsmokers, non-daily smokers may experience an increased risk for hazardous drinking and for receiving a DSM-IV alcohol diagnosis . Previous studies have made salient how co-use of both substances may increase their acute rewarding effects , and promote cross-tolerance of both substances , further perpetuating co-use. The negative health consequences from cigarette use and alcohol use , including increased risk for various cancers and cardiovascular diseases, underscores the need to concomitantly reduce the use of both substances. Alcohol use hinders smoking cessation attempts. Over the last two decades, the number of adult cigarette smokers who have engaged in a smoking cessation attempt has increased . The average smoker attempts to quit smoking multiple times with estimates ranging from 6 to upwards of 30 or more attempts before one is successful in sustaining abstinence from cigarettes for at least 1 year .

Previous studies found that moderate and heavy alcohol use increases the risk of smoking lapses during a smoking cessation attempt . A recent study by Lynch and colleagues found that in comparison to nondrinkers, at 1-month post smoking cessation treatment, moderate drinkers experienced greater odds of continued smoking, however, at 7- months post-treatment, the odds of continued smoking were not different to that of nondrinkers. For heavy drinkers, in comparison to non-drinkers, the increased odds of continued smoking remained for 1-month and 7-months post-treatment . These studies underscore the importance of addressing alcohol co-use, particularly at higher levels, during an initial smoking quit attempt and thereafter. A previous clinical trial integrated a brief alcohol intervention in the context of smoking cessation treatment and found greater smoking abstinence among those who received integrated treatment compared to those who only received standard smoking cessation treatment . Transitioning results such as these into clinical practice, it is recommended that those trying to quit smoking limit or abstain from alcohol as much as possible . Taken together, these findings highlight the need for interventions that can simultaneously address smoking cessation and drinking reduction to target the amplified, negative effects of conjoint use in treatment. One of the main limitations of the field has been that clinical trials focus either on smoking or on drinking as a primary outcome, but rarely target both behaviors simultaneously. To address this limitation, our group has recently completed a 12-week clinical trial combining varenicline and naltrexone for smoking cessation and drinking reduction in a sample of heavy drinking daily smokers . Varenicline, a selective nicotinic acetylcholine partial agonist, is an FDA approved medication for smoking cessation . While naltrexone, a non-selective opioid receptor antagonist, is an FDA approved for the treatment of alcohol use disorder . This recently completed clinical trial provides a unique opportunity to examine behavior change across the two substances as both measures of alcohol and cigarette consumption were assessed concurrently throughout the clinical trial. This study randomized heavy drinking smokers to receive varenicline plus placebo or varenicline plus naltrexone.

Results indicated that smoking abstinence at 26 week follow-up was significantly higher in the varenicline plus placebo group, compared to the varenicline plus naltrexone group . For the primary drinking outcome of drinks per drinking day,pots for cannabis plants there was a main effect of medication in favor of the combined medication group at the 12 week end of medication phase; however, this effect was not sustained at the 26 week follow-up . These results shed light on the impact of combination pharmacotherapy in the context of smoking cessation and drinking reduction. The present study leverages data from the aforementioned clinical trial to interrogate the relationship between smoking and drinking across the treatment and follow-up periods . Using a cross-lagged panel model, we examine the directional influence that drinking and smoking variables have on each other over time. We were primarily interested in testing whether drinking outcomes mediate the relationship between pharmacotherapy and smoking outcomes. Through using cigarettes per smoking day as our smoking outcome, we were able to test how reductions in drinking are associated with reductions in smoking beyond a binary quit or no quit. Our primary drinking variable of interest was drinks per drinking day which aligns with the previously mentioned trial such that drinks per drinking day was the primary drinking outcome of that study. Our secondary drinking mediators of interest are percent heavy drinking days and percent days abstinent. These were also two secondary drinking outcomes in the primary trial . Based on the literature we hypothesize that compared to participants in the varenicline plus placebo condition, those in the varenicline plus naltrexone condition will experience greater reductions in drinking, thus leading to greater reductions in smoking. While the primary outcomes of the study found varenicline alone was associated with greater smoking abstinence, we hypothesized that the combined medication condition may be sensitive to a wider range of smoking behaviors, via cigarettes per smoking day. We also hypothesized that drinking and smoking will be related across the duration of the trial, and that reductions in drinking would lead to reductions in smoking. This study provides a unique contribution by extending beyond the main effect of medication on smoking and drinking outcomes and by interrogating mechanisms of action of the combination of varenicline plus naltrexone on drinking and smoking reduction. Participants were required to produce a breath alcohol concentration of 0.00 g/dl at all study visits and to test negative for all substances excluding cannabis. Participants deemed eligible after the in-person screening visit completed a physical exam to establish medical eligibility and were then randomized to one of two medications: 2mg of varenicline tartrate plus matching placebo pills or 2mg of varenicline tartrate plus 50mg of naltrexone. All participants took the first dose of medication under observation during the randomization visit. A detailed description of the study procedures, including medication titration procedures and monitoring of side effects, is provided in Ray et al. .

During the randomization visit, participants engaged in a 30–45-minute counseling session specifically for heavy drinking smokers , set a smoking quit date, and discussed a drinking goal of abstinence or reduction. Post-randomization, participants returned to the laboratory for in-person assessment visits at Weeks 4, 8, 12, 16, and 26. A series of individual differences measures were collected at the in-person screening visit, including: a) demographics questionnaire; b) Structured Clinical Interview for DSM-5 ; c) Fagerström Test of Nicotine Dependence ; d) Clinical Institute Withdrawal for Alcohol ; e) Timeline Follow-back to assess for past alcohol consumption and cigarette use ; and f) Smoking History Questionnaire to assess for past smoking behavior. During each post-randomization visit, research assessments were completed including the TLFB, along with carbon monoxide recordings. For the present study, the primary outcome measure was cigarettes per smoking day derived from the TLFB. The primary mediator of interested was drinks per drinking day also derived from the TLFB. The primary mediator was selected given that it represents the a priori registered drinking outcome for the trial. The secondary mediators of interest were two of the secondary registered drinking outcomes, namely percent heavy drinking days and percent days abstinent also derived from the TLFB. Both drinking and smoking outcomes derived from the TLFB were measured concurrently. We report how we determined our sample size, all data exclusions , all manipulations, and all measures in the study. This study was not preregistered and the data and study materials are not available online. All analyses were conducted in SAS University Edition version 9.4 . A cross-lagged panel model with PROC CALIS was used to test the proposed mediation models of drinking outcomes mediating the effects of medication on cigarettes per smoking day. We conducted a total of 2 cross-lagged panel models across 5 time points during the active medication phase and follow-up phase. The second model tested percent heavy drinking days and percent days abstinent as secondary mediators. A conceptual diagram of the cross-lagged panel models is presented in Figure 1A and Figure 1B for drinks per drinking day, and Figure 2A and Figure 2B for percent heavy drinking days and percent days abstinent. Our predictor across all models was medication condition and our outcome was cigarettes per smoking day. For each visit, cigarettes per smoking day was averaged across the 28 days leading up the visit. In other words, cigarettes per smoking day at Week 12 consisted of cigarettes per smoking day averaged across 28 days prior to week 12 of participant enrollment in the trial. The same approach was used to define drinks per drinking day, percent heavy drinking days, and percent days abstinent. For the functional relationships between observed variables in the cross-lagged panel models, the path from medication to drinking variables and cigarettes per smoking day during the active medication phase was a free parameter. All drinking and smoking variables had fixed first-order autoregressions from Week 4 through Week 16 due to equal spacing of 4-weeks between each measurement. We controlled for baseline drinking and smoking by allowing them to freely predict the respective variable at Week 4 .

The two most prominent models to explain the co-use of nicotine and alcohol are: cross reinforcement through the mesolimbic dopamine pathway and cross-tolerance through shared genetic and nicotinic acetylcholine receptor interactions . The first mechanism of comorbidity is cross-reinforcement which is defined as the ability of nicotine to increase the motivation to consume alcohol and vice versa due to a shared neurobiological mechanism . Both nicotine and alcohol have been shown to activate the mesolimbic pathway. For nicotine, previous studies have shown nicotine self-administration to occur to activate the mesolimbic dopamine pathway through the VTA and the activation of nAChRs may stimulate the VTA neurons to release dopamine in the NAcc . Alcohol has also been shown to affect the mesolimbic pathway through interacting with nAChRs that have been shown to increase the rewarding properties of alcohol , and alcohol self-administration has been linked with dopamine release in the NAcc . The second mechanism perpetuating co-use is cross-tolerance. Tolerance is defined as continued use of a fixed amount of a substance resulting in a suppression of the effect, thus a greater amount of the substance is needed to produce the same effect. Both alcohol and nicotine have been shown to lead to tolerance .In the alcohol literature, individuals with a family history of alcohol dependence may experience a blunted sensitivity to the effects of alcohol , thus leading to potentially greater alcohol consumption. Of note, current smokers have been shown to have a diminished intoxicating effect of alcohol in comparison to non-smokers or former smokers . A second hypothesis contributing to cross-tolerance is the role of nicotinic receptors,cannabis indoor greenhouse as alcohol has been shown to alter the function of several nAChR subtypes, and subsequently alter neurotransmitter transmission at these receptors .

A previous study found that alcohol-induced impairments in coordination were reduced by nicotine via nAChR sub-type function, specifically alpha-7 sub-types further suggesting the role of these receptors in cross-tolerance of nicotine and alcohol . Taken together, these are two possible mechanisms of action whereby nicotine and alcohol continue to potentiate the rewarding effects of the opposing substance, while increasing use through cross-tolerance, resulting in the observed high rates of co-use. Human laboratory studies serve as one methodological avenue by which some of these mechanisms of action have been examined in humans. Alcohol may increase the rewarding aspects of cigarette smoking as it has been associated with greater satisfaction of the cigarette and relief of craving a cigarette . Administering alcohol to those who co-use is associated with dose-dependent increases craving for cigarettes , and this effect may be mediated by the stimulating effects of alcohol . Conversely, nicotine administration has been shown to increase alcohol consumption in both animal studies and human studies . Nicotine has also been shown to increase the sedative effects of alcohol . Notably, a majority of studies have focused on the effect of alcohol on nicotine use and less research thus far has examined the effect of nicotine on alcohol. Interestingly, there has been some evidence to suggest that the effects of nicotine on alcohol may differ by gender. Acheson and colleagues found an increase in alcohol consumption among men but not women. An ecological momentary assessment study demonstrated that when both substances were administered simultaneously, there was a joint increase in craving for both cigarettes and alcohol . Taken together, these studies highlight how individuals who co-use do qualify as a unique subgroup of heavy drinking smokers with a distinctive clinical profile and treatment needs In sum, there is ample evidence highlighting the strong bidirectionality of these two substances and their associated long-term health consequences. Emerging evidence continues to support the two mechanisms of cross-reinforcement and cross-tolerance; however translational research is needed to bridge the gap between earlier pre-clinical studies and examining these mechanisms of action in human studies.

As mentioned above, more research to date has examined the impact of alcohol use on cigarette smoking. While this bidirectional relationship exists, there is evidence to suggest that alcohol may more strongly influence cigarette smoking than vice versa. This may in part be due to the lack of research examining the impact of nicotine on alcohol and may highlight the robust role of alcohol increasing the complexity of treatment for smoking cessation. One of the major difficulties in treating heavy drinking smokers is the increased likelihood they have of experiencing a smoking lapse while drinking particularly in the early stages of their smoking cessation attempt where time between initial smoking lapse and return to daily smoking has been associated with pre-treatment confidence . Estimates suggest that up to 95% of smokers who experience a smoking lapse will progress to relapse . Previous studies have shown that smokers who smoke more during their first lapse, and experience greater hedonic ratings, have a greater risk of progressing to relapse . This first lapse has been hypothesized to represent the transition from abstinence to relapse with regular smoking has . Earlier smoking cessation trials often excluded smokers with current or past AUD, resulting in under representation of smokers with alcohol problems in pharmacotherapy smoking cessation trials . Given the impact of alcohol on smoking quit attempts and the overlapping neurobiological mechanisms that maintain co-use, it is imperative to address alcohol use in smoking cessation treatment for heavy drinking smokers. Few studies to date have examined behavioral treatments for combined cigarette and alcohol use that did not involve some form of pharmacotherapy. One pilot study examined whether including personalized feedback on alcohol response phenotype would improve brief intervention outcomes among young adult heavy drinking smokers . At 6-month follow-up, the group with the personalized feedback reported decreasing their drinking and smoking co-use by 39% which was comparably greater than the reductions made by the group that did not receive personalized alcohol feedback .

Arandomized controlled trial examining tobacco quit-lines found the inclusion of a brief alcohol intervention resulted in significantly higher smoking cessation rates for individuals with hazardous drinking . A recent Cochrane review found that individually delivered smoking cessation counseling was more effective than minimal contact , and evidence to suggest a smaller relative benefit in treatment outcomes when participants also received pharmacotherapy, specifically nicotine replacement therapy . The Clinical Practice Guidelines for smoking cessation recommend that pharmacological treatments are used in combination with psychotherapy or behavioral therapy . Next, we briefly review the evidence base for pharmacological treatment of smoking, drinking, and their co-use. Varenicline is a high affinity, partial agonist,cannabis growing equipment at the α4β2 nAChR receptor subtype and was FDA approved in 2006 for the treatment of nicotine dependence. The α4β2 nAChR receptor subtype has been strongly implicated in the addictive properties of nicotine and has become a novel molecular target for smoking cessation medications . The rationale behind using a partial agonist is to leverage the benefits of an agonist in reducing withdrawal symptoms and an antagonist in attenuating the rewarding effects of smoking . In 2009 the FDA issued a black box warning, the strongest safety warning the FDA can administer due to concerns regarding suicidal thoughts and depression with varenicline. A systematic review and meta-analysis examined the neuropsychiatric adverse events associated with varenicline and found no evidence of an increased risk of suicidal ideation or suicide . The authors suggested the initial black box warning was likely due to early studies consisting of observation cohorts that are more likely to be confounded by indication and possible bias regarding industry sponsored trials reporting favorable outcomes to the study sponsor . In 2016, the FDA removed the black box warning. Clinical trials have supported varenicline’s safety and efficacy as a smoking cessation aid . A review of pharmacotherapies for smoking cessation found varenicline as more effective than singe forms of Nicotine Replacement Therapy and bupropion . An additional review also demonstrated that in comparison to an unaided quit attempt, varenicline increases the chances of smoking cessation two- to threefold . Varenicline has also been examined for long-term efficacy and was found to be safe to administer for up to 1 year with efficacy greater than placebo in the short-term and long-term . Despite these results, success rates for varenicline remain low, which may suggest that there are unexplored individual difference factors that may be influencing varenicline’s efficacy. Varenicline has also been examined as a possible treatment for reducing alcohol consumption, as the nAChR receptors in the ventral tegmental area of the brain have been proposed to mediate the reinforcing effects of alcohol . Human laboratory studies have found varenicline to reduce craving, self-administration, and alcohol consumption in comparison to placebo . The first multisite clinical trial examining varenicline for AUD in a sample of smokers and non-smokers found varenicline to reduce percent heavy drinking days, drinks per day, drinks per drinking day, and craving for alcohol in comparison to placebo . There was a similar average treatment effect across smokers and non-smokers . These results support the potential for using varenicline in a sample of smokers to both reduce cigarette and alcohol consumption. Alcohol triggers several neurotransmitter systems and the endogenous opioids plays a key role in mediating the rewarding effects of alcohol . Evidence suggests that alcohol increases the rewarding effects through release of endogenous opioids and interactions with the dopaminergic system .

Previous studies have found that both consumption of alcohol and exposure to alcohol cues prior to drinking may increase dopamine activity in the NAcc highlighting the role of learning and reinforcement on activation of the mesolimbic dopamine pathway . Naltrexone is an FDA approved pharmacotherapy treatment for alcohol use disorder. Naltrexone is a relatively selective opioid antagonist, with the highest affinity for the mu-opioid receptor . Numerous clinical trials supported naltrexone as a safe, tolerable, and effective pharmacotherapy option for reducing drinking days, drinks per drinking day, and relapse rates . A recent meta-analysis of the effect of naltrexone in the human laboratory setting found naltrexone to reduce craving and alcohol self-administration in comparison to placebo . Four biobehavioral mechanisms of action have been suggested to explain the positive effects of naltrexone for alcohol use: reduction of craving for alcohol, blunting the stimulating effects of alcohol, potentiation of sedative and unpleasant effects of alcohol, and increasing cognitive control . Emerging evidence suggests that naltrexone may also be an effective pharmacotherapy option for reducing tobacco use among heavy drinking smokers. The opioidergic system has also been implicated in modulating the pharmacological effects of nicotine . Naltrexone has been shown to improve smoking cessation rates , while also reducing the frequency of heavy drinking days . Interestingly, one study examining data gathered as part of the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence found that smokers who received naltrexone experienced better drinking outcomes than smokers who received placebo . Additionally, naltrexone has been associated with gender differences in response to naltrexone. King and colleagues found women to have greater reductions in weight gain while men had greater reductions in smoking. Previous studies have also examined naltrexone in combination with traditional pharmacotherapies of smoking cessation. Naltrexone in combination with nicotine replacement therapy has been shown to have beneficial outcomes in improving smoking cessation outcomes . Taken together, these results suggest that naltrexone may improve both alcohol and smoking outcomes for this sub-group of heavy drinking smokers. Evidence for pharmacological treatments for this treatment-resistant subgroup of smokers has been limited and thus warrants further investigation. Currently, there are no pharmacological treatments or guidelines specific to heavy drinking smokers. It has been suggested that medications aiming to block the addictive rewarding effects, increase the aversive effects, and/or reduce drug-conditioned reactivity to cues may serve as effective treatment options for heavy drinking smokers . As varenicline and naltrexone have both exerted effects on smoking outcomes as detailed above, these two medications in combination may serve as a promising treatment combination. Previous work from our laboratory has shown initial promising evidence for the combination of these two medications for smoking cessation outcomes . Ray and colleagues randomized 130 heavy drinking smokers to varenicline , low dose naltrexone , varenicline plus low dose naltrexone , and placebo to examine differences in these medications on subjective response to alcohol and cigarettes craving in the human laboratory. Following nine days on study medication, participants received a priming dose of alcohol to raise their breath alcohol concentration to 0.06g/dl then smoked their first cigarette of the day in laboratory .

Activation of PPAR-a in vivo causes an upregulation of the mRNA and protein levels of a number of peroxisome- and nonperoxisome-associated enzymes and structural proteins, including the antioxidant enzymes catalase, superperoxide-dismutase and mediators of the glutathione pathway. In this context, pretreatment with fenofibrate reduces cerebral infarct volume in apolipoprotein E-deficient mice. The neuroprotective effect of fenofibrate is completely absent in PPAR-a-deficient mice, suggesting that PPAR-a activation is involved as a protective mechanism against cerebral injury . We failed to confirm the initially hypothesized increase of anandamide after sleep deprivation questioning its proposed role in sleep induction in humans . This is in line with findings on cannabinoid CB1- receptor gene expression, which is suggested to be modulated by sleep. While sleep rebound significantly increased CB1-receptor protein and decreased respective mRNA, no effects were found following sleep deprivation . Interestingly, according to the product information, the CB1-receptor antagonist rimonabant induces sleep disturbances frequently but also sedation in clinical trials. Several shortcomings might have influenced our somehow preliminary data; first, a randomized, balanced crossover design would have been the ideal design for the trial. Second, EEG recordings might have provided more detailed information on sleep quality instead of an actigraphy for control of sleep deprivation only.More high school students smoked little cigars and cigarillos than cigarettes in 33 US states in 2015. Concern is growing about co-use of tobacco and marijuana among youth,rolling benches hydroponics particularly among African-American youth.In a 2015 survey, for example, one in four Florida high school students reported ever using cigars or cigar wraps to smoke marijuana. One colloquial term for this is a “blunt.”

Adolescent cigar smokers were almost ten times more likely than adults to report that their usual brand offers a flavored variety. Since the US ban on flavored cigarettes , the number of unique LCC flavors more than doubled.Anticipating further regulation, the industry increasingly markets flavored LCCs with sensory and other descriptors that are not recognizable tastes. For example, after New York City prohibited the sale of flavored cigars, blueberry and strawberry cigarillos were marketed as blue and pink, but contained the same flavor ingredients as prohibited products.Among the proliferation of such “concept” flavors , anecdotal evidence suggests that references to marijuana are evident.Cigar marketing includes the colloquial term, “blunt”, in brand names and product labels . Other marketing techniques imply that some brands of cigarillos make it easier for users to replace the contents with marijuana.For example, the image of a zipper on the packaging for Splitarillos and claims about “EZ roll” suggest that products are easily manipulated for making blunts. We use the term “marijuana co-marketing” to refer to such tobacco industry marketing that may promote dual use of tobacco and marijuana and concurrent use . In addition to flavoring, low prices for LCCs also likely increase their appeal to youth. 10 In California, 74% of licensed tobacco retailers sold cigarillos for less than $1 in 2013. Before Boston regulated cigar pack size and price in 2012, the median price for a popular brand of grape-flavored cigars was $1.19. In 2012, 78% of US tobacco retailers sold single cigarillos, which suggests that the problem of cheap, combustible tobacco is widespread. Additionally, the magnitude of the problem is worse in some neighborhoods than others. Popular brands of flavored cigarillos cost significantly less in Washington DC block groups with a higher proportion of African Americans and in California census tracts with lower median household income.For the first time, this study examines neighborhood variation in the maximum pack size of cigarillos priced at $1 or less and assesses the prevalence of marijuana co-marketing in the retail environment for tobacco.

School neighborhoods are the focus of this research because 78% of USA teens attend school within walking distance of a tobacco retailer. In addition, emerging research suggests that adolescents’ exposure to retail marketing is associated with greater curiosity about smoking cigars and higher odds of ever smoking blunts. In California, 79% of licensed tobacco retailers near public schools sold LCCs and approximately 6 in 10 of these LCC retailers sold cigar products labeled as blunts or blunt wraps or sold cigar products with a marijuana-related flavor descriptor. A greater presence of marijuana co-marketing in neighborhoods with a higher proportion of school-age youth and lower median household income raises concerns about how industry marketing tactics may contribute to disparities in LCC use. The study results also suggest that $1 buys significantly more cigarillos in California school neighborhoods with lower median household income. Policies to establish minimum pack sizes and prices could reduce the widespread availability of cheap cigar products and address disparities in disadvantaged areas.After Boston’s 2012 cigar regulation, the mean price for a grape-flavored cigar was $1.35 higher than in comparison communities.The industry circumvented sales restrictions in some cities by marketing even larger packs of cigarillos at the same low price, 2and the industry’s tipping point on supersized cigarillo packs for less than $1 is not yet known. The retail availability of 5- and 6-packs of LCCs for less than $1 observed near California schools underscores policy recommendations to establish minimum prices for multipacks .A novel measure of marijuana co-marketing and a representative sample of retailers near schools are strengths of the current study. A limitation is that the study assessed the presence of marijuana co-marketing, but not the quantity. The protocol likely underestimates the prevalence of marijuana co-marketing near schools because we lacked a comprehensive list of LCC brands and flavor varieties. Indeed, state and local tobacco control policy research and enforcement would be greatly enhanced by access to a comprehensive list of tobacco products from the US Food and Drug Administration, including product name, category, identification number and flavor. Both a routinely updated list and product repository would be useful for tobacco control research, particularly for further identifying how packaging and product design reference marijuana use. This first assessment of marijuana co-marketing focused on brand and flavor names because of their appeal to youth.However, the narrow focus is a limitation that also likely underestimates the prevalence of marijuana co-marketing. Other elements of packaging and product design should be considered in future assessments. Examples are pack imagery that refers to blunt making, such as the zipper on Splitarillos, as well as re-sealable packaging for cigarillos and blunt wraps, which is convenient for tobacco users who want to store marijuana. Coding for brands that are perforated to facilitate blunt making and marketing that refers to “EZ roll” should also be considered.

Future research could assess marijuana co-marketing across a larger scope of tobacco/nicotine products. The same devices can be used for vaping both nicotine and marijuana. Advertising for vaping products also features compatibility with “herbs” and otherwise associates nicotine with words or images that refer to marijuana . Conducted before California legalized recreational marijuana use, the current study represents a baseline for understanding how retail marketing responds to a policy environment where restrictions on marijuana and tobacco are changing, albeit in opposite directions.The prevalence of marijuana co-marketing near schools makes it imperative to understand how tobacco marketing capitalizes on the appeal of marijuana to youth and other priority populations. How marijuana co-marketing contributes to dual and concurrent use of marijuana and tobacco warrants study,hydro tray particularly for youth and young adults. In previous research, the prevalence of adult marijuana use in 50 California cities was positively correlated with the retail availability of blunts. Whether this is correlated with blunt use by adolescents is not yet known. Consumer perception studies are necessary to assess whether marijuana co-marketing increases the appeal of cigar smoking or contributes to false beliefs about product ingredients. Research is also needed to understand how the tobacco industry exploits opportunities for marijuana co-marketing in response to policies that restrict sales of flavored tobacco products and to policies that legalize recreational marijuana use. Such assessments are essential to understand young people’s use patterns and to inform current policy concerns about how expanding retail environments for recreational marijuana will impact tobacco marketing and use.Oleoylethanolamide is a fatty acid ethanolamide and a natural analog of the endogenous cannabinoid anandamide. There is no detailed research on the role of endocannabinoids in sleep in humans. Anandamide is known to engross slow-wave sleep by increasing adenosin levels in the forebrain of rodents . This is blocked by the cannabinoid CB1-receptor antagonist rimonabant. Oleamide is an endogenous sleepinducing lipid with putative cannabinomimetic properties . Murillo-Rodriguez et al. supposed oleoylethanolamide, which—unlike oleamide— activates the nuclear peroxisome proliferator-activated receptor-a to increase alertness and to participate in the regulation of waking. Up to now, elevated levels of oleoylethanolamide and anandamide were found in human microdialysates within the first day of ischemia as well as following neural injuryor other stressors associated with necrosis. Furthermore, massive increases in FAEs and their precursor phospholipids have been found during the acute phase of stroke in the adult rat brain . Thereby it was suggested that increases of brain FAE levels serve a neuroprotective function mediated by CB1-receptors. Oleoylethanolamide does not bind to cannabinoid CBreceptors but to PPAR-a, thereby activating a different neuroprotective mechanism. Sleep deprivation has been hypothesized to represent an oxidative challenge for the brain and that sleep may have a protective role against oxidative damage. While Gopalakrishnan et al. found no change in antioxidant enzymatic activities or increased oxidant production in the brain or in peripheral tissues after prolonged sleep deprivation, other studies suppose that sleep deprivation may result in a condition of oxidative stress including a reduction in glutathione levels in whole brains of rats . Ramanathan et al. showed that prolonged sleep deprivation results in significant decreases in the activity of superperoxide-dismutase in rat hippocampus and brainstem. This effect may be due to the degradation of antioxidative enzymes after prolonged activation during wakefulness, which suggests an alteration in the metabolism resulting in oxidative stress. Even if sleep deprivation might not show extensive effects comparable to cerebral injury or tissue necrosis, FAEs have been shown previously to be elevated during situations of cellular stress and oxidative stress factors are elevated following sleep deprivation . Therefore, in this study, we investigated whether the levels of the endogenous PPAR-a agonist oleoylethanolamide and the endocannabinoid anandamide were elevated in CSF and serum of healthy individuals after acute sleep deprivation.The Ethics Committee of the Medical Faculty of the University of Cologne reviewed and approved the protocol of this study and the procedures for sample collection and analysis. All volunteers gave written informed consent twice at least 1 day prior to each lumbar puncture after extensive introduction into the procedures and goal of this study. The healthy subjects received an allowance for the participation in this trial. All investigations were conducted in accordance with the Declaration of Helsinki. This study was integral to a larger project on endocannabinoid levels in CSF and serum of healthy volunteers and patients suffering psychiatric disorders. As part of that, volunteers were investigated to establish baseline levels of endocannabinoids in a healthy control population . Twenty healthy volunteers with no family history and no clinical indication for any relevant medical, psychiatric or neurological disturbances were included in our study to investigate effects of sleep withdrawal on endocannabinoid levels. Necessary criteria for inclusion were absence of cannabis use within the last year and lifetime cannabis use not exceeding five times.Living circumstances for those volunteers selected did not change substantially during this period. Subjects were lumbar-punctured twice during the course of our study using a nontraumatic LP procedure. The first LP was done under regular sleep condition. The second LP took place after 24 h of sleep deprivation about 1 year later to avoid seasonal influences and artificial alterations in cerebrospinal fluid due to a previous LP in the near past. All subjects spent the nights before both LPs at home; sleep quality before the first lumbar puncture was assessed by the self-rating questionnaire for fatigue and for sleep and awakening quality . The night of sleep deprivation was spent in the habitual environment of the volunteers. Alertness was monitored by wrist actigraphy, using the ‘‘Actiwatch2000,’’ a piezoelectric transductor recording a maximum of 240 wrist motions per minute. Actiwatch was given to the volunteers 24 h before the second lumbar puncture. Volunteers showing a mosaic of inactivation at the actiwatch-scan of more than 5 min during the 24-h period were excluded from the experiment. This approach allowed us to continuously monitor the subjects during the night of sleep withdrawal .

The symposium addressed the intricate relationship between epilepsy and other medical conditions. Dr Scott Mintzer kicked off the symposium with his talk “Epilepsy & Heart Disease: Tips for the Consultant.” He identified the impacts of anticonvulsants on the cardiovascular system and the interactions between antiepileptic drugs and cardiac medications. Hepatic enzyme inducing anticonvulsants are associated with worse lipid profiles and vascular risk markers and reduce the efficacy of some cardiovascular medications, such as statins.1 Older anticonvulsants, such as carbamazepine, may even be associated with increased risk of myocardial ischemia. Dr Steven Pacia presented “Syncope and Other Seizure Mimics,” where he reviewed key clinical features that distinguish seizures fromsyncope and other seizure mimics such as migraine, transient ischemic attacks, metabolic disorders, nonepileptic psychogenic seizures, transient global amnesia, and sleep disorders.Some, such as prolonged QT syndrome, should not be missed.Dr. Andres Kanner led the discussion on “Do Psychotropic and Antibiotic Drugs Cause Seizures? A Review of the Evidence.” He reviewed selection of antibiotics and psychiatric medications that would minimize seizure risk. Therapeutic doses of serotonin and norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, and tricyclic antidepressants appear to be associated with reduced seizure incidence, though overdoses of these classes of medications can be associated with increased risk of seizures.Bupropion and clomipramine were the exceptions to the rule,vertical grow system and seizure risk was increased with these medications compared to placebo. Antibiotics may increase the risk of seizures.

The mechanism by which antibiotic lower seizure threshold may be decreased GABAergic activity. Dr Page Pennell discussed the management of AEDs during pregnancy to optimize seizure control and pregnancy outcomes in her talk “Seizure Management during Pregnancy.” Her presentation reviewed the teratogenic risk of AEDs and other pregnancy outcomes including “small for gestational age” .Valproate was also associated with lower IQ in childhood and increased risk of autism. On the other hand, folate prescribed before pregnancy or at start of pregnancy was associated with higher IQ and lower risks of autism. There are changes in pharmacokinetics of AEDs during pregnancy and dose adjustments are needed to maintain seizure control. Dr Jeanne Young discussed “Anticonvulsants and the Skin Hypersensitivity”. Dr Young emphasized the diversity in hypersensitivity associated with AEDs, distinguishing drug rash based on pathophysiology and clinical characteristics, and recognizing clinical features that could alert us to severe cutaneous adverse reactions. The most common type of reaction is a morbilliform rash with erythematous papules or plaques due to immune complex deposition and cell-mediated immunity. These rashes characteristically begin 7 to 10 days after starting medication and typically resolve in 2 to 3 weeks. Patients usually feel well, though they may complain of pruritis. Interestingly, in some cases it is possible to “treat through” the rash, or re-challenge later with the same medication, with the patient under close observation by dermatology. Signs characteristic of more severe drug reactions are swelling of the face, presence of pustules, bullae, or vesicles, dusky or painful lesions, mucous membrane involvement, or signs of systemic involvement. Morbilliform skin eruptions beginning later than expected along with systemic symptoms and patient feeling ill are more concerning for progressing to Drug Rash with Eosinophilia and Systemic Symptoms syndrome.

The neurobiology of memory has long been a central issue in epilepsy, particularly for syndromes involving mesial temporal lobe structures. While Ramon y Cajal first detailed the neuroanatomical structure of the hippocampus more than 100 years ago,it was the well-known case of “H.M.” that revealed the prominent role of the hippocampal formation and related structures in declarative memory.Patients undergoing temporal lobe resection for control of pharmacoresistant seizures may experience postoperative memory decline. Preoperative reorganization of the posterior hippocampus with transfer of function to contralateral and extratemporal structures including anterior cingulum and insula may be a key factor in preservation of memory function,and there may be a role for memory functional magnetic resonance imaging studies in individualized outcome prediction.There is also evidence that the choice of surgical approach has important implications for postoperative memory outcomes.Even apart from surgical intervention, memory deficits are a common comorbidity in epilepsy. At the cellular level, seizureinduced epigenetic dysregulation likely plays an important— but little understood role. Abnormally regulated BDNF DNA methylation was explored in a rodent temporal lobe epilepsy model, and was shown to have a dual role in modulating both epileptiform abnormalities and memory impairments.Memory consolidation is an important mechanism supporting long-term memory that may also be disrupted by epileptiform activity. Studies of human multi-scale and animal recordings demonstrated locally recorded cortical replay of waking patterns during subsequent sleep periods.This process involves an intricate coordination of cortical up and down states, hippocampal sharp-wave ripples and thalamocortical spindle activity, with distinct roles played by the anterior and posterior hippocampus. Finally, building on the previous year’s symposium, early results from a recent high-profile study of the use of cortical electrical stimulation to improve memory function were presented.

In a promising development, successful enhancement of hippocampal-dependent memory in patients with epilepsy has now been reported with lateral temporal stimulation and independently in entorhinal white matter using q-burst stimulation.Emilio Perucca, MD, PhD, focused on the rational use of anticonvulsant medication and reviewed a systematic approach to sequencing and combining antiepileptic medications. Given the extensive choice of treatments, an evidence-based systematic approach is important when treating patients.The literature contains a number of comparative studies, though more evidence is needed, particularly when planning polytherapy. Different clinical scenarios were provided to illustrate his approach, and he highlighted areas in which further knowledge must be obtained. This approach to therapy, which is driven by data and experience, offers a masterful way to treat epilepsy. The second lecture, given by Dennis Dlugos, MD, “What’s in the Pipeline? Newly Approved and Almost Ready Antiepileptic Drugs” provided a review of both recently approved medications and drugs that are presently in the pipeline, but anticipated to enter the clinical arena. Professor Dlugos reviewed pivotal trial data, both with regard to efficacy and adverse effects. Pipeline drugs show promise for both generalized and focal epilepsy. It is hoped that the information provided in this lecture will enable the practicing physician to integrate the use of these agents into practice once they are available. The third lecture, delivered by Barbara Dworetzky, MD, reviewed rescue therapy, with a particular focus on new and emerging treatments. Trials have been conducted employing several benzodiazepines, including diazepam, midazolam, and alprazolam. These new therapies may be administered intranasally, or in the case of alprazolam, by inhalation, though the latter agent has only recently entered the trial phase. Professor Dworetzky reviewed the pharmacology and trial results; these preparations do not require rectal administration and may prove a popular choice by patients and their families when rescue is needed. The final lecture, given by Jukka Peltola, MD, reviewed deep brain stimulation of the anterior nucleus of the thalamus for intractable epilepsy. This therapy was recently approved by the Food and Drug Administration in the United States,indoor vertical garden systems but has been in use in Europe since 2011. Professor Peltola reviewed both clinical trial data and the European clinical experience, and proposed suitable indications for employing this therapy.The symposium encompassed topics ranging from basic science, translational research, clinical trials, adverse effects, nutritional guidance, and possible anti-inflammatory benefits. Dr Susan Masino covered “Cellular metabolism as a paradigm for experimental therapeutics in epilepsy.” She discussed the 4 major possible therapeutic targets of metabolism-based therapies: changes in blood and cerebrospinal fluid , improved mitochondrial function and energy reserves, synaptic stability, and cellular changes including alterations in the gut microbiota.Dr Kristina Simeone then tackled “Metabolic approaches for treating complications and comorbidities of epilepsy.” She focused on how these therapies have been shown in preliminary studies to benefit cognition, autism, behavior, sleep, and even SUDEP .Dr Elizabeth Donner reviewed “Clinical evidence for metabolism-based therapies in children: trials and guidelines.” In her lecture, Dr Donner first covered the strong evidence from multiple randomized controlled trials for ketogenic diet therapy, then provided an overview of the updated 2018 revised international consensus guideline.The fourth lecture was given by Dr Anita Devlin and was titled “Ketogenic Diet for Infants?”

Two specific epileptic encephalopathies affecting infants have evidence for treatment response to ketogenic diet.20 Dr Devlin ended by discussing the ongoing “KIWE” trial in the United Kingdom which has been enrolling infants 1 to 24 months of age into a randomized trial of the ketogenic diet versus further antiseizure drugs. Robyn Blackford, RD, provided a dietitian’s perspective on handling the adverse effects from these dietary interventions in a lecture entitled “Safety and prevention of risks from metabolism-based therapies.” Finally, Dr Stephane Auvin ended the symposium with a basic and clinical science lecture on “Are there anti inflammatory effects of metabolic therapies?”, with a focus on refractory status epilepticus and Febrile Infection-Related Epilepsy Syndrome .In summary, this symposium achieved its goal of highlighting how the ketogenic diet and other metabolism-based treatments have become “state of the art.” This symposium addressed bioethics in 4 areas: transition to adult care delivery of behavioral health services using technology self-management interventions and outcome measures, and anti-seizure medication. General ethical principles, including respect for autonomy, nonmaleficence, beneficence, and justice as they pertain to comprehensive care of persons with epilepsy were covered. Dr Eric Racine articulated the nuances of respect for autonomy in the transition from pediatric to adult care for persons with neurodevelopmental disabilities. Autonomy includes 6 component abilities: voluntariness , information , control , deliberation , authenticity , and enactment .Dr Hamada Altalib discussed ethics in employing technology to deliver behavioral health care to PWE, including specifically challenges related to consent, privacy, confidentiality, and the patient–provider relationship. Insight into howtele health and mobile health can improve justice and equity by removing barriers to care such as transportation and resource disparities. The VA Epilepsy Center of Excellence was presented as a model for mobile behavioral health care. Appropriately implemented technology can revolutionize the range and standard of care. Dr Martha Sajatovic covered self-management support and collecting behavioral outcomes. Given the high rate of mental health comorbidities and barriers to in-person behavioral health care, the SMART intervention contains one in-person session with a nurse educator-peer educator dyad and then 7 group sessions in a web-based format. Following SMART, PWE who had experienced a negative health event reported decreased depressive symptoms and improved quality of life versus people on a wait list.23 There are ethical considerations, such as group confidentiality and the role of patients as peer educators. Findings from 5 pooled managing epilepsy well network randomized controlled trials demonstrated a reduction in depressive symptoms following self-management interventions. Research relies on integrated research datasets.However, there are multiple ethical issues to consider, including protected health information, data sharing agreements, firewalls, and authorship. Dr Viet Nguyen addressed ethics in selection of AED therapy. Beneficence and nonmaleficence must be balanced when identifying epilepsy management goals and related costs, and the role of justice was also discussed. Patients express concerns with AED changes, and clinicians must manage adverse effects to promote improved quality of life. Patients have a right to choose their therapy and there must be the balance of autonomy of choice with adequate treatment.Caring for patients with epilepsy is both a science and an art. This statement has never been more accurate than today. Faced with an exponential growth in diagnostic technology and novel therapeutics, the variety of choices that we have to make have become much more complex. Yet, robust data on comparative effectiveness and for evidence-based decision making are lacking. This information deficit is at the root of the significant variation in our practices, and sub-optimal patient care. Considering several current controversies in the management of difficult epilepsies, some challenges stand out. First, the frequency and indications for some tests that are considered cornerstones of our epilepsy management remain highly variable and require balancing multiple factors, including the treatment goals of the patients, risks, alternatives, and cost. The indication for a video EEG study is a perfect example. This inpatient testing is warranted to confirm the diagnosis of epilepsy and rule out psychogenic nonepileptic seizures in patients who continue to have seizures despite 2 or more adequate and appropriate antiepileptic drug trials. Conversely, holding off the initiation of seizure medications until a diagnosis of epilepsy can be positively confirmed with video EEG is clearly inappropriate in patients at high risk of seizure related injuries, nocturnal convulsions with increased risk of sudden death in epilepsy, existing medical comorbidities , severeictal or postictal behavioral disturbance, and in resource-limited communities.

Proposals to equalize these limits would likely spur greater tax revenue collection in certain parts of the state. Thus far, beyond funds earmarked for school construction, marijuana revenue has financed the regulatory apparatus necessary to oversee the state’s growing recreational and medical marijuana marketplace. Marijuana revenue has also been allocated to youth drug prevention, public safety, and public education. State officials have launched several advertising campaigns to inform residents and tourists about marijuana laws and regulations regarding its use. To date, more than $5 million has been spent on these public awareness campaigns with more to come. The amount the state is permitted to spend may depend on whether voters collectively decide to let it keep revenues in excess of TABOR limits. Close to one billion people are affected by mental illness and substance misuse worldwide. In many developed countries, mental illness ranks top for burden of disease , is more common, impactful and costly than other health conditions, and is a core component of overall health. The total cost of mental illness in the USA is estimated to be $2.5 trillion , the global antidepressant market is worth over $13.5billion and the wellness sector is estimated to be worth over $4.5 trillion . Despite record increases in psychiatric medication prescription rates, the prevalence of mental illness is not reducing and may well be increasing in certain populations,flood tables for greenhouse such as the young . There are indications that rates of mental illness have increased during the coronavirus disease 2019 pandemic .

Evidence indicates that the efficacy of leading drug and psychological interventions is modest, and there is scope for improved tolerability and access . Most mental health interventions are reactive. Effective prophylactic intervention would be hugely valuable . Relatedly, early life trauma and mental illness are reliable predictors of future morbidity. There is a legacy of division between the biological and psychological arms of mental health care and research. A notable initiative towards innovation in biomedical psychiatry is the Research Domain Criteria . The main principle of RDoC is that, since diagnostic criteria are a product of clinical expediency, transdiagnostically relevant pathological mechanisms and treatment targets may have been overlooked. Relatedly, there is now good evidence for genetic overlap between psychiatric disorders . RDoC is primarily a biological initiative that aims to translate mental illness into ‘brain illness’, for the purpose of discovering candidate brain biomarkers and treatment targets . Notable initiatives towards innovation in psychological health care include efforts to improve the cost-effectiveness of , access to and reach of psychotherapy – e.g. through utilising technological advances and social and familial networks . So-called ‘third wave’ psychotherapeutic approaches have gained traction, e.g. with a spike in the popularity of mindfulness and growing interest in – and evidence for – acceptance and commitment therapy . Bearing in mind relevance to RDoC, one important characteristic of these approaches is their alleged transdiagnostic relevance, i.e. that they seek to identify and target a common pathological mechanism, but more work is needed to link the relevant psychological constructs, such as ‘psychological flexibility’, with biological processes. There are promising signs of confluence between psychiatry’s biological and psychological divisions however, including a growing appreciation of the value of both psychological and neurobiological accounts of mental illness and its aetiology, as well as how environment, mind, brain and body interface and interact – consistent with the ‘biopsychosocial’ model .

Specific examples of biopsychosocial research in psychiatry include studying: gene × environment and drug × environment interactions – of which drugassisted psychotherapy can be considered an example , neurophenomenology and the biological mechanisms of psychological interventions . Into this arena comes psychedelic therapy, a quintessentially biopsychosocial intervention. Evidence indicates that psychedelic therapy is a particularly promising and progressive mental health care solution . Classic serotonergic psychedelics can be most precisely defined by their pharmacology, i.e. agonist action at the serotonin 2A receptor, which, if blocked, effectively abolishes their signature psychological effects . Psychedelic therapy is defined here as psychologically supported classic psychedelic drug experiences – although we recognise that psychotherapy alongside experiences induced by certain other psychoactive substances, e.g. MDMA and ketamine, bears relation to classic psychedelic therapy. Psychedelic therapy has shown promise for a range of different mental health conditions, including: depression , end-of-life anxiety , addiction and obsessive compulsive disorder . Indirect evidence also supports its potential for treating eating disorders and chronic pain . See Andersen et al. for a review. The Food and Drug Administration has granted ‘breakthrough therapy’ status to two independent multi-site double-blind randomised controlled trials , aiming to bring psilocybin therapy to marketing authorisation for depression, while related work is currently underway across Europe. Population and controlled studies , as well as large retrospective and prospective surveys , are generating evidence for improved mental well-being across a large demographic, potentially opening psychedelic therapy up to a sizeable wellness market. The successful initiative to legalise psilocybin therapy in Oregon, USA, intentionally included access for healthy individuals. In addition to its putative transdiagnostic utility, other reasons to feel optimistic about psychedelic therapy include: its novel action , and rapid and enduring therapeutic impact . Unlike traditional psychiatric drugs, positive effects have been observed for several months after just one or two doses. In terms of safety, psychedelics such as psilocybin have a favourable toxicity profile and therapeutic index, and negligible addiction potential .

Not wishing to neglect rare cases of putative iatrogenesis, including those of so-called ‘hallucinogen persisting perceptual disorder’ , the main hazards of psilocybin therapy relate to the intensity of the psychological state produced by higher doses, and associated need for a carefully engineered contextual container, e.g. with effective psychological preparation, supervision and aftercare. The utilisation of a drug-induced period of heightened cortical plasticity is likely to be a core component of psychedelic therapy’s mechanism of action and candidate functional and anatomical biomarkers of this are already being examined. In the context of a predictive processing framework, the ability of psychedelic therapy to relax and recalibrate cognitive and behavioural biases may be a central part of its action – as may an accelerated learning rate . How can we best advance the science of psychedelic medicine? Here we advocate pragmatic considerations , the utilisation of ‘basket’ protocols , as well as digitally aided data registries. Distinguishing pragmatic from confirmatory trials, the former refers to the actual, realistic conditions under which a therapeutic intervention will be received , whereas confirmatory trials typically engineer experimental conditions to support strong scientific inferences, but these often poorly reflect real-world conditions. Basket protocols are defined as single protocols, approved by relevant research regulatory bodies, that allow for a single intervention to be tested for multiple different disorders or conditions, such as a single drug for different types of cancer. Developers may be right to adhere to convention in delivering confirmatory trials, but, if resources and conditions allow, considerable benefits could be gained from more explorative study designs. Such exploration may be best served by research that can address a greater range of questions of clinical and real world relevance. Similarly, whereas confirmatory trials may choose to constrain eligibility and treatment criteria, pragmatic trials may benefit from broadening them, while maintaining a sensibly high-bar for contraindication-related exclusion criteria. Easy to sample biometrics and behavioural sampling could accrue large pools of objective data with potential predictive value. If such studies and data registries are designed with careful consideration of data quality and fitness, pragmatic research could create significant value for various different stakeholders, e.g. scientists, clinicians, regulators, health care systems, payers and investors. As has been the case with medical cannabis,indoor growing trays treatment-seeking patients will look for guidance from clinicians who take theirs from scientific evidence. Liberal policy changes occurring prior to the conducting of sufficient research could create similar problems for clinicians as occurred with medical cannabis. Such imperfect clinical scenarios could, however, also represent opportunities for innovative pragmatic and observational research. The creation of electronic data registries, e.g. for prescribers of psilocybin therapy in regions legally permitting access , may be one appealing example, enabling the collection of valuable real-world data. Data registries and pragmatic trials will collect data from broad and diverse samples. Data on use among healthy individuals can be supplemented by data from individuals seeking psychedelic therapy treatment for depression, particularly as safety is being established in this population . An even more ambitious project would be to utilise a protocol to only exclude individuals where there are good reasons to suspect elevated risk and inadequate specialist support. Indeed, future psychedelic therapy clinics in areas supporting legal access and/or operating under a research mandate may support such a scenario. Moreover, utilising digital tools, such as cellphone apps , to track outcomes linked to psychedelic use could generate large data pools that could be mined to inform on such matters as patient screening and treatment optimisation. Whether via data registries annexed to legal-access psychedelic therapy or approved pragmatic research trials, or both, the proposed approaches can serve the agenda of identifying transdiagnostic treatment targets . The RDoC initiative pays selective attention to phenotypes associated with pathology, neglecting parameters associated with wellness, and this may be an oversight. Evidence of reliable and sustained improvements in well-being and lifestyle with psychedelic therapy, as well as the maintenance of psychological wellness , recognition of the bidirectional relationship between psychological and physical health, and awareness of the substantial costs required to implement any human drug study, let alone a clinical trial with a psychedelic, and combined with a need for greater safety data across a diverse demographic, particularly given the liberalising political climate surrounding psychedelics, are all good reasons to justify innovative and pragmatic approaches to researching psychedelic medicine.

Collecting large sample sizes will enable better prediction-of response modelling , which will help mitigate risk and inform the potential customisation of care. A multi-site ‘trial’ or centralised registry would help generate and store the large data needed for reliable prediction-of-response modelling, with the added benefit of being able to assess between site discrepancies and consistencies. Confirmatory trials constrain important treatment parameters such as dosage and frequency of interventions, whereas pragmatic psychedelic trials could exercise flexibility here, particularly given the nascent nature of the treatment model, where practitioners cannot confidently claim to know the best parameters for all individuals and indications. In the context of psychedelic therapy, what dosage, frequency-of-dosing, as well as frequency and nature of post-dosing psychotherapy sessions are optimal, and for which cases, are all key questions that may be best addressed via pragmatic research under a basket protocol – and/or via digital data collection. Upper limits on the number of dosing sessions and lower limits on the intervals between them may be set to reduce the risk of bad practice, but redosing in response to relapse and based on clinical judgement may be permitted, thereby reflecting the conditions of clinical practice post roll-out. Most modern trials of psychedelic therapy have employed just one or two fixed-dose treatment sessions for all participants within relatively small and homogeneous samples, not because of assumptions about best practice, but because of alignment with regulatory traditions and budget constraints. This article argues that carefully designed pragmatic trials implemented under a basket protocol could offer a powerfully progressive model for advancing our understanding of the safety, effectiveness, mechanisms, impact, best-use and pitfalls of a promising but vulnerable new treatment model in psychiatry. Progressive policy changes would likely be needed to actualise the proposed approach – but these are already occurring. For such policy changes to occur, a vision of the societal value of improved mental health care, and how this can be safely and effectively achieved via psychedelic therapy, will need to be well communicated to the public and policy makers. For the time being, DB-RCTs will continue to sway sceptical opinions and aid progress with regulators, who presently base pivotal licensing decisions on data derived from such trials. Our view, however, is that data derived from pragmatic trials may be able to teach us more about how best to deliver the treatment and how it could impact on the lives of a broad cross-section of people. To be clear, the argument here is for the complementary value of pragmatic trials, not for their superiority over DB-RCTs. At the same time, however, we do challenge, as others have previously, the hierarchical preeminence of DB-RCT derived evidence .

Outlier images were modeled as nuisance covariates. Each outlier image was represented by a single regressor in the GLM, with a 1 for the outlier time point and 0s elsewhere. Time series of all the voxels within each seed were averaged, and first-level correlation maps were produced by extracting the residual BOLD time course from each seed and computing Pearson’s correlation coefficients between that time course and the time course of all other voxels. Correlation coefficients were converted to normally distributed z-scores using the Fisher transformation to allow for second-level General Linear Model analyses. DMN connectivity was calculated from the averages of the time series from MPFC and PCC seeds , given their similar connectivity patterns. Functional connectivity of left and right DLPFC were analyzed separately, as were left and right amygdala due to evidence of differential roles in emotion processing . First-level connectivity maps for each participant were entered into a between-group t-test to determine connectivity differences for each seed between groups. Clusters-level threshold was set at p < .05 using false discovery rate correction for multiple comparisons , with voxel-wise t-value threshold of 2.42 . Bonferroni correction was applied to the FDR-corrected cluster-level p-values to correct for multiple comparisons of the five a priori seeds tested . Regions that showed significant connectivity differences between groups were further examined for their connectivity values using one sample t-tests in each group. Based on prior evidence of DMN-sgACC hyperconnectivity in MDD and its implication in depressive rumination ,vertical grow racks for sale we examined the within group correlations between DMN-sgACC connectivity values and CBCL scores. Given the higher CBCL total score in the at-risk group, we re-tested group differences by including CBCL total scores as a covariate. Classification models of at-risk children and controls discrimination.

We trained two linear classification models using logistic regression, implemented in machine learning software Weka , in order to categorize individual participants to the at-risk or control groups based on their rs-fMRI or behavioral data. To create robust prediction models that can be generalized to new cases, we performed leave-one-out cross-validation so that each individual was classified on the basis of data from the other individuals. Specifically, data from all participants except one were used as the training set to build a classification model, and the remaining participant was classified with the model and used as the validation case. This procedure was iterated for each participant and used to estimate specificity/sensitivity from the out-of-sample predictions. In the first model, we used anatomically defined regions-of-interest that were independent from the regions that showed between-group connectivity differences. Connectivity values between the five a priori seeds and 116 clusters defined by the AAL atlas were estimated and used in the prediction model. We constructed a second model based on CBCL scores , to compare with classification accuracies from the model based on rs-fMRI data in anatomically defined ROIs. We found differential intrinsic functional connectivity patterns in unaffected children with familial risk for MDD compared to children without such familial risk in the DMN, the cognitive control network, and the amygdala. At-risk children showed hyperconnectivity between the DMN and the sgACC/OF. Furthermore, although none of the at-risk children was clinically depressed, DMN-sgACC/OFC connectivity was positively correlated with individual CBCL scores among those children. At-risk children also showed hypoconnectivity within the cognitive control networ k, lacked the typical anticorrelation between the DMN and the right parietal region, and exhibited lower connectivity between left DLPFC and sgACC. In addition, at-risk children showed hyperconnectivity between amygdala and the right IFG. Finally, classification between at-risk children and controls based on resting-state connectivity yielded high sensitivity and specificity. These findings appear to identify trait neurobiological underpinnings of risk for major depression in the absence of the state of depression.

Increased connectivity between DMN and sgACC in at-risk children, and the positive correlation between DMN-sgACC connectivity and current symptom scores, are consistent with findings reported in adult and pediatric patients with MDD. The fact that these findings were observed in unaffected children at familial risk for MDD suggests that hyperconnectivity with sgACC is not a consequence or manifestation of MDD, but instead may be a biomarker of predisposed risk for MDD.In line with our finding, stimulation of the sgACC resulted in attenuation of hyperactivation in sgACC and increased activation in previouslyunderactive DLPFC in adults with MDD . The left DLPFC region that showed maximum anticorrelation with the sgACC has been identified as a target for TMS treatment of MDD . A prospective study would be needed to determine if atypical sgACC connectivity at this age predicts later development of MDD. The lack of typical anticorrelation between the DMN and supramarginal gyrus / inferior parietal lobule, an important attention control region , in at-risk children is consistent with cognitive control deficits in depressed adult patients and reduced DMN deactivation during an emotional identification task in depressed adolescents . Greater anticorrelation between DMN and cognitive control networks in healthy adults has been linked to better performance in cognitive control and working memory tasks and may reflect an individual’s capacity to switch between internally and externally focused attention . This dynamic interplay between DMN and cognitive control networks in MDD was examined in a task-based connectivity study. During an external attention condition, adults with MDD exhibited increased DMN connectivity and decreased cognitive control network connectivity . The present study suggests that an imbalance between DMN and cognitive-control networks is a developmental risk factor for MDD. With regards to decreased connectivity within the cognitive control regions in at-risk children, a previous study of adolescents with familial risk for depression also reported reduced connectivity between cognitive control regions . In that study, lower connectivity in the control network was associated with more severe parental depression symptoms. These results in at-risk children and adolescents are consistent with findings from depressed adults of reduced connectivity in attention control regions including the DLPFC .

Studies consistently show that the DLPFC is under-activated in depressed adults , which might contribute to their difficulty in cognitive control and emotion regulation . It is possible that children at-risk for depression have an underconnected control network that is also a developmental risk factor for MDD. There was increased connectivity between the right amygdala and the right IFG and supramarginal gyrus in at-risk children. The right IFG is a key region in emotion regulation . The top-down IFG-amygdala circuitry is disrupted during emotion regulation in adults with mood disorders . A study of children with MDD and children of mothers with MDD also reported reduced negative correlation between the amygdala and lateral parietal regions including the supramarginal gyrus . The atypically high level of connectivity between amygdala and emotion regulation and cognitive-control regions might reflect emotion dysregulation in MDD. To test whether intrinsic functional organization of the brain, as measured by rs-fMRI,rolling hydro tables can be a potential biomarker for risk for depression in children, we performed a classification analysis to discriminate children in the at-risk group and control group based their resting-state functional connectivity data. This classification based on functional connectivity yielded high accuracy, sensitivity, and specificity in discriminating between children at risk for MDD and controls compared to classification based on CBCL scores. Importantly, the rs-fMRI classification was based on analyses that, at the level of each individual child, were independent of the group differences in functional connectivity. Such generalizable and individually robust classification is important if brain measures are to be used for early identification . Future prospective and longitudinal studies can determine whether such biomarkers predict which high-risk children progress to MDD and whether early intervention reduces the likelihood of developing MDD. Also, perhaps such biomarkers may be helpful in identifying children at risk for developing depression independent of parental histories of depression. Our findings need to be viewed in light of some methodological limitations. First, we did not exclude children born prematurely, and premature births can lead to neurological complications. However, we did exclude children with known developmental delays such as autism and intellectual disability. Second, because parental MDD confers a spectrum of risk to offspring , the at risk children were also at risk for anxiety and other disorders. Parents with MDD also have higher rates of comorbid anxiety than the general population. Thus we cannot rule out that the brain differences we found were due to the children being at risk for anxiety and other disorders. Third, although our sample size of at-risk children was moderate, the control group was small .

Lastly, our resting-state scans were acquired with a repetition time of 6 seconds, which is longer than most resting state fMRI studies so that we could acquire high-resolution whole brain data without the use of parallel imaging. A previous study found there was no significant difference in correlation strengths within and between resting-state functional networks when comparing TR = 2.5 and 5 seconds resting scans, and that correlation strengths stabilized with acquisition time of 5 min . In the current and previous studies using the same acquisition parameters , we observed the typical resting-state network patterns observed in other studies. Nonetheless, an additional issue of the long TR is that cognitive and emotional processes internally initiated at the beginning and the end of each scan can be different. We cannot rule out the possibility that the group difference observed here might be in part due to systematic differences in chronometry between the two groups. The present study consisted of a sample of pre-adolescent children who were at familial risk for depression but not currently affected with depression and therefore functional connectivity differences cannot reflect an expression of depression as could be the case in patients with ongoing MDD. Rather, the differences in intrinsic functional brain architecture likely reflect neural traits that predispose children towards MDD or related disorders. Importantly, we demonstrated that discrimination between at-risk and control children occurred with high sensitivity and specificity based on resting-state functional connectivity. Future studies that track the development of children at familial risk for MDD and determines which children develop MDD or other mood and anxiety disorders are needed to build predictive models based on findings from the present study so as to identify high-risk individuals for early intervention.The regulation of both cognition and emotion is thought to depend upon top-down modulation of multiple neural circuits by prefrontal cortex, and in particular the dorsolateral prefrontal cortex. Because prefrontal-dependent cognitive control mechanisms regulate the focus of attention and regulate mood, it stands to reason that they play a key role in mental health. There is indeed ample evidence that adult psychiatric patients exhibit an attenuation or failure of top down control mechanisms in depression, anxiety, and Attention Deficit Hyperactivity Disorder 14. Given that these prevalent mental health problems tend to emerge during childhood and adolescence, it is important to know whether dysregulated top-down control can be detected even before behavioral symptoms are evident. The strength of coupling between regions involved in top-down control and their targets can be measured with resting state fMRI . Regions of the brain that are highly temporally correlated during rest form resting state profiles which are intrinsic, spontaneous, low-frequency fluctuations in the fMRI blood-oxygen-level dependent signal that define specific networks of the brain in the absence of any task. There is great heterogeneity in the functional organization of the brain that is captured by RSNs. In fact, they may be considered “fingerprints” of the human brain, as they can accurately identify individual subjects from a large group of individuals. Furthermore, RSN profiles are known to be robust and reliable. RSNs are particularly relevant to studying psychiatric and pediatric populations because 1) they are task-independent, so individual differences in task performance cannot explain differences observed in the BOLD data, 2) they are easy and fast to acquire which make them more accessible to a wide variety of subjects including young children and a wide range of clinical populations, and 3) they are plastic and have been shown to change during typical development and can be modulated by behavioral or pharmacological interventions. An RSN that is particularly relevant for mental health is the Central Executive Network , of which the DLPFC is a key node.