Novel Flurbiprofen Derivatives as Antioxidant and Anti-Inflammatory Agents: Synthesis, In Silico, and In Vitro Biological Evaluation.

In this study, we present the synthesis of five novel compounds by combining flurbiprofen with various substituted 2-phenethylamines. The synthesized derivatives underwent comprehensive characterization using techniques such as 1H- and 13C-NMR spectroscopy, UV-Vis spectroscopy, and high-resolution mass spectrometry (HRMS). Detailed HRMS analysis was performed for each of these newly created molecules. The biological activities of these compounds were assessed through in vitro experiments to evaluate their potential as anti-inflammatory and antioxidant agents. Furthermore, the lipophilicity of these derivatives was determined, both theoretically using the cLogP method and experimentally through partition coefficient (RM) measurements. To gain insights into their binding affinity, we conducted an in silico analysis of the compounds' interactions with human serum albumin (HSA) using molecular docking studies. Our findings reveal that all of the newly synthesized compounds exhibit significant anti-inflammatory and antioxidant activities, with results statistically comparable to the reference compounds. Molecular docking studies further explain the observed in vitro results, shedding light on the molecular mechanisms behind their biological activities. Using in silico method, toxicity was calculated, resulting in LD50 values. Depending on the administration route, the novel flurbiprofen derivatives show lower toxicity compared to the standard flurbiprofen.

Interventions for prevention and treatment of substance use in youth with traumatic childhood experiences: a systematic review and synthesis of the literature.

Most substance use begins in adolescence. Both childhood trauma and associated post-traumatic stress disorder (PTSD) increase risk for early substance use, which is associated with greater eventual severity of substance use disorders (SUDs). When co-occurring, PTSD and SUD can reinforce and exacerbate each other, necessitating integrated treatment approaches. To systematically review existing literature on interventions for prevention or treatment of SUDs among adolescents (aged 10-24) with a history of trauma, with or without PTSD, we searched databases (PubMed, PsycInfo, CINAHL, Cochrane CENTRAL) using search terms related to substance use, trauma, adolescents, and interventions. Searches identified 8134 unique articles, 68 of which prompted full-text screening. Authors extracted data, applied the Effective Public Health Practice Project Quality Assessment Tool to evaluate the evidence, and synthesized findings. Thirty three articles met eligibility criteria, including 13 RCTs. Twenty studies (10 RCTs) evaluated interventions for substance use and co-occurring problems among youth with a history of trauma, predominantly via individual therapy based on cognitive-behavioral principles, although group therapy, case management, and other approaches have also been studied. Interventions with exposure-based components were infrequent but had robust results and minimal adverse outcomes. Thirteen studies examined differential response of youth with a history of trauma to standard SUD treatments, compared to youth without a history of trauma, with mixed findings. Youth with a history of trauma face elevated risk of SUDs and may respond differently to SUD treatments. Several promising interventions have been recently developed.

Characterization of Polyphenols from Chenopodium botrys after Fractionation with Different Solvents and Study of Their In Vitro Biological Activity.

In the present work, we have investigated the polyphenolic composition of Chenopodium botrys from Bulgaria. The polyphenols were fractionated with solvents of varying polarity (n-hexane, chloroform, ethyl acetate, and n-butanol). The fractions were analyzed by HPLC-PDA and UHPLC-MS. The ethyl acetate fraction contained mono- and di-glycosides of quercetin, di-glycosides of kaempferol, and isorhamnetin and monoglycosides of hispidulin and jaceosidine. We found quercetin triglycosides in the butanol fraction. The ethyl acetate and butanol fractions contained 168.82 mg/g Extr and 67.21 mg/g Extr of quercetin glycosides, respectively. The main components of the polyphenolic complex in C. botrys were 6-methoxyflavones (355.47 mg/g Extr), which were found in the chloroform fraction. The flavonoids pectolinarigenin, demethylnobiletin, and isosinensetin, and the glycosides of quercetin (triglycosides, acylglycosides), kaempferol, isorhamnetin, hispidiulin, and jaceosidine, were discovered and reported in Chenopodium botrys for the first time. We used in vitro methods to assess the biological activity against oxidative stress (hydrogen peroxide scavenging activity (HPSA) and hydroxyl radical scavenging activity (HRSA)), nitrosative stress (nitric oxide scavenging activity (NOSA)), anti-inflammatory activity (IAD inhibition), and anti-tryptic activity (ATA). Quercetin mono- and di-glycosides exhibited greater HPSA and HRSA (IC50 = 39.18, 105.03 µg/mL), while 6-methoxyflavones had a greater NOSA (IC50 = 146.59 µg/mL). The same components showed the highest ATA (IC50 ranging from 116.23 to 202.44 µg/mL).

HPLC Analysis and In Vitro and In Silico Evaluation of the Biological Activity of Polyphenolic Components Separated with Solvents of Various Polarities from Helichrysum italicum.

Helichrysum italicum has piqued the interest of many researchers in recent years, mostly for its essential oil, but increasingly for its polyphenolic content as well. In the current study, we examine the polyphenolic composition of H. italicum grown in Bulgaria. The polyphenolic complex was fractionated with solvents of various polarities, including hexane, chloroform, ethyl acetate, and butanol, in order to assess the biological impact of the components. HPLC-PDA and UHPLC-MS/MS were used to examine all fractions. The green coffee fingerprint profile was employed as a "surrogate standard" in the polyphenolic components detection approach. From the UHPLC-MS/MS analysis, we identified 60 components of the polyphenolic complex such as quercetin 3-O-glucuronide, quercetin acetyl-glycoside, isorhamnetin acetyl-glycoside, isorhamnetin caffeoyl-glycoside, quercetin caffeoyl-malonyl-glycoside, isorhamnetin coumaroyl-glycoside, coumaroyl-caffeoylquinic acid, and diCQA-acetyl-derivative were first reported in the composition of H. italicum. The biological activity of the fractions was evaluated in vitro and in silico, which included the fight against oxidative stress (hydrogen peroxide scavenging activity (HPSA), hydroxyl radical scavenging activity (HRSA), metal-chelating activity (MChA)) and nitrosative (nitric oxide scavenging activity) (NOSA)), in vitro anti-inflammatory, and anti-arthritic activity. Results are presented as IC50 ± SD µg/mL. The analysis showed that the EtOAc fraction was characterized by highest HPSA (57.12 ± 1.14 µg/mL), HRSA (92.23 ± 1.10 µg/mL), MChA (5.60 ± 0.17 µg/mL), and NOSA (89.81 ± 2.09 µg/mL), while the hexane and chloroform fractions showed significantly higher in vitro anti-inflammatory activity (30.48 ± 2.33 µg/mL, 62.50 ± 1.69 µg/mL) compared to the standard ibuprofen. All three fractions showed potential anti-arthritic activity (102.93 ± 8.62 µg/mL, 108.92 ± 4.42 µg/mL, 84.19 ± 3.89 µg/mL).

An overview of the first 5 years of the ENIGMA obsessive-compulsive disorder working group: The power of worldwide collaboration.

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive-compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.

Synthesis, In Vitro Anti-Inflammatory Activity, and HRMS Analysis of New Amphetamine Derivatives.

Herein, we report the obtaining of new hybrid molecules of amphetamine with different profens (amfens). The obtained amfens are characterized by their melting points, UV, 1H-, 13C-NMR, and HRMS spectra. A complete and detailed mass spectral analysis of the newly obtained derivatives of amphetamine with ibuprofen, flurbiprofen, ketoprofen, naproxen, and carprofen was performed. In vitro inhibition of albumin denaturation of each new compound was assessed, and they showed significant activity. The IC50 values of the obtained amphetamine-profen derivatives ranged from 92.81 to 159.87 µg/mL. This indicates that the new hybrids inherit the anti-inflammatory properties of profens. Using in silico method, the toxicity was also calculated. The obtained results are given in LD50 values. Depending on the route of administration, the amfens are less toxic compared to the standard amphetamine.

Sleep Disordered Breathing and Risk for ADHD: Review of Supportive Evidence and Proposed Underlying Mechanisms.

BACKGROUND: Accumulating evidence suggests that sleep disordered breathing (SDB) is under-recognized in youth and adults with ADHD. SDB may contribute to exacerbating pre-existing ADHD symptoms and may play a role in the development of cognitive deficits that may mimic ADHD symptoms. METHOD: We conducted a focused review of publications on cross-prevalence, overlapping clinical and neurobiological characteristics and possible mechanisms linking SDB and ADHD. RESULTS: Exiting studies suggest that co-occurrence of SDB and ADHD is as high as 50%, with frequent overlap of clinical symptoms such as distractibility and inattention. Mechanisms linking these conditions may include hypoxia during sleep, sleep fragmentation and activation of inflammation, all of which may affect brain structure and physiology to produce disturbances in attention. CONCLUSIONS: The relationship between SDB and ADHD symptoms appear well-supported and suggests that more research is needed to better optimize procedures for SDB assessment in youth being evaluated and/or treated for ADHD.

Effects of Stimulant Treatment on Changes in Brain Activation During Reward Notifications in Drug Naïve Youth With ADHD.

BACKGROUND: Research examining the potential effects of stimulant exposure in childhood on subsequent development of substance use disorder (SUD) have focused on differences in the brain reward system as a function of risk. METHODS: 18 drug naïve children ages 7 to 12 years (11 High Risk [ADHD + ODD/CD]; 7 Low Risk [ADHD only]), underwent fMRI scans before and after treatment with mixed amphetamine salts, extended release (MAS-XR). We examined correlations between clinical ratings and fMRI activation at baseline and following treatment as a function of risk status. RESULTS: High Risk children had higher activation than Low Risk children at baseline during both the Reward and Surprising Non-Reward conditions. Treatment produced strong differential effects on brain activation pertinent to group and reward outcome. CONCLUSIONS: Findings support the hypothesized role of reward mechanisms in SUD risk, and suggest that stimulant treatment may have differential effects on reward processing in relation to SUD risk.

Neurobiological basis of reinforcement-based decision making in adults with ADHD treated with lisdexamfetamine dimesylate: Preliminary findings and implications for mechanisms influencing clinical improvement.

BACKGROUND: ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation. METHODS: Twenty adults (M = 11, 55%, F = 9, 45%), ages 19-52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3-5 weeks of treatment with LDX and 3-5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels. RESULTS: Improvement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri). CONCLUSIONS: These findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD. Trial RegistrationClinicaltrials.gov Identifier: NCT01924429.

Silica-supported polyphosphoric acid in the synthesis of 4-substituted tetrahydroisoquinoline derivatives.

We report herein an application of an α-amidoalkylation reaction, as an alternative efficient synthesis of 4-aryl- and 4-methyl-1,2,3,4-tetrahydroisoquinoline derivatives. The amides required for this purpose would result from reaction of aminoacetaldehyde dimethylacetal with different substituted benzenes in polyphosphoric acid, followed by acylation of the obtained amines with different acid chlorides or sulfochlorides. We compared the cyclisation step using conventional (milieu of acetic-trifluoracetic acid = 4:1) and solid supported reagents (SiO2/PPA), as recovered, regenerated and reused without loss of its activity catalyst. We found that in comparison to conventional methods, the yields of the reaction are greater and the reaction time is shorter.

Parental substance abuse and function of the motivation and behavioral inhibition systems in drug-naïve youth.

It is hypothesized that the development of substance abuse (SA) may be due to imbalance in functions of the motivation-reward and behavioral inhibition systems in the brain. This speaks to the search for biological risk factors for SA in drug-naïve children who also exhibit motivational and inhibitory control deficits; however, this type of research is currently lacking. The objective of this study was to establish a neurobiological basis for addiction vulnerability using functional magnetic resonance imaging (fMRI) in drug-naïve youth with attention deficit/hyperactivity disorder (ADHD). We hypothesized that children with ADHD alone would show higher activity in regions of the motivation-reward and behavioral inhibition systems than children with ADHD and a parental history of SA. Toward this goal we scanned 20 drug-naïve children with ADHD ages 8-13 while performing an event-related reward task. High (N=10) and low (N=10) risk subjects were identified, based on parental history of SA. The effects of anticipation, conflict, and reward were assessed with appropriate linear contrasts, and between-group differences were assessed using statistical parametric mapping. The two groups did not differ on behavioral measures of the task. The fMRI results show heightened activation in the brain motivational-reward system and reduced activation of the inhibitory control system in high-risk compared to low-risk children. These results suggest that a functional mismatch between these two systems may represent one possible biological underpinning of SA risk, which is conferred by a parental history of addiction.

Attachments: How the Jack of All Trades Becomes the Master of All.

Immigration is a rich experience, probably like no other, in relation to both unexpected and even unimagined returns but also colossal difficulties. One of the most fascinating aspects of immigration is learning the language of your newly adopted home. I don't mean simply learning the basics, but attempting to master the nuances of expression, the word play, and the subtleties of phrase choices.

Sensitization-based risk for substance abuse in vulnerable individuals with ADHD: Review and re-examination of evidence.

Evidence of sensitization following stimulants administration in humans is just emerging, which prevents reaching more definitive conclusions in favor or against a purported protective role of stimulant treatments for ADHD for the development of substance use disorders. Existing evidence from both animal and human research suggest that stimulants produce neurophysiological changes in the brain reward system, some of which could be persistent. This could be relevant in choosing optimal treatments for young patients with ADHD who have additional clinical risk factors for substance abuse (e.g. conduct disorder (CD) and/or familial addictions). Here we stipulate that, while the majority of youth with ADHD greatly benefit from treatments with stimulants, there might be a subpopulation of individuals whose neurobiological profiles may confer risk for heightened vulnerability to the effects of stimulants on the responsiveness of the brain reward system. We propose that focused human research is needed to elucidate the unknown effects of prolonged stimulant exposure on the neurophysiology of the brain reward system in young patients with ADHD.

A Meta-Analysis of fMRI Studies of Youth Cannabis Use: Alterations in Executive Control, Social Cognition/Emotion Processing, and Reward Processing in Cannabis Using Youth.

Background: Adolescent cannabis use (CU) is associated with adverse health outcomes and may be increasing in response to changing cannabis laws. Recent imaging studies have identified differences in brain activity between adult CU and controls that are more prominent in early onset users. Whether these differences are present in adolescent CU and relate to age/developmental stage, sex, or cannabis exposure is unknown. Methods: A systematic review and subsequent effect-size seed-based d mapping (SDM) meta-analysis were conducted to examine differences in blood-oxygen-level-dependent (BOLD) response during fMRI studies between CU and non-using typically developing (TD) youth. Supplemental analyses investigated differences in BOLD signal in CU and TD youth as a function of sex, psychiatric comorbidity, and the dose and severity of cannabis exposure. Results: From 1371 citations, 45 fMRI studies were identified for inclusion in the SDM meta-analysis. These studies compared BOLD response contrasts in 1216 CU and 1486 non-using TD participants. In primary meta-analyses stratified by cognitive paradigms, CU (compared to TD) youth showed greater activation in the rostral medial prefrontal cortex (rmPFC) and decreased activation in the dorsal mPFC (dmPFC) and dorsal anterior cingulate cortex (dACC) during executive control and social cognition/emotion processing, respectively. In meta-regression analyses and subgroup meta-analyses, sex, cannabis use disorder (CUD) severity, and psychiatric comorbidity were correlated with brain activation differences between CU and TD youth in mPFC and insular cortical regions. Activation differences in the caudate, thalamus, insula, dmPFC/dACC, and precentral and postcentral gyri varied as a function of the length of abstinence. Conclusions: Using an SDM meta-analytic approach, this report identified differences in neuronal response between CU and TD youth during executive control, emotion processing, and reward processing in cortical and subcortical brain regions that varied as a function of sex, CUD severity, psychiatric comorbidity, and length of abstinence. Whether aberrant brain function in CU youth is attributable to common predispositional factors, cannabis-induced neuroadaptive changes, or both warrants further investigation.

Social Isolation-Mediated Exacerbation of Negative Affect in Young Drinkers during the COVID-19 Pandemic.

Emerging research on psychological adjustment during the COVID-19 outbreak has suggested that young people may be particularly vulnerable to increases in negative affect during the pandemic. However, the association between alcohol use in youth and change in negative affect during this unprecedented time is not clear. Using an online survey, this study obtained scores on negative affect (before and during the COVID-19 pandemic), pandemic-related stress, change in drinking frequency, and traits including resilience, impulsivity and anhedonia, from a sample of drinkers and non-drinkers, up to the age of 21. Young drinkers experienced a greater increase in negative affect during the pandemic compared to non-drinkers, and this differential rise in negative affect was mediated by the pandemic-related stress of social isolation. Young drinkers also experienced a decrease in alcohol use during the pandemic, but this was not associated with a change in negative affect. Interestingly, young drinkers with greater resilience and lower anhedonia reported less increase in negative affect during the COVID-19 pandemic. Taken together, these results show that the greater increase in negative affect that young drinkers experienced during the COVID-19 pandemic, compared to their non-drinking counterparts, was mediated by pandemic-related social isolation. Moreover, greater resilience and lower anhedonia may have served as protective factors for mitigating the social isolation-induced worsening of negative affect in young drinkers during the pandemic. These findings may inform future studies investigating potential indicators of maladaptive affective responses to public health crises in vulnerable adolescent populations.

Associations of medication with subcortical morphology across the lifespan in OCD: Results from the international ENIGMA Consortium.

BACKGROUND: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs. METHODS: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6-65) was divided into six successive 6-10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients. RESULTS: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6-13 and adults aged 50-65 with OCD taking SRIs (Cohen's d = -0.24 to -0.74). Volumes of putamen, pallidum (d = 0.18-0.40), and ventricles (d = 0.31-0.66) were greater in patients aged 20-29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = -0.27 to -1.31). CONCLUSIONS: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20-29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response.

Posterior cortical atrophy: an exemplar for renovating diagnostic formulation in neuropsychiatry.

Neurodegenerative dementias represent among the most clinically and pathologically complex syndromes in neuropsychiatry. Phenomenologically protean, and often initially presenting with subtle subsyndromal characteristics, neurodegenerative behavioral syndromes can manifest with an assortment of cognitive, mood, personality, and comportmental changes, often alloyed with elementary neurologic (e.g., motor) signs. A range of pathogenic mechanisms (e.g., amyloid plaques, Pick bodies, etc) typically underlie corresponding clinical syndromes. However, overlap in both clinical expression and histopathologic comorbidities frequently exist among cortical and subcortical neurodegenerative disorders. Moreover, secondary central nervous system pathologies (e.g., cerebrovascular disease) commonly coexist with neurodegenerative processes, further complicating clinical phenomenology-based nosologic categorization. Evolving insight into the etiologic mechanisms of neurodegenerative dementias, and correspondingly improving potential for intervention, require more precise differentiation among dementia subtypes and comprehensive identification of contemporaneous neurodegenerative processes. Increasing appreciation of this diagnostic complexity is prompting the need for renovation of existing diagnostic schemas. We address these issues by reviewing the atypical dementia type known as posterior cortical atrophy. We then use posterior cortical atrophy as an exemplar for renovating neuropsychiatric diagnostic classification to better account for the layered complexity of clinical and pathologic domains needing to be characterized to accurately and completely diagnose neuropsychiatric disturbances.

Synthesis and contractile activity of substituted 1,2,3,4-tetrahydroisoquinolines.

A series of different 1-monosubstituted and 1,1-disubstituted 1,2,3,4-tetrahydro-isoquinolines was synthesized in high yields from different ketoamides. We have developed a convenient method for the synthesis of disubstituted derivatives by interaction of ketoamides with organomagnesium compounds, followed by cyclization in the presence of catalytic amounts of p-toluenesulfonic acid (PTSA). A number of substituents at the C-1 in the isoquinoline skeleton were introduced varying either carboxylic acid or organomagnesium compound. Some of the obtained 1,1-dialkyl-1,2,3,4-tetrahydro-isoquinolines possess contractile activity against guinea pig's gastric smooth muscle preparations.

Why Psychotropic Drugs Don't Cure Mental Illness-But Should They?

While pharmacological treatments for psychiatric disorders have offered great promise and have provided clinically meaningful symptom relief these treatments have had less effect on altering the course of these disorders. Research has provided many new insights about the effects of different psychotropic agents on the functions of various brain systems as investigators have embraced the "translational research model." However, this theoretical approach of deconstructing complex behaviors into smaller measurable behavioral units and targeting brain systems that are hypothesized to underlie these discrete behaviors has offered little of practical clinical relevance to significantly improve the treatment of psychiatric disorders in this century. Radical new treatments have not emerged, and available treatments continue to provide symptom relief without resolution of the underlying conditions. Recent publications on the subject have attempted to identify the barriers to progress and have pointed out some of the limitations of the translational approach. It is our position that, given the present limitations of our therapeutic arsenal, both researchers and clinicians would be well-advised to pay closer attention to human specific factors such as the role of language, the creation of personal narratives, and how factors such as these interface with underlying biological diatheses in mental illness. These interactions between pathophysiology and intrapersonal processes may be critical to both the in vivo expression of the underlying biological mechanisms of psychiatric disease states, and to the development of enhancements in therapeutic efficacy. Lastly, we discuss the implications of more coherently integrating neuroscientific research and clinical practice for more effectively addressing the challenges of understanding and treating mental illness.

Substance Use Initiation, Particularly Alcohol, in Drug-Naive Adolescents: Possible Predictors and Consequences From a Large Cohort Naturalistic Study.

OBJECTIVE: It is unclear whether deviations in brain and behavioral development, which may underpin elevated substance use during adolescence, are predispositions for or consequences of substance use initiation. Here, we examine behavioral and neuroimaging indices at early and mid-adolescence in drug-naive youths to identify possible predisposing factors for substance use initiation and its possible consequences. METHOD: Among 304 drug-naive adolescents at baseline (age 14 years) from the IMAGEN dataset, 83 stayed drug-naive, 133 used alcohol on 1 to 9 occasions, 42 on 10 to 19 occasions, 27 on 20 to 39 occasions, and 19 on >40 occasions at follow-up (age 16 years). Baseline measures included brain activation during the Monetary Incentive Delay task. Data at both baseline and follow-up included measures of trait impulsivity and delay discounting. RESULTS: From baseline to follow-up, impulsivity decreased in the 0 and 1- to 9-occasions groups (p < .004), did not change in the 10- to 19-occasions and 20- to 29-occasions groups (p > .294), and uncharacteristically increased in the >40-occasions group (p = .046). Furthermore, blunted medial orbitofrontal cortex activation during reward outcome at baseline significantly predicted higher alcohol use frequency at follow-up, above and beyond behavioral and clinical variables (p = .008). CONCLUSION: These results suggest that the transition from no use to frequent drinking in early to mid-adolescence may disrupt normative developmental changes in behavioral control. In addition, blunted activity of the medial orbitofrontal cortex during reward outcome may underscore a predisposition toward the development of more severe alcohol use in adolescents. This distinction is clinically important, as it informs early intervention efforts in preventing the onset of substance use disorder in adolescents.