Faculty Bibliography

BACKGROUND:Endocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5-21 years) with ASD. METHODS:We tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and Δ9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and Δ9-tetrahydrocannabinol at the same ratio. Participants (N = 150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability. Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI). RESULTS:Changes in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n = 45) versus 21% on placebo (n = 47; p = 0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n = 34) versus 3.6 points after placebo (n = 36); p = 0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n = 95); 23% and 21% on pure-cannabinoids (n = 93), and 8% and 15% on placebo (n = 94). Limitations Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results. CONCLUSIONS:This interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended. Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226.

Previous studies have shown that the gene encoding the adhesion G protein-coupled receptor L3 (ADGRL3; formerly latrophilin 3, LPHN3) is associated with Attention-Deficit/Hyperactivity Disorder (ADHD). Conversely, no studies have investigated the anatomical or functional brain substrates of ADGRL3 risk variants. We examined here whether individuals with different ADGRL3 haplotypes, including both patients with ADHD and healthy controls, showed differences in brain anatomy and function. We recruited and genotyped adult patients with combined type ADHD and healthy controls to achieve a sample balanced for age, sex, premorbid IQ, and three ADGRL3 haplotype groups (risk, protective, and others). The final sample (n = 128) underwent structural and functional brain imaging (voxel-based morphometry and n-back working memory fMRI). We analyzed the brain structural and functional effects of ADHD, haplotypes, and their interaction, covarying for age, sex, and medication. Individuals (patients or controls) with the protective haplotype showed strong, widespread hypo-activation in the frontal cortex extending to inferior temporal and fusiform gyri. Individuals (patients or controls) with the risk haplotype also showed hypo-activation, more focused in the right temporal cortex. Patients showed parietal hyper-activation. Disorder-haplotype interactions, as well as structural findings, were not statistically significant. To sum up, both protective and risk ADGRL3 haplotypes are associated with substantial brain hypo-activation during working memory tasks, stressing this gene's relevance in cognitive brain function. Conversely, we did not find brain effects of the interactions between adult ADHD and ADGRL3 haplotypes.

Early life is a sensitive period in which enhanced neural plasticity allows the developing brain to adapt to its environment. This plasticity can also be a risk factor in which maladaptive development can lead to long-lasting behavioral deficits. Here, we test how early-life exposure to the selective-serotonin-reuptake-inhibitor, fluoxetine, affects motivation and dopaminergic signaling in adulthood. We show for the first time that mice exposed to fluoxetine in the early postnatal period exhibit a reduction in effort-related motivation. These mice also show blunted responses to amphetamine and reduced dopaminergic activation in a sucrose reward task.Interestingly, we find that the reduction in motivation can be rescued in the adult by administering bupropion, a dopamine-norepinephrine reuptake inhibitor used as an antidepressant and a smoke cessation aid, but not by fluoxetine. Taken together, our studies highlight the effects of early postnatal exposure of fluoxetine on motivation and demonstrate the involvement of the dopaminergic system in this process.Significance StatementThe developmental period is characterized by enhanced plasticity. During this period, environmental factors have the potential to lead to enduring behavioral changes. Here we show that exposure to the SSRI fluoxetine during a restricted period in early-life leads to a reduction in adult motivation. We further show that this reduction is associated with decreased dopaminergic responsivity. Finally, we show that motivational deficits induced by early-life fluoxetine exposure can be rescued by adult administration of bupropion but not by fluoxetine.

Rhythms of the brain are generated by neural oscillations across multiple frequencies. These oscillations can be decomposed into distinct frequency intervals associated with specific physiological processes. In practice, the number and ranges of decodable frequency intervals are determined by sampling parameters, often ignored by researchers. To improve the situation, we report on an open toolbox with a graphical user interface for decoding rhythms of the brain system (DREAM). We provide worked examples of DREAM to investigate frequency-specific performance of both neural (spontaneous brain activity) and neurobehavioral (in-scanner head motion) oscillations. DREAM decoded the head motion oscillations and uncovered that younger children moved their heads more than older children across all five frequency intervals whereas boys moved more than girls in the age of 7 to 9 years. It is interesting that the higher frequency bands contain more head movements, and showed stronger age-motion associations but weaker sex-motion interactions. Using data from the Human Connectome Project, DREAM mapped the amplitude of these neural oscillations into multiple frequency bands and evaluated their test-retest reliability. The resting-state brain ranks its spontaneous oscillation's amplitudes spatially from high in ventral-temporal areas to low in ventral-occipital areas when the frequency band increased from low to high, while those in part of parietal and ventral frontal regions are reversed. The higher frequency bands exhibited more reliable amplitude measurements, implying more inter-individual variability of the amplitudes for the higher frequency bands. In summary, DREAM adds a reliable and valid tool to mapping human brain function from a multiple-frequency window into brain waves.

PURPOSE OF REVIEW/OBJECTIVE:Neuroimaging research on attention-deficit/hyperactivity disorder (ADHD) continues growing in extent and complexity, although it has yet to become clinically meaningful. We review recent MRI research on ADHD, to identify robust findings, current trends and challenges. RECENT FINDINGS/RESULTS:We identified 40 publications between January 2019 and September 2020 reporting or reviewing MRI research on ADHD. Four meta-analyses have presented conflicting results regarding across-study convergence of functional and resting-state functional (fMRI and R-fMRI) studies on ADHD. On the other hand, the Enhancing NeuroImaging Genetics Through Meta-Analysis international consortium has identified statistically robust albeit small differences in structural brain cortical and subcortical indices in children with ADHD versus typically developing controls. Other international consortia are harnessing open-science efforts and multimodal data (imaging, genetics, phenotypic) to shed light on the complex interplay of genetics, environment, and development in the pathophysiology of ADHD. We note growing research in 'prediction' science, which applies machine-learning analysis to identify biomarkers of disease based on big data. SUMMARY/CONCLUSIONS:Neuroimaging in ADHD is still far from informing clinical practice. Current large-scale, multimodal, and open-science initiatives represent promising paths toward untangling the neurobiology of ADHD.

OBJECTIVE:Resting-state fMRI (R-fMRI) studies of the neural correlates of medication treatment in attention-deficit/hyperactivity disorder (ADHD) have not been systematically reviewed. Systematically identify, assess and summarize within-patient R-fMRI studies of pharmacological-induced changes in patients with ADHD. We critically appraised strengths and limitations, and provide recommendations for future research. METHOD/METHODS:Systematic review of published original reports in English meeting criteria in pediatric and adult patients with ADHD up to July 1, 2020. A thorough search preceded selection of studies matching prespecified criteria. Strengths and limitations of selected studies, regarding design and reporting, were identified based on current best practices. RESULTS:We identified and reviewed 9 studies (5 pediatric and 4 adult studies). Sample sizes were small-medium (16-38 patients), and included few female participants. Medications were methylphenidate, amphetamines, and atomoxetine. Wide heterogeneity was observed in designs, analyses and results, which could not be combined quantitatively. Qualitatively, the multiplicity of brain regions and networks identified, some of which correlated with clinical improvements, do not support a coherent mechanistic hypothesis of medication effects. Overall, reports did not meet current standards to ensure reproducibility. CONCLUSION/CONCLUSIONS:In this emerging field, the few studies using R-fMRI to analyze the neural correlates of medications in patients with ADHD suggest a potential modulatory effect of stimulants and atomoxetine on several intrinsic brain activity metrics. However, methodological heterogeneity and reporting issues need to be addressed in future research to validate findings which may contribute to clinical care. Such a goal is not yet at hand.

OBJECTIVE:We conducted a meta-analysis of resting state functional magnetic resonance imaging (R-fMRI) studies in children/adolescents and adults with ADHD to assess spatial convergence of findings from available studies. METHOD/METHODS:, 2019, with no language/type-of-document restrictions. Study authors were systematically contacted for additional unpublished information/data. R-fMRI studies using seed-based connectivity (SBC) or any other method (non-SBC) reporting whole-brain results of group comparisons between individuals with ADHD and typically developing controls were eligible. Voxel-wise meta-analysis via activation likelihood estimation with cluster-level Family Wise Error (FWE) (voxel-level: p < 0.001; cluster-level: p < 0.05) was used. The full dataset used for analyses will be freely available online in an open source platform (http://anima.fz-juelich.de/). RESULTS:30 studies (18 SBC and 12 non-SBC), including a total of 1978 participants (1094 ADHD; 884 controls) were retained. The meta-analysis focused on SBC studies found no significant spatial convergence of ADHD-related hyper- or hypo-connectivity across studies. This non-significant finding remained after integrating 12 non-SBC studies into the main-analysis and in sensitivity analyses limited to studies including only children or only non-medication naïve patients. CONCLUSION/CONCLUSIONS:The lack of significant spatial convergence may be accounted for by heterogeneity in study participants, experimental procedures and analytic flexibility, as well as in ADHD pathophysiology. Alongside other neuroimaging meta-analyses in other psychiatric conditions, our results should inform the conduct and publication of future neuroimaging studies of psychiatric disorders.

Serotonin and dopamine are associated with multiple psychiatric disorders. How they interact during development to affect subsequent behavior remains unknown. Knockout of the serotonin transporter or postnatal blockade with selective serotonin reuptake inhibitors (SSRIs) leads to novelty-induced exploration deficits in adulthood, potentially involving the dopamine system. Here, we show in the mouse that raphe nucleus serotonin neurons activate ventral tegmental area dopamine neurons via glutamate co-transmission and that this co-transmission is reduced in animals exposed postnatally to SSRIs. Blocking serotonin neuron glutamate co-transmission mimics this SSRI-induced hypolocomotion, while optogenetic activation of dopamine neurons reverses this hypolocomotor phenotype. Our data demonstrate that serotonin neurons modulate dopamine neuron activity via glutamate co-transmission and that this pathway is developmentally malleable, with high serotonin levels during early life reducing co-transmission, revealing the basis for the reduced novelty-induced exploration in adulthood due to postnatal SSRI exposure.

Reports an error in "Meditation effect in changing functional integrations across large-scale brain networks: Preliminary evidence from a meta-analysis of seed-based functional connectivity" by Yang-Qian Shen, Hui-Xia Zhou, Xiao Chen, Francisco Xavier Castellanos and Chao-Gan Yan (Journal of Pacific Rim Psychology, 2020[Mar][3], Vol 14[e10]). In the original article, there was an error in the abstract. The correction is given in the erratum. (The following abstract of the original article appeared in record 2020-55329-001). Meditation is a type of mental training commonly applied in clinical settings and also practiced for general well-being. Brain functional connectivity (FC) patterns associated with meditation have revealed its brain mechanisms. However, the variety of FC methods applied has made it difficult to identify brain communication patterns associated with meditation. Here we carried out a coordinate-based meta-analysis to get preliminary evidence of meditation effects on changing brain network interactions. Fourteen seed-based, voxel-wise FC studies reported in 13 publications were reviewed; 10 studies with seeds in the default mode network (DMN) were meta-analyzed. Seed coordinates and the effect sizes in statistically significant regions were extracted, based on 170 subjects in meditation groups and 163 subjects in control groups. Seed-based d-mapping was used to analyze meditation versus control FC differences with DMN seeds. Meditation was associated with increased connectivity within DMN and between DMN and somatomotor network and with decreased connectivity between DMN and frontoparietal network (FPN) as well as ventral attention network (V

In the above published article there was an error in the abstract, the sentence should read as follows: "Meditation was associated with decreased connectivity within DMN and between DMN and somatomotor network and with increased connectivity between DMN and frontoparietal network (FPN) as well as ventral attention network (VAN)." The authors apologise for this error.