To assess the cost-effectiveness of LEGO-based therapy compared with usual support.Cost-utility analysis alongside randomised control trial.Mainstream primary and secondary schools in the UK.248 children and young people (CYP) with autism spectrum disorder (ASD) aged 7–15 years.LEGO-based therapy is a group social skills intervention designed specifically for CYP with ASD. Through play, CYP learn to use the skills such as joint attention, sharing, communication and group problem-solving. CYP randomised to the intervention arm received 12 weekly sessions of LEGO-based therapy and usual support, while CYP allocated to control arm received usual support only.Average costs based on National Health Service (NHS) and personal social services perspective and quality-adjusted life years (QALYs) measured by EQ-5D-Y over time horizon of 1 year were collected during the trial. Incremental cost-effectiveness ratio (ICER) was calculated, and non-parametric bootstrapping was conducted. The uncertainty around the ICER estimates was presented using cost-effectiveness acceptability curve (CEAC). A set of sensitivity analyses were conducted to assess the robustness of the primary findings.After adjustment and bootstrapping, on average, CYP in LEGO-based therapy group incurred less costs ) and gained marginal improvement in QALYs (QALYs gained 0.009 (95% CI −0.008 to 0.028)). The CEAC shows that the probability of LEGO-based therapy being cost-effective was 94% at the willingness-to-pay threshold of £20 000 per QALY gained. Results of sensitivity analyses were consistent with the primary outcomes.Compared with usual support, LEGO-based therapy produced marginal reduction in costs and improvement in QALYs. Results from both primary and sensitivity analyses suggested that LEGO-based therapy was likely to be cost-effective.ISRCTN64852382. The first economic evaluation study of LEGO-based therapy.The data are from a large sample size trial in autism spectrum disorder, and the method followed published best-practice guidance.The study accounts for the costs measured from a range of perspectives and the quality-adjusted life years measured by different instruments.Resource use data were collected retrospectively and may be affected by inaccurate recall.Further model-based evaluation is required to assess long-term cost-effectiveness of LEGO-based therapy.Autism spectrum disorders (ASDs) are a group of lifelong developmental conditions defined by impairments in social interactions, communication skills, and presence of restricted and stereotypical behaviours.5Due to the substantial financial burden borne by the healthcare system, education system and families of CYP with ASD, the Lancet Psychiatry Commission emphasises the need to not only focus on the effectiveness of mental health services but also on their economic benefits.LEGO-based therapy12This economic evaluation was embedded in the I-SOCIALISE trial, a multisite, pragmatic, two-arm, school-level cluster randomised controlled trial for CYP with ASD. Details of I-SOCIALISE trial have been published elsewhere.10.1136/bmjopen-2021-056347.supp1Supplementary dataLEGO-based therapy is a group social skills intervention designed specifically for CYP with social communication difficulties such as ASD. CYP build LEGO models together in small groups with light facilitation by a trained adult.The health outcomes for the current study were quality adjusted life years (QALYs) measured by the EQ-5D-Y (3 L proxy version)17Individual-level responses to EQ-5D-Y and CHU-9D were used to estimate utilities based on UK population valuation sets.Two cost perspectives were considered in this study: (1) a National Health Service (NHS) and personal social service (PSS) perspective, which included costs related to healthcare  and services provided by allied health professionals ) and social services ) and (2) a societal perspective, which additionally included costs of education-related services, parental out-of-pocket expenses (such as childcare and private courses) and parental productivity costs (time off work due to child’s autism) without taking social charges  into consideration.Cost of the intervention included the cost of training and the cost of delivering LEGO-based therapy. Training costs were measured by the time spent by the trainer and included travel costs and the cost of materials used in the training. Costs associated with delivering the LEGO-based therapy were measured based on the time spent by facilitators to plan and conduct sessions and included relevant overhead costs. All relevant data were collected using the tailored questionnaires completed by the study team and therapists.Service use was collected using the tailored questionnaires (completed by the parent/guardian and separately by an associated teacher of each CYP in the study who knew the CYP well), which was originally developed based on Barrett’s studyService use was multiplied by unit costs to arrive at total cost in each arm. Unit costs of health and social service use were obtained from published sources  based on the costs from NHS/PSS perspective and the QALYs measured by EQ-5D-Y. To account for uncertainty around ICER and imbalanced utility and costs at baseline, seemingly unrelated regression equations (SURE) that adjusted SEs for clustering and controlled for baseline utility,36To assess the robustness of our findings, a set of sensitivity analyses were conducted. First, a cost-utility analysis (CUA)All analyses were performed on an intention-to-treat basis using Stata V.16 .This study was funded by the National Institute for Health Research Public Health Research (PHR) programme (PHR15/49/32).No patient involved.A total of 284 CYP with ASD were recruited in the trial. After removing 34 ineligible CYP and 2 CYP who were not eligible for multiple imputation due to missing baseline utilities, 248 CYP with ASD were available for primary analysis . This sample constitutes the base-case group. On the other hand, only 139 (56.0%) CYP had both EQ-5D and resource use (from the NHS/PSS perspective) data at all three data collection time points. This sample constitutes the complete-case group. Overall, 27.8% of cost or QALY measurements was missing and were imputed for primary analysis.Descriptive statistics of CYP’s baseline characteristics for both complete-case and base-case are presented in On average, the estimated intervention cost per session per CYP was £6.5 (£2.45 for training and £4.05 for intervention delivery). The main cost driver of training costs was trainer fees, while the main cost drivers of intervention delivery costs were the costs for preparation and delivery the intervention and the costs for LEGO materials .3, respectively.In terms of service costs, the average total service costs over 52 weeks to the NHS providers (after imputation) were £524 (95% CI £428 to 808) for the LEGO-based therapy arm compared with £678 (95% CI £427 to 928) for the usual care arm. The cost difference is larger when the societal perspective was considered, as CYP in the LEGO-based therapy arm incurred less costs across all the perspectives. The largest cost differences occurred in education-related services followed by healthcare and social services. It is worth noting that some of cost differences were likely to have been driven by high-cost cases. For instance, in complete-case, higher average cost of CAMHS-related services in the usual care arm was driven by two high-cost cases, and higher average cost of school-based health-related services in the LEGO-based therapy arm was driven by one high-cost case. These high-cost cases were kept in the analysis, as they were plausible. However, due to the high-cost cases, the cost differences need to be interpreted with caution. A more detailed overview on the service costs over 52 weeks and the resource use are presented in After accounting for uncertainty and unbalanced baseline utility and characteristics, on average, CYP with ASD receiving LEGO-based therapy incurred £251 (95% CI −£268 to £752) less costs from the NHS/PSS perspective and gained 0.009 (95% CI −0.008 to 0.028) extra QALYs measured by EQ-5D-Y than those having usual support. The bootstrapped ICER results are presented in Results of sensitivity analyses are detailed in To the best of our knowledge, this is the first study evaluating the cost-effectiveness of LEGO-based therapy for CYP with ASD. Compared with usual care, the LEGO-based therapy marginally decreased the service use costs and increased the QALYs from the NHS/PSS perspective. This is evident in both primary and sensitivity analyses, which considered costs derived from various perspectives and QALYs measured by different instruments.The average QALYs measured by both the EQ-5D-Y (proxy version) and the CHU9D for those in the intervention arm were higher compared with the control arm. Although the differences are small, it is observed that the bootstrap estimates plotted on the CE planes for both primary and sensitivity analyses were mainly in the bottom right quadrant. This indicates that after taking uncertainty into consideration and adjusting for the imbalanced baseline utility, the differences in QALYs remain positive. It is also worth noting that such differences were unaffected regardless who filled the questionnaire. Both the parent-completed (EQ-5D) and CYP-completed (CHU9D) questionnaires showed the same positive differences.The study also shows a reduction in average total NHS/PSS costs , particularly through attendance at CAMHS. As mentioned in section Results: Costs, the lowered CAMHS costs found in the LEGO-based therapy arm was more related to a small number of CYP receiving high levels of high-tariff CAMHS support in the control arm  than the intervention arm rather than a general drop across the whole group. Such a finding indicates that CYP who had co-occurring emotional and behavioural problems seemed to be receiving approximately similar support from CAMHS across both trial arms, and LEGO-based therapy did not overshadow the needs of CAMHS support. It was also found that, at the baseline, CYP in LEGO-based therapy arm had higher frequency of CAMHS support compared with control arm. Given the high threshold for receiving CAMHS support, it is likely that the CYP in LEGO-based therapy arm had more severe needs at baseline. However, after the intervention, CYP in LEGO-based therapy arm had similar support from CAMHS as those in control arm (see above) suggesting some amelioration effect or a reduced need for such high-level support. Based on the literature of general research on CAMHS referrals, such reduction could be because the LEGO-based therapy improves comorbid problems of CYP and consequently leads to a reduced likelihood of referral to CAMHS40The reduction in school intervention costs was also observed in this study. One possible explanation is that CYP in a LEGO-based therapy intervention might be less likely to be put forward for other interventions  for costing. Hence, the summarised cost results for different perspectives need to be treated with caution. However, both arms were treated the same way and the overall costs  should remain robust. Second, a small number of high but plausible values were observed in cost estimations. Although the values did not affect the cost-effectiveness conclusions (data not shown), such values can potentially bias the cost reduction results of LEGO-based therapy. Hence, care should be taken when interpreting the cost estimates. It is none-the-less important to include this real-world data and be aware of this for future studies. Third, the calculated intervention costs might have been underestimated. This is because several items associated with training and intervention sessions were not costed, due to data constraints. These included opportunity costs of trainee time, opportunity costs of school venue for delivering interventions, recruitment cost if intervention rolled out and supervision costs. However, this is unlikely to have affected the results of the dominance of the intervention over usual support, as these costs are considered to be small. This is especially the case after the allocating to every CYP for every session. Further research on the exploration and measurement of the costs with considerations is desirable. Finally, our study used SURE to model the uncertainty around the incremental costs and QALYs and account for their correlation. Alternatively, costs and QALYs can be modelled separately using generalised linear models without considering the correlation. It is beyond the scope of our study to compare the two methods. However, further research on the method comparison and their impacts on the results are desirable in order to draw robust conclusions.Our study measured the short-term cost-effectiveness of LEGO-based therapy on CYP with ASD over 1-year follow-up. For the long-term cost-effectiveness of LEGO-based therapy, a modelled-based economic evaluation study would be desirable to allow life time cost-effectiveness and children’s lost productivity during adulthood to be measured. Further research is also needed on exploring potential impacts on other outcomes such as academic achievement or quality of life of other family members. In future research, it would be also helpful to explore whether a longer duration of intervention  or more frequent sessions  would further improve outcomes while remaining cost-effective.This study demonstrates the potential cost-effectiveness of delivering LEGO-based therapy to CYP with ASD in mainstream school settings. The findings will be of interest to NHS health and social care providers, local authorities, families and community professionals including school staff members.


A Cochrane review of school-based asthma interventions  found improved health outcomes. Self-management skills, however, vary according to age. We assessed effectiveness of primary school-based self-management interventions and identified components associated with successful programmes in children aged 6–12 years. We updated the Cochrane search (March 2020) and included the Global Health database. Two reviewers screened, assessed risk-of-bias and extracted data. We included 23 studies ; four at low risk-of-bias. Twelve studies reported at least one positive result for an outcome of interest. All 12 positive studies reported parental involvement in the intervention, compared to two-thirds of ineffective studies. In 10 of the 12 positive studies, parental involvement was substantial  rather than being provided with written information. School-based self-management intervention can improve health outcomes and substantial parental involvement in school-based programmes seemed important for positive outcomes among primary school children. Asthma guidelines recommend supported self-management to improve asthma control and reduce the use of urgent healthcare services4. Supported self-management, which includes discussion about self-management and provision of a personalised asthma action plan supported by regular asthma review, can be delivered effectively in diverse cultural and demographic groups6.Asthma, the commonest long-term condition among children, causes significant morbidity and mortality globally11. However, most systematic reviews analysed combined data from primary and secondary schools (5–18 years)10. One scoping review conducted in 2014 focused on primary school children, but the aim was to identify research gaps rather than assess outcomes11. The Cochrane review  used meta-analyses to assess intervention effectiveness and qualitative comparative analysis to examine the components of successful implementations7. The authors identified a number of components as being important: theoretical underpinning, parental involvement, child satisfaction and conducting the intervention during lesson time. However, the Cochrane review included interventions directed at children and adolescents (5–18 years), and did not distinguish the components associated with effective interventions in primary school children, which may differ from adolescents7. Educational intervention needs to be age-appropriate as primary school children will have less autonomy and capability to self-manage asthma compared to adolescents12. Thus, we aimed to review the effectiveness of school-based self-management interventions for primary school children with asthma and to examine the components associated with successful programmes.School-based asthma self-management interventions have been reported to improve asthma control and reduce school absenteeism and asthma exacerbations28, five studies from the updated database search33 and two studies from the pre-publication update35. The total number of participants was 10,682. Some studies did not report numbers in each group so we cannot provide number by allocation24. We contacted all authors for information not reported in the papers, and nine (39%) responded34.Figure 32, three individual RCTs34), three were non-randomised studies35 and three were uncontrolled pre-and-post studies33. Fifteen studies were conducted in the United States35, four in Canada20, one each in Spain32 and United Kingdom26, and two in low- and middle- income countries (China and Thailand)33. All but one17 of the studies in the United States were conducted in minority populations35, two Canadian studies were conducted in majority population20; none of the others33 reported ethnicity of population studied.The interventions were conducted from 1992 to 2019. Seventeen studies were randomised controlled trials (RCTs)  or tailored RAP20, and the other studies developed novel interventions35. The programmes ranged from one to eight sessions, and all were delivered by healthcare personnel,  except for two that were delivered by trained school teachers32. Fifteen studies delivered the intervention in group sessions34, four used individual face-to-face sessions35, one used individual computer-assisted programme18 and another used individual telemedicine sessions31. Two studies were unclear33.The programmes were used to deliver self-management intervention varied. Eight studies used standard programmes (Open Airway for School (OAS) or tailored OAS32, eleven had high risk of bias35 and eight were unclear31. Only seven (30%) studies were categorised at low risk in random sequence generation34. All uncontrolled studies were categorised as high-risk in four domains 33.The overall RoB is given in summary Supplementary Table 35 and eleven studies (two at low risk-of-bias) as having no effect32. No study was categorised as harmful or mixed effect. The Harvest plot 35, though this varied in intensity . See Supplementary Table 35, while others had minimal parental involvement e.g. passive information in a letter34. Ten studies used theory to guide the development of the interventions; six used social cognitive theory22, two used Orem self-care theory34, one used life stress model29, and another was guided by Bruhn’s theoretical model25. Nine studies considered access to healthcare of their study population33.The CIFR domains addressed in the studies are summarised in column 2 in Supplementary Table Tables 35 compared to seven studies with no effects (7/11)31. The Harvest plot  showed no effect in any of the outcomes of interest32. Of the five interventions with minimal parental involvement34, the three positive studies were at high RoB and of short duration (≤ 6 months), and either small in sample (study population less than 100 children)34 or pre/post design16. Studies with substantial parental involvement35 were the only studies to report reduction in absenteeism, though impact on clinical outcomes varied. Cicutto et al.13 , an example of a study that included parents in care coordination and a showcase at school, had positive effects in school absenteeism and urgent healthcare service use at 12 months. No difference was found in other CFIR subdomains between studies with positive and no effects.All studies with positive effects 12/12) reported parental involvement in their intervention/12 reporWe identified 23 studies (four at low RoB) that evaluated the effectiveness of school-based asthma self-management intervention among primary school children. Twelve of the studies were categorised as being overall positive, though individual outcomes varied; no study reported overall negative impact. The number of CFIR sub-domains addressed varied between studies, but the only component that seemed to be associated with positive outcomes was substantial parental involvement. This was particularly apparent in studies at low RoB.8. Parental involvement was also found to be important in other school-based interventions for obesity prevention studies37, self-management of mental health/disorders38, and academic enhancement39.We found substantial parental involvement to be a crucial component of a school-based asthma self-management intervention among primary school children. Reviews that included interventions targeted at teenagers, in whom parental influence might be expected to be less important, have reached similar conclusions7. The differences in the findings were most probably due to a difference in the age group of the children as the Cochrane review included studies among older school children. Our review defined fun, interactive delivery of intervention, as a strategy promoting child satisfaction and engagement, whereas the Cochrane review examined measurement of child satisfaction, an evaluation used mainly in studies targeting adolescents7. Primary school children had good participation rates when the sessions were conducted during school hours including during recess, in contrast to adolescents who were less willing to devote their free time including during recess16. Social cognitive and Orem self-care theories were the most used theories, adapted from adults which focuses on self-efficacy and skills of individuals42. These theories may be suitable for interventions targeting parents and adolescents, but may not be age-appropriate for primary school children with limited decision-making abilities and independent self-management skills43.However, we did not find other components of interventions  to be essential for successful intervention, as was found in the Cochrane review45. Six-year-old children can express opinions, typically reflecting their parents’ actions and views44. Over primary school years, they learn from their own experiences and gain the confidence to make independently decisions45. Although involving parents to support and empower their children’s self-management behaviour is a key concept in the clinical management of children3, direct parental involvement was not always included in school-based intervention among primary school children32. A key challenge for involving parents is the difficulty of engaging them to attend session(s) delivered in school46. With the ease of modern telecommunication, alternative methods of engagement such as the use of telephone calls or video sessions could be explored as a convenient alternative to enable substantial parental involvement in the intervention47.Primary school years are a critical time for children as they spend increasing time away from their parents and begin to learn asthma self-management for themselves49. Studies in this review included up to eight educational sessions for children compared to only one to two sessions for parents30. A recent school-based health intervention has recommended the socio-ecological theory where children are the primary focus of an intervention that also involves the children’s social network, e.g. parents, teachers, friends and the school plan/policy50. Schools could be an ideal setting for this approach, smoothing children’s transition to independent self-management by being located in the child’s environment and including parents as part of the children’s social network53. Schools also provide a platform for interactive fun groups activities and peer support for children with similar conditions, which could reduce stigma and support self-management practices32.Although parental involvement is important, an aim of a school-based intervention is to shift the focus of self-management education from parents to children5. ‘Access to healthcare’, however, was a sub-domain least likely to be addressed in the studies included in this review. Although most US-based studies were conducted among minority deprived populations, in whom poor health outcomes may be due to the large disparities in healthcare provision54, only five studies reported the access of the children to effective controller medication30. Even in countries with universal health coverage, such as Canada and United Kingdom, equitable access to high quality healthcare for children cannot be assumed55. In low- and middle-income countries, socio-cultural beliefs, physical inaccessibility and lack of education and information are extremely common barriers to healthcare despite universal health coverage57. Similar barriers are widely described in the US34. Encouragingly, bridging school-based education with the children’s healthcare providers has been a core component of recent school-based interventions58.The effectiveness of self-management also depends on access and adherence to evidence-based treatments such as controller asthma medications, which is conventionally delivered in healthcare settingsA strength of this review is that we used comprehensive search terms similar to the Cochrane review and searched seven relevant databases. Two reviewers conducted full text screening and data collection was duplicated. A pre-publication update was performed to ensure the findings was up to date this review.This review has some limitations. Despite a rigorous search strategy, it is possible that we may miss some studies. The screening of title and abstract was conducted by one reviewer, but good agreement resulted after training. Only two studies were conducted in low- and middle-income countries and many studies 15/23) were conducted in the US, reducing generalisability of the review. The included studies were variable in methodologies, instrumentation and data analysis. However, three low RoB studies coincided with the findings and some variability was illustrated in the Harvest plot with the other details described in Supplementary Table 5/23 wereA multi-level intervention focusing on the children and involving their social network could provide a useful self-management interventions framework for primary school children and their parents. Specifically, there is a gap in our current understanding of school-based self-management education in younger children in low- and middle-income countries. Future research needs to focus on implementation strategies and effectiveness using this framework. Partnership between schools, parents and healthcare services could create a pragmatic and effective school plan/policy to improve asthma control among children.School-based self-management interventions for asthma among primary education children can improve asthma outcomes and reduce absenteeism. Parental participation is an important component in this age group, but other features highlighted in secondary school interventions proved less relevant, perhaps reflecting the greater role of parents in younger children.59, and PRISMA reporting standards. The protocol is registered with the PROSPERO database (registration number: CRD42019131955).This systematic review follows Cochrane methodology60, using definitions similar to the Cochrane review61. Self-management intervention was defined as the active transfer of information to children with asthma to enhance their self-management skills; this was interpreted with reference to components of self-management recommended by global guidelines  strategy to define eligible studies Table 60, usinges Table 2,3. In l61.We chose three outcomes of interest  to reflect the impact on children with poorly controlled asthma7. Using the same search terms, with no language limitations, we updated the search in February 2019 in six-core databases 7. In addition, we searched the Global Health database using similar search terms without date limits to include studies from low- and middle-income countries. We included all studies identified in the review that met our eligibility criteria . We checked the reference list and undertook forward citation of studies in the Cochrane review conducted among primary school children62.The details of the search terms and databases used are in Supplementary Table 7 and all the studies included in this review62.A pre-publication update was conducted on 17th March 2020 using forward citation of the Cochrane review (published 28 January 2019)5. A 96.3% agreement was achieved prior to discussion, which reached total agreement after clarification of the screening criteria. SNR then completed title and abstract screening. Both reviewers independently conducted full-text screening , met to discuss discrepancies and decided on the final included papers. Supplementary Table 63. SNR contacted authors for missing data by email and any further information received was added to the data extraction forms59.We imported the list of articles from the electronic databases into Endnote software (version 7) to facilitate screening, de-duplication and overall management of the results. SNR and JS independently screened a random selection of 10% of the titles and abstractsAt all stages, any discrepancies not resolved by discussion between the two reviewers were arbitrated by the study team .64 to categorise risk into low, high and unclear risk in nine domains, which were then used to generate an overall assessment of the RoB for each study. The Cochrane EPOC RoB tool applies to randomised trials and non-randomised trials64. Studies with at least one high-risk domain were summarised as high risk; studies with no high-risk domains but at least one unclear domain were summarised as unclear risk and studies at low risk in all domains were summarised as low risk64.We used the Cochrane Effective Practice and Organisation of Care (EPOC) Risk of Bias (RoB) tool65. Supplementary Table 67.The Consolidated Framework for Implementation Research (CFIR) is a comprehensive framework that systematically identifies factors (sub-domains) that influence the effectiveness of implementation in multi-level interventions68. This was a two-step process.We used a structured approach to divide the studies into four categories according to the change in the outcomes of interestFirst, we determined the direction of effect in each of the three outcomes of interest  for each included study. In some studies, several measures mapped to each outcome of interest: for example, emergency room visits and hospitalisation are both measures of unscheduled care potentially with conflicting findings. The rules at the top of Supplementary Table Positive : Studies with a positive effect in ≥1 of the outcomes and no negative effects.Negative (harmful): Studies with a negative effect in ≥1 of the outcomes and no positive effects.No effect: Studies with no positive effects in any of the outcomes.Mixed: Studies with at least one positive and one negative outcome.Second, we categorised the overall effect of the intervention in each study as positive, negative, no effect or mixed effects, as follows:69  to illustrate the effectiveness of the interventions on the three outcomes of interest for each study. A Harvest plot graphically displays not only outcomes but also the weight of the evidence in complex and diverse studies by illustrating selected methodological criteria69. We used a matrix to examine the association of the CIFR sub-domains with the overall effectiveness of the interventions. Supplementary Table Our preliminary scoping suggested that the studies would be heterogenous in terms of context, components delivered and study design, so we undertook a narrative analysis. We used a Harvest plotFurther information on research design is available in the Supplementary InformationReporting Summary


The finding that human hippocampal-cortical functional connectivity is nonunitary, separated along functional network borders  in the anterior–posterior axis, raises various possibilities as to why this organization might be beneficial and could inform updates to current models of human hippocampal function, memory, and the self. The hippocampus is critically important for a diverse range of cognitive processes, such as episodic memory, prospective memory, affective processing, and spatial navigation. Using individual-specific precision functional mapping of resting-state functional MRI data, we found the anterior hippocampus (head and body) to be preferentially functionally connected to the default mode network (DMN), as expected. The hippocampal tail, however, was strongly preferentially functionally connected to the parietal memory network (PMN), which supports goal-oriented cognition and stimulus recognition. This anterior–posterior dichotomy of resting-state functional connectivity was well-matched by differences in task deactivations and anatomical segmentations of the hippocampus. Task deactivations were localized to the hippocampal head and body (DMN), relatively sparing the tail (PMN). The functional dichotomization of the hippocampus into anterior DMN-connected and posterior PMN-connected parcels suggests parallel but distinct circuits between the hippocampus and medial parietal cortex for self- versus goal-oriented processing. The hippocampus is critically important for a diverse range of cognitive processes, such as episodic and prospective memory, affective processing, and spatial navigation –7. The h9The hippocampus seems to exhibit functional heterogeneity along its longitudinal axis . Studies of the rodent hippocampus have demonstrated modular differentiation along its longitudinal axis in patterns of gene expression, function, and anatomical projections , 13, 14.In humans, evidence for structural differentiation between the anterior and posterior hippocampus is provided by age and Alzheimer’s disease–related hippocampal volume reduction differences  and diffResting-state functional connectivity (RSFC) studies in humans have provided additional insights into the hippocampal connectivity that underlies hippocampus-mediated cognition. RSFC exploits the phenomenon that even in the absence of overt tasks, spatially separated but functionally related regions exhibit correlations in blood oxygen level–dependent (BOLD) signal –24. Grou2529Recent precision functional mapping studies have highlighted that RSFC group-averaging approaches obscure individual differences in network architecture in both the cortex and subcortical structures –41. The The medial parietal cortex is one of the main targets of hippocampal anatomical and functional connectivity , 43–47 a432550The DMN, PMN, and CAN are all thought to be important for memory. The DMN and PMN have been associated with different aspects of episodic memory processing. Autobiographical retrieval  preferentially increases activity in the DMN, whereas memory for recently experienced events preferentially engages the PMN , 53, 54.n = 10 participants; 300 min. of resting-state fMRI data/subject)  dataset (subject)  and addisubject) , 58. We SI Appendix, Fig. S1).To characterize individual-specific hippocampal functional connectivity, we used a winner-take-all approach, such that each voxel was assigned to the cortical network with which it was most strongly functionally connected , 35. We SI Appendix, Fig. S2). Half of the subjects also exhibited connectivity of the anterior hippocampus to the CAN. In all subjects, the most posterior portion of the hippocampus (tail) was most strongly functionally connected to the PMN . In MSC06, the lower-resolution data  showed the posterior hippocampus to be most strongly functionally connected to the FPN. However, winner-take-all of the higher-resolution dataset  also showed the posterior hippocampus to be most strongly connected to the PMN .Individual-specific winner-take-all parcellations of the hippocampus revealed that the anterior hippocampus was most strongly functionally connected to the DMN in all individuals . Similarly, the runner-up to the DMN in the anterior portion of the hippocampus was the CAN.Given that the winner-take-all parcellation scheme cannot account for more than one winning network within a voxel, we also considered the second strongest cortical connection for each voxel, as previously published . We founSI Appendix, Fig. S2) including higher-resolution 2.6-mm validation data , we found a separation between the anterior/middle (DMN) and most posterior (PMN) hippocampus. We also found that the DMN was most strongly connected to the anterior ∼80% of the hippocampus (range: 62 to 88%), with the posterior ∼20% connecting to the PMN (range: 12 to 38%).The winner-take-all analyses using all 15 functional networks showed differences in network organization between anterior (DMN) and posterior hippocampus (PMN). To clarify this anterior–posterior dichotomy, we next utilized a two-alternative (DMN versus PMN), forced-choice, winner-take-all approach. In all 10 MSC subjects . SI Appendix, Fig. S8 visualizes the individual-specific functional connectivity of the DMN and PMN hippocampal parcels to the remaining networks.Supplemental analyses demonstrated that the functional connectivity strength of each individual-specific hippocampal parcel to its winner cortical network was at least z(r) ≥ 0.2 . The DMN parcels (left and right) were strongly positively correlated with DMN in every subject but negatively correlated with the PMN (Top). The PMN parcels were strongly positively correlated to the PMN and uncorrelated with the DMN (Bottom).The differences in network connectivity between anterior and posterior hippocampus allowed us to generate individual-specific DMN and PMN hippocampal parcels B. Next,  the PMN , Top. Th the DMN , Bottom.SI Appendix, Figs. S4 and S8). We again computed the winner-take-all on the hippocampus using two network candidates (CAN and FPN) . The functional connectivity of the resulting parcels was also significantly different from the null distribution . The CAN–FPN division of the hippocampus strongly spatially overlapped with the DMN–PMN border .We similarly tested the statistical significance of the anterior and posterior hippocampus’ preferential functional connectivity to CAN and FPN . Using the hippocampal DMN and PMN parcels as regions of interests, we generated seed maps (Bottom).To visualize the cortical functional connectivity of the individual-specific hippocampal parcels , we displayed it over the previously defined  individueed maps A and B. eed maps C. Despiteed maps , Bottom.2 across the 10 MSC subjects for parcels . We also entered the gradient and parcel identity factors into a single analysis of covariance to calculate the variance explained by one factor after controlling for the other factor . We found that both factors simultaneously explained separate variance, demonstrating potentially superimposed gradient and parcel organization in the hippocampus.To evaluate gradient versus parcel explanations of hippocampal organization, we tested whether the hippocampus’ functional connectivity was better explained by an anterior–posterior gradient or by network parcels using a one-way ANOVA . For eacferences . The r2 SI Appendix, Fig. S11). We defined border voxels as adjacent to the other parcel within a two-voxel radius and calculated the connectivity similarity (to cortex) for all possible pairs of border voxels. We sorted the similarity values based on whether the pair of voxels belonged to the same or different parcels  and generated an ROC curve for each individual . We found that border voxels that belonged to the same hippocampal parcel (DMN or PMN) were significantly more similar than voxels that belonged to different parcels for every individual . Thus, all 10 subjects had a discernible functional border between the DMN and PMN parcels.Having established that parcels and gradients explain similar amounts of variance, we tested for a functional border between hippocampal DMN and PMN parcels using receiver–operator characteristic (ROC) analyses . We found a high degree of spatial overlap between anatomical segments and winner-take-all parcels  across all subjects  replicated the functional connectivity differences observed with functionally defined parcels , as well as the DMN and PMN parcels in the medial parietal cortex (P < 0.001), and the hippocampus (P = 0.02). Thus, the dichotomization into parallel DMN and PMN hippocampal-parietal circuits was borne out by anatomy, functional connectivity, and task fMRI.To validate the segregation of the DMN from the PMN, seen with resting-state and structural MRI, we next examined task-driven deactivations during spatial coherence and noun–verb discrimination tasks (mixed blocked event-related design) , 60. We Prior studies have largely conceptualized the organization of the hippocampus along gradients—e.g., size of place field representations , 14 or sTo test whether these results were affected by data amount, quality, or resolution, we used higher-resolution 2.6-mm) data from MSC06-Rep , which again showed a parcel and gradient organization. The parcellation of the hippocampus, based on resting-state fMRI data  and 2, w.6-mm datOur results more precisely define the anterior 80% of the hippocampus as the hippocampal subregion that interacts with the cortical DMN, likely mediated by adjacent perirhinal and parahippocampal cortex , 61. TheSI Appendix, Fig. S3). In contrast to the functional border between head/body (DMN + CAN) and tail (PMN + FPN), the network representation of both DMN and CAN in the hippocampal head/body appears to be intermixed. The interdigitated nature of the DMN and CAN in the head/body of the hippocampus even with 2,610 min of 2.6-mm data (MSC06-Rep) suggests that this is not caused by noise or blurring. This could be due to the fact that 1) the DMN proportionally occupies a larger part of the neocortex and/or 2) the CAN is a subnetwork of the DMN  and more highly sampled  data, we were able to replicate the observation that the anterior hippocampus is functionally connected to both the DMN and CAN. With more and higher-resolution data, CAN functional connectivity of the anterior hippocampus becomes more readily apparent  generated from a lifetime of repeating patterns of co-occurrences , 63, 64.The presence of both CAN and DMN functional connectivity highlights the importance of integrating contextual, social, and affective information in the anterior hippocampus, which is consistent with prior notions of the anterior hippocampus’ interactions with the ventro-medial prefrontal cortex in schema generation , 8, 67. The circuit between posterior hippocampus, PMN, and medial parietal parts of the FPN may be part of a system that integrates PMN and FPN functions in order to allow attention-directed memory retrieval. The PMN is deactivated relative to baseline by novel stimuli , 53, 70.While it is known that the hippocampus is involved in novelty–familiarity discrimination tasks , 74, ourA notable finding in the present study is that the hippocampal tail was not dominantly functionally connected to occipitotemporal cortex but rather to medial parietal cortex. Prior studies asserted that the posterior hippocampus is functionally connected, perhaps weakly, to visual/perceptual neocortical networks in support of fine, detailed, perceptually rich representations of memories , 75. We In addition to being strongly functionally connected to the PMN, the hippocampal tail was also connected to the FPN. Chen et al. found that episodic memory retrieval triggered by recently seen stimuli preferentially activated the PMN and parts of the FPN . This PMThe hippocampus is patterned on its long axis in rodents  and primates (anterior–posterior) , 4. In rGoing forward, studies of human brain function should take into account the dichotomy of hippocampal functional connectivity to cortex, ideally using individual-specific methods. While precision functional mapping may not be feasible in all cases, close approximations could be obtained by anatomically segmenting the hippocampus  3)..3).Prior group-averaged human functional connectivity studies, including those reporting anterior–posterior connectivity differences, presumed the hippocampus to be exclusively associated with the DMN. The DMN was originally defined as the brain regions that collectively deactivated during goal-oriented, attention-demanding tasks, independent of the specific task demands . SubsequThe discovery that the tail of the hippocampus is specifically and selectively functionally connected to task-oriented regions thought to be important for controlling attention and memory retrieval suggests that it is specialized for providing hippocampal computations in the task mode. Much larger parts of the hippocampus and cortex seem dedicated to the self- or internally directed default mode , 62, 76.Analyses of high- and low-frequency neural activity in rodents (sharp-wave ripples and theta) and humans (delta-band and infra-slow activity) show that the information flow encoded in high-frequency activity between the hippocampus and cortex reverses its direction during sleep, compared to the awake (resting) state –83, prim83The previously unrecognized neuroanatomical dichotomization of brain systems for orienting and sequencing in spacetime raises fundamental questions about human memory and the mental processes responsible for our sense of self. Given the functional differentiation of the hippocampal tail from the head/body, does information flow between the tail and neocortex during activity, rest, and sleep follow that of the anterior hippocampus’ DMN parcel? Do anterior and posterior segments still perform the same basic computations coordinated by theta oscillations , 86 or shttps://openneuro.org/datasets/ds000224). Details of the dataset and processing pipeline have been previously described , who were recruited from the Washington University in St. Louis community. Participants completed 10 sessions of scanning that were 1.5 h each. Each session consisted of 30 min of resting-state fMRI, in which subjects maintained open-eyed fixation on a white crosshair presented against a black background. The resting-state run was followed by fMRI scans for other tasks: a motor task, semantic judgment task, motion coherence task, and an incidental memory task.https://openneuro.org/datasets/ds002766). Details of the dataset and processing pipeline have been previously described (The MSC06-Rep data are part of a publicly available dataset (escribed .https://github.com/MidnightScanClub/MSCcodebase). We describe the MRI data processing in SI Appendix.The processing pipeline was developed for use in individual subjects. The pipeline is available on GitHub . The hippocampal mask was individual specific. Outlines were inspected and adjusted in the coronal view of the T1-weighted image from posterior to anterior sections. The segmentations were subsequently modified in the axial and sagittal views. The left and right hemispheres were independently outlined. Anatomical boundaries generally followed the approaches of Watson and Thompson, with reference to an anatomic atlas –90.SI Appendix, Fig. S1). Two medial temporal lobe networks were excluded due to signal bleed from the hippocampus and their poor signal-to-noise ratio.All sessions were concatenated together for each individual before proceeding with the Infomap community detection to 17 cortical networks for each individual MSC subject   preprocessing” in the escribed , 91. We escribed , 91.Task fMRI data were entered in a General Linear Model (GLM) separately for each session from each individual using in-house software (FIDL) . The mixSupplementary File


Psychedelics probably alter states of consciousness by disrupting how the higher association cortex governs bottom-up sensory signals. Individual hallucinogenic drugs are usually studied in participants in controlled laboratory settings. Here, we have explored word usage in 6850 free-form testimonials about 27 drugs through the prism of 40 neurotransmitter receptor subtypes, which were then mapped to three-dimensional coordinates in the brain via their gene transcription levels from invasive tissue probes. Despite high interindividual variability, our pattern-learning approach delineated how drug-induced changes of conscious awareness are linked to cortex-wide anatomical distributions of receptor density proxies. Each discovered receptor-experience factor spanned between a higher-level association pole and a sensory input pole, which may relate to the previously reported collapse of hierarchical order among large-scale networks. Coanalyzing many psychoactive molecules and thousands of natural language descriptions of drug experiences, our analytical framework finds the underlying semantic structure and maps it directly to the brain. Natural language–processing tools mine 6850 real-world narratives about 27 different psychedelic drugs. For thousands of years, humans have been drawn to consume hallucinogenic substances to deliberately alter states of consciousness. These drug-induced mental states frequently involve mystical experiences, the dissolution of boundaries between self and world, changes of social-emotional perception, and a dramatic intensification of sensoria . As such, there are a number of subject-specific and compound-related reasons for why subjective experience may differ between sessions of hallucinogenic substance consumption.Nevertheless, in a rapidly growing number of successful clinical studies, psychedelic drugs show promise as treatments for a variety of psychiatric conditions (d-lysergic acid diethylamide), psilocybin, mescaline, DMT , and phenethylamines. For several decades, pharmacological research has placed a strong focus on 5-HT2A as a putative essential mechanism of hallucinogenic experiences  antagonist and dissociative anesthetic], MDMA , ibogaine, and Salvia divinorum (a novel kappa-opioid agonist). As a key motivation for our present investigation, such drugs interact minimally, indirectly, or not at all with 5-HT2A receptors in the brain  We have extracted knowledge by mining 6850 post hoc reports of real-world experiences, in which participants freely describe the subjective hallucinogenic experiences that they have had. In contrast, laboratory studies or randomized clinical trials on hallucinogens have been restricted to testing drug effects in a handful of participants. (ii) Our data-driven approach allowed rigorous testing for the existence of receptor-experience mappings across a diverse array of hallucinogenic drugs. This is a prerequisite for exploring overarching principles that may encapsulate how specific sets of receptor bindings are linked to specific drug-induced alterations of subjective awareness. (iii) We have aimed to deconstruct the hallucinogenic perturbations of subjective awareness by cutting across a spectrum of molecular receptor subtypes. In an ecologically faithful approach, we describe an anatomic grounding for the subjective experience of altered states of consciousness.We aimed to illuminate key principles that mediate hallucinogenic states of consciousness. For this purpose, we have charted regularities across a large corpus of naturalistic hallucinogenic experiences. Our pattern-learning strategy has dissected phenomenologically rich anecdotes into a ranking of constituent brain-behavior factors: each characterized by a unique neurotransmitter fingerprint of action and a unique experiential context. The cortex-wide distribution of receptor-experience factors was located to anatomical regions across the deepest and shallowest neural network layers. The genetic factor expressions implicated regions, ranging from the higher association cortices to the unimodal sensory cortices. The dominant factor elucidated mystical experience in general and the dissolution of self-world boundaries (ego dissolution) in particular. The second and third most explanatory factors evoked auditory, visual, and emotional themes of mental expansion. Each subjective drug experience was modeled as a specific combination of the brain-behavior factors. In this way, we have carefully deconstructed the changes of conscious awareness triggered by hallucinogenic drugs into its component parts.Although not imposed by our analysis approach, the cortical mappings of factor expression often turned out to be spatially contiguous with smooth transitions of expression strength between neighboring brain regions. Clusters of adjacent brain regions with a particular expression strength also respected well-known anatomical and functional divisions. Moreover, salient brain-behavior effects were often found to be mirrored in homologous brain regions in the left and right hemisphere. These observations are noteworthy because all steps of our modeling pipeline are blind to the topographical position of particular brain atlas regions. The results across components were organized for ease of visualization: Because the directionality of the poles within each component is arbitrary in canonical correlation analysis (CCA), the pole most strongly associated with receptor transcription in the visual cortex was assigned the positive value and listed first.P < 0.05; N-methyltryptamine). Experiences mediated by modulation of these receptor combinations were located at the lower end of the neural processing hierarchy, especially highlighting extended parts of the visual sensory regions.As per our chosen pattern-learning algorithm (CCA), the strongest factor explained the largest portion of systematic joint variation between receptor affinity profiles and collective experiential terms , voice(s), tone, ringing, music, buzz, hear, and hearing, in addition to perturbations in sound perception like distortion, deeper, tinnitus, and the anatomical reference to ears. This experiential theme was linked to high affinity at molecular receptor 5-HT1A, in addition to lower-weighted affinity for serotonin transporter (SERT), Sigma-1, 5-HT7, 5-HT1D, and Sigma-2. These experience facets were also unique in being overwhelmingly associated with the DiPT drug. The auditory receptor-experience factor was preferentially localized to gene coexpression patterns in Heschl’s gyri, as well as the dorsomedial prefrontal cortex, dorsal anterior cingulate cortex, mid-cingulate cortex, medial temporal lobe extending into parahippocampal gyrus and temporal pole, and inferior parietal lobe. The primary auditory cortex in Heschl’s gyri is the first cortical region to receive incoming auditory signals, while the DiPT drug was documented for causing characteristic distortions of auditory perception , friends, loss, and happy; an intermediate time horizon suggested by the terms days, weeks, months, and years; as well as some auditory terms. This constellation of experiential facets was preferentially linked to drugs with highest affinity for imidazoline 1, calcium channel, M3, and NMDA receptors. This weighted receptor affinity was most closely associated with the drugs DiPT, MDMA, MDA, and ketamine. The anatomical brain regions that transcribe these combinations of cell surface receptor proteins were highlighted in high-level association cortices such as the rostral anterior cingulate cortex, dorsolateral prefrontal cortex, temporoparietal junction, and bilateral insula.P < 0.05; fig. S1) flagged term collections revolving around body load and somatic intensity  as well as several exteroceptive descriptors . Similar to ego dissolution in factor 1, a theme of immediate time horizon was indicated by the term seconds and also implied by references to transient physiological parameters . This constellation of experiential properties was linked most strongly to drug affinity with serotonergic  and adrenergic (Alpha-2C and Alpha-2B) molecular receptors. This pattern of receptor-binding weightings was most closely associated with tryptamines DMT, 5-MeO-MiPT, and 5-MeO-DMT. The regions that transcribe this graded array of receptor proteins were limited to the right side of the brain and included most prominently the primary visual cortex, temporoparietal junction, posterior insula, and somewhat less intensely in the medial frontal gyrus and temporal pole.The fourth most important receptor-experience factor  flagged the terms characterized by levels of comfort  and other somatic terms . The experiential horizon was temporally circumscribed by minutes. This constellation of conscious awareness alterations was strongly linked to drugs that preferentially bind to 5-HT1A, Sigma-1, and NMDA receptors. This fingerprint of receptor bindings was most especially associated with the drugs ketamine, 5-MeO-DMT, 2C-C, and DPT. The anatomical brain regions transcribe these combinations of receptor genes preferentially in the primary visual cortex, dorsomedial prefrontal cortex, temporoparietal junction, and premotor cortex.The fifth most relevant factor , green, sun, shapes, rain, sky, forest, and life]. This theme was complemented by perceptual terms  and references to entities, beings, and faces. This theme of subjective awareness alterations was linked preferentially to drug affinity at 5-HT2B, 5-HT5A, 5-HT1E, and 5-HT2C receptors as well as D1 and KOR. The derived profile of receptor implications was most closely associated with the drugs ibogaine, mescaline, LSD, and psilocin. The anatomical brain regions transcribe these combinations of synaptic receptor genes located to the visual cortex and portions of the medial temporal lobe.P < 0.05; fig. S3) highlighted a theme of euphoric sensations , perceptual impressions , and consistent references to entities and aliens. This theme of alterations in subjective awareness was linked most strongly to drug affinity at serotonergic , adrenergic (Alpha-2A and Alpha-2B), and NMDA and Sigma-1 receptors. The derived profile of receptor implications was mostly associated with the drugs 2C-C, DMT, 2C-D, ketamine, and 5-MeO-MIPT. The anatomical brain regions that coexpressed these receptor genes were in extended portions of the primary visual cortex, lateral prefrontal cortex, the temporoparietal junction, and the anterior insula.The sixth most relevant factor . This experiential constellation also appears to contain a parallel theme of apparent transcendence . This constellation of alterations of conscious awareness was linked to drugs that preferentially bind to serotonin receptors  as well as D3 and D1. This fingerprint of receptor bindings was most strongly associated with the drugs 5-MeO-DMT, ibogaine, 5-MeO-TMT, and mescaline. The anatomical brain regions that transcribe these combinations of receptor gene expressions were in the medial inferior temporal lobe, inferior parietal lobule, and portions of the primary somatosensory and premotor cortices.At its opposite extreme, the sixth factor was characterized by intense fear  and other dysphoric terms  emphasized terms relating to physical context, including room, house, park, sat, walls, tent, street, outside, and school. Apparent references to socio-emotional context were flagged by the terms friends, mom, scared, panic, laughing, funny, as well as remember, talking, said, knew, and thought. This constellation of conscious awareness changes was induced especially by drugs that bind serotonergic receptors 5-HT1B, 5-HT1D, 5-HT7, 5-HT2A, 5-HT2C, and 5-HT6 along with the D3 receptor. The drugs sharing the strongest affinity and experiential similarity with this receptor-experience constellation were 25-I-NBOMe, LSD, DOB, and psilocin. The brain regions that transcribe this graded array of receptor proteins occupied extended areas of the visual cortex, inferior temporal gyrus, a limited area of the inferior parietal lobule, bilateral temporoparietal junction, and portions of the somatosensory and motor cortices.The seventh most relevant receptor-experience factor  as well as perceptual and somatic modifiers . This constellation of experiential features was linked most strongly to drug affinity with Sigma-2, NMDA, imidazoline 1, DAT, and MOR (m-opioid receptor) molecular receptors. This pattern of receptor binding was overwhelmingly associated with the drug ibogaine. Brain regions found to preferentially transcribe combinations of these neurotransmitter receptor densities were located in the right dorsolateral prefrontal cortex, rostral anterior cingulate cortex, bilateral anterior insula, and right temporoparietal junction.P < 0.05; fig. S5). This factor delineated a theme of somatic relaxation, such as by flagging the terms euphoria, relaxation, pleasant, enhanced, positive, impressed, stimulation, tactile, and waves, along with contrasting terms such as negative, anxiety, and terror. These facets of drug-induced experience were associated with the time scale of years. The underlying emotional pattern was linked to a graded affinity for a narrow group of receptors: 5-HT1A, 5-HT1B, and D3. The cohesive variation between these receptor affinities and the emotionally flavored terms was linked to the drugs 2C-C, 2C-D, 5-MeO-MiPT, and salvinorin A. The cortical brain regions expressing this complex of cell surface receptor proteins preferentially occupied the wider visual cortex and portions of the superior parietal lobule and temporoparietal junction.The eighth and last factor revealed by our pattern-learning algorithm tracked joint variation between receptor affinity profiles and experiential terms . To this end, we have constructed demographic subgroups by selecting only reports from older or younger individuals or only from male or female individuals. For each of these subgroups, we have repeated the entire modeling pipeline, which yielded a set of receptor-experience factors for each subgroup. We then computed the similarity of these subgroup-specific modeling solutions on the basis of Pearson’s correlation between the estimated model parameters  obtained from two different demographic subgroups. These supplementary findings confirm that, focusing on certain age or sex strata, our results and scientific conclusions remain virtually identical. Moreover, we have examined the possibility that the semantic structure of the experience reports or the length of drug experience may have unduly influenced our modeling results (fig. S7). To this end, language complexity was measured on the basis of the number of distinct words that have been used in each experience report, as a proxy for the richness of used verbal descriptions. The duration of experience was captured on the basis of the usual length of time that a particular drug is known to show effects. We then quantified the association (Pearson’s correlation rho) between these indicators and the expression strength of each receptor-experience factor .Subjective hallucinogenic experience is commonly studied in the strictly controlled laboratory setting: After participants consume a particular hallucinogenic drug and lie down in the bore of a brain imaging scanner, their functional activity changes are measured and compared to those of control subjects. Our study confronts the neurophysiological basis of hallucinogenic states of consciousness from a different direction: We have translated natural language processing tools from machine learning to mine a large corpus of 6850 real-world narratives with 27 different drugs. By adopting a data-driven strategy, we sought to uncover general principles that delineate how drug-induced changes in subjective conscious awareness are anatomically rooted in 40 neurotransmitter receptors. Cutting across a variety of drugs, we have assigned concrete numbers to distinct facets of hallucinogenic episodes and have mapped differences in transcriptomic proxies of synaptic receptor densities onto cortical regions. In so doing, we have uncovered a set of complementary principles that describe how different aspects of subjective experience may be triggered by receptor modulation in specific cortical regions. We have developed a framework that can inform the design of new classification systems and treatment options for psychoactive substances in the future.To deepen understanding of the neurobiological and behavioral effects of hallucinogenic drugs, it is beneficial, we argue, to consider its action within defined neurotransmitter systems and their transcriptomic gene expression within different anatomical regions. Since the 1990s, it has been known that predosing with 5-HT2A antagonist ketanserin can negate the effects of psilocybin in a dose-dependent manner  organizing influence on neural activity in subordinate brain networks . However, the affinity weightings of our receptor-experience factors suggest important roles for other brain regions in distorting visual perception. While the visual cortex was predictably most strongly linked to these visual changes, the medial temporal lobe, ventromedial prefrontal cortex, dorsolateral prefrontal cortex, and rostral anterior cingulate cortex were also consistently implicated in an array of serotonergic receptors. These findings implicate a variety of specific regions and receptors  that may play important roles in instantiating the powerful and diverse array of visual changes that hallucinogens can elicit.Our analysis also uncovered hidden relationships between receptor affinities and perceptual themes that both confirm prior findings and suggest exciting new directions for future research. Visual distortions are ubiquitous in hallucinogenic states and are commonly characterized by vivid colors and fractal patterns. Visuals emerged as the top hit among >14,000 candidate terms in several significant receptor-experience factors in our study. Prior research has indicated that stimulation of 5-HT2A receptors concentrated in layer 5 pyramidal neurons can induce elementary  and more complex visualizations  several of our data-driven findings dovetail with experimental, invasive evidence in animals; (ii) the drug-induced “experience of time” may actually affect more than the dopamine receptor system alone; and (iii) different types of experience of time are potentially linked to different receptor-binding constellations.Ki values, cf. methods) for each of the 40 cell surface receptors, previously established in binding assays. In addition, ascertainment biases may have affected parts of our results. For example, the subpopulation who are drawn to explore hallucinogenic drugs may be different in specific ways from the rest of the population. Consumers who volunteer to report their personal experiences online may also systematically differ in some ways from other consumers.Several limitations need to be taken into account when interpreting findings from the present investigation. The nature of our approach to “let the data speak for themselves” . This approach involved in vitro autoradiography in serially sectioned postmortem brain tissue to create multireceptor fingerprints. Moreover, extensions of our work for drug dosage and other parameters that control the drug experience will be important for future research.Future extensions of our present proof of principle should capitalize on the precise topographical maps of neurotransmitter receptors from other modalities. In particular, positron emission tomography is an established means to carefully map out the binding potential of specific cell surface receptors using radioactive ligands  several thousand real-world anecdotes about hallucinogenic drug episodes, (ii) synaptic binding affinities for various neurotransmitter systems, and (iii) human brain tissue probes of receptor gene transcription. By bringing into contact these disparate levels of investigation, our study could detail the consequences of the chaotic breakdown of the hierarchical functional organization.Changes in functional interaction among large-scale networks probably induce rebalancing between bottom-up sensory signaling and highly integrative top-down control. In all our leading explanatory factors, hallucinogenic consciousness states have pinpointed manipulation at both extremes of the neural processing hierarchy: the deepest layers of our neural networks, especially the higher-order association circuits, as well as the shallowest layers of brain hierarchy, especially the primary visual cortex. The disintegration of ordinary regimes of top-down influence may index the subjective confusion between internal sensations and facts of the external world.Ultimately, hallucinogens may come to serve as a tool to study the mechanistic receptor basis of how the higher association cortex orchestrates its subordinate large-scale circuits to impose structure on sensory perception. Hallucinogens have a meandering history. Yet, they offer potential to break the long drought in novel drug therapies for psychiatric patients.Existing brain imaging efforts to study hallucinogens have typically concentrated on gross differences in neural activity after administering one particular drug. General principles of drug-induced brain changes cannot be derived by studying an isolated neurotransmitter system or a single drug. To overcome several of these limitations, our analytical strategy sought to chart principled patterns that link free-form testimonials of drug-induced experience with synaptic binding profiles of hallucinogenic drugs.On the one hand, each text report was modeled as a histogram of word usages . This encoding of first-person narratives directly captured how individuals have articulated the changes in conscious awareness, which touches on thinking, perception, emotions, and other psychological alterations. On the other hand, each examined drug  has docuBy invoking a doubly multivariate pattern-learning algorithm (CCA), we aimed to deconvolve cross-connections between constellations of neurotransmitter modulations and constellations of experiential terms, which cut across 6850 written reports of hallucinogenic experience. In this bottom-up approach, we have also explicitly modeled the possible coexistence of several separate receptor-experience factors. That is, each unique report of hallucinogenic experience was modeled as a weighted combination of distinct receptor-experience factors to be discovered. In an attempt to complement previous hallucinogenics research, we thus designed an analytical framework that can extract several hidden representations of rich subjective experiences across a diversity of hallucinogenic drugs.www.erowid.org) aims to provide an educational resource on the effects of psychoactive substances—both legal and illegal ones. This overall collection now includes >38,000 testimonials in English language in free-text form from >800 different drugs, plants, and fungi. The testimonials have been written and submitted without any financial incentives. There were no constraints on the length, format, and no externally imposed structure on the content of the reports. These real-world experiences of psychoactives provided a unique window into the effects of these compounds. The database of drug narratives from Erowid’s “experience vault” is entirely anonymous. Rigorous quality control is conducted by trained experts with careful consideration given to “quality, credibility, and focus on effects or outcomes” (www.erowid.org). By means of that mechanism, all reports that provided the basis for the present investigation have successfully exceeded a standard quality filter.Erowid Center is a not-for-profit, member-supported organization. This initiative hosts a collection of first-hand accounts of experiences that were elicited by psychoactive drugs. The library aims to educate the public about the expected and unwanted consequences of each drug to help fight misuse or harm. This web platform  Compounds with a high number of testimonials in the Erowid database.2) Compounds with well-known receptor binding affinity (3) Compounds that are believed to mediate effects through multiple receptor systems.4) Classical psychedelics.5) Closely related research chemicals purported to have psychedelic-like hallucinogenic effects, including substituted phenethylamines and tryptamines.6) Drugs known to have hallucinogenic properties  indexed in the columns. This word matrix M, we have used the term-frequency inverse-document-frequency (tf-idf) transformation that is widely used for text mining in the natural language processing community . Each testimonial was thus decomposed into a vector of k component projections whose value is the sum of vectors standing for its component words.To automatically search and organize the space of semantic representations in the experience reports, latent semantic analysis (LSA) was a natural choice of pattern-learning algorithm .k = 800 semantic components, preserving 60.7% of the variation in the corpus testimonials, for all subsequent analyses. Sensitivity analyses here showed that varying the number of LSA components between k = 50 and 5000 components, preserving 50.0 to 99.9% of the variance in the testimonial-word matrices M, gave substantially similar results and led to the same neuroscientific conclusions. This setup resulted in a final vocabulary of 14,410 words in the dictionary.To counteract class imbalance between the available testimonials per drug, we have drawn a random sample of 300 testimonials from each particular drug. Sensitivity analyses have confirmed that similar semantic components are found when applying LSA to different subsets of testimonials. Different sampling proportions of drug testimonials have changed the ordering of the components, but the underlying semantic components themselves proved to be robust. Furthermore, we have committed to Ki) for 40 targets: G protein–coupled receptors, molecular transporters, and ion channels. Binding data were aggregated primarily from two sources: (+), and NMDA glutamate receptor.To elucidate the spatial distribution of hallucinogenic compounds that modulate neuronal activity throughout the cortex during subjective “trips,” we compared normalized measurements of their relative binding strengths. For each of the 27 drugs to be analyzed, we built an affinity vector that captures the binding strengths . In addition to NMDA, ketamine was found to have significant binding values for Sigma opioid receptors, an outdated nomenclature that is now differentiated into Sigma-1 and Sigma-2 receptors. A sensitivity analysis was performed, and we found that using both values as negative, positive for Sigma-1 only, and positive for Sigma-1 and Sigma-2 all yielded indistinguishable final results. The sources for all studies cited can be found in the Supplementary Materials (tables S1 and S2).The binding values for 20 of the hallucinogenic drugs found in previous work (Ki): a raw measure of the molar concentration  that is necessary to displace 50% of a known ligand from the binding site of a given cell surface receptor. While such Ki values do not capture differences in functional activity induced by specific drugs at these targets, our ultimate aim was, instead, to contrast where these compounds act in the brain. Ki values are an optimal proxy for this purpose of simulating spatial distributions of drug-receptor binding during hallucinogenic experiences. This standard measurement of receptor affinity in pharmacology is computed as followsA] denotes the fixed concentration of agonist and EC50 is the excitatory concentration of agonist that results in half maximal stimulation of the receptor. The IC50 value for a drug is the inhibitory concentration to reduce the biological activity to half of its maximal activity on a receptor. The resulting Ki is the inhibition constant for a drug: the concentration of a ligand in a competition assay that would occupy 50% of the receptors if no ligand was present.To enable apples-to-apples comparisons between different drugs in terms of their spatial concentration within cortical tissue, our study relied on the inhibitory constant . A second variable set Y|testimonials| × 40 was constructed from each drug’s known pharmacological properties regarding molecular affinity to the neurotransmitter receptors. As one key advantage that made CCA a natural choice, this tool appropriately handles mutually correlated inputs in a variable set , such as functionally coupled neurotransmitter receptors.Next, we sought dominant factors—“modes” of joint variation—that provide insight into how semantic components emerging from word usage patterns are interlinked with receptor binding affinities from 40 neurotransmitter receptor subclasses. The CCA algorithm was ideally suited to interrogate the possible existence of such a multimodal correspondence between two high-dimensional variable sets (a and b that maximize the relationship between a linear combination of semantic contexts (X) and a linear combination of receptor affinity profiles (Y) across testimonials. CCA thus searched a large space of possible combinations by identifying the two projections Xa and Yb that yielded maximal association between the semantic context features of the drug experience and the neurotransmitters in the brain to which the drug binds.The affinity profile vector of each drug corresponded to the drug taken during each testimonial. Unmeasurable affinity values and values for which there were no available data were imputed with the minimum affinity level for the purpose of the present investigation. CCA involved computation of the projection vectors More formally, we have solved the doubly multivariate matrix decomposition problem on the basis of the following optimization objectiveX and Y as the first canonical factor h, it is possible to continue to seek additional pairs of linear combinations that are uncorrelated with the first canonical mode(s). This process may be continued up to min times. While a and b here denote the canonical vectors, U and V are commonly referred to as the canonical variates. The canonical correlation is a performance statistic that denotes the correlation rho between the canonical variates for each factor hIn addition to maximizing the correspondence between the variable sets X and Y) and the derived canonical variates  can be understood as the best way to rotate the left variable set and the right variable set from their original representation to new representations that maximize their linear association. The fitted parameter values of the CCA model thus described the rotation of the coordinate systems: the canonical vectors encapsulating how to transition from the original measurement coordinate system to the new hidden space and the canonical variates encapsulating the position of each data point  in that new embedding space.The relationship between our original data  factors of joint variation were modeled with the optimization constraint to be linearly independent from each other. CCA also yielded factors that were already ordered from the most to least important receptor-experience pattern. The first and strongest factor therefore explained the largest fraction of covariance between molecular features of receptor pharmacology and experiential features of semantic context. Each particular factor captured a unique fraction of the multivariate covariation in the Erowid corpus that was not explained by one of the h − 1 other factors.The set of X was held constant, while the receptor affinity matrix Y was subject to testimonial-wise random shuffling. The constructed surrogate data preserved the statistical structure idiosyncratic to the type of our input data yet permitted to selectively destroy the signal properties related to the CCA statistics to be tested . Each explained-variance metric rho indicated a given factor’s strength of variation that is common to both semantic contexts of experience reports and drug-specific receptor-binding profiles.To assess statistical significance, we have determined the robustness of each estimated CCA factor by hypothesis testing in a nonparametric permutation procedure used previously (http://human.brain-map.org). To strengthen reproducibility and comparability, we have used the abagen tool to map the receptor gene expression information to the 200 Schaefer-Yeo regions  were obtained from the Allen Human Brain Atlas  measure of gene expression activity for a specific brain region z. b denotes the canonical vector of a particular factor h that carries the linear combination obtained from fitting receptor binding affinity profiles (Y) from the CCA step of our analysis (cf. above). The transcriptomic expression data were transformed to a minimum gene transcript expression of zero to ensure the directionality of the CCA factors. The ensuing region-wise quantities indicated the degree to which the semantic structure captured by LSA is linked to variation in the receptor expression profile of a specific brain region. The ensuing region-specific estimates of genetic factor expression were demeaned and variance-scaled for the sake of visualization. The factor-specific coexpression of receptor genes was directly topographically mapped to each of the 200 target brain regions of the Schaefer-Yeo reference atlas.For each of the 200 anatomical brain regions More generally, the DNA microarray probes of postmortem brain tissue have previously been successfully used for genome-wide mapping to build transcriptomic cortical atlases (http://scikit-learn.org). This general-purpose machine learning library was interfaced with the nilearn library for design and efficient execution of brain imaging data analysis workflows (http://github.com/nilearn/nilearn). Data plots were generated by Matplotlib (https://github.com/matplotlib/matplotlib). All scripts for the analysis pipelines that reproduce the results of the present study are readily accessible and open for reuse by the reader: https://github.com/lucidtronix/Trips-and-Neurotransmitters-Discovering-Principled-Patterns-across-6850-Hallucinogenic-Experiences.Python was selected as the scientific computing engine. Capitalizing on its open-source ecosystem helps enhance replicability, reusability, and provenance tracking. The scikit-learn package provided efficient, unit-tested implementations of state-of-the-art machine learning algorithms (


The evolution of the COVID-19 pandemic features the alternation of oscillations and abrupt rises. The oscillations are attributable to weekly and seasonal modulations, while abrupt rises are stimulated by mass gatherings. SARS-CoV-2 has been circulating in the human population for more than a year and has caused over 150 million cases globally as of 1 May 2021. Although a lot of regions have relied on measures such as social distancing, contact tracing and quarantine to slow its spread . Since tThe transmission of SARS-CoV-2 is regulated by various processes on multiple timescales. Isolating these processes on different timescales can help to identify the major inducements of the COVID-19 pandemic. We used the Ensemble Empirical Mode Decomposition (EEMD) method (Supplementary Section 1) to separately decompose the time series data of daily confirmed cases and deaths in the northern and southern hemispheres (NH and SH). The time series data consist of the oscillations over weekly and seasonal timescales and the long-term trend that drives the increase in COVID-19 cases . These abrupt shifts could be attributable to changes in governmental response and public adherence, as well as the unexpected natural and socio-economic crisis. In either case, these incidents result in a higher risk of mass gathering, which has directly led to super-spreading events and the subsequent COVID-19 disaster. An anomaly detection algorithm (Supplementary Section 2) has identified four major outbreaks along the COVID-19 time series data, which are shaded in Fig. Russia is among the four countries with the highest number of confirmed COVID-19 cases as of May 2020. However, during the first outbreak, the initial rise of cases in Russia happened later than many of the neighboring countries. This is possibly due to the effective implementation of proactive non-pharmaceutical interventions (NPIs), which limited the virus import from Asian countries. Unfortunately, the Russian authorities did not react quickly enough to prevent case importation from European countries, in which local transmissions had already occurred until mid-March 2020. As of 15 March, 74.2% of the inbound flights from other European countries were still operating . Although the number of protests across the US peaked in early June and steadily declined afterwards, mass gatherings during the protests caused a 52.2% increase in total cases as of 1 September 2020, as shown in Fig. 0. AlthouSustained and intensive public health interventions have drastically disrupted almost entire sectors of society. As a result, signs of pandemic fatigue among policymakers and the public have emerged worldwide. For example, steady declines in the government stringency index have been recorded in Brazil and India since May 2020 , which aThe performed statistical analysis and dynamical simulations in this work both indicate multifaceted influences on COVID-19 transmission dynamics. We found limited weekly and seasonal modulations on COVID-19 evolution, while public behaviors and governmental decisions that determine the frequency of mass gatherings were able to cause abrupt shifts in the daily new cases. If gathering activities could be accurately parameterized, then reliable predictions of COVID-19 cases are achievable. Additionally, our study also highlights the decisive role of NPIs. Given the facts of emerging SARS-CoV-2 variants and unguaranteed effectiveness of developed vaccines, NPIs remain one of the most effective measures to control the epidemic in the foreseeable future before high levels of vaccine-mediated protection can be achieved across the world.nwab100_Supplemental_FileClick here for additional data file.


Efficient and effective viral detection methodologies are a critical piece in the global response to COVID-19, with PCR-based nasopharyngeal and oropharyngeal swab testing serving as the current gold standard. With over 100 million confirmed cases globally, the supply chains supporting these PCR testing efforts are under a tremendous amount of stress, driving the need for innovative and accurate diagnostic solutions. Herein, the utility of a direct-to-PCR method of SARS-CoV-2 detection grounded in mechanical homogenization is examined for reducing resources needed for testing while maintaining a comparable sensitivity to the current gold standard workflow of nasopharyngeal and oropharyngeal swab testing. In a head-to-head comparison of 30 patient samples, this initial clinical validation study of the proposed homogenization-based workflow demonstrated significant agreeability with the current extraction-based method utilized while cutting the total resources needed in half. The COVID-19 global pandemic caused by SARS-CoV-2 has dominated the clinical and research landscapes since its designation by the World Health Organization in March of 2020 . EfficieIn the traditional model of RT-PCR viral testing, swab samples are collected from the patient, stored in viral transport media at the collection site, and sent to the laboratory for processing via molecular techniques including viral RNA extraction and purification utilizing a series of chemical reagents followed by RT-PCR for viral detection , 5, 6. WWith the demand for testing increasing secondary to viral spread throughout communities, the need for cost effective and accurate diagnostic capabilities drove the innovation of novel viral detection methodologies , 4, 6, 7in vitro simulated nasopharyngeal swab samples spiked with clinically significant levels of human coronavirus 229E (HCoV-229E) for proof of concept testing ..11].2 value  and negative predictive value (NPV) for the homogenization-based workflow were calculated using the extraction-based workflow as the gold standard method to compare against . Additio2 value .2 of 0.763 (When directly comparing the capabilities of homogenization-based, direct-to-PCR workflow to traditional, extraction-based methodology for SARS-CoV-2 detection off nasopharyngeal and oropharyngeal swabs there was an overall 80% agreeability between both methods. A strong positive correlation was observed when plotting Ct values produced utilizing both examined methods linked to the same patient sample as demonstrated with an Rof 0.763 . Except of 0.763 . Howeverof 0.763 . There wof 0.763 . These dof 0.763  and 2. Wof 0.763 .2 of 0.763 and positive predictive value of 80% demonstrate a moderate level of acceptability for implementing the proposed direct-to-PCR method into clinical practice. Additionally, when moving the negative detection cut off Ct value from 40.0 to 37.0 the improvement of both the positive predictive value and negative predictive value to 100% and agreement of 100% between both methodologies warrants further investigation while strengthening the argument for clinical implementation.In this clinical validation study, we utilized 30 paired nasopharyngeal and oropharyngeal swab samples participants in a prospective cohort study to assess the occupational risk of SARS-CoV-2 infection or exposure in Blantyre, Malawi to examine the efficacy of a direct-to-PCR, homogenization-based workflow when compared to the gold standard extraction-based workflow for detection of SARS-CoV-2. 80% agreeability between all samples following processing was noted, with a positive direct correlation between the resultant Ct values produced when processing each sample with both methods. An RThroughout the progression of the COVID-19 global pandemic, the need for efficient and effective diagnostic testing has proven paramount to the global response, with PCR based viral detection off swabs serving as the current gold standard for testing –4. HowevIn addition to the high cost associated with the accurate extraction-based workflow, the total run time for each sample to be processed in this method can take up to 3 hours from extraction to PCR results when using a fully automated workflow. When receiving thousands of samples per day, a backlog can easily be created utilizing the extraction-based method causing delays in relaying critical positive or negative results to patients and local health officials. Developing approaches to reduce the total time per test while maintaining accuracy also emerged as an area of needed innovation in response to the COVID-19 pandemic.To address these limitations in viral testing many approaches have been proposed ranging from point of care, lateral flow antigen tests to rapid PCR tests that offer solutions on either time or cost associated with testing –8. While2 value when plotting Ct values from both methods against each other supports the reliability of the direct-to-PCR workflow when dealing with the variability of viral loads in a clinical sample.Of note, the demonstrated agreeability between the direct-to-PCR and traditional methods displayed a pattern of all except for one of the SARS-CoV-2 positive samples had a lower Ct value following the extraction protocol versus the homogenization protocol. This is representative of the PCR inhibitors present in the lysate following homogenization that are not removed due to the lack of chemical purification steps when compared to the extraction protocols. Given the presence of inhibitors, it is expected that the Ct values are greater than the purified samples from kit-based extractions. However, the high agreeability in detecting SARS-CoV-2 between the methods demonstrates that these inhibitors remaining in the lysate transferred to the RT-qPCR in the homogenization method do not prohibit adequate RNA amplification for detection. This pattern confirmed with a strong RWhile we acknowledge that this initial clinical validation study demonstrated inconsistent detection when the Ct values were greater than 37, the 100% positive predictive value and 100% negative predictive value at Ct values less than 37 qualifies this methodology for further large-scale evaluations . It has Using the small mechanical footprint of a bench top homogenizer and a standard thermocycler, and without the need of a multitude of chemical reagents, the direct-to-PCR workflow can be set up almost anywhere. The ease of system configuration and simple operational steps needed to complete this workflow support the adaptability of this novel method to be implemented in any area, including resource challenged settings without the funds or laboratory spaces to support fully automated extraction based viral testing systems. It is critical that we as a global community continue to commit to the development of testing strategies to assist in COVID-19 public health efforts in all areas of the world if we are going to implement successful pandemic mitigation efforts.Given the high levels of agreeability between the observed workflows, in conjunction with the significant reduction in cost and processing time by utilizing a 30 second mechanical homogenization step versus an hour-long reagent heavy extraction procedure, this direct-to-PCR methodology has potential to be further incorporation into global COVID-19 detection strategies. Herein, we believe our novel direct-to-PCR workflow is a potential solution to increase access to efficient SARS-CoV-2 detection in resource challenged areas.