Current experimental stroke research faces the same challenge as neuroscience: to transform correlative findings in causative ones. Research of recent years has shown the tremendous potential of the central nervous system to react to noxious stimuli such as a stroke: Increased plastic changes leading to reorganization in form of neuronal rewiring, neurogenesis, and synaptogenesis, accompanied by transcriptional and translational turnover in the affected cells, have been described both clinically and in experimental stroke research. However, only minor attempts have been made to connect distinct plastic remodeling processes as causative features for specific behavioral phenotypes. Here, we review current state-of the art techniques for the examination of cortical reorganization and for the manipulation of neuronal circuits as well as techniques which combine anatomical changes with molecular profiling. We provide the principles of the techniques together with studies in experimental stroke research which have already applied the described methodology. The tools discussed are useful to close the loop from our understanding of stroke pathology to the behavioral outcome and may allow discovering new targets for therapeutic approaches. The here presented methods open up new possibilities to assess the efficiency of rehabilitative strategies by understanding their external influence for intrinsic repair mechanisms on a neurobiological basis. Although huge efforts have been made in recent years, both by clinicians and basic researchers, we have still gained limited insights into a neurological disease such as stroke preventing us from developing specific cures and resulting in poor statistical numbers: Of 15 million people suffering from an ischemic brain attack every year, a third dies, a third remains permanently disabled, and a third recovers as the stroke itself has not been too devastating. On the clinical side, stroke units have been created, which combine experts in intensive care medicine, neurology, physiotherapy, and speech therapy, to accelerate and coordinate the diagnostic and therapeutical processes aiming at improving recovery rates for patients. According to the neurologists' saying “time is brain,” even mobile units have been established to bring the hospital to the patient , 3.On the side of basic research, we study the neurobiology of stroke, but seem to be stuck in a “black box” situation: We have accumulated data showing the tremendous capacities of the brain to reorganize by synaptogenesis and even neurogenesis and by neuronal circuit rewiring and new circuit formation. We find cortical map shifts and hyperactive brain regions after stroke; we detect genetic and proteomic turnover within a distinct spatiotemporal profile and sequence of events . HoweverIn recent years, new technology has been designed which is starting to fill the gap between correlative and causative research.The aim of this review is to first discuss current state-of-the-art technology of experimental stroke research which enables a deeper understanding of neuronal reorganization and circuit formation. In the second part, techniques for distinct neuronal circuit manipulation are introduced which help to reveal causal relationships between anatomy and behavior. Finally, new approaches combining cytology with molecular profiles are provided which elucidate the underlying molecular mechanisms of neuronal rewiring and repair. The principles of the techniques are explained together with exemplary studies in experimental stroke research which have already applied the described methodology. The here discussed tools may not only enhance our understanding of stroke pathology but also help to identify crucial anchor points for new therapeutic interventions.A classical approach to study reorganizational processes across the whole brain is functional resonance imaging (fMRI), allowing the monitoring of neuronal rewiring processes on a macroanatomical level within the same animal. However, although significant contributions to the understanding of the interplay between altered functional status and structural connectivity have been made in stroke models , 6 usingIn contrast, intrinsic optical imaging sticks out by a high spatial resolution enabling the visualization of small domains within larger brain areas demonstrating the functional organization and the spatial relationships among those smaller domains, for example, in the barrel or visual cortex . IntrinsAnother technique to study in particular sensory map shifts is millisecond-timescale voltage-sensitive dye (VSD) imaging which unlike functional fMRI and intrinsic optical signal imaging measures electrical activity with relatively high spatial and temporal resolution . VSD imaWhile VSD imaging was the first demonstration of wide-field optical imaging of neural activity , the necThat wide-field calcium imaging might be also a powerful tool to study brain-wide cortical reorganization on a high-resolution level over time in animals monitoring their rehabilitative courses or recording rehabilitative training after stroke was demonstrated by Murphy et al. . His labIntracortical microstimulation (ICMS) and surface stimulation with electrode arrays have been used for many years to map cortical regions, to study cortical reorganization, and to find first hints if projections in the motor cortex are functionally relevant. This technique applies electrical stimulation of cortical sites to induce, for example, stimulus-evoked movement responses, which can be detected visually, by EMG responses or by the usage of accelerometers. Several studies have used this technique to either examine cortical map shifts in sensorimotor areas after spontaneous recovery or different therapeutical applications –24 or usA new noninvasive strategy to study the reorganization of the motor cortex after stroke in the same animal over time is light-based motor mapping: This technique makes usage of the possibility to stimulate neurons by light, either by uncaging neurotransmitters , 28 or bHowever, although all described mapping approaches are powerful tools, they can only provide information about map shifts and representation of general movement dynamics. They stay far beyond cellular resolution and do not allow studying local neuronal circuitry or single neuron contribution to neuronal networks. In particular after stroke, it is not clear how activity in single neurons changes in relation to cortical map shifts. The analysis of single neurons in relation to the neuronal circuit in which they are embedded may elucidate whether stroke-induced plasticity is a result of the capacity of surviving neurons to process multiple functional streams. In vivo two-photon calcium imaging is a potent method which not only allows studying activity of a single neuron or ensembles of neurons in a network but also enables cell type and neuronal subtype-specific analysis. Only a few in vivo two-photon calcium imaging studies focusing on neuronal reorganization and circuit rewiring after stroke have been conducted so far. In an acute in vivo calcium imaging experiment during the induction of a transient global ischemia model in mice, Murphy et al.  saw a wiTwo-photon calcium imaging enables recordings of individual neuronal activity within a neuronal network and allows subtype-specific functional analysis of brain tissue. However, neuronal activity with cellular resolution level can only be examined in small (<1 millimeter) fields of view. Collective dynamics across different brain regions are inaccessible. Recent advances in two-photon microscopy allow the simultaneous imaging of neuronal networks with cellular resolution level in the active animal in multiple areas, which are even not directly connected –35. ThisIn a 1979 Scientific American article, Nobel laureate Francis Crick stated that the major challenge facing neuroscience was the need to control one type of cell in the brain while leaving others unaltered. In a lecture from 1999, he further confined: “One of the next requirements is to be able to turn the firing of one or more types of neuron on and off in the alert animal in a rapid manner. The ideal signal would be light, probably at an infrared wavelength to allow the light to penetrate far enough. This seems rather farfetched but it is conceivable that molecular biologists could engineer a particular cell type to be sensitive to light in this way” .Manipulation of neuronal circuits or single neurons has two prerequisites: Manipulation has to be quick and very specific. Over the years, a very diverse set of tools has been developed to manipulate whole brain regions as well as the activity of individual cells and subtypes in the alert behaving animal.The first constraint for specific manipulation implies a high spatial control allowing the selective modulation of a whole brain area, a distinct anatomical sub region  or a particular cell type .For inhibiting neuronal activity in whole brain regions, agents such as the GABA agonist muscimol have been used , 38 resuThe Tet system uses at least two viral vectors plus an antibiotic drug which in a sequential way activate each other to induce the transcription and translation of the gene of interest: A tissue-specific promoter initiates the expression of a transcription factor, either the tetracycline transactivator (tTA) or the reverse tetracycline transactivator (rtTA). The tTA or rtTA then becomes the key player for the transcription of a tetracycline response element (TRE) promotor, which in dependence of the presence of tetracycline or doxycycline drives the expression of the gene of interest. Expression of the gene of interest is fully reversible as administration or removal of tetracycline or doxycycline will turn its expression on or off. In a study by Kinoshita et al.  a Tet-onSimilar to the Tet system, the Cre-flox system also requires two transgenes: A tissue-specific promotor regulates the expression of Cre recombinase, a bacteriophage enzyme which recombines DNA at specific recognition sequences called loxP sites. Cre recombinase then excises DNA within two loxP sites (“floxed”). As in most cases, floxed-stop constructs are knocked in by homologous recombination to a gene of interest ; the stoAs the second prerequisite for specific neuronal manipulation in addition to a high degree of spatial resolution, temporal resolution and directional modulation of signaling are required for remotely controlling neuronal firing. Temporal resolution implies the precise control when a receptor or pathway is active or inactive and for how long it should be in a specific active status. Temporal resolution can vary from milliseconds (see “opsins” described below) to hours . Important are also “onset” kinetics  and “offset” kinetics . Directq-coupled hM3 DREADD receptor stimulated a cascade of inositol phosphate hydrolysis, calcium release and ERK1/2 activation, while the hM4Di DREADD receptor, derived from the Gi-coupled human muscarinic M4 receptor, inhibited forskolin-induced cAMP formation and activation of GIRK causing hyperpolarization and inhibition of neuronal firing [For manipulation of neuronal networks for minutes to hours, designer G protein-coupled receptors have been developed. G protein-coupled receptor pathways are involved in a multitude of cellular functions. Unlike opsins, which are functionally silent without excitation in vivo as they are not directly activated by endogenous compounds, G protein-coupled receptors (GCPRs) are constantly modulated by endogenous ligands in vivo or reveal ligand-independent activity , 45. In l firing .Since the first development of DREADD receptors, reports of their usage in vivo are now appearing: The pharmacokinetic properties of the DREADD ligands and the particular route of administration  determine how quickly neurons response to experimental manipulation by ligand application. Responses typically emerge 5 to 15 min after systematic application, for example, of CNO and usually last for 2 h—but this time period can be further enlarged upon dose-dependent increase of CNO . When FeAlthough manipulation of GPCR signaling pathways by DREADD receptor induction and activation is highly efficient and shows a very specific spatial resolution (depending on the constructs or transgenic mouse lines used), the temporal resolution remains limited to an activation within minutes—due to the slower nature of GPCR signaling—and the necessary ligand delivery to the location of neuronal manipulation. In contrast, high-temporal (milliseconds) and cellular precision within intact mammalian neural tissue for fast, specific excitation or inhibition even within a freely moving animal can only be achieved with optogenetics .Drosophila by coexpression of the drosophila photoreceptor genes encoding arrestin-2, rhodopsin, and the alpha subunit of the cognate heterotrimeric G protein which enabled the sensitization of neurons to light [Chlamydomonas reinhardtii which depicted similarities to the vertebrate rhodopsin which opens in response to blue light allowing potassium ions to enter the cell. Two years later, the first optogenetic experiment in neuroscience was conducted by expressing ChR2 using a lentiviral vector in cultured rat hippocampal neurons [Early approaches to use light to stimulate neuron activity included the selective photostimulation of neurons in to light . In a seto light . Howeverto light , 61 had to light . In 2003to light  cloned c neurons . Illumin neurons –68.However, although the numerous advantages of optogenetics are evident—such as the highest specificity, the ultrafast millisecond time scale dissection, and basically no adverse effects due to the light (unless the light source is not too strong or applied too long)—optogenetics stays an invasive procedure for many in vivo experiments: As the light source has to be brought close to the neuronal tissue, targeting deep brain areas or diffuse neuronal populations remains challenging. New development of step function or bistable opsins and opsins such as Jaws—an inhibitory opsin, which is activated by light of infrared wavelength —opens upOnly very few studies have applied optogenetics in experimental stroke research so far: Optogenetics was mainly used in the context of light-based motor mapping as described above . Other sThat optogenetics can also be used to demonstrate a causal relationship between a rewiring neuronal circuit and recovery of a specific (sensorimotor) behavior was demonstrated by Wahl et al. : The autNew advanced technology in microscopy allows the precise optogenetic stimulation of individual neurons  and evenAlthough optogenetics have revolutionized the field of neuroscience, the examination of deeper, subcortical brain regions remains a challenge, as the light has to be somehow delivered to the tissue often requiring invasive implantation of fiber optics causing collateral damage of the surrounding brain tissue. A new emerging method which overcomes the spatial limitations is magnetogenetics: It relies on a principle known as thermal relaxation , implyinHowever, although individual neuron and specific neuronal circuit manipulation with high spatial and temporal control is possible as discussed above, there still is a need for good behavioral readouts: In particular, in experimental stroke research studying, for example, motor impairment and recovery, it is crucial to quantitatively understand true recovery versus compensation of impaired function : While aSo far, we have discussed how stroke reorganization can be examined on the macrolevel of map shifts or by studying single neurons in neuronal circuits using 2-photon calcium imaging approaches. We have reviewed how individual neurons and whole neuronal populations can be manipulated with high spatiotemporal resolution disclosing new possibilities of causally linking individual neuronal activity with a distinct behavioral phenotype. However, an understanding of the underlying molecular crosstalk which induces anatomical and behavioral changes is still lacking. Classically, tracing techniques  have been applied to visualize cells involved in structural reorganization after stroke , 23. Li In addition, new constructs have been recently developed for molecular profiling of projecting neurons and thus bridging the gap between anatomical modifications and underlying molecular mechanisms. Using, for example, bacterial artificial chromosome (BAC) transgenic mice which express EGFP-tagged ribosomal protein L10a in defined cell populations allowed purification of polysomal mRNAs from genetically defined cell populations in the brain , 87. In Here, we have reviewed current and new promising state-of-the-art techniques for studying reorganization after stroke, for the identification and manipulation of distinct neuronal populations and approaches which allow examining molecular profiles of neurons being part of the cortical reorganization process. While for decades studies in basic stroke research have only described and reported correlative findings, these techniques open up tremendous possibilities to analyze plastic processes and identify and target key players for the development of new therapies in stroke.


Large mental health systems are increasingly using fiscal policies to encourage the implementation of multiple evidence-based practices (EBPs). Although many implementation strategies have been identified, little is known about the types and impacts of strategies that are used by organizations within implementation as usual. This study examined organizational-level responses to a fiscally-driven, rapid, and large scale EBP implementation in children’s mental health within the Los Angeles County Department of Mental Health.Qualitative methods using the principles of grounded theory were used to characterize the responses of 83 community-based agencies to the implementation effort using documentation from site visits conducted 2 years post reform.Findings indicated that agencies perceived the rapid system-driven implementation to have both positive and negative organizational impacts. Identified challenges were primarily related to system implementation requirements rather than to characteristics of specific EBPs. Agencies employed a variety of implementation strategies in response to the system-driven implementation, with agency size associated with implementation strategies used. Moderate- and large-sized agencies were more likely than small agencies to have employed systematic strategies at multiple levels  to support implementation.These findings are among the first to characterize organizational variability in response to system-driven implementation and suggest ways that implementation interventions might be tailored by organizational characteristics. Efforts to implement evidence-based practices (EBPs) in community mental health systems have increased considerably , 2, withThe MHSA was passed by voters in 2004 and each county was responsible for developing a PEI plan for state approval. Following a lengthy stakeholder-engaged planning process, the State approved LACDMH’s PEI plan in August, 2009, which included a systematic roll-out of 52 approved evidence-based, promising and community-defined, evidence-informed practices . HoweverIn May 2010, LACDMH facilitated the rapid launch of an initial set of six evidence-based/informed practices (hereafter referred to as “practices”) to address a range of prevalent youth mental health problems, including Cognitive Behavioral Intervention for Trauma in Schools [CBITS], Child-Parent Psychotherapy [CPP], Managing and Adapting Practice [MAP], Seeking Safety [SS], Trauma-Focused Cognitive Behavioral Therapy [TF-CBT], and Triple P Positive Parenting Program [Triple P] , place innovation on formularies , centralize technical assistance , develop a formal implementation blueprint , develop and implement tools for quality monitoring/provide local technical assistance , promote network weaving  and use advisory boards and workgroups .Understanding EBP implementation in routine care requires attention to both the interventions to be deployed and the implementation strategies used to facilitate their deployment. Powell and colleagues  used a mPEI Implementation Handbook [Some of the strategies were part of the initial, state-approved PEI Implementation Plan and developed through the stakeholder-involved planning process . Other strategies were employed during the acute transformation prompted by the fiscal crisis . The remaining strategies were developed in response to challenges and needs that arose during the initial phase of implementation . Use ofAlthough the outer context and system-level implementations strategies may be held constant across the agencies, individual organizations may vary in response based on their own contexts and characteristics. Research has identified several inner-context organizational factors that influence implementation. Having a supportive and open organizational climate has been linked to lower staff turnover and greater sustainment of practices , 13. OrgIn contrast, structural characteristics of agencies have not been as well-studied. An early review identified structural characteristics, including organizational size, functional differentiation and specialization  associated with adopting innovations in healthcare settings . HoweverAlthough there is growing research on leader and therapists’ perceptions of EBPs , 18 and Few studies have examined strategies agency leaders have independently put into place following a large-scale system reform . It is nThis qualitative study provides an in-depth examination of organizational-level responses to a rapid, fiscally-driven EBP implementation in children’s mental health within the LACDMH PEI Transformation. Qualitative methods were used to characterize the responses of 83 community-based agencies to the system-wide implementation of multiple practices based on archived materials from site visits conducted 2 years after the PEI Transformation began. Documents from these site visits offer a view into the inner context of organizations undergoing a large-scale operations change. We examined site visit documentation to characterize the perceptions of agency leaders and system leaders concerning the use of specific organization-level implementation strategies and perceptions of the impact of system-level implementation strategies during the initial implementation of PEI practices. Lastly, we examined whether organizational structural characteristics were associated with the types of implementation strategies agencies used in this context.As of August 2012, 124 agencies were contracted to provide PEI services and 119 site visits were conducted. Inclusion for the current analyses involved agencies providing PEI services to children or transition-age youth (TAY) in outpatient settings. Documents for 36 agencies were excluded, 19 based on age of population served and 15 based on service setting . Documents for 83 agencies were included.Agency size was indexed by the average number of child clients  and TAY clients  served per agency within the fiscal year of the site visit (2011-12 or 2012-13). Based on these figures, agencies were categorized into those that served fewer child or TAY clients , those that served a moderate number of child or TAY clients , and those that served a significant number of child or TAY clients . Agency centralization was based on whether agencies had a single program site (55%) or more than one program site (45%).Two structural agency characteristics were extracted from utilization management reports. Utilization Management Reports. Prior to the site visits, LACDMH provided each agency with a utilization management report detailing client demographics, PEI allocations and claims for fiscal years 2010-11, 2011-12 and/or 2012-13, and outcome measurement compliance by practice. Agency characteristics, including size and cost per client, were based on data from these reports.PEI Technical Assistance Site Visit Provider Pre-Site Visit Questionnaire (PSVQ). An agency leader or program manager completed the mandatory PEI Provider PSVQ prior to their site visit. The PSVQ included specific questions related to: 1) plans for practices, 2) outcome measurement, 3) PEI implementation successes, 4) PEI implementation challenges, 5) unique infrastructure created to facilitate PEI implementation, 6) fidelity monitoring, 7) plans for sustainment, 8) practice-specific challenges/questions, and 9) training/technical assistance needs.PEI Technical Assistance Site Visit Summary Report (TASV). Site visits included a three-hour meeting led by LACDMH staff and attended by agency program managers, supervisors, and therapists. Regarding individual informants, a range of two to 15 agency representatives attended their agency’s site visit  and a range of two to 11 system leaders  attended each meeting. One or two of the four consultants was present for each site visit meeting and consolidated their findings into the site visit reports. A third-party company produced summary reports within 3 weeks of each visit. Each TASV included five standard components: 1) site visit participant information, 2) characteristics of the agency and an overview of PEI implementation, 3) strengths and successes, 4) challenges and concerns, 5) next steps and follow-up actions.The LACDMH PEI Implementation Unit conducted site visits with each PEI-contracted agency from August 2012 to September 2013. The purpose of these visits was to assess implementation milestones  and provide technical assistance for compliance with system-level functions.http://atlasti.com/). The initial coding team  independently reviewed six TASV reports and developed inductive, descriptive codes to categorize the content of the reports. After discussion about the clarity, comprehensiveness, and distinctiveness of the codes, the team agreed upon 32 codes  and corresponding definitions. This revised list of 32 codes was applied to approximately 20% of the reports, which resulted in the addition of six inductive codes . After independent coding of additional site visit reports using the revised code list, the initial coding team evidenced high agreement and reached consensus resulting in a final coding scheme of 38 codes (available upon request). Two coders were added to the team to complete coding of all documents and evidenced high agreement with the initial six coded TASVs. The full coding team individually applied the final coding scheme to the remaining reports. As the content of the PSVQs was very similar to the TASVs, the same coding system and methodology was applied.A methodology of “Coding Consensus, Co-occurrence, and Comparison”  rooted iOnce all documents were coded, individual codes were clustered into what ATLAS terms “code families” that captured similar content to identify emergent themes . Themes were determined to reflect agency or system perspectives according to which party was referenced in relation to that theme in the TASV text. All comments in the PSVQs were attributed to agencies. The role of agency characteristics was examined by creating ATLAS “document families,” or clusters of documents based on key characteristics. These families allowed us to compare and contrast code content within and across document families. For this analysis, we examined two structural agency characteristics: agency size and agency centralization. Document families for these two characteristics were unique . Themes regarding agency structural characteristics were considered to differ substantially from one another if the theme occurred considerably more frequently (determined by consensus) in one document family as opposed to the comparison families.Themes that emerged from both data sources were grouped into the following three categories: 1) Perceptions of System Implementation Strategies, 2) Perceptions of PEI Practice Implementation, and 3) Types of Agency Implementation Strategies. See Table important role of training/technical assistance in supporting continued practice use. Specifically, almost all agency leaders considered the initial limited availability of therapist training an obstacle (1ai). Thus, most agencies stated that having their staff trained in multiple practices during the initial rollout was a source of pride (1aii). Regarding ongoing training, agency leaders and system leaders had different perspectives on where the burden of funding should rest. Agency leaders cited the need for continued funding from the county to maintain a trained workforce in the face of turnover (1aiii), whereas, LACDMH representatives encouraged agency leaders to plan for sustainment of PEI practices including assuming fiscal responsibility for continued training (1aiv).Both agency and system leaders commented on the difficult for them to use their full PEI funding allocation (1bi). With only few clinicians able to attend PEI practice trainings at a time, agency leaders did not initially have the capacity to bill for these services. In addition, they did not immediately have access to client populations most likely to benefit from early intervention. As such, agencies needed to launch time-intensive outreach initiatives to cultivate appropriate referral sources, which necessitated staff time that was not eligible for reimbursement (1bii).Related to the lack of available trainings, agency leaders also reported that it was Challenges with outcome monitoring (a required change to services concurrent with the PEI practice implementation) was another major theme. Agency leaders described the burden of non-billable time for scoring and entering outcome measures (1ci) and reported that practices with greater routine progress monitoring presented more challenges, especially when delivering in-home services. They also noted that outcome measures were not available in the languages spoken by their clients and existing translations were often confusing to families particularly with limited literacy skills (1cii). Clinicians feared that outcome measures may not capture progress given language barriers and client reluctance to endorse sensitive items, such as trauma exposure (1ciii). Agency leaders further emphasized the difficulty of collecting post-treatment measures in the context of high levels of drop-out and client mobility. However, system leaders focused on increasing completion of outcome measures, and provided agencies with feedback on their rates of outcome reporting (1civ).compliance with PEI practice claiming allowances, agency and system leaders both indicated concerns regarding treatment length. Clinicians expressed that they struggled to complete treatment within the recommended time frame due to clients presenting with multiple stressors, such as new trauma exposures (1di). Therapists also reported needing to slow the pace of treatment to ensure that clients understood treatment principles and could implement skills outside session. Because many agencies had previously served more severe and chronic clients, some agency leaders discussed the challenges associated with adjusting their care to fit brief models designed for early stage illness and prevention (1dii).Regarding compliance with PEI requirements. During site visits, they frequently emphasized fidelity, which was often framed in terms of compliance to PEI practice guidelines,  rather clinical fidelity marked by adherence to the protocol (1diii). Time was devoted to discussion of errors in processing claims for reimbursement  and under- or over-utilization of PEI-allocated funds. LACDMH staff often made suggestions for remedying these issues .LACDMH representatives were concerned with guidelines were being developed during implementation. Agencies reported that it was difficult to track current requirements as they were changed over time. One agency described the process as trying to “fly the PEI Transformation plane while building it.” Agency leaders expressed the need for centralized communication regarding requirements and readily-available documentation to ensure that agencies could achieve compliance.Finally, agency leaders commented on the challenges of complying with PEI implementation requirements as these Overall, agency leaders recognized that the PEI Transformation had multiple impacts on their staff and their clients. Numerous agencies reported that at least one EBP addressed some portion of their clients in terms of demographics or presenting problem (2ai). However, many also reported that practices had to be adapted  to better fit the population; and yet some clients were still not covered by these practices (2aii). Agencies that had implemented a PEI practice prior to the transformation often had existing infrastructure and reported having since further developed their capacity to implement (2bi).staff impact, a concern voiced across almost all agencies was the struggle to balance clinician availability and resources with the need to serve clients. Agency leaders would have ideally offered multiple practices to maximize the range and number of clients treated, but this was not feasible due to difficulties accessing trainings and the demands of learning multiple practices. More than half of agency leaders stated that it would be optimal for clinicians to be trained in 2-3 practices so they could serve a large contingent of clients. Agency leaders also reported that therapists differed in their opinions about PEI practices. Multiple agencies reported that their clinicians were enthusiastic about using the practices, especially early career therapists with less experience. However, several leaders reported that their clinicians were concerned about brief treatment in the face of frequent client stressors, low literacy and chronically disadvantaged caregivers, which often derail continuity and necessitate longer treatment.Related to practice selection. Although they predominantly focused on existing client needs in selecting practices, many agency leaders considered clinician preferences as well to increase the potential for sustainment (3ai). Moderately-sized and large agencies selected a greater number of PEI practices to implement than smaller agencies, likely due to their greater capacity. Once practices were selected, many agency leaders indicated that they changed their intake case assignment procedures to prioritize both clinical and fiscal considerations (3bi), assigning clients to a practice rather than basing case assignments on therapist availability.A major aim of the current study was to characterize the implementation strategies used by agency leaders to facilitate delivery of PEI practices. In the context of multiple EBP implementation, a theme emerged concerning changing staffing. Multiple agencies created new positions, such as practice coordinators or leads (3ci), or reallocating the existing staff time to new functions. For example, intake coordinators took over entering outcome data, and clinical supervisors were tasked with monitoring PEI implementation compliance (3cii). Beyond staffing considerations, some agencies instituted other types of infrastructure for implementation support. These included structured opportunities for line staff and management to communicate, such as focus groups, all-staff meetings, or PEI-practice consultation groups (3di). A number of agencies also utilized technology to facilitate PEI implementation, particularly through using Electronic Health Records (EHR) or information systems to monitor outcomes and remind staff to administer measures, create feedback reports, flag billing concerns, and provide example progress notes (3dii). Multiple agencies also reported addressing PEI requirements by making changes to clinical supervision procedures, such as devoting part of supervision to monitoring compliance , or creating practice-specific supervision groups (3eii) to provide additional support on skill development.In order to manage the transition to providing PEI practices, agency leaders reported making infrastructure changes, including sustainment of practices, most reported adopting a train-the-trainer model  (3fi). Staff turnover was discussed as a perpetual problem in community mental health settings that threatened practice sustainment. Staff members trained in multiple practices are especially valuable and the transfer of even one clinician who could serve multiple client types represents a significant loss. Thus, some agencies mentioned innovative strategies to deter turnover, including seniority incentive systems, creating greater opportunities for internal advancement, and maximizing fit of therapist professional goals with the agency mission during hiring (3fii).For agencies that discussed a high investment in increase their outreach and engagement efforts to generate a base of clients who would benefit from PEI services. Some agencies discussed employing innovative practices to increase referrals, such as holding mental health fairs in partnership with non-mental health agencies, offering services in non-traditional formats , and partnering with local schools and organizations (4gi). Strategies to increase client engagement were also frequently discussed, including conducting home visits and providing bilingual services. A few agencies reported offering client incentives, such as food, childcare, or transportation vouchers, or incorporating a family resource center (4gii). Once clients entered services, some agency leaders discussed the need to adapt PEI practices based on age, developmental level, and culture. Some practices originally developed for adults had to be adapted to be developmentally appropriate for youth . Agencies that serve youth with intellectual disabilities discussed reducing emphasis on the cognitive components of practices.Many agencies reported that it was necessary to significantly Use of specific implementation strategies differed by agency structural characteristics , agencies established strategies that appeared to fit within the context of their resources. Results revealed differences in organizational responses to the PEI roll-out as a function of agency structural characteristics. In general, moderate, large, and multi-site agencies were more likely to utilize a range of implementation strategies and to exhibit greater flexibility in redistributing and utilizing resources. Large organizations with a more decentralized, multi-site structure appeared better equipped to adopt multiple innovations to support implementation, perhaps because they had a greater amount of slack in their resources to prepare for changes within this major reform . Single-Notably, although specific PEI practices were often discussed in the site visits, they were predominately discussed in the context of PEI implementation requirements . References to specific PEI practices were typically brief and varied widely across agencies, with no consensus or clear emergence of themes. This was surprising because agencies were implementing multiple practices simultaneously and practice-specific concerns have been noted in similar implementation efforts , 32. It implementation was initiated by the system (LACDMH), in contrast to other efforts initiated by researchers, intervention purveyors, or service organizations. The system used a reform of fiscal reimbursement policies and practices to facilitate rapid implementation. This occurred in the context of a state budget crisis which put significant financial strain on service organizations that threatened their viability. In response, LACDMH amended and accelerated the PEI implementation plan in order to preserve the viability of agencies and availability of services to clients. As such, many of the themes that emerged related to agencies rapidly restructuring to comply with new and evolving requirements for reimbursement. Additionally, the themes reflected the context of simultaneous and rapid implementation of multiple practices. As such, this introduced the complexity of selecting practices to meet the characteristics of the agency workforce and target client populations. Furthermore, the themes observed were likely influenced by the characteristics of the client population served in LACDMH, which includes a predominantly ethnically- and linguistically-diverse community with relatively high levels of acuity. These client characteristics often required more intensive levels of care than intended within the prevention and early intervention focus of these services. Lastly, the EBP implementation occurred in the context of multiple, concurrent shifts in services including the target population and implementation of an outcome collection requirement.These findings were likely shaped by both characteristics of the implementation approach and conditions of the outer context during the initial implementation of PEI. First, this System and agency leaders both highlighted barriers and facilitators regarding adequate training resources, ongoing funding, progress monitoring, and billing allowances, which have been identified as important themes in implementation as usual , 23, 33.Given that the EBP implementation described in the present study occurred within a unique and rapidly-changing environment, it is difficult to know the extent to which the findings are attributable to the agencies themselves or the external context. It is also a challenge to estimate the relative importance or impact of each implementation strategy on the outcomes. As this is a neutral, observational study in which there was no manipulation of the variables, this is a limitation of the data and should be considered when interpreting findings. As dissemination and implementation science continues to progress, it would be beneficial to conduct dismantling studies of implementation strategies as well as prospective studies of implementation to determine unique and defined benefits of different implementation strategies. It is imperative to customize implementation strategies to an organization’s needs rather than using a prescriptive, one-size-fits-all approach, and more work is needed to determine how to tailor individual strategies .There are important limitations to note regarding this study. Utilization management reports furnished data regarding factors at the organizational level . These measures were used as proxies that were intended to provide information regarding organizational characteristics and therefore do not directly measure features of agencies, such as their staffing resources. The TASVs were also prepared by a third-party organization and, as such, are not a direct representation of agency and LACDMH perspectives. Given the length of time that has passed between these meetings and the current study as well as high turnover rate of agency staff since the meetings occurred, we were not able to independently validate these documents. These documents were also intended to provide a record of the major points discussed during the visit and, therefore, may not provide the level of detail and consistency regarding themes that would be provided by primary data collection. Surveys and interviews directly querying therapists and program managers about organizational factors and their perceptions of PEI implementation are currently being administered and can provide this level of analysis. Lastly, given that this is retrospective, cross-sectional study that occurred within a unique context, it is important to consider that the conclusions may not be generalizable to other contexts undergoing implementation efforts, particularly given that implementation was marked by a time-sensitive budget process.Despite these limitations, there are a number of important implications of this study, which add to the limited body of research regarding system-driven implementation efforts of multiple EBPs. Overall, this study highlights the complexity involved in rapid large-scale system reform and suggests that there are unique factors to consider at each level in the inner and outer context that may facilitate successful implementation. At the agency level, it is important to select and utilize implementation strategies that fit well with the organization, such as making changes to triage procedures or re-organizing staff positions. At the systems-level, it is important to facilitate collaboration between agencies and disseminate strategies that agencies find beneficial. It may also be important for leaders at both the agency and the systems levels to consider agency characteristics when selecting implementation strategies as these may affect the feasibility and fit of strategies, such as utilizing technology or hiring new staff. Whereas larger agencies may have the capacity to enact these implementation strategies independently, smaller agencies might require additional supports. Finally, simultaneous implementation of multiple practices requires shifts in care delivery and requirements associated with individual EBPs  may pose challenges for agencies to consider beyond the clinical components of delivering the intervention itself. This is particularly salient as system leaders may rank implementation priorities differently than agency leaders. In preparing agencies to deliver multiple EBPs, it is important to choose practices that fit the agency’s structure and organization and the client population, but it may be equally or even more important to consider streamlining implementation requirements and providing initial and ongoing support in meeting requirements across agencies.


Four themes were identified across the three trauma groups that were labeled as physiological impact of trauma on sexuality, cognitive-genital dissociation (CGD), sexual disenfranchisement (SD) and sexual rediscovery (SR). Trauma injury has a significant impact on sexuality, which is not routinely addressed within rehabilitation services. Further sexuality research is required among all trauma groups to improve rehabilitation services and in turn QoL outcomes for all trauma survivors.Restoration of the quality of life (QoL) of trauma injury survivors is the aim of trauma rehabilitation. It is generally acknowledged that sexuality is an important component of QoL; however, rehabilitation services frequently fall short of including sexuality as a matter of routine. The literature was reviewed to examine the experiences of trauma survivors from three groups: spinal cord injury (SCI), traumatic brain injury (TBI) and burns. The focus was on the impact of trauma on the QoL to identify future research directions and to advocate for the inclusion of sexuality as an integral part of rehabilitation. Databases searched were Proquest, Ovid, Cinahl, Medline, PsycInfo and Cochrane Central Register of controlled trials. A total of 36 eligible studies were included: SCI ( Improved rate of survival post-trauma has precipitated a shift from outcomes measured in terms of mortality to outcomes being measured in terms of activities of daily living (ADLs) and quality of life (QoL).,2Sexuality is a component of many of the QoL domains; however, current QoL measures do not adequately incorporate sexuality within their assessment components, thus perpetuate the exclusion of sexuality as a matter of discourse within trauma rehabilitation.Access thet al.,[et al.,[et al.,[The incidence and prevalence of sexuality issues for trauma survivors is impossible to estimate due to a lack of consistency within sexuality research with regard to sexuality domain definitions, data collection methods, and measurement tools. Phelps et al., study of,[et al., in their,[et al., study ofet al.,[n = 92) reported dissatisfaction with the frequency of sexual activity with 31% identifying a lack of intimate partner being the main contributing factor. In contrast, 86% of the respondents who had an intimate partner were satisfied with their sexual lives and 75% were satisfied with the frequency of intercourse. Ponsford[n = 280) reporting a decrease in sexual frequency. In addition, 41% expressed a decrease in sexual drive, 39% felt the ability to satisfy their partner had decreased, 38% had a decreased ability to engage in sexual intercourse, and 38% reported less enjoyment in sexual activity. The author concluded that more than 50% of people following a TBI experience significant sexual changes up to 5 years post-injury.Changes to sexual functioning have also been documented following brain injury. In Kreuter et al., study ofn = 362) report a loss of sexual interest up to 12 months post-injury.[There has been very little research regarding sexuality following burn injuries, thus research involving adequate methods and sample sizes are scarce. Evidence from a western Australian burn unit sample suggests that burn injuries have a significant impact on sexuality and body image satisfaction and that these changes are potentially long standing. ,10 Our pt-injury. Body imat-injury. A signift-injury. We conclt-injury.Sexuality is a dynamic entity in which the interplay of biological, psychological, sociological, spiritual and cultural factors influence personality development sense of self-esteem and ability to form interpersonal relationships.,12 In orThe research question guiding this literature review was as follows: What are the experiences of adult trauma survivors regarding how changes in their sexuality impact their QoL? SCI, TBI and burn trauma groups were chosen for this review on the basis that they represented common trauma diagnoses and provided a wide range of biopsychosocial rehabilitation issues in which to compare.A search was conducted up to March 2013 using ProQuest, Ovid, CINAHL, PubMed, and Medline databases. SCIs, TBIs, acquired brain injury, burns and disfiguring scarring were used as the free text word searched with sexResearch articles published between January 1990 and January 2013 pertaining to sexuality following SCI, TBI and burns were included within this review to look at current issues in sexual rehabilitation.Both quantitative (QUAN) studies that evaluated sexual changes through outcome measures and qualitative (QUAL) studies that investigated the ‘lived experience’ of sexuality changes in adult trauma survivors were included in this review.Research articles were included if they described research in which sexuality of the individual trauma groups was investigated. Case studies were initially excluded from the eligibility criteria, as they provided anecdotal information only. However, due to low numbers of research articles regarding sexuality following burns and TBIs compared with SCI literature, they were subsequently included for these 2 trauma groups to provide potential insight regarding sexuality issues to compare with the SCI literature.Reviews, opinion pieces, expert opinions and papers that did not deal specifically with the 3 trauma groups were excluded. Research articles focusing solely on the physiological aspects of sexual function were eliminated; however, research regarding sexual functioning that encompassed the broader aspects of sexuality as outlined by the WHO’s (2002) working definition of sexuality were incIn order to analyze qualitative data within the literature, themes were identified and labeled to attribute meaning to phenomena. Themes wet al.,[A phenomenological study conducted by Tepper et al., of sexuan = 25), TBI (n = 6), and burns (n = 5) [Table Publication titles and abstracts were reviewed online. A total of 36 eligible studies were identified for review: SCI (5) Table .Table 1:Physiological issues affected sexuality across all 3 trauma groups with sexual function, pain, medication side effects, and decreased desire/libido being the most common factors. Gender comparisons have not been made due to the lack of gender specific sexuality research.Decreases in sexual arousal and desire were common factors across most of the trauma groups reviewed.,8,17–24 Psychotropic medications commonly used in the treatment of post-traumatic stress disorder (PTSD) and depression following trauma injuries have been noted to have secondary sexual dysfunction side effects. AntideprDifficulties relating to sexual function including erectile or ejaculatory function, lubrication,,24,27,28Bladder and bowel incontinence during sexual activity was among the most significant areas of concern for people with SCI and the associated embarrassment of this issue lead to sexual and relationship avoidance in this trauma group.,27,29–31The process of “shutting down” or “shutting out” of sexuality based on the internalized perception that following trauma injury individuals are no long capable of giving or receiving sexual pleasure,33 was iPotgieter and Khan describeThe importance of including sexuality within rehabilitation programs was reiterated throughout the literature for all trauma groups, as well as, an overall dissatisfaction with how sexuality is currently addressed. In general, research indicated that trauma survivors receive little or no advice from health professionals regarding potential direct and indirect changes to their sexuality as a result of their injury.,16,27,33There was anecdotal evidence that standard sex therapy techniques, such as sensate focus, can facilitate significant improvements in QoL and intimate partner relationships in burn survivors. Four potDecreased body image was a common phenomenon throughout the trauma research articles. Body image issues were generally seen as a complex issue, with a possible stronger impact on female QoL outcomes, due to the perceived greater importance of internalized stereotypes of concepts of beauty on female self-esteem.,12,18,27The disconnection and disappointment associated with SD may result in individuals avoiding engagement in sexual activity with their partners due to the internalized belief or experience that sex is less satisfying post-injury. This mayThe negative impact of societal stereotypes on sexual self-esteem was evident across the 3 trauma groups reviewed. Internalizing stereotypical scripts that people with disabilities are asexual, undesirable and the Body image dysphoria (BID) studies in non-trauma populations emphasize a multidimensional concept of body image that includes perceptual , subjective  and social-behavioral  facets. ConnectiResearch regarding severity of trauma and functional limitations on an individual’s sexuality and relationship development are limited and contradictory. Several studies across the trauma groups indicate against popular thought that there is no significant correlation between injury severity as a predictor of psychosocial and sexual adjustment.,41,43–45SR has been characterized by an increase in sexual self-esteem, where thBroadening the definitions of sexuality within the rehabilitation settings away from genitally focussed influences, to incorporate intimacy, pleasure and variability sexual expression, would assist sexual adjustment.,32,41Timing of addressing issues of a sexual nature is a crucial consideration within rehabilitation treatment planning. Trauma set al.,[Sexual medicine and rehabilitation is concerned with sexuality changes, dysfunction, or problems in people who have a congenital or acquired physical impairment due to disease, injury, or secondary to medical interventions. The artiet al., outlininet al.,, 2) applet al.,[Hatzichristou et al., classifyet al., They deset al.,,49,50While any classification system of health-related issues should be utilized with caution and/or care, they do provide a potential framework in which the combination of biopsychosocial issues can be factored into screening within the clinical setting for assessment and treatment planning. Unfortunately, there were no individual or multicenter clinical trials of screening or assessment tools of sexuality changes for use by health professionals in any of the trauma group literature included in this review. This finding highlights a significant gap in evidence-based knowledge and practice for all trauma diagnostic groups that require further attention with empirical research.Of the 36 eligible articles included in this review, only 3 included a validated sexuality-related outcome measure. The 3 measures that were included within the literature reviewed were all designed primarily for research use and are potentially not suited for the multidisciplinary clinical setting. In addition, there have also been some construct validity issues identified with ‘The Sexuality Scale’ used in one of the studies.et al.,[There are scales available that could be considered for future research and clinical practice in the area of sexuality and trauma injury. The Female Sexual Function Index (FSFI) developed by Rosen et al., was desiet al., The FSFIet al., There aret al., and the et al., AlthoughThe Derogatis Sexual Functioning Inventory (DFSI) is another human sexual function inventory for use with both males and females that has been widely used in sexuality research. This is et al.,[Hatzichristou et al., endorse et al., This endLastly, the Procurement Management Information System (PROMIS®) Sexual Function and Satisfaction Measures Brief Profile (PROMIS® SexFS) is a customizable research tool that can be self-administered by participants of diverse gender and sexual orientation. While itOwing to the lack of research articles for burn and TBI trauma, results must be viewed with caution. For example, there was no evidence from the literature in relation to burns survivors having difficulties with libido/sexual arousal; however, with only a limited number of research articles sourced that focused solely on aspects of sexuality, it is possible that this issue has not been researched adequately within this trauma cohort.Trauma injury can have a significant impact on an individual’s sexuality resulting in difficulties in psychosocial adjustment. Although this is an important issue, sexuality has been largely ignored within trauma research and rehabilitation. There is an urgent need for quality empirical research across all trauma groups to develop effective comprehensive therapeutic rehabilitation strategies relating to sexuality in order to facilitate improvements in the QoL of all trauma survivors.Collaborative research with medical, allied health, and sexuality-based researchers is required to ensure that research includes sexual diversity and broader perspectives of sexuality and acknowledges the differences in sexual response between males and females.


Relationships between neuroimaging measures and behavior provide important clues about brain function and cognition in healthy and clinical populations. While electroencephalography (EEG) provides a portable, low cost measure of brain dynamics, it has been somewhat underrepresented in the emerging field of model-based inference. We seek to address this gap in this article by highlighting the utility of linking EEG and behavior, with an emphasis on approaches for EEG analysis that move beyond focusing on peaks or “components” derived from averaging EEG responses across trials and subjects . First, we review methods for deriving features from EEG in order to enhance the signal within single-trials. These methods include filtering based on user-defined features , filtering based on data-driven properties , and generating more abstract representations of data . We then review cognitive models which extract latent variables from experimental tasks, including the drift diffusion model (DDM) and reinforcement learning (RL) approaches. Next, we discuss ways to access associations among these measures, including statistical models, data-driven joint models and cognitive joint modeling using hierarchical Bayesian models (HBMs). We think that these methodological tools are likely to contribute to theoretical advancements, and will help inform our understandings of brain dynamics that contribute to moment-to-moment cognitive function. It is increasingly common to use computational models to distill the latent features mediating brain-behavior relationships. Indeed, the field of computational psychiatry has emerged to formally address how such latent factors may inform clinically relevant expressions of disease  latencies and wave magnitudes. These arbitrarily defined components depend generally upon the location of the recording electrode, behavioral state or sleep stage of the subject under study, and upon the nature of the stimulating signal. Therefore, the interpretation of these arbitrarily defined components is very difficult …”  may not hold at the individual subject or individual trial level  or multiset Canonical correlation analysis . Morlet wavelets are constructed by multiplying a complex exponential carrier with a Gaussian window. A family of Morlet wavelets may include 50 frequency-specific sine waves , each tapered  with a Gaussian function  as well as the amplitude of this signal . This decomposition is tremendously important for continued specification of the neural features that underlie cognitive operations. If multiple trials of an event are associated with consistent phase angles, the event is likely re-setting ongoing phase dynamics or instantiating a phase-dependent neural process  is conceptually and procedurally quite simple. However, many free parameters are critical for successful usage such as frequency range selection, taper dynamics, signal length and selection of an appropriate baseline to obviate the non-linear distribution of power between frequencies . An interested scientist can find a full description of each of these issues as well as MATLAB code in the book a Cohen, .Time-frequency decompositions  can emphasize signals that correspond to a distinct frequency band, removing artifacts that typically fall outside biologically plausible frequencies . However, broadband artifacts and artifacts which overlap in frequency with biological oscillations are more problematic for this filtering approach. These scalp signals are superimposed with various sources of noise, including eye blinks, eye movement, muscle tension, heartbeat, AC electrical line current, and skin potentials. In addition, some sources of noise influence neural signals directly, e.g., when the content of visual stimuli changes with eye movements or blinks. Thus, various blind source separation (BSS) techniques have been applied to derive data-driven filters which disentangle these signal mixtures.N ≥ 3 dimension) tensor decomposition . The term deep learning was coined as a reference to deep artificial neural networks (ANNs) with more than one hidden  layer of neurons. Most notably, these techniques are able to learn complex non-linear functions that transform raw signals into feature representations or derive probability distributions over latent variables. The latter can be achieved through probabilistic graphical models like restricted Boltzmann machines (RBMs) or deep belief nets (DBNs). Popular approaches for the former are convolutional and recurrent neural networks—CNNs and RNNs respectively  are used to pool trials into groups across which the neural signal is then compared , that quantitatively modulate the computations made by the model. Model fitting techniques allow us to infer the parameters that are most likely to give rise to the observed behavior. Then, given a set of parameters for a model, it is also possible to obtain the latent variables that are part of the models’ computations, and thus that putatively are the underlying variables needed to account for the observed behavior.Thus, cognitive modeling may provide two types of benefits to relate behavior and EEG signal. First, fitting computational models to behavioral data allows researchers to extract model parameters that are putatively related to mechanisms underlying behavior; these parameters may then capture variability  better than raw behavior would. Second, model fitting also allows researchers to extract latent variables that putatively reflect the computations supporting behavior. These variables may then be better candidates to reflect the trial-by-trial neural signal. In the next paragraphs, we give an overview of the computational modeling process with these two target benefits, and focus on two key examples: drift diffusion modeling (DDM) for perceptual decision making  we focus on here. The DDM is a used to account simultaneously for accuracy and reaction time observations in binary perceptual decision tasks, such as the random dots motion task , the difference between the observed reward and the predicted reward: rpe = rt − Vt. By how much the estimate is incremented is controlled by the learning rate parameter α, such that the new estimate at time t + 1 is Vt+1 = Vt + αrpe. The choice between two options depends on the estimated values, and can be controlled by a noise parameter ” section), but nevertheless hold considerable utility in revealing the relationship between EEG responses and behavior.In the sections that follow, we highlight approaches to link EEG data and behavioral data without imposing cognitive modeling constraints on their relationships. Single trial regression identifies associations between the two measures based upon their linear relationships, while the data-driven approaches  link EEG and behavior based upon the particular assumptions of the BSS model. These approaches do not incorporate an explicit link to cognitive parameters as the joint cognitive models discussed within the subsequent section  is a robust EEG marker of motor errors of commission ” section), or by using the regression weight of the Level 1 analysis as a first-order statistical summary for input into standard General Linear Models . This simple approach has been used to show that people with Generalized Anxiety Disorder indeed have different single trial brain-behavior relationships than controls, suggesting that (Level 2) individual differences influence (Level 1) mechanisms for instantiating cognitive control  may be constructed from pairwise correlation distances, pairwise classification accuracies  than among individuals diagnosed with schizophrenia  allele frequencies, cognitive state estimates, or behavioral measures. The Source Power Comodulation (SPoC) approach, for example, is effective at identifying components which correlate with a target variable , especially low SNR responses  regression analyses  responses to flickering signals and noise to account for how individual differences in the deployment of spatial attention can predict accuracy data  have been developed using ERP time courses and fMRI spatial maps as features  framework is ideally suited for the joint analysis of multiple modes of data  of human cognition is one of the most powerful methods to integrate EEG and behavior, since these datasets are linked with respect to the ata Lee, . In addiBayesian inference refers to underlying probability theory and methods used to obtain conclusions about data  have been obtained using hierarchical Bayesian modeling with ERP amplitude estimates on single trials, time-locked to the onset of visual stimuli. Such work is described in Nunez et al. . It was https://github.com/mdnunez/mcntoolbox  sampling techniques (see Table post hoc, decomposed jointly with behavior, or integrated with behavior to derive estimates of latent variables which represent cognitive function. In doing so, we hope to further our understanding of brain dynamics that contribute to moment-to-moment cognitive function.Neuroimaging research is focused on understanding the links between neural activity and observable behavior. This knowledge will help us understand how individual differences in the brain contribute to individual differences in cognitive processes. EEG is low cost, portable and provides millisecond resolution of brain activity. Thus, it is a promising tool for examining neural measures at the time scales of cognitive function. In order to relate EEG features with behavior, it will be important to obtain reliable single-trial estimates of EEG features using advanced processing and machine learning tools described within this review, and to move beyond the conventional focus on evoked components derived after averaging across trials and subjects. In addition, the accumulation of EEG depositories through data sharing and quantitative extensions beyond binary comparisons will also help advance the field. The resulting single trial EEG measures may be correlated with direct or latent measures of behavior DAB, JFC, AGEC, MDN, RS, SS and VDC wrote the manuscript and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We were pleased to read the systematic review of studies investigating associations between breast milk fatty acids and allergic disease outcomes by Waidyatillake et al. . A comprWe have published an original study  after thAs in the majority of the studies reviewed by Waidyatillake et al. , we idenSince our results diverge from previous studies likely due to different statistical methodology, we believe a good first step could be to re-examine existing data using simple statistical methodology similar to our own . As the In addition, breastfed children often constitute their own specific subgroup who may be more likely to have healthier and more educated mothers than children who were never breastfed or were breastfed for only a short period of time . To overFurthermore, fatty acid concentrations in breast milk have been shown to vary over the course of lactation . Infant Finally, early infancy is a particularly important period for development of the immune system and of the gut microbiome which may potentially be associated with childhood atopic outcomes. Therefore, we agree with the current review and believe future studies should add to ours by analyzing fatty acids and other constituents in colostrum which may be differentially associated with disease outcomes.To move forward, we suggest (i) building on the existing systematic reviews, (ii) employing the centered log ratio transformation to overcome spurious correlation, (iii) considering alternative ways of grouping fatty acids, (iv) reducing selection bias by sampling infant formula, (v) further investigating other forms of exposure assessment , and (vi) bearing in mind timing of exposure.Both CL and JG have conceived and written this commentary.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Drug-using offenders with co-occurring mental health problems are common in the criminal justice system. A combination of drug use and mental health problems makes people more likely to be arrested for criminal involvement after release compared to offenders without a mental health problem. Previous research has evaluated interventions aimed broadly at those with a drug problem but rarely with drug use and mental health problems. This systematic review considers the effectiveness of interventions for drug-using offenders with co-occurring mental health problems.We searched 14 electronic bibliographic databases up to May 2014 and five Internet resources. The review included randomised controlled trials designed to reduce, eliminate, or prevent relapse of drug use and/or criminal activity. Data were reported on drug and crime outcomes, the identification of mental health problems, diagnoses and resource information using the Drummond checklist. The systematic review used standard methodological procedures as prescribed by the Cochrane collaboration.Eight trials with 2058 participants met the inclusion criteria. These evaluated: case management , motivational interviewing and cognitive skills,  and interpersonal psychotherapy . None of these trials reported significant reductions in self-report drug misuse or crime. Four trials evaluating differing therapeutic community models showed reductions in re-incarceration  but not re-arrest  or self-report drug use . Mental health problems were identified across the eight trials and 17 different diagnoses were described. Two trials reported some resource information suggesting a cost-beneficial saving when comparing therapeutic communities to a prison alternative.Overall, the studies showed a high degree of variation, warranting a degree of caution in the interpretation of the magnitude of effect and direction of benefit for treatment outcomes. Specifically, tailored interventions are required to assess the effectiveness of interventions for drug-using offenders with co-occurring mental health problems. This systematic review stems from a previous Cochrane review which evaluated the effectiveness of interventions for drug using offenders (anonymised author and web link). The original Cochrane review was updated to produce three further reviews which explored the effectiveness of interventions aimed at reducing drug use and criminal activity in, i) drug using female offenders  of jail inmates in the US reporting a serious mental health problem  is not always the best place to manage people suffering from mental health problems. In the case of less serious offenders, several diversionary schemes have been established to provide a mechanism for diverting individuals with mental health problems into treatment programmes instead, or combined with incarceration Clarke . FindingEvidence from previous systematic reviews have tended to investigate the effectiveness of interventions for either (i) drug using offenders, or (ii) offenders with mental health problems. Evidence supporting the case for treatment include a range of different treatment options. Some examples include case management, therapeutic community models, cognitive skills and behavioural management and motivational interviewing. Case management evolved to address the needs of prisoner re-entry programmes covering employment, education, health, housing and family support via assessment and connecting clients with the appropriate services  also has a proven theoretical background showing that such techniques can lead to improved retention in treatment, enhanced motivation to change and reduced offending, McMurran . Miller Therapeutic communities (TCs) have been used in the US since the 1960s and more recently in the UK to rehabilitate offenders over a relatively long period of time. The TC ethos focuses on treatment of the ‘whole self’ and not on the drug abuse per se. Residents are instrumental in running the TC and supporting each other through the process and this encompasses the transition between prison and working within the community  comprising adult offenders with mental health problems. The findings showed that clozapine was favoured over alternative treatments for improving psychiatric symptoms. The review identified limited evidence to show that discharge planning with benefit application assistance and the use of mental health services on release from incarceration was effective. The authors called for more comparative trials to increase their confidence in the findings  Does any treatment for drug-using offenders with co-occurring mental health problems reduce drug use? (2) Does any treatment for drug-using offenders with co-occurring mental health problems reduce criminal activity? (3) How are people identified and diagnosed of a mental health problem? (4) Is there any resource information to enable a cost evaluation?The previous evidence demonstrates varied success with reductions in mental health, crime and drug outcomes but we know little about how interventions for drug using offenders and co-occurring mental health problems can help address treatment and rehabilitation opportunities. For this reason, we believe a systematic evaluation of the existing evidence might help add to the current body of evidence by identifying specific interventions for this group of people. We are also interested in learning more about how such individuals are identified, what diagnoses they are given and how much such interventions might cost. The review was therefore broad and included www.york.ac.uk/inst/crd/intertasc/) were used. The following are examples of the search terms used in the searches; prison, offender, substance or drug and reoffend. The search terms and strategies are documented in full in the following publication, (insert anonymised reference).This review stems from an original Cochrane review (insert anonymised reference). The results of this update meant that we began our searching where the previous review finished (insert anonymous reference). We searched 14 databases and identified records between 2004 and May 2014.In addition to the electronic databases, we searched relevant Internet sites ) and we scrutinised the reference lists of all retrieved articles for further references. We undertook catalogue searches of relevant organisations and contacted experts for their knowledge of other published or unpublished studies relevant to the review.The review included RCTs whereby the intervention was designed to reduce, eliminate, or prevent relapse of drug use and/or criminal activity. The comparison arm could contain no treatment, minimal treatment, a waiting list, treatment as usual or another treatment alternative.offenders as individuals who were involved in the CJS as residing in special hospitals, prisons, community diversion into court schemes or placed on arrest referral schemes for treatment. Offenders were judged to have a co-occurring mental health problem if the mechanism of identification was explicitly stated in the paper. The mechanism could include one or more of the following methods: i) use of diagnostic gold standard test ), and/or ii) whereby the nature of the intervention was specifically designed for people with mental health problems , and/ or iii) the participants were described as having a ‘history of psychiatric illness’ or a ‘serious mental disorder’ with co-occurrence of drug use. In some cases, this information was obtained from the participant description and demographic characteristics.We included drug-using offenders with co-occurring mental health problems regardless of gender, age or ethnicity. Drug misuse included any study that referred to individuals using occasional drugs or were drug dependent. We defined The interventions were designed, wholly or in part, to eliminate or prevent relapse to drug-use and/or criminal activity among participants. Based on these criteria we included a number of different psychosocial interventions. Psychosocial interventions have been defined as any intervention that focuses on social or psychological factors rather than biological factors  were reported as dichotomous and continuous outcome measures. Drug use measures were reported as: (1) self-report drug use ; and (2) biological drug use . Criminal activity measures were reported using self-report or official criminal justice records. These included arrest for any offence, drug offences, re-incarceration, convictions, charges and recidivism. Where papers evaluated a number of different follow-up periods, we chose to report the longest follow up period as we felt that such measures provided the most conservative estimate of effectiveness.Mental health diagnoses were taken from participant sample descriptions about how people were identified to take part within the trial. For this purpose, we used diagnostic gold standard test evidence, the nature of the intervention and demographic and background characteristics of the persons included.Resource information was examined with a full critical appraisal using the  independently inspecting the search hits by reading the titles and abstracts in a bibliographic database, ii) obtaining a full copy of each potentially relevant study, iii) assessing each study for inclusion, and iv) independently conducting a data extraction and agreement process. In the case of discordance, a third independent reviewer arbitrated. One reviewer undertook all the above stages in the translation of articles that were not written in English. The data extraction was completed using a standardised reporting system and a range of items coded . We also grouped the studies by intervention type and setting creating four intervention groups: case management, motivational interviewing and cognitive skills, interpersonal therapy and therapeutic community models.We conducted a narrative presentation of the study details , study methods (e.g. random assignment), participants , interventions , outcomes , resource information  and made notes on the study methodology and quality appraisal information using the Cochrane risk of bias tool.We were able to standardize our outcome measures using a mean difference (MD) for continuous outcomes measured on the same scale and a standardized mean difference (SMD) for outcomes measured on different scales. Higher scores for continuous measures represented greater harm. We risk ratios (RR) for dichotomous outcomes, and all were presented with 95 % confidence intervals (CIs).To avoid double counting of our outcome measures  and follow up time periods  all trials were checked to ensure that multiple studies reporting the same evaluation did not contribute towards multiple estimates of program effectiveness. We followed Cochrane Collaboration guidance and combined intervention and control groups to create single pair wise comparisons. Where this was not appropriate we selected one treatment arm and excluded the others see (Higgins and Green We used Summary of Findings Tables (SoF Table) to provide a concise and transparent summary of the key findings on the quality and certainty of the evidence using GRADE PRO software , the risk of bias, the consistency of the results across studies, and the precision of the overall estimate across studies. The recommended approach for assessing risk of bias in studies involves the use of a two-part tool that addresses six specific domains, namely, sequence generation and allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessor (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other sources of bias. This provides a rating of either Low, Medium or High risk of bias. These ratings use an independent risk of bias score see n = 23), they did not have co-occurring mental health problem (n = 41), the intervention was not aimed at reducing drug use or criminal activity (n = 7), the study did not report the required drug or crime outcome measures at the pre and/or post-intervention stages (n = 36) and the study did not report mental health information (n = 16). See the full report for further details (insert anonymised reference),We identified a total of 5988 records see Fig. . We acquSeven of the eight trials were conducted in the US; one trial was conducted in Spain. The publications ranged between 1999 and 2014 with a follow up period across the studies between 3 months to 5 years. The treatment length of the interventions (described further in the review) ranged from 8 weeks  court based sentencing with acceptance commitment therapy (ACT) and case management in comparison to treatment as usual  inThe remaining four trials evaluated different models of TC intervention. These included (i) a modified TC in comparison to a combined mental health and substance use education programme . The dichotomous outcomes were represented by one trial  to prison takes longer to process and often involves a court case which means that it is likely to be recorded within the time frame of an experimental evaluation. In comparison, ‘arrest’ (or ‘re-arrest’) is more frequent and is recorded in the CJS within a shorter time frame. Sacks et al.  also argOne specifically adapted TC treatment for women offenders compared women assigned to TC treatment or standard treatment, a cognitive behavioural recovery and relapse prevention curriculum referred to in the system as the Intensive Outpatient Program  or interpersonal psychotherapy  when compared to the control (18.2 %). These findings are similar to other studies that have used ACT albeit in non-incarcerated populations , and in some studies sample sizes were small. The Stein et al.  study waAnother possible selection bias concern in the series of Wexler studies was that participants were randomly assigned to the prison TC treatment and regular prison conditions but not to aftercare (Prendergast et al. We have identified several research implications. First, good-quality research is required to evaluate the effectiveness of interventions in offenders with substance misuse problems and co-occurring mental health problems. Of particular interest are the extended long-term effects of aftercare and the level of contact required with services in the community. Further research to enhance to explore the intensity of different community treatment alternatives following release may help to unravel this process. Second, better descriptions of participants’ mental health problems and more detailed information about mental health diagnoses are required to enable the transferability of information to clinical practice. Such information could also facilitate the use of mental health diagnoses as a moderator within the analysis of the outcomes. Third, trial interventions specifically focusing on females and adolescents are required. In the current review one study contained females, and one study reported on adolescents. Fourth, little is known about the interaction between mental health problems, individual personal characteristics and positive outcomes relating to treatment success. In terms of depression, Stein et al.  attempteFinally, standardising cost and cost-effectiveness information within trial evaluations would help policymakers make decisions about health versus criminal justice costs. New outcome evaluations should consider the length of time to a parolee’s re-arrest or re-incarceration, as this has cost implications. For example, the Prendergast et al.  study foTwo studies employing therapeutic community interventions with aftercare showed a reduction in subsequent re-incarceration. However, the studies generally showed a high degree of variation, warranting a degree of caution in the interpretation of the magnitude of effect and direction of benefit for treatment outcomes. More evaluations are required to assess the effectiveness of interventions for drug-using offenders with co-occurring mental health problems with better mental health descriptions and outcome measurement.


Economically and politically disruptive disease outbreaks are a hallmark of the 21st century. Although pandemics are driven by human behaviours, current surveillance systems for identifying pandemic threats are largely reliant on the monitoring of disease outcomes in clinical settings. Standardized integrated biological–behavioural surveillance could, and should, be used in community settings to complement such clinical monitoring. The usefulness of such an approach has already been demonstrated in studies on human immunodeficiency virus, where integrated surveillance contributed to a biologically based and quantifiable understanding of the behavioural risk factors associated with the transmission dynamics of the virus. When designed according to Strengthening the Reporting of Observational Studies in Epidemiology criteria, integrated surveillance requires that both behavioural risk factors – i.e. exposure variables – and disease-indicator outcome variables be measured in behavioural surveys. In the field of pandemic threats, biological outcome data could address the weaknesses of self-reported data collected in behavioural surveys. Data from serosurveys of viruses with pandemic potential, collected under non-outbreak conditions, indicate that serosurveillance could be used to predict future outbreaks. When conducted together, behavioural surveys and serosurveys could warn of future pandemics, potentially before the disease appears in clinical settings. Traditional disease-outcome surveillance must be frequent and ongoing to remain useful but behavioural surveillance remains informative even if conducted much less often, since behaviour change occurs slowly over time. Only through knowledge of specific behavioural risk factors can interventions and policies that can prevent the next pandemic be developed. Following the outbreak, calls for pandemic-threat warning systems came from both traditional public health policy-makers,Although human behaviours often increase the risk of acquiring an infectious disease, the systematic investigation of human risk behaviours is seldom included in disease surveillance strategies.,–Approximately half of the emerging pandemic threats are zoonotic in origin.The remainder of this article presents an overview of issues relevant to the design of rigorous behavioural surveys to assess the spillover of emerging zoonotic disease and the associated transmission risk factors, which is the first step in designing effective integrated surveillance. We identified community-based serological surveys of viruses with pandemic potential as a possible source of useful biological outcome data. We summarize the results of such serosurveys, conducted in non-outbreak settings in Africa, and evaluate their usefulness – especially when used in combination with behavioural surveillance – in the prediction of future outbreaks.When designed according to Strengthening the Reporting of Observational Studies in Epidemiology criteria,,In studies on zoonoses, the assessment of behavioural risk factors is complicated because different zoonotic diseases may be associated with different kinds of animal exposure. The spillover of zoonotic viruses from wildlife, the source of most emerging zoonoses,Syndromic surveillance is widely used to monitor illnesses of unknown etiology in clinical settings and can provide a useful referent in the identification of the outcome variables to be measured in behavioural surveys. Several zoonotic diseases, such as avian influenza,,The risks posed to humans by exposure to animals may be modified by various biological, ecological, economic, political and sociocultural factors.Even in the absence of detailed biological outcome data, behavioural surveillance may be used to assess relationships between behavioural risk factors and self-reported experiences of unusual illness that are consistent with the symptoms of zoonotic disease. This could be done both rapidly and at a scale that facilitates epidemiologically relevant analyses. Although not as conclusive as biological data, self-reported data could provide substantially more information than is currently available.In the field of pandemic threats, biological outcome data could address the weaknesses of any self-reported data collected in behavioural surveys. The ideal source of biological outcome data, i.e. data that provide the strongest evidence of zoonotic disease spillover, would be community-based screening for acute infection with zoonotic viruses. However, as such infection is rare under non-outbreak conditions, many thousands of individuals would usually have to be screened for a meaningful analysis of the behavioural risk factors. Serological assays, in which previous exposure to a virus is demonstrated by a positive result, can provide alternative biological outcome data. Since many more individuals may have been exposed to a virus than are currently ill with the virus, serology can provide the larger number of individuals, with known viral exposure, required for powerful analyses of behavioural risk factors. We therefore investigated the results of serosurveys for their potential usefulness in the prediction of future outbreaks. We focused on studies conducted in communities under non-outbreak settings in Africa. We collated results presented in peer-reviewed publications – in English, French or Spanish – that we identified via Google Scholar and Web of Science searches that ended on 31 December 2015 (available from the corresponding author). We used “Africa”, “antibody”, “serology”, “serosurvey”, “zoonoses” and “zoonotic disease” as search terms. We identified additional relevant results through the citations in the articles identified in the searches.,,–,,,,,,,,,,,Serosurveys of zoonotic viruses have been conducted since the discovery of the Ebola virus in the 1970s, mostly during or shortly after an outbreak of zoonotic disease. Our searches revealed 38 serosurveys of zoonotic viruses in Africa that had been conducted during non-outbreak conditions.Serological assays for several different zoonotic pathogens were conducted as part of serosurveillance in each of the 14 studies included in our analysis. Use of these assays led to the recording of a total of 38 unique zoonotic pathogen seroprevalences that ranged from 0% to 24%. Of these 38 seroprevalences, nine were recorded for high-risk population subgroups, 19 for medium-risk and 10 for low-risk. Evidence of previous exposure to a zoonotic pathogen, i.e. a seroprevalence of more than zero, was detected in eight (89%) of the high-risk population subgroups, 16 (84%) of the medium-risk and seven (70%) of the low-risk (available from the corresponding author). High seroprevalences, i.e. seroprevalences of at least 1%, represented the results for all eight of the high-risk subgroups with evidence of previous exposure to a zoonotic pathogen, 12 (75%) of the medium-risk subgroups with such evidence and three (48%) of the low-risk subgroups with such evidence (available from the corresponding author). Exposure to wildlife therefore appeared to be associated both with any evidence of viral exposure and with high seroprevalence.,,Since the first known outbreak in 1976, the United States Centers for Disease Control and Prevention have recorded 35 documented Ebola outbreaks in Africa.,,,Although serological assays exist for the coronaviruses that cause MERS and SARS, Hantaan viruses and paramyxoviruses, most serosurveys of zoonotic viruses in Africa have focused on haemorrhagic fevers. Most of the serosurveys we reviewed had also been done before the widespread availability and use of viral detection tests. Recently, population-based serosurveys have been increasingly adopted, in recognition of their utility in preparing health authorities for potential outbreaks or epidemics.We review the potential contributions that integrated biological–behavioural surveillance could make to pandemic-threat prediction, prevention and risk mitigation. If we are to mitigate the risk of a zoonotic disease outbreak, we need a better understanding of the mechanisms behind the spillover of zoonotic disease into human populations. By making such mechanisms the focus of integrated surveillance, we should be able to: (i) monitor the presence and prevalence of behavioural risk factors and the seroprevalence of specific zoonotic pathogens within particular population subgroups; (ii) deploy targeted control and mitigation strategies rapidly; and (iii) evaluate the efficacy of prevention policies and interventions.Although traditional disease surveillance must be frequent and ongoing to remain useful, behavioural surveillance remains informative even if conducted much less often, since behaviour change occurs slowly over time. To be effective as a prevention tool, integrated biological–behavioural surveillance should be implemented as a baseline measure – to identify behavioural risk factors, determine the prevalence of those risk factors, especially in any population subgroups that are considered at higher risk of zoonotic spillover, and establish seroprevalence. Should an outbreak occur, a database that documents local behaviours and practices, as well as the context within which such behaviours occur, can contribute to the development of appropriate and feasible strategies for disease control and mitigation. Finally, data from integrated surveillance will be invaluable in both informing realistic and effective interventions and policies for the prevention of zoonotic spillover and transmission, and evaluating the impact of such interventions and policies efficiently.,,Relative to the economic, social and political costs of epidemics, prevention will always be less expensive,There is substantial overlap between areas considered to be hotspots for zoonotic disease spillover and those considered hotspots for HIV, perhaps the best known zoonotic virus.Integrated surveillance will never be a viable alternative to traditional clinical disease surveillance for assessing active viral infections. Rather, it can serve to complement virus detection efforts, by potentially identifying pandemic threats before the need for large-scale clinical intervention. As current behaviours may not reflect the behaviours that originally exposed the individuals who are found seropositive to the virus of interest, both current and lifetime behaviours need to be investigated. This is the strategy that has proved successful in identifying subtle exposure risks in the field of HIV, such as backloading of syringes with drug solution by injecting drug users.Current pandemic-threat warning systems rely almost exclusively on disease surveillance in clinical settings. Standardized biological–behavioural surveillance, in which both disease outcome data – self-reported and biological – and behavioural risk factors are measured, would complement traditional surveillance and greatly advance the understanding of behaviours and practices that could be targeted for risk mitigation and, ultimately, for prevention. The implementation of integrated biological–behavioural surveillance need not be frequent to be informative and useful in preventing the spillover of zoonotic agents with pandemic potential.