Ethical Challenges in Contemporary FASD Research and Practice.

Fetal alcohol spectrum disorder (FASD) is increasingly recognized as a growing public health issue worldwide. Although more research is needed on both the diagnosis and treatment of FASD, and a broader and more culturally diverse range of services are needed to support those who suffer from FASD and their families, both research and practice for FASD raise significant ethical issues. In response, from the point of view of both research and clinical neuroethics, we provide a framework that emphasizes the need to maximize benefits and minimize harm, promote justice, and foster respect for persons within a global context.

Disclosing incidental findings in brain research: the rights of minors in decision-making.

MRI is used routinely in research with children to generate new knowledge about brain development. The detection of unexpected brain abnormalities (incidental findings; IFs) in these studies presents unique challenges. While key issues surrounding incidence and significance, duty of care, and burden of disclosure have been addressed substantially for adults, less empirical data and normative analyses exist for minors who participate in minimal risk research. To identify ethical concerns and fill existing gaps, we conducted a comprehensive review of papers that focused explicitly on the discovery of IFs in minors. The discourse in the 21 papers retrieved for this analysis amply covered practical issues such as informed consent and screening, difficulties in ascertaining clinical significance, the economic costs and burden of responsibility on researchers, and risks (physical or psychological). However, we found little discussion about the involvement of minors in decisions about disclosure of IFs in the brain, especially for IFs of low clinical significance. In response, we propose a framework for managing IFs that integrates practical considerations with explicit appreciation of rights along the continuum of maturity. This capacity-adjusted framework emphasizes the importance of involving competent minors and respecting their right to make decisions about disclosure.

Comments and reflections on ethics in screening for biomarkers of prenatal alcohol exposure.

Early identification of and intervention for fetal alcohol spectrum disorder (FASD) has been shown to optimize outcomes for affected individuals. Detecting biomarkers of prenatal alcohol exposure (PAE) in neonates may assist in the identification of children at risk of FASD enabling targeted early interventions. Despite these potential benefits, complicated ethical issues arise in screening for biomarkers of PAE and these must be addressed prior to the implementation of screening programs. Here, we identify and comment, based on a North American perspective, on concerns raised in the current ethical, social, and legal literature related to meconium screening for PAE. Major ethical concerns revolve around the targeting of populations for PAE screening, consent and respect for persons, stigma and participation rates, the cost-benefit analysis of a screening program, consequences of false-positive and false-negative test results, confidentiality and appropriate follow-up to positive screen results, and the use of screen results for criminal prosecution. We identify gaps in the literature on screening for PAE, most notably related to a lack of stakeholder perspectives (e.g., parents, healthcare providers) about screening and the ethical challenges it presents.

Role of dopamine D1 receptors in the prefrontal dorsal agranular insular cortex in mediating cocaine self-administration in rats.

RATIONALE: Orbital/insular areas of the prefrontal cortex (PFC) are implicated in cocaine addiction. However, the role of dopamine D1 receptors in mediating cocaine self-administration in these sub-regions remains unknown. OBJECTIVES: To define the role of the dorsal agranular insular (AId) sub-region of the PFC, we investigated the effects of D1 receptor manipulation on self-administration behavior maintained by cocaine and cocaine-related stimuli. MATERIALS AND METHODS: Rats were trained to lever press for cocaine (1 mg/kg) under a fixed-interval 5-min (fixed-ratio 5:S) second-order schedule of reinforcement in the presence of conditioned light cues and contextual sound cues. Intra-AId infusions of vehicle, the D1-like receptor agonist SKF 81297 (0.1, 0.2, 0.4 microg/side) or the D1-like receptor antagonist SCH 23390 (1.0, 2.0, 4.0 microg/side), were administered prior to 1-h self-administration test sessions. Food-maintained responding under a second-order schedule was examined in separate rats to determine if pretreatment with D1 ligands produced general impairments in responding. RESULTS: Infusion of SKF 81297 (0.2 and 0.4 microg/side) reduced active lever responses during the first 30 min of 1-h test sessions, but did not influence cocaine intake. Infusion of 4.0 microg/side SCH 23390 reduced active lever responses and cocaine intake throughout the 1-h test sessions. Additionally, this dose of SCH 23390 disrupted food-maintained responding and intake. CONCLUSIONS: D1 receptor agonists and antagonists in the AId have diverse consequences and time courses of action. D1 receptor stimulation in the AId may reduce the motivating influence of cocaine-related stimuli on responding whereas D1 receptor blockade in this PFC sub-region produces global disruptions in behavior.

In the Know and in the News: How Science and the Media Communicate About Stem Cells, Autism and Cerebral Palsy.

Stem cell research has generated considerable attention for its potential to remediate many disorders of the central nervous system including neurodevelopmental disorders such as autism spectrum disorder (ASD) and cerebral palsy (CP) that place a high burden on individual children, families and society. Here we characterized messaging about the use of stem cells for ASD and CP in news media articles and concurrent dissemination of discoveries through conventional science discourse. We searched LexisNexis and Canadian Newsstand for news articles from the US, UK, Canada and Australia in the period between 2000 and 2014, and PubMed for peer reviewed articles for the same 10 years. Using in-depth content analysis methods, we found less cautionary messaging about stem cells for ASD and CP in the resulting sample of 73 media articles than in the sample of 87 science papers, and a privileging of benefits over risk. News media also present stem cells as ready for clinical application to treat these neurodevelopmental disorders, even while the science literature calls for further research. Investigative news reports that explicitly quote researchers, however, provide the most accurate information to actual science news. The hope, hype, and promise of stem cell interventions for neurodevelopmental disorders, combined with the extreme vulnerability of these children and their families, creates a perfect storm in which journalists and stem cell scientists must commit to a continued, if not even more robust, partnership to promote balanced and accurate messaging.

A Dichotomy of Information-Seeking and Information-Trusting: Stem Cell Interventions and Children with Neurodevelopmental Disorders.

Parents and primary caregivers of children with Cerebral Palsy (CP) and Autism Spectrum Disorder (ASD) are faced with difficult treatment choices and management options for their children. The potential of stem cell technologies as an interventional strategy for CP and ASD has gained attention in the last decade. Information about these interventions varies in quality, resulting in a complex landscape for parent decision making for a child's care. Further complicating this landscape are clinics that advertise these interventions as a legitimate treatment for a fee. In this study, we surveyed individuals who considered taking their child with ASD or CP abroad for stem cell interventions on their use of different sources of stem cell related health information and their level of trust in these sources. Participants reported that while the Internet was their most frequent source of information, it was not well-trusted. Rather, information sources trusted most were researchers and the science journals in which they publish, other parents of children with CP and ASD, and healthcare providers. These findings highlight a dichotomy between information-seeking preferences and information-trusted sources. We discuss the challenges of health science communication and present innovative opportunities to increase communication with trusted and reliable sources as part of an integrated multi-pronged approach.

Influence of cocaine self-administration on learning related to prefrontal cortex or hippocampus functioning in rats.

RATIONALE: Individuals who abuse cocaine have cognitive deficits, particularly in functions associated with the orbitofrontal cortex. It is not clear to what extent the impact of cocaine on cognitive functioning is related to its role as a behavioral reinforcer. A preclinical means to investigate this issue is to use a yoked-triad procedure in which sets of three animals either contingently self-administer cocaine or receive passive administration of cocaine or saline in a noncontingent manner. OBJECTIVE: Using this procedure, we assessed cocaine's effect on learning that requires a functionally intact prefrontal cortex (prelimbic or insular/orbital subregions) or hippocampus. METHODS: Rats self-administering 1-mg/kg unit doses of cocaine responded under a fixed-ratio 5, time-out 20-s schedule of drug delivery. Testing took place in a radial-arm maze within the first 30 min after 2-hr drug sessions ended, beginning after 2.5 months of cocaine or saline exposure. RESULTS: Rats self-administering cocaine earned 14-18 infusions on average throughout different phases of the study. In groupwise comparisons, learning in the visually guided delayed win-shift (prelimbic prefrontal cortex-related) and win-shift (hippocampus-related) tasks was not influenced by contingent or noncontingent cocaine exposure. Session latency, though, was shorter in both cocaine-exposed groups during the win-shift task. During the odor-guided delayed win-shift task (insular/orbital prefrontal cortex-related), learning was disrupted in rats self-administering cocaine, with no influence of noncontingent cocaine exposure. CONCLUSIONS: Based on these and previous findings, learning related to functioning of the insular/orbital prefrontal cortex and amygdala is the most consistently disrupted in cocaine-intoxicated rats after long-term drug exposure.

Complementary tasks to measure working memory in distinct prefrontal cortex subregions in rats.

Acquisition of odor-guided or visually-guided delayed win-shift behavior was evaluated in rats after lidocaine-induced inactivation within the agranular insular area of the prefrontal cortex (PFC) or the prelimbic area of the PFC. Additional sites and tasks were used to control for neuroanatomical and behavioral specificity of lidocaine inactivation of the agranular insular and prelimbic areas. Results showed that acquisition of the odor-guided delayed win-shift task was dependent on the agranular insular area, whereas acquisition of the visually-guided version was dependent on the prelimbic area. This dissociation suggests that the stimulus modality used is critical for revealing working memory functions of different PFC subregions. The described methods provide a complementary means to study working memory in PFC subregions using a radial-arm maze.

Disparities in Canadian indigenous health research on neurodevelopmental disorders.

OBJECTIVE: To map the landscape of research on autism (ASD), cerebral palsy (CP), and fetal alcohol spectrum disorder (FASD) in Canadian Aboriginal children. METHOD: The authors used a detailed search strategy to identify and access publications on ASD, CP, and FASD involving Canadian Aboriginal children, families, and communities from online databases. They analyzed these materials for the type of research, stated objectives, methodologies, and the level of engagement of Aboriginal Peoples. RESULTS: The authors found a total of 52 reports published since 1981 relevant to Aboriginal children. Of these, 51 focused exclusively on FASD. They also found a near-complete failure to acknowledge community involvement in research decisions or dissemination of results in any of the publications. CONCLUSIONS: The focus on FASD in Aboriginal children and the absence of research on the other 2 major childhood disorders are at odds with rates of these disorders across Canadian children. The authors argue that this trend violates fundamental principles ensuring equitable representation of all children regardless of background in research and access to benefits of research in health care and perpetuates stigma in an already marginalized population.

Treatments for neurodevelopmental disorders: evidence, advocacy, and the Internet.

The Internet is a major source of health-related information for parents of sick children despite concerns surrounding quality. For neurodevelopmental disorders, the websites of advocacy groups are a largely unexamined source of information. We evaluated treatment information posted on nine highly-trafficked advocacy websites for autism, cerebral palsy, and fetal alcohol spectrum disorder. We found that the majority of claims about treatment safety and efficacy were unsubstantiated. Instead, a range of rhetorical strategies were used to imply scientific support. When peer-reviewed publications were cited, 20 % were incorrect or irrelevant. We call for new partnerships between advocacy and experts in developmental disorders to ensure better accuracy and higher transparency about how treatment information is selected and evidenced on advocacy websites.

Dopamine and serotonin interactively modulate prefrontal cortex neurons in vitro.

BACKGROUND: Dopamine (DA) and serotonin (5-HT) are released in cortex under similar circumstances, and many psychiatric drugs bind to both types of receptors, yet little is known about how they interact. METHODS: To characterize the nature of these interactions, the current study used in vitro patch-clamp recordings to measure the effects of DA and/or 5-HT on pyramidal cells in layer V of the medial prefrontal cortex. RESULTS: Either DA or 5-HT applied in isolation increased the evoked excitability of prefrontal cortex neurons, as shown previously. Coapplication of DA and 5-HT produced either a larger increase in excitability than when either was given alone or a significant decrease that was never observed when either was given alone. Dopamine or 5-HT also "primed" neurons to respond in an exaggerated manner to the subsequent application of the other monoamine. CONCLUSIONS: These data reveal the unappreciated interactive nature of neuromodulation in cortex by showing that the combined effects of DA and 5-HT can be different from their effects recorded in isolation. On the basis of these findings, we present a theory of how DA and 5-HT might synergistically modulate cortical circuits during various tasks.

Evidence-based neuroethics for neurodevelopmental disorders.

Many neurodevelopmental disorders affect early brain development in ways that are still poorly understood; yet, these disorders can place an enormous toll on patients, families, and society as a whole and affect all aspects of daily living for patients and their families. We describe a pragmatic, evidence-based framework for engaging in empiric ethics inquiry for a large consortium of researchers in neurodevelopmental disorders and provide relevant case studies of pragmatic neuroethics. The 3 neurodevelopmental disorders that are at the focus of our research, cerebral palsy (CP), autism spectrum disorder (ASD), and fetal alcohol spectrum disorder (FASD), bring unique and intersecting challenges of translating ethically research into clinical care for children and neonates. We identify and discuss challenges related to health care delivery in CP; neonatal neurological decision making; alternative therapies; and identity, integrity, and personhood.

Context-dependent prefrontal cortex regulation of cocaine self-administration and reinstatement behaviors in rats.

Evidence of stimulus attribute-specificity within the prefrontal cortex (PFC) suggests that different prefrontal subregions may contribute to cocaine addiction in functionally distinct ways. Thus, the present study examined the effects of lidocaine-induced inactivation of two distinct PFC subregions, the prelimbic (PL) or dorsal agranular insular (AId) cortices, on drug-seeking and drug-taking behaviors under cocaine maintenance and reinstatement testing conditions in rats trained to self-administer 1 mg/kg cocaine under a second-order schedule of drug delivery. Throughout maintenance and reinstatement phases, rats were exposed to conditioned light cues and contextual odor or sound cues. Results showed that PL inactivation during maintenance test sessions significantly reduced drug-seeking and drug-taking behaviors, and disrupted patterns of responding in rats exposed to light-sound, but not light-odor, cues. Moreover, lidocaine-induced inactivation of the PL significantly attenuated drug-seeking behavior during cue-induced and cocaine prime-induced reinstatement in rats exposed to light-sound cues only. In contrast, AId inactivation significantly attenuated cue-induced reinstatement of drug-seeking behavior in rats exposed to light-odor cues only. Drug-seeking and drug-taking behaviors in these rats were not disrupted during maintenance and cocaine prime-induced reinstatement testing regardless of the type of contextual cues used. Together, these data suggest that PL and AId subregions play separate yet overlapping roles in regulating cocaine addiction in rats in ways that are dependent on the presence or absence of cocaine and on the types of contextual cues present in the cocaine self-administration environment.