According to the World Health Organization, mental illness is one of the leading causes of disability worldwide. The first onset of mental illness usually occurs during childhood or adolescence, with nearly 12 million diagnosed cases in the United States alone. Neuroimaging and genetic testing have been invaluable in research on behavioral, affective, and attentional disorders, particularly with their potential predictive capabilities, and ability to improve diagnosis and to decrease the associated burdens of disease. The present study focused specifically the perspectives of mental health providers on the role of neuroimaging and genetic testing in clinical practice with children and adolescents. Methods We interviewed 38 psychiatrists, psychologists, and allied mental health professionals who work primarily with youth about their receptivity toward either the use of neuroimaging or genetic testing. Interviews probed the role they foresee for these modalities for prediction, diagnosis, treatment planning, and the benefits and risks they anticipate. Practitioners anticipated three major benefits associated with clinical introduction of imaging and genetic testing in the mental health care for youth: (1) improved understanding of the brain and mental illness, (2) more accurate diagnosis than available through conventional clinical examination, and (3) legitimization of treatment plans. They also perceived three major risks: (1) misuse or misinterpretation of the imaging or genetic data, (2) potential adverse impacts on employment and insurance as adolescents reach adulthood, and (3) infringements on self-esteem or self-motivation. Limitations The nature of the interview questions focused on the future of neuroimaging and genetic testing research in the context of clinical neuroscience. Therefore, the responses from interview participants are based on anticipated rather than actual experience. Continued expansion of brain imaging and genetic testing into clinical care will require a delicate balance of brain biology and respect for autonomy in the still-evolving cognitive and affective world of young individuals.
In vivo animal models of familial amyotrophic lateral sclerosis (fALS) are widely used to delineate the potential role that genetic mutations play in the neurodegenerative process. While these models are extensively used for establishing the safety and efficacy of putative therapeutics during pre-clinical development, effective clinical translation of pharmacological interventions has been largely unsuccessful. Results In this report we compare a recent cohort of G37R (line 29) mice generated from mating wild-type females with transgenic males obtained commercially to a previous set of offspring produced with transgenic male breeders from a colony established at a local collaborator’s facility. Commercially derived progeny presented with a tightly clustered genomic signature for the mutant human superoxide dismutase1 transgene (hSOD1) locus, and exhibited a greater than two-fold reduction in the number of transgene copies present in the genome compared to offspring derived locally. Decrease in transgene levels corresponded with delayed ALS progression and a significant increase in overall lifespan (146%). ConclusionsThese results highlight some key challenges inherent to the use of G37R (line 29) animals in pre-clinical studies for the development of ALS therapeutics. Without stringent assessment of mutant SOD1 copy number/protein levels, heterogeneity of transgene levels within cohorts may influence the behavioural and pathological presentation of disease and thus calls to question the validity of any detected therapeutic effects. Nuanced changes in mutant SOD1 copy number that currently remain unreported may undermine research endeavours, delay efforts for clinical translation, and compromise the rigor of animal studies by limiting reproducibility amongst research groups.
We used existing and customized bibliometric and scientometric methods to analyze publication trends in neuroimaging research of minimally conscious states and describe the domain in terms of its geographic, contributor, and content features. We considered publication rates for the years 2002–2011, author interconnections, the rate at which new authors are added, and the domains that inform the work of author contributors. We also provided a content analysis of clinical and ethical themes within the relevant literature. We found a 27% growth in the number of papers over the period of study, professional diversity among a wide range of peripheral author contributors but only few authors who dominate the field, and few new technical paradigms and clinical themes that would fundamentally expand the landscape. The results inform both the science of consciousness as well as parallel ethics and policy studies of the potential for translational challenges of neuroimaging in research and health care of people with disordered states of consciousness.
Adult onset amyotrophic lateral sclerosis (ALS) arises due to progressive and irreversible functional deficits to the central nervous system, specifically the loss of motor neurons. Sporadic ALS causality is not well understood, but is almost certainly of multifactorial origin involving a combination of genetic and environmental factors. The discovery of endemic ALS in the native Chamorro population of Guam during the 1950s and the co-occurrence of Parkinsonism and dementia in some patients led to searches for environmental toxins that could be responsible. In the present paper, we report that an environmental neurotoxin enhances mutant superoxide dismutase (SOD)-induced spinal motor neuron death and pathology and induces motor axon abnormalities. These results cumulatively confirm earlier findings that exposure to an environmental toxin is sufficient to produce the disease phenotype and indicate a role for gene-environment interaction in some forms of the disease.
A mouse model of amyotrophic lateral sclerosis–parkinsonism–dementia complex based on the consumption of cycad seed flour was used to determine whether the observed pathology of motor neuron loss begins in the distal axons or the spinal cord. Assessments of neuromuscular junction integrity and motor neurons were performed at multiple time points. Mice fed cycad pellets performed worse on the wire hang than controls. Microglial activation in cycad-fed mice was observed with motor neuron degeneration at 12 weeks, but reactive astrocyte proliferation was not observed. After 33 weeks of cycad feeding, motor neuron loss had stabilized, with no evidence of neuromuscular junction endplate denervation. These data suggest that neuronal pathology begins at the soma and proceeds distally in a ‘dying forward’
The temporal course of cellular pathology in virus-infected oligodendrocytes in vivo is not well defined. Here we study these events in the mouse brain using a novel system in which large numbers of oligodendrocytes can be reproducibly infected. In the mouse, following extraneural inoculation, the A7(74) strain of the alphavirus Semliki Forest virus (SFV) is efficiently neuroinvasive and central nervous system (CNS) infection leads to predominantly perivascular lesions of immune-mediated demyelination. This study demonstrates that direct intracerebral inoculation with SFV A7(74) or the SFV1 vector results in dramatic, selective and widespread infection of the major white matter tract of the brain, the corpus callosum. Mature oligodendrocytes are the predominant cell type infected. Subsequent events are complex; early virus-induced necrotic death of infected cells is followed by apoptotic death of adjacent apparently uninfected cells. A strong inflammatory response and considerable myelin loss are evident from 10 days and virus-positive cells are not observed after this time. In contrast, in athymic nu/nu mice, in the absence of T-cell responses, no inflammatory infiltrates are observed and virus-infected cells persist for over 30 days with extensive vacuolation but less demyelination. The change from an early destructive to a potentially persistent infection of oligodendrocytes is likely to reflect activation of innate immune responses. Activation of peripheral innate defences by inoculation of poly I : C prior to CNS virus infection abrogates the widespread corpus callosum infection. This widespread infection of the corpus callosum provides a novel in vivo system in which to study virus-oligodendrocyte interactions.
Background: Familial adult onset amyotrophic lateral sclerosis (FALS) poses injuries to the central nervous system that lead to progressively debilitating and irreversible motor deficits. The loss of motor neurons results from a poorly understood, multifactorial neurodegenerative process. Mutations in the gene encoding superoxide dismutase 1 (SOD1) are one cause of FALS. In contrast, sporadic ALS occurs with a vastly greater incidence occurs from unknown etiologies. Among suspected causes are various environmental toxins. An early report of environmental causes of neurodegenerative disease, including a form of ALS, pointed to a long latency neurotoxin in cycad seeds amongst the Chomorro people of Guam. Both washed cycad as well as isolated water insoluble steryl glucosides (SG) similar to that found in cycad seeds reproduced an ALS-PDC phenotype in an in vivo model. Objectives: To determine whether environmental agents such as those from cycad accelerate disease onset in an otherwise late-onset condition, we combined two in vivo models of ALS testing dietary SGs for their potential synergistic properties in combination with genetic predisposition to adult onset ALS in the G37R mouse. Methods: Male and female mice were treated with 42 mg of SG per kilogram of body weight daily in their diet. A cohort of animals harboured the SOD1G37R mutation for genetic predisposition to ALS. Results: Results showed an additive effect of SG on spinal motor neuron loss and caused decreases in average soma diameter. While the presence of the transgene alone caused a leftward shift towards smaller diameter ventral root axons, SG exposure alone resulted in a bimodal distribution resembling a more immature state. The presence of the transgene alone markedly increased the amount of GFAP- and Iba1-positive cells in the spinal cord grey matter, with a heterogeneous expression of ramified (resting) and activated morphologies. The transgene in combination with SG did not significantly change glial numbers, but caused all glial cells to become extensively activated. Discussion and Conclusions: Although the mechanism of cycad toxin-induced neurodegeneration remains uncertain, the current results showed that dietary exposure to SGs alone was sufficient to produce a disease phenotype, but that when implemented in conjunction to a genetic predisposition to ALS was sufficient to produce a more severe disease phenotype. In conclusion, the environmental agent studied here has direct cytotoxic effects and contributes to disease progression in ALS. The mouse model of disease exploited in this study may be used further to understand the mechanisms of motor neuron death and CNS pathology in degenerative conditions exacerbated by environmental agents.
Background: Amyotrophic lateral sclerosis with missense mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD1) account for approximately 1-2% of all ALS cases, and is purported to be both clinically and neuropathologically indistinguishable from sporadic forms of the disease. The underlying pathobiological mechanism implicated in SOD1-mediated familial ALS (fALS) involves a toxic gain-of-function mutation with resultant misfolding and aggregation of the aberrant protein. The above observations, coupled with research demonstrating that both wild-type and mutant SOD1 can misfold and aggregate upon in vitro oxidation, has led to a hypothesis that aberrant SOD1 conformational changes underlie all ALS etiology. However, a recent study by Liu et al (2009) using the misfolded SOD1-specifi c SEDI antibody in sporadic and familial ALS cord samples does not support this interpretation. Objectives: Previous work conducted by our group has shown that a Guamanian ALS-Parkinsonism dementia complex (ALS-PDC) phenotype can be replicated by exposing mice to stigmasterol β-D-glucoside (SG). Utilizing SOD1 conformation-specifi c antibodies, our studies attempted to determine if SG induced SOD1 conformational changes, as well as to probe for any synergistic effect on SOD1 misfolding arising from exposure of mSOD G37R mice to this toxin. Methods: The human IMR-32 neuroblastoma cell line was exposed to SG at a concentration of 50 μM for a period of up to 9 days. Wild-type and transgenic mSOD G37R mice were treated with 42 μg/kilogram of body weight daily starting at 10 weeks of age. The role of SG regarding induction of aberrant SOD1 protein folding was investigated with the use of novel antibodies selective for epitopes indicative of misfolded SOD1. Results: The results do not implicate SOD1 misfolding and aggregation as the mechanism of SG mediated neurotoxicity. Prolonged SG treatment of IMR-32 cells exhibited cell loss but failed to induce SOD1 misfolding. Additionally, SG exposure in mice did not demonstrate a synergistic interaction on SOD1 conformational state with the G37R mutation. Discussion: Although the mechanism of SG toxin neuropathology is uncertain, it has been shown that dietary exposure to SG alone is sufficient to produce a disease phenotype and a more severe phenotype in conjunction with a genetic predisposition to ALS. These results posit that aberrant SOD1 folding is not implicated as a mechanism for SG neuropathology and support the notion that SOD1 conformational changes are unique to some forms of fALS.
Adult onset amyotrophic lateral sclerosis (ALS) poses progressive and irreversible functional deficits to the central nervous system due to loss of motor neurons, caused by some poorly characterized, multifactorial etiology. Research focused on sporadic ALS cases with vastly greater incidence than hereditary ALS describes the potential causes to be of environmental origin. The discovery of endemic ALS in the native Chamorro population of Guam during the 1950s and the co-occurence of Parkinsonism and dementia led to searches for an environmental cause. To determine whether a genetic predisposition to adult-onset ALS could be exacerbated by atoxin that is known to produce a similar phenotype, I combined genetic and environmental models of ALS and tested a known neurotoxin (steryl glucosides) for its potential synergistic properties in combination with the genetic defect. Transgenic SOD1 G37R mice were treated with 42 mg toxin per kilogram of body weight daily in their daily diet. Results showed an additive effect of toxin on spinal motor neuron death, and caused decreases in average soma diameter on surviving motor neurons. The presence of the transgene alone resulted in smaller diameter ventral root axons. Toxin exposure alone resulted in a bimodal configuration of the ventral root size histogram resembling a more immature state of motor axons. The transgene alone markedly increased the amount of GFAP-and Iba1-positive glial cells in the spinal cord grey matter, with a heterogeneous expression of ramified (resting) and activated morphology. The transgene in combination with toxin did not significantly change glial numbers, but caused all glial cells to become extensively activated. Although the mechanism of cycad toxin-induced neurodegeneration remains uncertain, these results showed that dietary exposure to environmental toxin alone was sufficient to produce a disease phenotype, and when implemented in conjunction to a genetic predisposition to ALS was sufficient to produce a more severe disease phenotype. In conclusion, the environmental agent studied here has direct cytotoxic effects, contributes to disease progression in ALS, and indicate an additive effect of dietary neurotoxin in combination with genetic mutations leading to familial ALS.
Traumatic brain injuries (TBI) affect an estimated 1.7 million people annually in North America and Europe (US Census Bureau 2004), while more than 3 million are already living with a permanent disability resulting from neurologic trauma (CDC 2009). Consequences of brain injury leave many in a disordered state of consciousness and unable to communicate or respond to their environment. Neuroscience research with functional MRI, PET, MEG, and EEG aims to develop avenues for improving diagnosis and prognosis of these patients, and may eventually open up unprecedented channels of quantitative diagnostics and communication with them. Such progress signals potentially actionable changes in care and management of this historically neglected group of patients. Concurrently, key stakeholders face a host of ethical, legal and financial challenges for health policy development and public communication that require proactive consideration. To address this convergence of neurotechnology and society, we hypothesize that the tension between the scientific, translational, and ethics challenges related to hope for recovery and end-of-life decision-making for TBI patients is a convergent key priority for assessing clinical actionability. We test this hypothesis through a qualitative analysis framework that explores the current and future ability of neuroimaging to be translated to clinical applications. The framework uses seven test nodes: the patient and patient care, family, public communication, health care resource allocation, research finances allocation, legal implications, and medical knowledge. Each node represents an impact variable evaluated in the context of actionability within health care systems, health policy, and the heterogeneity of TBI, patient autonomy, and human values.
Familial adult onset amyotrophic lateral sclerosis (FALS) is the result of injuries to the central nervous system that lead to progressively debilitating and irreversible motor deficits. The loss of motor neurons results from a poorly understood, multifactorial neurodegenerative process. Mutations in the gene encoding superoxide dismutase 1 (SOD1) are one cause of FALS. In contrast, sporadic ALS occurs with a vastly greater incidence occurs from unknown etiologies. Among suspected causes are various environmental toxins. An early report of environmental causes of neurodegenerative disease, including a form of ALS, pointed to a long latency neurotoxin in cycad seeds amongst the Chomorro people of Guam. Both washed cycad as well as isolated water insoluble steryl glucosides (SG) similar to that found in cycad seeds reproduced an ALS-PDC phenotype in an in vivo model. To determine whether environmental agents such as those from cycad accelerate disease onset in an otherwise genetic late-onset condition, we combined two in vivo models of ALS, testing dietary SGs for their potential synergistic properties in combination with genetic predisposition to adult onset ALS in the G37R mouse. Male and female mice were given 42 mg of SG per kg of body weight in their daily diet. A cohort of these animals harboured the G37R SOD1 mutation for genetic predisposition to ALS, while wild type littermates served as controls. Comparisons of motor dysfunction between groups were made by using unpaired two-tailed Student’s t tests (95% confidence intervals) using PRISM 3.02 software (GraphPad, San Diego) and repeated measures two-way ANOVA. Assessment of motor neuron loss, gliosis, and end plate innervation were analysed using unpaired two-tailed Student’s t test and results are presented as means and SDs. The current results showed that dietary exposure to SGs alone was sufficient to produce a disease phenotype, and in combination with the G37R genotype produced additive, not synergistic, degenerative effects.
Click here for conference programme and reports from Sydney 2011.
Adult onset amyotrophic lateral sclerosis (FALS) poses progressive and irreversible function deficits to the central nervous system due to loss of motor neurons, caused by some poorly characterized, multifactorial etiology. Research focused on sporadic ALS describes the potential causes to be of environmental origin. The discovery of endemic ALS in Guam during the 1950s and the co-occurrence of parkinsonism and dementia led to searches for an environmental cause. The earliest etiological studies of this neurodegenerative disease cluster pointed to a long latency neurotoxin in cycad seeds now known as steryl glucosides (SG). Hypothesis: Spinal motor neurons are vulnerable to cycad toxicity in the ageing mouse spinal cord (single stressor), particularly in transgenic mice with a genetic predisposition to ALS (combined stressors). The CNS response to cycad toxins originates in the spinal cord. To determine whether a genetic predisposition to ALS could be exacerbated by a toxin that is known to produce a similar phenotype, I combined genetic and environmental models of ALS and tested SG for its potential synergistic properties in combination with the genetic defect. Twenty male mice and an equal number of female mice were given 42 mg of SG per kg of body weight in their daily diet. Half of these animals of each sex harboured the G37R SOD1 mutation for genetic predisposition to ALS, while wild type littermates served as controls. Similarly, an equal number of transgenic and wild type mice of each sex were given 42 mg/kg control food pellets. Comparisons of motor dysfunction between groups were made by using unpaired two-tailed Student’s t tests (95% confidence intervals) using PRISM 3.02 software (GraphPad, San Diego) and repeated measures two-way ANOVA. Assessment of motor neuron loss, gliosis, and end plate innervation were analysed using unpaired two-tailed Student’s t test and results are presented as means and SDs. These results indicate that a genetic predisposition to a severe ALS phenotype yields a CNS that has heightened sensitivity to environmental insults that contribute to motor dysfunction, and point to a dynamic interplay of genes and environment in the aetiology of ALS. The environmental agent studied here has cytotoxic effects approaching significance, contributes to disease progression in ALS, and suggest an additive effect of dietary neurotoxin in combination with genetic mutations leading to familial ALS. The environmental mouse model of ALS-PDC developed in this study may be used to further elucidate the role of gene-environment dynamics and its application in the aetiology of other neurodegenerative diseases.
Familial adult onset amyotrophic lateral sclerosis (FALS) poses injuries to the central nervous system that lead to progressively debilitating and irreversible motor deficits, which result from a poorly understood, multifactorial neurodegenerative process. Although it is well known that mutations in the gene encoding superoxide dismutase 1 (SOD1) are reported to be one cause of FALS, a secondary group of ALS cases with vastly greater incidence occurs with unknown causes. Research dedicated to these sporadic ALS cases describes the potential causes to be of environmental origin. The earliest report of environmental causes of neurodegenerative disease pointed to a long latency neurotoxin in cycad seeds responsible for the high incidence of ALS-parkinsonism dementia complex among the Chomorro people of Guam during the 1950s and 1960s. Recently isolated water insoluble steryl glucosides from cycad have been shown to reproduce an ALS-PDC phenotype in feeding animals. Methods: Twenty male mice and an equal number of female mice were treated with 42 mg of SG per kilogram of body weight daily in their daily diet. Half of these animals harboured the mSOD1G37R mutation for genetic predisposition to ALS. The role of SG regarding: a) progressive loss of motor coordination and grip endurance; b) onset of motor neuron dysfunction; c) severity of gait abnormalities and aberrant roaming activity; and d) enhancement of ALS neuropathology was investigated. Conclusion: These results indicate that a genetic predisposition to a severe ALS phenotype yields a CNS that has heightened sensitivity to environmental insults that contribute to targeted motor neuron loss, and point to a dynamic interplay of genes and environment in the aetiology of ALS. The environmental mouse model of ALS-PDC developed in this study may be used to further elucidate the role of gene-environment dynamics and its application in the aetiology of other neurodegenerative diseases.
Click here for conference programme from Orlando 2010.
Familial amyotrophic lateral sclerosis (FALS) is a motor neuron disorder due to a single gene defect that results in progressive degeneration of upper and lower motor neurons. FALS accounts for only 10% of all ALS cases, approximately 20% of which are due to mutations in the copper/zinc superoxide dismutase gene (SOD1). Mutations in SOD1 have also been identified in 3–7% of sporadic ALS cases, which blurred the distinction between familial and sporadic ALS. The development of transgenic animals mimicking human ALS phenotypes enables research into understanding SOD1 FALS, but falls short of representing sporadic disease. Studies of the ALS/Parkinsonism-dementia complex in the western Pacific over the past 60 years have revealed the prominent etiological role of environmental (dietary) factors. Particularly, affected populations developed the ALS variant of this disease after heavy exposure to the cycad plants. Animal models of ALS/PD complex are reproduced by dietary administration of cycad neurotoxins, and recapitulate many of its prominent clinical and pathological ALS features. In light of the limitations of transgenic animal models and the greater prevalence of sporadic disease, studies of gene-environment relationships are a more inclusive representation of ALS as a motor neuron disease. Therefore, we studied the effect of exposure to steryl glucoside, a known neurotoxin in cycad, on transgenic mice that express the human mutant SOD1. The FALS mutation in these mice is a substitution of arginine for glycine at position 37 (G37R) with 5 times the endogenous human SOD1 in spinal cord (line 29). This line of G37R mice were chosen because their later age of onset of disease (10–12 months) allows for a detailed study of such orally administered neurotoxins with long latency effects.
Background: The ALS2 gene encodes alsin, a protein with guanine nucleotide exchange factor (GEF) activity and a role in the development and regulation of neurite and axonal outgrowth. Loss-of-function mutations in ALS2 are characterized by juvenile onset, slow progression, and heterogeneous clinical phenotypes including juvenile onset primary lateral sclerosis (JPLS), infantile onset ascending hereditary spastic paraplesia (IAHSP), and juvenile onset ALS (ALS2). However, Als2-deficient mouse models have failed to reproduce the classical hallmark symptoms of motor neuron disease or ALS23. Therefore, we investigated the possibility that ALS2-linked pathologies arise from the combinatorial effects of genetic predisposition and neurotoxins in the diet. In particular, we examined the effect of exposure to neurotoxic dietary sterol glucosides (SG) on the onset and progression of an ALS2 motor phenotype in both Als2-knockout (KO) and their wild-type littermates. We hypothesize that Als2-/- mice were more susceptible to neuropathological changes when exposed to neurotoxins. Methods: We have established a colony of Als2-/- mice started from mice produced by Devon et al. The colony was maintained by breeding homozygotes to produce Als2-/- offspring (N=33) and breeding homozygotes to hemizygotes to yield Als2+/- (N=9). Wild type littermate controls of the same strain (n=20) were obtained from Jackson Laboratories. Starting at 10 weeks of age, a total of 23 mutant mice received daily dietary mouse chow pellets containing SG at 42mg SG/kg body weight (to a total weight of 1.5g per pellet). At the same time, 19 age-matched mutants also received SG-containing pellets. Both treated and control mice were provided with a daily total food intake of 2.5g. Animals were assessed monthly for motor dysfunction by measuring grip strength, motor coordination, and clasping reflex. Assessments for gait disturbances were administered at 5, 7, 9, and 12 months of age. Upon reaching 15 months of age, animals were euthanized and perfused intracardially. Spinal cord and brain were collected and processed for histology. Results and conclusion: Als2-deficient mice demonstrate significant differences in muscle strength and motor function compared to wild type counterparts, including superior overall performance on the Rotarod and grip strength tests. SG-treated mice demonstrated significant gait disturbances compared to controls while walking on a treadmill. Exposure to sterol glucosides in combination with genetic predisposition produces the greatest motor deficits than either stressor alone.
Dominant mutations in the Cu2+/Zn2+ superoxide dismutase (mSOD1) gene are the most frequent cause of familial amyotrophic lateral sclerosis (fALS), a progressive and fatal disease characterized by the degeneration of motor neurons in the cortex, brainstem, and spinal cord. One form of mSOD1-mediated ALS occurs when arginine is substituted for glycine at the 37th position of the gene (G37R). The etiology of ALS remains largely unknown, but current evidence suggests that motor neuron injury is non-cell-autonomous and involves damage caused by mSOD1 proteins within glia of the central nervous system. The mSOD1 model of ALS is an example of neurodegenerative disease with a primary etiological factor that is genetic. The recently identified gene ALS2 encodes the protein alsin. Alsin has been shown to have guanine nucleotide exchange factor (GEF) activity for Rab5- and Rho-GTPases, and has been implied to play a role in the development and regulation of neurite and axonal outgrowth. In humans, loss-of-function mutations in this gene have been linked to autosomal recessive forms of motor neuron disease (MND). Yet, Als2-deficient mouse models have failed to reproduce the classical hallmark symptoms of MND or ALS2. Other forms of ALS, such as ALS-PDC syndrome, have been suggested to be multifactorial diseases caused by gene-environment interactions. The neurological disease amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) is characterized by a range of behavioural and neuropathological attributes shared with several neurodegenerative diseases, including ALS, Alzheimer’s Disease (AD), and Parkinson’s Disease (PD). Recent work by our group has shown that sterol glucosides (SG) are neurotoxic to motor neurons and induces an ALS-PDC phenotype in an in vivo model of disease3. Such work provides evidence that neurotoxin can be the sole necessary and sufficient condition for neurodegenerative disease. We have hypothesized that exposure to SG in combination with a genetic predisposition will act as combined stressors in the events leading to motor neuron degeneration in the central nervous system (CNS) to produce a more pronounced phenotype than either stressor introduced alone.
Background: Autosomal recessive juvenile onset amyotrophic lateral sclerosis (ALS2) are reported to be caused by loss of function mutations of the ALS2 gene encoding alsin, a protein with suggested roles in endosomal transport and guanine nucleotide exchange activity. To establish an animal model of ALS2, mice that are deficient in the Als2 gene are generated, and have previously been shown to exhibit significant but subtle neuropathological changes and behavioural alterations. This raises the possibility that the ALS2 phenotype is a result of the interaction of genetic and environmental factors. Therefore, we studied the influence of dietary exposure to β-sitosterol β-D-glucoside (BSSG) on the motor performance of Als2-/- and wild-type mice, hypothesizing that Als2-/- mice are possibly more susceptible to such neurotoxicity. BSSG is the largest fraction of steryl glucoside in cycad seeds and has been shown to induce amyotrophic lateral sclerosis-parkinsonism dementia complex in mice, with a dominant phenotype resembling ALS. Results: Mice deficient in Als2 gene show subtle differences in gait patterns when exposed to BSSG. These mice show shorter stance duration, stride duration and stride length than control-fed KO mice (p < 0.05). In addition, these mice also exhibit increased stride frequency (p< 0.05). WT mice fed BSSG exhibit a greater stride frequency than their KO counterparts (p < 0.05). Exposure to BSSG results in a shorter stride and faster, more frequent steps during locomotion irrespective of genotype. Als2 deficient mice are less active, exhibiting slower and wider turns during meandering. The pathological features of anterior horn cells in these animals resembles clinical ALS. Conclusion: BSSG effects gait dynamics while Als2 genotype exerts its effects on open field activity.
Autosomal recessive juvenile onset amyotrophic lateral sclerosis (ALS2) are reported to be caused by loss of function mutations of the ALS2 gene encoding alsin, a protein with suggested roles in endosomal transport and guanine nucleotide exchange activity. To establish an animal model of ALS2, mice that are deficient in the Als2 gene are generated, and have previously been shown to exhibit significant but subtle neuropathological changes and behavioural alterations. This raises the possibility that the ALS2 phenotype is a result of the interaction of genetic and environmental factors. Therefore, we studied the influence of dietary exposure to β‐sitosterol β‐D‐glucoside (BSSG) on the motor performance of Als2‐/‐ and wild‐type mice, hypothesizing that Als2‐/‐ mice are possibly more susceptible to such neurotoxicity. BSSG is the largest fraction of sterylglucoside in cycad seeds and has been shown to induce amyotrophic lateral sclerosis‐parkinsonism dementia complex in mice, with a dominant phenotype resembling ALS.
Background: An almost classical form of ALS, ALS parkinsonism dementia complex (ALS-PDC) was first described on Guam in years immediately after WWII. Incidence levels were up to 400 times higher than in North America. The disease peaked in the 1960s then began to decline to a current level similar to that of the industrialized world. The clearest epidemiological link to the disease was consumption of flour made from the seeds of a type of cycad, Cycas micronesica. Disease levels declined in step with decreased use of cycad as food. Intensive studies identified various novel amino acid toxins in cycad seeds, including MAM, BOAA, and BMAA. None of these were able to induce an ALS phenotype in animal models. We re-examined the “cycad hypothesis” by feeding washed cycad seed flour in which the above toxins had been removed to CD-1 adult male mice for a prolonged period while testing motor and other behaviours. Post sacrifice, we examined the CNS using histological and biochemical methods. Cycad-fed mice displayed an early ALS phenotype, including deficits in leg extension and gait; motor neurons were lost in ventral spinal cord and elsewhere in the CNS. The impacts at the behavioural and anatomical levels were progressive. Similar experiments in which one of the active cycad neurotoxins, a sterol glucoside (bsitosterol b-D glucoside, BSSG) was fed to mice showed qualitatively similar outcomes. Objectives: To determine the temporal progression of the ALS phenotype at behavioural, systems, cellular, and biochemical levels. Methods: Adult male (5 mo old) CD1 or C57/Bl6 mice were used. Motor tests included leg extension, rotarod, gait, wire hang, detailed gait analysis, social interaction, and object memory. Mice were sacrificed at various time points following the onset of cycad or BSSG feeding and processed for histological analysis. Neuromuscular junction (NMJ) integrity was assessed by co-labelling of nicotinic receptors (bungarotoxin) and nerve terminals (neurofilament/SV2) in the gastrocnemius muscle. In vitro studies using NSC-34, a motor neuron-derived cell line, exposed to sterol glucosides complemented the in vivo work. Results and Discussion: Behavioural results are presented in an accompanying abstract and poster (P185). Lumbar ventral cord showed significant losses of motor neurons accompanied by microglial proliferation early during cycad treatment. Neither spinal cord astrogliosis nor NMJ denervation were detected at this time point. In vitro, treatment with synthetic sterol glucosides reduced NSC34 cell viability in a dose- and time-dependent fashion. Treated NSC34 cells showed morphological alterations, including the formation of Tau-positive TDP-43-negative axonal beading. Conclusions: Cycad neurotoxins such as BSSG can reproduce aspects of Guamanian ALS-PDC, with the first events apparently involving the motor system in which motor neurons and microglia are the earliest cells affected.
Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disease that targets motor neurons, leading to widespread denervation atrophy of muscle. Transgenic mice that carry mutations in the gene encoding Cu, Zn superoxide dismutase (SOD) are by far the most common model of ALS. Such models have their limitations since 5 – 10% of ALS cases are familial and of these, only 20–25% are due to mutations in the gene encoding SOD. Previously, a mouse model of ALS-parkinsonism dementia (ALS-PDC) was generated by in vivo feeding of washed cycad flour, and shows motor deficits that mimic human pathology. In the present study, we assessed previously unexplored aspects of the behavioural and neuropathological pattern of cycad-fed mice, namely detailed gait analysis, social and object memory, and neuromuscular junction integrity. Washed cycad flour pellets were fed to mice as part of their daily diet, while control mice were received regular white flour pellets. All animals were housed individually, with unlimited access to water. A detailed gait analysis was performed weekly using ventral plane videography (DigiGait). Cycad-fed animals show a transient, but significant, deficit in their gait pattern, as revealed by ventral plane videography. In addition, subtle deficits in tasks of social recognition were also detected, whereas object memory seemed to be preserved. Animals were perfused at 12, 19, and 33 weeks after implementation of their diet. Quantitative analysis in spinal cord showed a significant increase in microglia activation at each time point as determined by two-way ANOVA, whereas no differences in astrocyte proliferation were apparent. At 33 weeks, motor neuron loss was greater in cycad-fed animals whereas there was no evidence of significant end-plate denervation in either group. This suggests that motor neuron pathology may begin at the motor neuron soma and proceed distally. This is different from the SOD mouse model of ALS, where axonopathy was shown to begin distally at the motor end-plates and proceed proximally. These results are important in comparing what may be diseases with different etiopathological mechanisms.
Amyotrophic lateral sclerosis–parkinsonism dementia complex (ALS-PDC) is a unique progressive neurological disorder first characterized among the indigenous Chamorro people of Guam. The clinical phenotype of ALS-PDC is one of either classical ALS/motor neuron disease, or an Alzheimer’s dementia with parkinsonism features, or a combination of both. In a lengthy epidemiologic surveillance of the disease, evidence revealed that the strongest epidemiologic link was the correlation to consumption of the seeds from Cycas micronesica, a species of cycad. We have previously generated a mouse model of ALS-PDC by in vivo feeding of washed cycad flour. Treated mice show phenotypes that mimic or correspond to human pathology in all aspects, especially the expression of an ALS phenotype: mice show inappropriate clasping reflexes, tremor, and deterioration of motor coordination and/or muscle strength and a loss of motor neurons in lumbar cord and motor cortex. In the present study, immunohistochemistry together with fluorescence microscopy was used to compare the morphological features of axons and their endplates of cycad-fed and control mice.
Loss-of-function mutations of the alsin gene (Als2) are related to a juvenile-onset form of motor neuron disease known as ALS2. Alsin is involved in the regulation of guanine nucleotide signalling pathways. Although knock-out Als2-/- mice show subtle behavioural alterations, they do not fully exhibit the neurological deficits observed in individuals with ALS2. This raises the possibility that the ALS2 phenotype is attributed to the interaction of genetic and environmental factors. Therefore, we studied the influence of the dietary exposure to cycad seeds on the motor performance of Als2-/- and wild-type mice hypothesizing that Als2-/- mice are possibly more susceptible to neurotoxic insults. The neurotoxins in cycad seeds have been proposed as a causative environmental agent of the amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC), a neurological syndrome clustered in Guam and other locations in the Western Pacific. Als2-/- and wild-type mice were fed cycad flour as part of their normal diet (0.5 g cycad flour/day during 6 months) and subjected weekly to motor function tests including rotarod, wire hang, clasping reflex, stride length, and beam walking. A group of wild-type cycad-fed animals showed significant motor neuron loss in the lumbar spinal cord. No significant differences in motor function between knock-out and wild-type mice were observed using these tests. At the end of the feeding period, a detailed gait analysis was performed using ventral plane videography (DigiGait). Als2-/- mice showed a more athletic gait by a smaller hind limb splay angle (p < 0.05) and a less variable stance width (p < 0.05). The cause of this supernormal gait performance in alsin knock-out mice is unclear, but a similar phenomenon has been observed in the SOD G93A genetic model of ALS. This may represent an over compensatory response of the motor system to an underlying pre-symptomatic neurodegenerative event. In conclusion, our findings suggest that Als2-/- mice exposed to cycad toxins do not show an obvious behavioural impairment as compared to wild-type animals. These data underscore the complexity of the gene-environment interaction in neurodegenerative diseases.
Semliki Forest Virus (SFV) infection of mice is used as a model to study pathogenic processes occurring in viral encephalitis. It has previously been shown that the avirulent A7(74) strain strictly infects white matter tracts of the corpus callosum following intracerebral inoculation in adult Balb/c mice. The aim of the present study was to determine the dynamics of virus spread in the mouse brain following intracerebral viral inoculation, to help in understanding the mechanism of viral infection along white matter tracts. Microscopic examination of brains from mice inoculated with either small, medium, or high titres of virus and stained against a viral antigen revealed an initial spread of virus in all groups from 18 hours to 3 days post infection. Spread throughout the length of the corpus callosum and into the surrounding tissue was observed. At the higher viral titres, a decrease in viral distribution is observed from three days to six days post infection, whereas low viral tires show an increase in the extent of viral distribution at each consecutive time post infection. These results show that the virus is able to spread from cell to cell, and this is the mechanism by which the virus infects the length of the white matter tracts. Following the construction of the infections SFV4 strain, a vector system was previously developed which induces transient expression of cloned genes in transfected cells. Virus-like particles carrying green fluorescent protein were previously harvested from initial transfections of SFV vectors. This study demonstrates that these virus-like particles exhibit a similar CNS distribution to virus at corresponding times post infection following intracerebral inoculation into adult Balb/c mice. The whole-cell morphology and neuroanatomical distribution of cells expressing enhanced green fluorescent protein were consistent with that of oligodendrocytes. In addition, the quantity of fluorescing cells and the extent of their distribution were observed to fluctuate in a temporal pattern similar to virus. The ability of these virus-like particles to replicate and share the cell tropism of its parental strain is clearly a potential for use in studying SFV pathogenesis in vivo.
Background: Acquired brain injury is a critical public health and socioeconomic problem in Canada, leaving many patients in vegetative, minimally conscious, or locked-in states, unresponsive and unable to communicate. Recent advances in neuroimaging research have demonstrated residual consciousness in a few exemplary patients with acquired brain injury, suggesting potential misdiagnosis and changes in prognosis. Such progress, in parallel with research using multimodal brain imaging technologies in recent years, has promising implications for clinical translation, notwithstanding the many challenges that impact health care and policy development. This study explored the perspectives of Canadian professionals with expertise either in neuroimaging research, disorders of consciousness, or both, on the potential clinical applications and implications of imaging technology. Methods: Twenty-two professionals from designated communities of neuroimaging researchers, ethicists, lawyers, and practitioners participated in semistructured interviews. Data were analyzed for emergent themes. Results: The five most dominant themes were: (1) validation and calibration of the methods; (2) informed consent; (3) burdens on the health care system; (4) implications for the Canadian health care system; and (5) possibilities for improved prognosis. Conclusions: Movement of neuroimaging from research into clinical care for acquired brain injury will require careful consideration of legal and ethical issues alongside research reliability, responsible distribution of health care resources, and the interaction of technological capabilities with patient outcome.
Perspectives canadiennes à propos de l’«actionnabilité» clinique de la neuroimagerie dans les troubles de la conscience. Contexte: Une lésion cérébrale acquise est un problème de santé publique et un problème socioéconomique important au Canada et ce type de lésions laisse plusieurs patients dans un état végétatif, de conscience minimale ou de verrouillage avec absence de réponse et incapacité à communiquer.Des progrès récents de la recherche en neuroimagerie ont montré la présence d’un état de conscience résiduel chez quelques patients particuliers ayant subi une lésion cérébrale, ce qui suggère la possibilité qu’un diagnostic erroné ait été posé et doncmodifie le pronostic. De tels progrès, en parallèle avec la recherche utilisant des technologies d’imagerie multimodales du cerveau dans les dernières années, comportent des implications prometteuses en cliniquemalgré les nombreux défis qui ont des incidences sur les soins de santé et l’élaboration de politiques. Cette étude a exploré les perspectives des professionnels Canadiens qui possèdent une expertise, soit dans la recherche en neuroimagerie, dans les troubles de la conscience ou dans ces deux domaines, concernant les applications et les implications cliniques potentielles de la technologie d’imagerie. Méthode: Vingt-deux professionnels de milieux désignés de neuroimagerie, soit des chercheurs, des éthiciens, des avocats et des praticiens ont participé à des entrevues semi-structurées. Les données ont été analysées pour déceler des thèmes émergents. Résultats: Les 5 principaux thèmes émergents étaient les suivants: (1) la validation et la calibration des méthodes; (2) le consentement éclairé; (3) le fardeau pour le système de santé; (4) les implications pour le système de santé canadien; et (5) les possibilités d’améliorer le pronostic. Conclusions: Le transfert de la neuroimagerie des lésions traumatiques cérébrales de la recherche à la clinique requerra qu’on effectue un examen approfondi tant des aspects légaux et éthiques que de la fiabilité de la recherche, de la distribution responsable des ressources en santé et de l’interaction entre les ressources technologiques et les résultats chez les patients.
Missense mutations in the gene encoding superoxide dismutase 1 (SOD1) are reported to be one cause of adult-onset familial amyotrophic lateral sclerosis (FALS). FALS causes injuries to the motor system that lead to progressively debilitating and irreversible motor deficits, which result from a poorly understood, multifactorial neurodegenerative process. FALS makes up only 10% of all ALS cases, while sporadic cases of unknown cause(s) occur with vastly greater incidence. The earliest report of environmental causes of neurodegenerative disease pointed to a long latency neurotoxin in cycad seeds responsible for the high incidence of ALS-parkinsonism dementia complex among the Chomorro people of Guam during the 1950s and 1960s. We have previously shown that an ALS-PDC phenotype can be demonstrated by feeding mice cycad seed flour as well as several various neurotoxic steryl glucosides isolated from this flour. To determine whether environmental toxins accelerate disease onset, we studied the influence of dietary exposure of β-sitosterol β-D-glucoside (BSSG) in mice over expressing the human SOD1G93A mutant. BSSG is the largest fraction of steryl glucoside in cycad seeds. Transgenic mSOD1G37R line 29 and wild-type littermates were fed 42 mg SG/kg body weight as part of their daily diet commencing at 3 weeks of age. Indications of motor neuron dysfunction were measured with hind limb clasping reflex scores. Gait abnormalities and aberrant open field activity were monitored for a subgroup of parameters. Mice were euthanized and spinal cord and brain tissues were dissected after perfusion with paraformaldehyde. Tissues were processed to be frozen for cryosectioning and lumbar cord sections were immunostained to visualize motor neurons, astroglia, and microglia. These results indicate that a genetic predisposition to a severe ALS phenotype yields a CNS that has heightened sensitivity to environmental insults that contribute to targeted motor neuron loss, and point to a dynamic interplay of genes and environment in the aetiology of ALS. The environmental mouse model of ALS-PDC developed in this study may be used to further elucidate the role of gene-environment dynamics and its application in the aetiology of other neurodegenerative diseases.
Approximately 20% of Canadians will experience a mental disorder in their lifetime, with the first onset of mental illness usually occurring during childhood or adolescence. Each year, the prevalence of mental illness among Canadian adults is nearly 2 million for mood disorders and 5 million for anxiety disorders. However, for clinical care of mental health disorders in youth, diagnostic criteria remain contentious and treatments under-researched. Advancements in neuroimaging and genetic testing promise to improve diagnostic and predictive capabilities in mental health care and, to some extent, alleviate the associated burden of disease. As these technologies become clinically viable, it is important to anticipate their impact on clinical practice and physician-patient relationships especially related to the care and classification of youth with mental disorders. We present findings from a semi-structured qualitative interview study that sought mental health care providers’ perspectives on the predictive power and risks of neuroimaging and genetic testing for youth. We interviewed 38 psychiatrists, psychologists, and allied mental health professionals who work primarily with children and adolescents about their receptivity towards either the use of neuroimaging or genetic testing in clinical practice and the roles they foresee for these modalities. Practitioners anticipated three major benefits associated with clinical introduction of imaging and genetic testing in the mental health care: (1) improved understanding of illness, (2) more accurate diagnosis, and (3) validation of treatment plans. They also anticipated three major risks: (1) potential impact on employment and insurance as adolescents transition to and reach adulthood, (2) misuse or misinterpretation of the imaging or genetic data, and (3) infringements on self-esteem or self-motivation. As susceptibility testing for mental illness and functional brain imaging broaden in appeal to patients and their families, these findings are essential for informing careful assessments of risks and benefits associating with emerging neurotechnologies, and consideration of both access to and standards regulating their use in clinical care is essential.
Click here for conference link
Disorders of consciousness resulting from traumatic or acquired brain injuries are a major cause of death and disability worldwide, with an annual incidence of 600 out of 100,000 in North America and Europe. Research has yielded novel neuroimaging methods to assess consciousness and potentially to communicate with patients who remain impaired. Public enthusiasm for this science is fueled by high media visibility cases and frequent press coverage, and when taken together with publicized debates about technical details of study design, can cause confusion within the academic and public communities. Here we present an analysis of trends in the academic literature for neuroimaging and minimally conscious states (MCS) to map the landscape of the domain in terms of its geographic, contributing, and content features. We used bibliometric analyses of MeSH terms to explore publication rates, the rate of new authorship growth, the relationships between publications and authors for the years 2001-2011, and content analysis of a subset of papers available from Open Access to characterize the nature of the clinical and ethical themes within these publications. Results from the 312 papers retrieved for analysis show that the scholarly literature on neuroimaging in MCS between 2001 and 2011 has grown at a rate of 27% per year. A small cohort of prominent researchers and their students from large clinical research hospitals in Canada, the USA and Belgium dominate the field. While there is a steady stream of contributions from new authors who represent a wide range of related disciplines, their contributions are largely peripheral to strong interrelationships among dominant authors. Content analysis revealed clinical themes in most of the 32 Open Access papers, discussing ethical decision-making in patient care, clinical management by the bedside, and clinical assessment. Although the science of consciousness continues to enjoy the public spotlight, it appears to attract few new contributors and develop new themes that would fundamentally expand its landscape. These results inform parallel ethics and policy studies of the potential for translational challenges of MCS and neuroimaging broadly in research and health care.
The second decade of neuroethics is well underway. While the goal of securing a future for neuroethics was largely accomplished during the first decade, the goal of shaping and refining that future remains central to the second decade. As young scholars in the field and members of the Student & Postdoctoral Fellow Committee of the International Neuroethics Society (INS), we pose important questions about defining its future, offer some preliminary responses, and challenge a set of assumptions about how the Academy and society should engage with neuroethics. These questions include: What is special about neuroethics that sets it apart from other disciplines in ethics or is it really just “bioethics for the brain”? What should the institutional structure of neuroethics look like by 2024 vis-à-vis its own trainees and existing disciplines? Should neuroethics be composed of clinicians, lawyers, philosophers, and neuroscientists, or should there be career “neuroethicists”? Is it possible to be a “neuroethicist”? How should work in neuroethics be funded? What visions of diversity should neuroethics adopt? What should the governance of neuroethics look like? We argue that the unique points of view offered by the field reside in the bilateral relationship neuroethics has with neuroscience. Specifically, neuroethics not only comments on responsible applications of neuroscience but on how developments in neuroscience can challenge our traditionally endorsed moralities and provide reasons to revise our moral philosophies in new ways. We observe and challenge the dominant opinion that one should engage with neuroethics from within one of the established core disciplines (e.g., medicine, neuroscience, law, philosophy, bioethics) and argue for a role of career neuroethicists as nodes for collaboration and idea transfer in a symposium model of neuroethics. We identify a series of institutional challenges to the optimal training and support of persons to act as these nodes and offer how we might surmount these challenges. Amongst these challenges, we note the siloization of the individual disciplines, where each adopt their own language and own valued outputs while heavily discounting the value of work accomplished in other silos. We consider the merits and drawbacks, therefore, of movements towards a departmental status for neuroethics. We also consider which visions of diversity neuroethics should adopt. We call for broad engagement between senior and junior scholars in the field, encourage deliberation about alternative visions for the future of neuroethics, and conclude by considering what role the INS should have in moderating between competing visions for that future.
Outline for a 60-minute panel session: Studies of functional brain imaging with various neurotechnologies have disclosed exciting findings that may improve our understanding of how consciousness is mapped in the brain. Such research advancements demonstrate a potential for neuroimaging to be included as a component in the clinical assessment of disorders of consciousness. However, they do not currently have sufficient evidentiary support to be included as a diagnostic option in routine clinical care. In line with the 2012 themes of tradition, innovation and moral courage, this panel discusses neuroimaging in this historically neglected patient population and raises awareness in the context of health policy specific to the management of health care.
Panelist 1 discusses the fundamentals of neuroimaging and how it deepens our understanding of cognitive control, emphasizing the role of neural networks in cognitive processes that are important in determining levels of consciousness. She presents her investigative work on clinical applications of EEG and fMRI techniques for disorders of consciousness. In light of this discussion, she addresses how integrating neuroimaging techniques may inform clinical assessment of disorders of consciousness.
Panelist 2 characterizes existing gaps between ethical and policy issues in disorders of consciousness, presenting the hope and promise of guided neuroimaging research towards formal applications in clinical diagnostic and treatment options.
Panelist 3 presents an overview of the current skepticism surrounding functional brain imaging findings and the shortcomings and limitations specific to research design. His presentation outlines the impending considerations necessary to establish scientific validity for clinical application. Panelist 3 also describes a significant discrepancy that is emerging between peer-reviewed neuroimaging reports and the information conveyed to the public through mass media.
Panelist 4 discusses how future research activities in brain imaging might affect health care policy and present particular ethical challenges. His presentation analyzes the potential for neuroimaging to reshape social, legal, and psychological conceptions of disorders of consciousness, particularly regarding treatment goals, decision-making considerations, and the public understanding of “consciousness” itself.
Acquired brain injury is a critical health problem in Canada, placing greater demands on health resources as improvements in intensive care lead to more patients in long-term care. Clinical diagnosis of patients with disorders of consciousness remains difficult, but advances in neuroimaging research have the potential to reshape clinical management of such patients or provide unprecedented ways to communicate with them. Building on our earlier work, this study identifies ethically salient priorities for research and policy before translation of this promising technology. Methods: We interviewed 27 Canadian researchers, ethicists, lawyers, practitioners, allied health care professionals, and patient advocacy leaders, with expertise in neuroimaging or disorders of consciousness. Interviews were semi-structured and data were analyzed for emergent themes. Results: Participants were optimistic that neuroimaging could lead to improved clinical care. They discussed mitigating the risks of misinterpreting results and communication, creating guidelines for clinical use, and defining legal competence in this neuroimaging context as key ethical priorities for translation. Conclusions: The transition of neuroimaging techniques for disorders of consciousness from research to clinical care may yield substantial benefits to these patients, but first requires resolution of research, policy, and translational issues.
Recent neuroimaging research on disorders of consciousness provides direct evidence of covert consciousness otherwise not detected clinically in a subset of severely brain-injured patients. These findings have motivated strategic development of binary communication paradigms, from which researchers interpret voluntary modulations in brain activity to glean information about patients’ residual cognitive functions and emotions. The discovery of such responsiveness raises ethical and legal issues concerning the exercise of autonomy and capacity for decision-making on matters such as healthcare, involvement in research, and end of life. These advances have generated demands for access to the technology against a complex background of continued scientific advancement, questions about just allocation of healthcare resources, and unresolved legal issues. Interviews with professionals whose work is relevant to patients with disorders of consciousness reveal priorities concerning further basic research, legal and policy issues, and clinical considerations.