The ethics of animal research: a survey of pediatric health care workers

INTRODUCTION: Pediatric health care workers (HCW) often perform, promote, and advocate use of public funds for animal research (AR). We aim to determine whether HCW consider common arguments (and counterarguments) in support (or not) of AR convincing. DESIGN: After development and validation, an e-mail survey was sent to all pediatricians and pediatric intensive care unit nurses and respiratory therapists (RTs) affiliated with a Canadian University. We presented questions about demographics, support for AR, and common arguments (with their counterarguments) to justify the moral permissibility (or not) of AR. Responses are reported using standard tabulations. Responses of pediatricians and nurses/RTs were compared using Chi-square, with P < .05 considered significant. RESULTS: Response rate was 53/115(46%) (pediatricians), and 73/120(61%) (nurses/RTs). Pediatricians and nurses/RTs are supportive of AR. Most considered ‘benefits arguments’ sufficient to justify AR; however, most acknowledged that counterarguments suggesting alternative research methods may be available, or that it is unclear why the same ‘benefits arguments’ do not apply to using humans in research, significantly weakened ‘benefits arguments’. Almost all were not convinced of the moral permissibility of AR by ‘characteristics of non-human-animals arguments’, including that non-human-animals may not be sentient, or are simply property. Most were not convinced of the moral permissibility of AR by ‘human exceptionalism’ arguments, including that humans have more advanced mental abilities, are of a special ‘kind’, can enter into social contracts, or face a ‘lifeboat situation’. Counterarguments explained much of this, including that not all humans have these more advanced abilities [the argument from species overlap], and that the notion of ‘kind’ is arbitrary [e.g., why are we not of the kind ‘sentient animal’ or ‘subject-of-a-life’]. Pediatrician and nurse/RT responses were similar. CONCLUSIONS: Most respondents were not convinced of the moral permissibility of AR when given common arguments and counterarguments from the literature. HCW should seriously consider arguments on both sides of the AR debate

Absence epilepsy subnetworks revealed by event-related independent components analysis of functional magnetic resonance imaging

Fulltext embargoed for: 12 months post date of publicationPURPOSE: The aim of this study was to provide better spatiotemporal description of the brain activity observed during generalized spike-and-wave (GSW) discharges. Simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) studies of these epileptiform events have shown regional differences in the timing of fMRI signal changes, which suggests activities within multiple interacting networks rather than a single unified network. METHODS: EEG-fMRI recordings from eight patients with childhood absence epilepsy (CAE) were studied using event-related independent components analysis (eICA). This technique separates the fMRI signal changes observed during GSW discharges into different spatial components, each showing different event-related timing. Unlike standard independent components analysis (ICA), which is applied to the entire fMRI time series, the eICA method is applied only to the event-related time courses at each voxel, which means that only a small number of components are generated that are all explicitly related to the event of interest. KEY FINDINGS: Six eICA components were identified, representing distinct GSW-related subnetworks. Activations were detected in a number of brain regions, including the striatum, which have not previously been reported in association with GSW in CAE patients. SIGNIFICANCE: The eICA results support previous findings that the earliest activity associated with GSW may be in posterior cortical regions and provide new evidence that the thalamostriate network may play a more important role in the generation of GSW than suggested by previous studies

Lennox-Gastaut syndrome and phenotype: Secondary network epilepsies

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe epilepsy phenotype with characteristic electroclinical features despite diverse etiologies. We previously found common cerebral networks involved during slow spike-and-wave (SSW) and generalized paroxysmal fast activity (PFA), characteristic interictal discharges. Some patients have a Lennox-Gastaut-like phenotype and cortical lesions. We wished to explore the interaction between cerebral networks and lesions in this group. METHODS: 3 Tesla electroencephalography-functional magnetic resonance imaging (EEG-fMRI) on six subjects with Lennox-Gastaut phenotype and a structural lesion. Timings of SSW and PFA events were used in an event-related fMRI analysis, and to estimate the time course of the hemodynamic response from key regions. RESULTS: (1) PFA-robust fMRI signal increases were observed in frontal and parietal association cortical areas, thalamus, and pons, with simultaneous increases in both "attention" and resting-state (default mode) networks, a highly unusual pattern. (2) SSW showed mixed increased and decreased fMRI activity, with preevent increases in association cortex and thalamus, and then prominent postevent reduction. There was decreased fMRI activity in primary cortical areas. (3) Lesion-variable fMRI increases were observed during PFA and SSW discharges. Three subjects who proceeded to lesionectomy are >1 year seizure-free. SIGNIFICANCE: We conceptualize Lennox-Gastaut phenotype as a being a network epilepsy, where key cerebral networks become autonomously unstable. Epileptiform activity in Lennox-Gastaut phenotype, and by implication in LGS, appears to be amplified and expressed through association cortical areas, possibly because the attention and default-mode networks are widely interconnected, fundamental brain networks. Seizure freedom in the subjects who proceeded to lesionectomy suggests that cortical lesions are able to establish and maintain this abnormal unstable network behavior. LGS may be considered a secondary network epilepsy because the unifying epileptic manifestations of the disorder, including PFA and SSW, reflect network dysfunction, rather than the specific initiating process

Tonic seizures of Lennox-Gastaut syndrome: Periictal single-photon emission computed tomography suggests a corticopontine network

Fulltext embargoed for: 12 months post date of publicationPURPOSE: Lennox-Gastaut syndrome (LGS) is a severe epileptic disorder with characteristic electroclinical features but diverse etiologies. The shared electroclinical characteristics suggest that common cerebral networks are involved in generating seizures. We sought to reveal these networks by comparing ictal and interictal single-photon emission computed tomography (SPECT). METHODS: We identified 10 ictal-interictal SPECT pairs from seven patients with LGS (median age 11 years; range 1-38) who were studied during video electroencephalography (EEG)-confirmed tonic seizures. We performed a voxel-wise comparison of ictal and interictal SPECT studies across the group. The evolution of blood flow changes was explored by examining early and late injection groups. KEY FINDINGS: Median duration of tonic seizures was 10 s (range 6-29 s), and injection latency from seizure offset was -8 to 48 s. In the early injection group (<10 s; three studies), there was hyperperfusion over pons and cerebellar hemispheres (p < 0.05 cluster corrected family wise error), and hypoperfusion bilaterally over the pericentral region, with a trend toward hyperperfusion over bilateral superior and middle frontal gyri, and lateral parietal cortex. In the late injection group, there was hyperperfusion over midline and lateral cerebellar regions, with hypoperfusion widely over bilateral frontal regions. SIGNIFICANCE: This study suggests that the tonic seizures of LGS result from activity in a network, containing bilateral frontal and parietal association areas and the pons. We postulate that tonic seizures recruit the corticoreticular system, which connects frontal attentional areas to the pontine reticular formation, and is normally responsible for postural tone and orienting behavior

Expectations for methodology and translation of animal research: a survey of health care workers

BACKGROUND: Health care workers (HCW) often perform, promote, and advocate use of public funds for animal research (AR); therefore, an awareness of the empirical costs and benefits of animal research is an important issue for HCW. We aim to determine what health-care-workers consider should be acceptable standards of AR methodology and translation rate to humans. METHODS: After development and validation, an e-mail survey was sent to all pediatricians and pediatric intensive care unit nurses and respiratory-therapists (RTs) affiliated with a Canadian University. We presented questions about demographics, methodology of AR, and expectations from AR. Responses of pediatricians and nurses/RTs were compared using Chi-square, with P < .05 considered significant. RESULTS: Response rate was 44/114(39%) (pediatricians), and 69/120 (58%) (nurses/RTs). Asked about methodological quality, most respondents expect that: AR is done to high quality; costs and difficulty are not acceptable justifications for low quality; findings should be reproducible between laboratories and strains of the same species; and guidelines for AR funded with public money should be consistent with these expectations. Asked about benefits of AR, most thought that there are sometimes/often large benefits to humans from AR, and disagreed that “AR rarely produces benefit to humans.” Asked about expectations of translation to humans (of toxicity, carcinogenicity, teratogenicity, and treatment findings), most: expect translation >40% of the time; thought that misleading AR results should occur <21% of the time; and that if translation was to occur <20% of the time, they would be less supportive of AR. There were few differences between pediatricians and nurses/RTs. CONCLUSIONS: HCW have high expectations for the methodological quality of, and the translation rate to humans of findings from AR. These expectations are higher than the empirical data show having been achieved. Unless these areas of AR significantly improve, HCW support of AR may be tenuous