From the prodromal stage of multiple sclerosis to disease prevention.

A prodrome is an early set of signs or symptoms that indicate the onset of a disease before more typical symptoms develop. Prodromal stages are well recognized in some neurological and immune-mediated diseases such as Parkinson disease, schizophrenia, type 1 diabetes mellitus and rheumatoid arthritis. Emerging evidence indicates that a prodromal stage exists in multiple sclerosis (MS), raising the possibility of intervention at this stage to delay or prevent the development of classical MS. However, much remains unclear about the prodromal stage of MS and considerable research is needed to fully characterize the prodrome and develop standardized criteria to reliably identify individuals with prodromal MS who are at high risk of progressing to a diagnosis of MS. In this Roadmap, we draw on work in other diseases to propose a disease framework for MS that incorporates the prodromal stage, and set out key steps and considerations needed in future research to fully characterize the MS prodrome, identify early disease markers and develop standardized criteria that will enable reliable identification of individuals with prodromal MS, thereby facilitating trials of interventions to slow or stop progression beyond the prodrome.

The agenda of the global patient reported outcomes for multiple sclerosis (PROMS) initiative: Progresses and open questions.

On 12 September 2019, the global Patient Reported Outcome for Multiple Sclerosis (PROMS) Initiative was launched at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The multi-stakeholder PROMS Initiative is jointly led by the European Charcot Foundation (ECF) and the Multiple Sclerosis International Federation (MSIF), with the Italian Multiple Sclerosis Society (AISM) acting as the lead agency for and on behalf of the global MSIF movement. The initiative has the ambitious mission to (i) maximize the impact of science with and of patient input on the life of people affected by MS, and (ii) to represent a unified view on Patient-Reported Outcomes for MS to people affected by MS, healthcare providers, regulatory agencies and Health Technologies Assessments agencies. Equipped with an innovative participatory governance of an international and interdisciplinary network of different stakeholders, PROMS has the potential to guide future breakthroughs in MS patient-focused research and care. In this paper we present the progresses of the global PROMS Initiative and discuss the open questions that we aim to address.

Nurses' perception of ethical climate at a large academic medical center.

BACKGROUND: Nurses are confronted daily with ethical issues while providing patient care. Hospital ethical climates can affect nurses' job satisfaction, organizational commitment, retention, and physician collaboration. PURPOSE: At a metropolitan academic medical center, we examined nurses' perceptions of the ethical climate and relationships among ethical climate factors and nurse characteristics. DESIGN/PARTICIPANTS: We used a descriptive correlational design and nurses ( N = 475) completed Olson's Hospital Ethical Climate Survey. Data were analyzed using STATA. Ethical considerations: Approvals by the Nursing Research Council and Institutional Review Board were obtained; participants' rights were protected. RESULTS: Nurses reported an ethical climate total mean score of 3.22 ± 0.65 that varied across factors; significant differences were found for ethical climate scores by nurses' age, race, and specialty area. CONCLUSION: These findings contribute to what is known about ethical climate and nurses' characteristics and provides the foundation to develop strategies to improve the ethical climate in work settings.

A global call for action to include gender in research impact assessment.

Global investment in biomedical research has grown significantly over the last decades, reaching approximately a quarter of a trillion US dollars in 2010. However, not all of this investment is distributed evenly by gender. It follows, arguably, that scarce research resources may not be optimally invested (by either not supporting the best science or by failing to investigate topics that benefit women and men equitably). Women across the world tend to be significantly underrepresented in research both as researchers and research participants, receive less research funding, and appear less frequently than men as authors on research publications. There is also some evidence that women are relatively disadvantaged as the beneficiaries of research, in terms of its health, societal and economic impacts. Historical gender biases may have created a path dependency that means that the research system and the impacts of research are biased towards male researchers and male beneficiaries, making it inherently difficult (though not impossible) to eliminate gender bias. In this commentary, we - a group of scholars and practitioners from Africa, America, Asia and Europe - argue that gender-sensitive research impact assessment could become a force for good in moving science policy and practice towards gender equity. Research impact assessment is the multidisciplinary field of scientific inquiry that examines the research process to maximise scientific, societal and economic returns on investment in research. It encompasses many theoretical and methodological approaches that can be used to investigate gender bias and recommend actions for change to maximise research impact. We offer a set of recommendations to research funders, research institutions and research evaluators who conduct impact assessment on how to include and strengthen analysis of gender equity in research impact assessment and issue a global call for action.

Functional brain mapping at 9.4T using a new MRI-compatible electrode chronically implanted in rats.

There is a need for acute and chronic stimulation of the brain within the MRI for studies of epilepsy, as well as deep brain stimulation for movement and behavioral disorders. This work describes the production and characteristics of carbon fiber-based electrodes for acute and chronic stimulation in the brain. Increasing MRI field strengths are making it increasingly difficult to introduce foreign objects without a susceptibility artifact. We describe the production of, and the characteristics of carbon fiber-based electrodes. These are biocompatible and can be implanted for chronic studies. We show the use of these electrodes at 9.4T for studying functional activation. Data are presented showing regional connectivity. Activation not only occurs near the electrode, but at sites distant and often contralateral to the electrode. In addition, there were sites showing strong negative activation to stimulation both with direct stimulation and during a kindling-associated seizure.

Sensory stimulation reduces seizure severity but not afterdischarge duration of partial seizures kindled in the hippocampus at threshold intensities.

Epilepsy is a family of neurological disorders that result in seizure activity that is characterized by transient hypersynchronous activation of a large population of neurons. In animal models, focal tetanic electrical stimulation of sufficient duration and intensity, can elicit epileptiform activity, that if repeated results in progressive intensification of seizure activity known as kindling. Kindling serves as a model of partial as well as secondarily generalized temporal lobe epilepsy. We utilized hippocampal kindling to provide a means of evaluating the effect of sensory stimulation on the duration and severity of the induced seizure activity. Sensory stimuli targeted either the olfactory, auditory or somatosensory systems in an attempt to retard or suppress seizure activity. To that end, rats were chronically implanted with electrodes in the CA1 region of dorsal hippocampus and kindled once daily until the seizure behaviour was fully generalized. Kindling stimulation consisted of daily application of 1-s trains of biphasic square wave pulses applied at a frequency of 60Hz, at the afterdischarge (AD) threshold. Sensory stimulation was applied 6-8s after the kindling stimulation every third day. One group of rats received a different sensory stimulus (novel) every third day, while another group was presented with the same sensory stimulus (repeated) every third day. Kindling stimulation applied to the dorsal hippocampus resulted in progression of the AD characteristics and seizure behavior, which typically developed very slowly in the early stages. The application of both the novel and repeated sensory stimulation during partial seizures (stages 1 and 2) resulted in a reduction in the seizure severity but not in the afterdischarge duration. Sensory stimulation delivered during secondarily generalized seizures (stages 4 and 5) failed to affect either parameter.

Kindling limits the interictal neuronal temporal response properties in cat primary auditory cortex.

PURPOSE: The present study examined the effect of electrical kindling on the interictal temporal response properties of single units recorded from primary auditory cortex (AI) of the adult cat. METHODS: Cats were permanently implanted with electrodes in AI, kindled twice daily for 40 sessions, and the contralateral AI was subsequently mapped. Kindling stimulation consisted of 1-s trains of biphasic square-wave pulses applied at a frequency of 60 Hz, 100 microA above the afterdischarge (AD) threshold. The EEG activity was recorded during each kindling session, and the behavioral manifestation was scored. Subsequent to kindling, multiple single-unit responses were recorded under ketamine anesthesia in response to 1-s-long periodic click trains, with click rates between 2 and 64 Hz. Neuronal responses were characterized according to their ability to respond in time-locked fashion to the clicks. RESULTS: Kindling stimulation resulted in progression of the AD characteristics and seizure behavior, with six of 10 kindled cats reaching a fully generalized state. In the fully kindled cats, the best modulation frequencies and limiting following rates for the single-unit responses were significantly lower compared with those of naive and sham controls. CONCLUSIONS: Repeated epileptiform activity interferes with temporal processing in cat auditory cortex in the interictal state. This may have implications for people with epileptic foci in auditory-related areas.

Stimulus dependence of spectro-temporal receptive fields in cat primary auditory cortex.

The frequency-tuning curve is a static representation of the neuron's sensitivity to stimulus frequency. The temporal aspects of the frequency sensitivity can be captured in the spectro-temporal receptive field (STRF), often presented as the average spectrogram of the stimulus preceding a spike but also as the average frequency-dependent post-stimulus time histogram (PSTH). The temporal envelope of the stimulus produces considerable smoothing, and as a consequence the PSTH representation is finer-grained than the spectrogram representation. Here we compare STRFs for 1/s and 20/s single-frequency stimuli with 120/s steady-state multi-frequency stimuli for 87 recording sites in primary auditory cortex of cats. For the 672 estimated STRFs, which for multi-frequency stimuli were mostly obtained at 55 dB SPL, we found lateral inhibition in 17% of the cases, in 32% post-activation suppression, and in 51% only excitation. In 35% of the recordings the excitatory frequency-tuning curves were very similar for single and multi-frequency stimuli, in the remaining 65% the common finding was the emergence of an intensity independent bandwidth for the multi-frequency stimuli. Comparison of the 20/s and 120/s stimuli showed that the resulting increase in inhibition was strongest in the center of the STRF.

Kindling changes burst firing, neural synchrony and tonotopic organization of cat primary auditory cortex.

The effect of electrical kindling, applied twice daily in primary auditory cortex on the neural response properties and tonotopic organization in the lightly ketamine anesthetized cat is presented. Kindling refers to a highly persistent modification of brain functioning in response to repeated application of initially sub-convulsant electrical stimulation, typically in the limbic system but here in auditory cortex, which results in the development of epileptiform activity. Kindling resulted in approximately two-thirds of the animals reaching a fully generalized state in 40 stimulation sessions. Multi-unit recordings were obtained from primary auditory cortex contralateral to the kindled site. Spontaneous activity of single units in fully kindled animals showed a decrease in the mean firing rate compared to sham controls, and a reduction in the rate of burst firing as well as in the mean interspike interval in a burst as compared with normal and sham controls. A 40% enhancement of spontaneous neural synchrony, as measured by spike cross-correlation, was found. Hearing sensitivity, measured by auditory brainstem response, was not affected by the kindling sessions. A profound alteration of the tonotopic map in AI was observed with a large extent becoming tuned to similar high characteristic frequencies. The percentage of double tuned neurons was significantly increased, nevertheless the frequency-tuning curve bandwidth was on average reduced. Thus, electrical kindling resulted in substantial alterations in unit firing characteristics and reorganization of cat auditory cortex.

Intracortical microstimulation induced changes in spectral and temporal response properties in cat auditory cortex.

Intracortical microstimulation (ICMS), consisting of a 40 ms burst (rate 300 Hz) of 10 microA pulses, repetitively administered once per second, for a total duration of 1 h, induced cortical reorganization in the primary auditory cortical field of the anesthetized cat. Multiple single-unit activity was simultaneously recorded from three to nine microelectrodes. Spiking activity was recorded from the same units prior to and following the application of ICMS in conjunction with tone pips at the characteristic frequency (CF) of the stimulus electrode. ICMS produced a significant increase in the mean firing rate, and in the occurrence of burst activity. There was an increase in the cross-correlation coefficient (R) for unit pairs recorded from sites distant from the ICMS site, and a decrease in R for unit pairs that were recorded at the stimulation site. ICMS induced a shift in the CF, dependent on the difference between the baseline CF and the ICMS-paired tone pip frequency. ICMS also resulted in broader tuning curves, increased driven peak firing rate and reduced response latency. This suggests a lasting reduction in inhibition in a small region surrounding the ICMS site that allows expansion of the frequency range normally represented in the vicinity of the stimulation electrode.

Social integration and life and family satisfaction in survivors of injury at 5 years postinjury.

This study assessed the relationship of social integration (SI) to life satisfaction and family satisfaction among survivors 5 years after injury. Thirty-four matched pairs of injured patients were interviewed by telephone 60 months after initial discharge from the acute care setting. Respondents were matched according to sex, race, education, injury severity, and employment status before comparing high and low socially integrated persons on measures of family and life satisfaction. High and low SI groups were formed based on the Craig Handicap Assessment and Reporting Technique (CHART) SI Scale. The former consisted of patients scoring 100; the latter consisted of patients scoring 50 or less. Analyses of covariance, with age and injury type as covariates, were used to test for group differences. The high and low SI groups differed on both the life and the family satisfaction measures, with the high SI group reporting greater life and family satisfaction.