Studies in rats have shown that they could be either woken up or put in an unconscious state from altering their brain activity by changing the firing rates of neurons in the central thalamus. The NIH funded study was published in eLIFE.
Located deep inside the brain the thalamus acts as a relay station sending neural signals from the body to the cortex. Damage to neurons in the central part of the thalamus may lead to problems with sleep, attention, and memory.
Previous studies have suggested that stimulation of thalamic neurons may awaken patients who have suffered a traumatic brain injury from minimally conscious states.
The researchers flashed laser pulses onto light sensitive central thalamic neurons of sleeping rats, which caused the cells to fire.
High frequency stimulation of 40 or 100 pulses per second woke the rats. In contrast, low frequency stimulation of 10 pulses per second sent the rats into a state reminiscent of absence seizures that caused them to stiffen and stare before returning to sleep.
Using functional magnetic resonance imaging (fMRI) they were able to show that high and low frequency stimulation put the rats in completely different states of activity. Cortical brain areas where activity was elevated during high frequency stimulation became inhibited with low frequency stimulation.
Electrophysiological studies confirmed this by showing that neurons in the somatosensory cortex fired more during high frequency stimulation of the central thalamus and less during low frequency stimulation.
This study besides demonstrating the power of using imaging technologies to study the brain at work, takes a big step towards understanding the brain circuitry that controls sleep and arousal.
How can changing the firing rate of the same neurons in one region lead to different effects on the rest of the brain?
Further experiments suggested the different effects may be due to a unique firing pattern by inhibitory neurons in a neighbouring brain region, the zona incerta, during low frequency stimulation. Cells in this brain region have been shown to send inhibitory signals to cells in the sensory cortex.
Electrical recordings showed that during low frequency stimulation of the central thalamus, zona incerta neurons fired in a spindle pattern that often occurs during sleep. In contrast, sleep spindles did not occur during high frequency stimulation.
Moreover, when the scientists blocked the firing of the zona incerta neurons during low frequency stimulation of the central thalamus, the average activity of sensory cortex cells increased.
Although deep brain stimulation of the thalamus has shown promise as a treatment for traumatic brain injury, patients who have decreased levels of consciousness show slow progress through these treatments.
Reference:
Liu et al. “Frequency-selective control of cortical and subcortical networks by central thalamus,” eLIFE, December 10, 2015. DOI: dx.doi.org/10.7554/eLife.09215
Cover image: Tuning consciousness in the brain: Scientists studied how the thalamus tunes brain activity during different states of consciousness in ratsLee lab, Stanford University, CA
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Results from the ICISS trial presented at the 69th Annual Meeting of the American Epilepsy Society (AES) suggest that a combination of hormonal therapy with vigabatrin reduces infantile spasms better than hormonal treatment alone. For this study, the ICISS trial researchers tested the hypothesis that combining prednisolone or tetracosactide with vigabatrin would result in a greater proportion of infants achieving spasm cessation compared with hormonal therapy alone.
Between March 2007 and May 2014, infants with IS and a compatible EEG were enrolled in a multicenter treatment trial. Infants were randomized to receive either hormonal therapy and vigabatrin or hormonal therapy alone. A second stage randomization allowed hormonal treatment to be allocated as either prednisolone or tetracosactide depot. Minimum doses were: vigabatrin 100 mg/kg/day, prednisolone 40 mg per day, or IM tetracosactide depot 0.5 mg on alternate days. The early primary outcome measure was cessation of spasms on and between days 14 and 42. Analysis was by intention to treat.
377 children were enrolled and early clinical outcome data will be available on 376 (1 case withdrew). 185 were allocated hormonal therapy and vigabatrin and 191 were allocated hormonal therapy alone. 133/185 (71.9%) on combination therapy versus 108/191 (56.6%) on hormonal therapy alone achieved a primary clinical response: treatment difference 15.3% (95% CI 5.4% to 25.2%, p=0.002). The treatment effect favouring combination therapy remained highly significant in a logistic regression analysis controlling for underlying aetiology, country of enrollment, whether hormonal therapy was randomized or not, and gender (Odds ratio 2.03, 95% CI 1.3 to 3.2, p=0.002). Treatment response was also significantly faster on combination therapy (median response time = 2 days, IQR 2–4 days) than hormonal therapy alone (median response time = 4 days, IQR 3–6 days, p<0.001).
The electro-clinical response, defined as cessation of spasms on and between days 14 and 42, in addition to resolution of hypsarrhythmia on electroencephalogram (EEG), as available for 374 infants showed that 123 of 185 (66.5%) on combination therapy versus 104 of 189 (55%) on hormonal therapy alone achieved an electro-clinical response, for a treatment difference of 11.5% (P = .02). The greater electro-clinical response in the combination therapy was also highly significant after multivariate logistic regression (OR, 1.7; P = .013).
The improved clinical and electro-clinical response to combined therapy was most marked in those children at lower risk of developmental delay at readmission.
Source: The International Collaborative Infantile Spasms Study (ICISS): Comparing Hormonal Therapies (Prednisolone or Tetracosactide Depot) and Vigabatrin Versus Hormonal Therapies Alone in the Treatment of Infantile Spasms: Early Clinical and Electro-Clinical Outcome. Abstract 2.255, AES 2015
Cover image credit: Hypsarrhythmia. Sorge and Sorge Italian Journal of Pediatrics 2010 36:36
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The Mitochondrial European Educational Training (MEET) Network presents:
From bench to bedside, and back: Patients MEET Researchers
MEET Symposium 2016, Nijmegen, The Netherlands
Free registration!
Deadlines: December, 22, 2015.
Here the official agenda and the registration link.
FELLOWSHIPS: Please read all of the information carefully before you apply!
The MEET Consortium offers 15 fellowships (covering travel, accommodation and subsistence costs) to attend the Symposium.
Fellowships are addressed ONLY to patients or Representative of Patients’ organizations.
Applicants for fellowships must submit their request together with a reference letter from Patients’ organization with whom applicants are collaborating or with a motivation letter with a cover letter.
Applications must be sent to This email address is being protected from spambots. You need JavaScript enabled to view it.
Deadline for sending applications: December 20, 2015 at 18.00 (Brussels time)
Within the context of a deep collaboration between various European fundamental and translational laboratories, the MEET project represents a platform for the training of 14 young scientific investigators in the field of mitochondrial medicine.
For more information visit: http://www.itn-meet.org/index.php?readMore=1&id0=symposium_2016
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Children from low income environments appear to have a higher risk of neurological impairment than those from more economically secure circumstances, according to researchers at the National Institutes of Health and other institutions. This neurological impairment appears to be distinct from the risk of cognitive and emotional delays known to accompany early-life poverty.
In most cases, the level of neurological impairment the researchers found would not be apparent to a casual observer. That level could, however, increase, the risk for childhood learning difficulties, attention deficit disorders and psychological conditions such as anxiety disorders and schizophrenia. “The size of the effect we saw was modest,” said the study’s senior author, Stephen Gilman, Sc.D., acting chief of the Health Behavior Branch at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
“However, the findings do indicate that an impoverished environment may pose a hazard for a child’s developing nervous system.” The study was published in the International Journal of Epidemiology. The researchers analyzed data from the Collaborative Perinatal Project (CPP), funded by NIH’s National Institute of Neurological Disorders and Stroke.
The current study was funded by NICHD and NIH’s National Institute of Mental Health. The CPP enrolled pregnant women from 1959 through 1966, obtaining health information on more than 50,000 pregnancies and the children resulting from them. Children in the study received comprehensive neurological examinations at birth, 4 months, 1 year and 7 years of age.
The physicians performing the examinations looked for obvious deformities, abnormalities in posture, motor skills, response to skin stimulation and muscle strength. The children also received evaluations of the autonomic nervous system — the part of the nervous system governing functions not under conscious control, such as breathing, heartbeat and digestion.
Based on interviews at the start of the study, the researchers classified the parents into three groups: those having a low, medium, or high likelihood of socioeconomic disadvantage based on such factors as educational level, income relative to the U.S. poverty level, occupation, employment status, and whether there were two parents living in the home.
When the researchers factored in the likelihood for pregnancy and birth complications—more common among women in poverty — they found little difference in neurological impairment at birth between the children, despite their parents’ socioeconomic disadvantage. However, beginning at age 4 months, the chance of having a neurological abnormality was higher in the most disadvantaged children (12.8 percent), compared to the least disadvantaged (9.3 percent). By age 7, the likelihood of a neurological abnormality increased to 20.2 percent among the most disadvantaged, compared to 13.5 percent among the least disadvantaged.
The greater frequency of pregnancy complications in the most disadvantaged group did not account for its higher percentage of neurological impairment. Although there have been advances in the techniques used to diagnose neurological impairment in the years since the data were collected, the study authors said that the diagnostic approaches used in the study are still effective for detecting neurological problems. Studies indicate that people living in poverty are at higher risk for substance abuse, anxiety, depression, and child abuse, and the authors theorize that these factors could explain the higher rates of neurological impairment their study found for children raised in impoverished environments.
The authors wrote that further research into how childhood poverty might contribute to neurological impairment could lead to ways to prevent neurological impairment from occurring. They added that the percentage of children living below the federal poverty threshold is higher today than it was when the CPP data were collected.
Researchers from the following institutions also participated in the study: Taipei City Hospital, Taiwan; Harvard School of Public Health, Boston; Lahey Hospital and Medical Center, Burlington, Massachusetts.; Brown University School of Public Health, Providence, Rhode Island.; Brigham and Women’s Hospital, Boston; Harvard Medical School and Boston Children’s Hospital, Boston; and Massachusetts General Hospital, Boston.
Reference:
Chin-Lun Hung G, Hahn J, Alamiri B, Buka SL, Goldstein JM, Laird N, Nelson CA, Smoller JW, Gilman SE. Socioeconomic disadvantage and neural development from infancy through early childhood. International Journal of Epidemiology, 2015
Source: National Institutes of Health (NIH)
Photo credit: Jose-Luis Olivares/MIT
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E-Rare-3 Call for Proposals 2016 for "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".
The eighth E-Rare joint call for funding multilateral research projects on rare diseases (JTC2016) will be open on the 7 December 2015. The following 14 countries intend to participate in this call: Austria, Canada (including Quebec), France, Germany, Hungary, Israel, Italy, Latvia, Poland, Portugal, Romania, Spain, Switzerland, Turkey.
The specific objective of this call is to promote the clinical and pre-clinical proof of concept for the potential application of medicinal products in rare indications either already marketed or having achieved a significant stage in the development process.
Two types of projects will be eligible for this call:
Type A: Preclinical studies to verify target engagement and to perform additional toxicity testing if necessary (for example in the case of paediatric indications where juvenile animal studies might be warranted) in a disease model for a maximum period of one year followed by the implementation of Phase 1b or Phase 2a clinical trials at the beginning of the second year of the project.
Type B: Milestone-driven Phase 2 clinical trials to demonstrate that the Agent modulates the target and has the potential to yield the desired clinical outcome in the proposed disease population for a period up to three years. Projects shall involve a group of rare diseases or a single rare disease following the European definition i.e. a disease affecting not more than five in 10.000 persons in the European Community, EC associated states and Canada.
The use of existing European health research infrastructures or initiatives is strongly encouraged when appropriate. The following European Research Infrastructures or Initiatives were identified as potentially useful for this kind of study: BBMRI; EATRIS; ECRIN; ELIXIR; EU-OPENSCREEN; INFRAFRONTIER; RD-Connect and European Medicines Agency
For more information, visit the E-Rare website http://erare.eu/
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- Abnormal cell cycle gene activity may control brain overgrowth in autistic toddlers
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- Seizure detection using multiple biosignals more accurate than detection by heart rate changes alone
- Seizure detection device sensitivity comparable to video EEG