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The medium chain triglyceride(MCT) ketogenic diet is an established treatment for drug-resistant epilepsy that increases plasma levels of decanoic acid and ketones. The general assumption is that the diet’s antiepileptic effect is due to ketone production.However there is a poor correlation between serum ketones and seizure control.
Recently decanoic acid within the MCT ketogenic diet has been shown to block seizures among people with epilepsy to a greater extent than medications currently used to treat the condition. Besides decanoic acid may even have fewer side effects.Indeed, in vitro, decanoic acid is more potent than valproic acid [a branched chain fatty acid isomer of octanoic acid],a common antiepileptic drug.
However the therapeutic mechanism of the MCT ketogenic diet remains unclear. In research published online in Brain, a team of researchers at the Royal Holloway University of London and University College London, has shown that a major constituent of the MCT ketogenic diet, decanoic acid, but not the ketones β-hydroxybutryate or acetone, exhibits antiseizure activity in two acute ex vivo rat hippocampal slice models of epileptiform activity.
Using heterologous expression of excitatory ionotropic glutamate receptor AMPA subunits in Xenopus oocytes, they show that this effect is through direct AMPA receptor inhibition, a target shared by a recently introduced epilepsy treatment perampanel.
Decanoic acid acts as a non-competitive antagonist at therapeutically relevant concentrations, in a voltage- and subunit-dependent manner, and this is sufficient to explain its antiseizure effects. This inhibitory effect is likely to be caused by binding to sites on the M3 helix of the AMPA-GluA2 transmembrane domain; independent from the binding site of perampanel.
These results indicate that the direct inhibition of excitatory neurotransmission by decanoic acid in the brain contributes to the anti-convulsant effect of the medium chain triglyceride ketogenic diet. According to Prof Robin Williams at Royal Holloway University, the possibility that mechanism of action of the ketogenic diet is related to the fat in the diet rather than the ketones will lead to the development of improved diets and suggests that the ketogenic diet should be renamed simply as the "MCT diet".
It is important to note, however, that there may be circumstances where ketones do play a greater role in seizure control such as in Glut1 deficiency, the ketones from the ketogenic diet providing the brain with an alternative energy source. In addition the ketogenic diet in the longer term may modify metabolic and gene expression, which could have important disease-modifying effects.
Citation
Chang P, Augustin K, Boddum K, Williams S, Sun M, Terschak JA, Hardege JD, Chen PE, Walker MC, Williams RS (2015) Seizure control by decanoic acid through direct AMPA receptor inhibition. BRAIN 2015. DOI: http://dx.doi.org/10.1093/brain/awv325 First published online: 25 November 2015
cover photo: courtesy The Charlie Foundation for ketogenic therapies
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SPRITAM (levetiracetam) has been approved in the form of a dissolvable pill for the treatment of seizures among people with epilepsy.
Each year, around 150,000 people in the US are diagnosed with epilepsy. Of the 2.9 million people living with the condition, around 460,000 are children.A 2002 study published in the journal Epilepsy and Behavior found that 71% of epilepsy patients reported forgetting, missing or skipping a dose of anti-seizure medication at some point. Almost half of these patients reported having a seizure after their missed dose.
The team at Aprecia Pharmaceuticals used their ZipDose Technology to develop SPRITAM - a technique that was originally created by researchers from the Massachusetts Institute of Technology (MIT).
This technology allows the drug to be layered and tightly packed into a single pill, which dissolves instantly with just one sip of liquid, making the medication much easier to administer.
Another advantage of the drug being created in this way is that up to 1,000 mg of the medication can be loaded into one dose. In addition, the layering technology allows drug doses to be closely controlled and tailored to the need of each individual patient.
It is hoped that the Food and Drug Administration's (FDA) approval of SPRITAM will improve medication adherence among epilepsy patients, and its creators believe it may open the door to the development of new drugs for the treatment of other neurological disorders. Aprecia say SPRITAM will be available from early next year.
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Stimulant medications for attention-deficit/hyperactivity disorder (ADHD) cause sleep problems among the children who take them, a new study from the University of Nebraska-Lincoln concludes. The study addresses decades of conflicting opinions and evidence about the medications' effect on sleep.
In a "meta-analysis,"published online Nov. 23 by the journal Pediatrics, the Nebraska researchers found children given the medicines take significantly longer to fall asleep, have poorer quality sleep and sleep for shorter periods.
About one in 14 children and adolescents in the U.S. are diagnosed with ADHD, a chronic condition that includes attention difficulty, hyperactivity and impulsiveness. About 3.5 million are prescribed stimulant medications such as Ritalin and Adderall, the most common form of ADHD treatment.
Many research articles have been written in the past 30 years on whether ADHD medications harm the ability to sleep. Some researchers have found that the drugs do interfere with sleep, particularly if taken later in the day. Others maintain the medications improve ADHD patients' ability to sleep, by relieving symptoms and reducing resistance to bedtime. Indeed, some suggest that sleep problems are caused by the medication wearing off near bedtime, creating withdrawal symptoms.
For the meta-analysis after screening nearly 10,000 articles, Kidwell and her colleagues reviewed 167 full texts before selecting nine studies of sufficient rigor for their analysis. Tori Van Dyk and Alyssa Lundahl, also psychology doctoral students, assisted in the effort. Studies included in the analysis were peer-reviewed, randomized experiments.
The studies did not rely on parental reports of their children's sleeping patterns, instead requiring objective measures obtained through clinical sleep studies or wristband monitors used at home. The researchers found that both methylphenidate medications like Ritalin and amphetamines like Adderall cause sleep problems, without identifying differences between the two. Although they were unable to determine whether varying dosage amounts changed the effect on sleep, they found that more frequent dosages made it harder for children to fall asleep. They found that drugs tend to cause more sleep problems for boys.
The problems dissipate, but never completely go away, the longer children continue to take the medication. Sleep impairment is related to many cognitive, emotional and behavioral consequences, such as inattention, irritability and defiance. Sleep adverse effects could undermine the benefits of stimulant medications in some cases. Pediatricians should carefully consider dosage amounts, standard versus extended release, and dosage frequencies to minimize sleep problems while effectively treating ADHD symptoms.
ADHD medications are generally well tolerated in general and there is evidence for their effectiveness. But physicians need to weigh the pros and cons in any medication decision, and considering the potential for disrupted sleep should be part of that cost-benefit analysis with stimulants.
Citation:
Stimulant Medications and Sleep for Youth with ADHD: A Meta-Analysis (Kidwell HM, et al. Pediatrics. Nov. 23, 2015, www.pediatrics.org/cgi/doi/10.1542/peds.2015-1708).
Coverphoto:Psychology doctoral student and lead author Katie Kidwell (right), doctoral student Alyssa Lundahl and Professor Tim Nelson authored the paper along with doctoral student Tori Van Dyk, who is away from UNL on an internship. (Craig Chandler/University Communications)
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Infants are starved of oxygen during difficult births. Children’s cognitive function is permanently damaged due to malnutrition or exposure to infections or toxins. Adults suffer from crippling depression or dementia. The breadth and complexity of these and other brain and nervous system disorders make them some of the most difficult conditions to diagnose and treat, especially in the developing world, where there are few resources.
An NIH-led collaboration has studied these complex issues that occur across the lifespan and today published a supplement to the journal Nature that lays out a research strategy to address them. “We may be at a tipping point for research related to global brain disorders,” according to an introductory article authored by co-editors Dr. Donald Silberberg, of the University of Pennsylvania, Philadelphia, and Dr. Rajesh Kalaria, of Newcastle University in the United Kingdom.
“Over the past few decades, exciting basic science discoveries have been made, effective interventions have been developed and advances in technology have set the stage for a research agenda that can lead to unprecedented progress in this field.” More than 40 scientists collaborated to produce nine review articles that detail research priorities for different aspects of brain disorders in low- and middle-income countries (LMICs).
The most strategic opportunities involve cross-disciplinary studies of the relationship among environmental, developmental and genetic factors on brain disorders, the co-authors note. Advances in genomics provide new clues for mental disorders research, including predispositions for substance abuse and addiction, which could be harnessed to improve diagnosis and identify tailored treatments. The miniaturization of diagnostic technologies and other mobile health advances could improve surveillance, assessment and treatment of mental and nervous system disorders in LMICs, where cell phones are widely used.
To address infection-related nervous system morbidity, scientists should produce accurate estimates of disease burden, develop point-of-care assays for infection diagnosis, improve assessment tools for cognitive and mental health impairment, and study ways to improve infection prevention and treatment. In addition, the authors note that because LMIC populations suffer exposures to toxins due to poorly regulated mining or other industries, there are opportunities to advance scientific understanding of brain responses to environmental challenges.
The authors also advocate for longitudinal studies that would be conducted across the lifespan in LMICs, to study the unique circumstances and risk factors in childhood, adolescence, adulthood and old age. Regional variations in the challenges posed by brain disorders mean that research priorities need to be addressed country-by-country, and by regions within countries. To explore these many research gaps, local scientific capacity must be developed, as these questions are best addressed by indigenous scientists who can seek context-sensitive solutions. Chart shows comparison of disability associated life years (DALYs) between high-income and low- and middle-income countries. Chart shows comparison of disability associated life years (DALYs) between high-income and low- and middle-income countries.
The data were derived from the World Health Organization and the Global Burden of Disease 2010 Study. Although they cause nearly one-third of the global burden of disease, brain and nervous system disorders have been largely absent from the global health agenda, according to authors. As the population ages, these disorders will make up a growing proportion of illness and disability. This rise will be steeper in LMICs, where early life trauma, infectious disease and malnutrition contribute to the development of these disorders, the co-authors of the study predict.
Although developing countries bear a disproportionately large share of these problems, they have minimal resources to cope with the challenges. “This burden significantly affects the ability of children and adolescents to thrive and live out their true potential, and the ability of young adults to be productive economically and support their families, as well as the opportunity for older adults to age in safe and nurturing settings,” the co-authors observe. The tide is changing, the supplement’s authors acknowledge, with mental health, substance abuse and chemical exposures among the priorities included in the new Sustainable Development Goals, announced by the United Nations last September.
The project, led by the Center for Global Health Studies at the NIH’s Fogarty International Center, grew from a meeting of grantees and other scientific experts, convened in February 2014. While advances in brain imaging, nanoscience and genetics hold much promise for research discoveries, more resources are needed, according to Fogarty Director Dr. Roger I. Glass, who contributed a foreword to the publication. “We hope this supplement inspires other scientists and funding partners to join us in addressing the full spectrum of research, training, implementation and policy questions needed to alleviate global suffering from mental and neurological disorders that occur across the lifespan.” The journal supplement is open-access and available at www.nature.com/brain-disorders
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Roustem KhazipovThe excitatory and inhibitory actions regulated by neurotransmitters are responsible for brain activity. Glutamic acid mediates excitatory actions while GABA is inhibitory. However it has been known for nearly two decades that during development, GABA exerts a depolarizing action on immature neurons. However, at the network level the effects of GABA are complex involving both excitatory and inhibitory actions.
A group of researchers from Kazan Federal University, Russia and Aix-Marseille University, France, has shown that the actions of GABA critically depend on the network state. They have found that although GABA depolarizes neurons at rest and at the onset of population bursts, it transiently becomes hyperpolarizing at the peak of the population bursts. These dynamic changes in GABA actions enable GABAergic interneurons not only to initiate the network discharge but also to control excitation to prevent epileptiform synchronization. Losing inhibitory and gaining excitatory action by GABA during epilepsy could contribute to the pathogenesis.
They characterized the dynamics of synaptic currents mediated by GABA(A) and glutamate receptors through an estimation of the changes in their conductance and driving forces in neonatal rat CA3 pyramidal cells during GDPs. They found that depolarizing GABAergic and glutamatergic currents act in synergy at the GDPs' onset. However, during the peak of the population discharge, the inward synaptic current was essentially mediated by glutamate receptors whereas GABA currents transiently switched their direction from depolarizing to hyperpolarizing as a result of neuronal depolarization above the GABA(A) reversal potential.
Thus, the action of GABA on CA3 pyramidal cells dynamically changes during GDPs from excitatory at the GDPs' onset to inhibitory at the GDPs' peak. Dynamic changes in GABA actions occurring during GDPs seem to enable GABAergic interneurons not only to initiate the discharge of pyramidal cells but also to control excitation in the recurrent CA3 network preventing epileptiform synchronization.
According to the research team led by Roustem Khazipov, from Kazan Federal University, Russia the brain appears to be in two states: sleeping and arousal and it switches between them quite rhythmically, e.g. during deep sleep a brain can change its state several times within a second. In their recent study published in Journal of Neuroscience they demonstrate that GABA performs excitatory actions in a "sleep" state in children, and vice versa, inhibitory actions when the brain is aroused. In addition to that, in adult brain GABA switches from inhibition to excitation in epilepsy and other conditions including post traumatic brain injury and ischemia.
The experiments were performed on neonatal rats and mice hippocampus since it relates closely to that of human fetus at the second half of pregnancy period. The findings have potential applications in the treatment of epilepsy, ischemia and brain trauma.
Citation:Khalilov I, Minlebaev M, Mukhtarov M, Khazipov R. Dynamic Changes from Depolarizing to Hyperpolarizing GABAergic Actions during Giant Depolarizing Potentials in the Neonatal Rat Hippocampus. J Neurosci. 2015 Sep 16;35(37):12635-42. doi: 10.1523/JNEUROSCI.1922-15.2015. PubMed PMID: 26377455. 
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