Stimulation to Stop the Seizing

[Source]

The brain controls how the body moves by sending out small electrical signals through the nerves to the muscles. Seizures, or convulsions, occur when abnormal signals from the brain change the way the body functions. The outward effect can be as dramatic as uncontrollable thrashing movement or as mild as a temporary loss of awareness. Epilepsy, affecting 0.5-1% of the population, is the medical syndrome of recurrent, unprovoked seizures. Seizures can also occur in individuals that do not have epilepsy and are referred to as non-epileptic seizures.

Dr. Robert Cressman, member of the Physics and Astronomy Department at George Mason University as well as a member of the Krasnow Institute for Advanced Study, presented the research he is currently working on with others. They are exploring a new means of treatment for epileptic seizures. A wide-range of medications are currently in use to treat epilepsy and while many individuals respond well to them, others do not. Some build up tolerance to these medications after a period of time while others develop 'refractory epilepsy' and have seizures that cannot be controlled with any type of drug. As a result of these cases, Dr. Cressman and his team felt it was necessary to develop a new means of treatment and are looking into electrical stimulation. Deep brain stimulation, used to treat tremors associated with Parkinson's disease, is now being considered a form of treatment for epilepsy (1).

PET scans can be used to evaluate patients with epilepsy.
[Source]

There are two general types of epilepsy that Dr. Cressman introduced. Idiopathic epilepsy is of a genetic origin, with no indication of the individual having epilepsy in a CT scan. Symptomatic epilepsy results from a physical lesion, tumor, or malformation, apparent on a CT scan that indicates that the individual is having seizures. All seizures are generally considered to have a foci from which they emanate from. The autonomous seizure focus consists of an area of tissue in the hippocampus that produces excessive activity which then spreads to other parts of the brain. The emergent seizure focus involves a couple of different overactive regions. This has more to do with the interactions of the different brain regions and how the conduction of activity from one place to another can ramp up to cause a seizure (1).

One type of epilepsy is primary generalized seizure, affecting both cerebral hemispheres

 [Source].

Dr. Cressman and his team began their work by investigating in-vitro rat hippocampal (specifically CA1 region of hippocampus, where seizures are generated) slices treated with 4-aminopyridine (4-AP), a voltage-gated, fast potassium channel blocker. In an excitatory neuronal cell, an action potential is initiated by sodium influx and restored by potassium efflux. Potassium channel blockers essentially keep the potassium in a neuron from flowing out as quickly, resulting in longer depolarization and a reduced refractory period. When 4-AP is added to the rat tissue, after a short period of time, a spontaneous emergence of seizures was observed (1). They analyzed the excitatory-inhibitory interactions and found alternating periods of activity between interneurons and pyramidal cells. Their findings highlighted the importance of understanding complex neuronal interactions in the formation of seizure patterns (2).

Neuronal action potential [Source].

They then went on to survey previous studies that were done investigating this phenomenon. In one study, potassium levels were elevated in a model of rat hippocampal epilepsy. The elevated potassium levels led to excitation of the cells and similar, repeated types of seizures (3). In another study with a high potassium and low calcium model, electrographic seizures were monitored. Researchers found that a network of isolated cells still resulted in generation of repeated seizures (4).

Depolarization of a neuron [Source].

After analyzing these studies, Dr. Cressman and his team developed a simple model of a single neuron with dynamic intra and extra-cellular sodium and potassium concentrations. The model was based on the standard Hodgkin-Huxley equations as well as on Nernst equations. An ASCF bath and a simple glial buffering system were also included. An essential function of glial cells is to regulate extracellular potassium levels and do so with inward-rectifying potassium channels. Autonomous seizures were generated through oscillations in the cell's intra and extracellular concentrations. The model they developed was able to reproduce these seizures. By stimulating the seizing cell with small positive signals, there was a decrease in the activity and concentrations were fixed at a level at which the cell can respond to normally (1). They figured that this was a way to control the effects of seizures. They also found that increasing the potassium levels in the ACSF bath resulted in faster generation of sparks, making the model more similar to physiological conditions.

Dr. Cressman concluded by saying that slow stimulation of the cell can lead to both the suppression of autonomous seizures as well as a significant reduction in seizure conduction. The model they developed exhibits periodic bursting. The bursting behavior arises as the fast spiking behavior of the neuron is modulated by the slow oscillatory behavior in ion concentration (2). In the future, they plan on testing these predictions and their neuronal model in the lab. He also mentioned the measurement of oxygen using an epifluorescence apparatus. This would be useful as it would provide them with a method of identifying the foci of seizure activity by measuring changes in oxygenation (1).

Dr. Cressman and his team have been conducting research that will be invaluable for future innovations. Their work emphasizes the importance of understanding ion concentration homeostasis in the maintenance of the normal physiological states. Their work suggests that by elucidating the mechanisms underlying this homeostasis, treatments for pathological conditions like epilepsy may be more effective. Vagus nerve stimulation (VNS) is often used as an alternative treatment for patients with medically refractory epilepsy and treatment-resistant depression. Studies have been conducted in which the mechanism of action of VNS has been heavily researched, revealing that various thalamic nuclei and the medial temporal lobe (MTL) play a role in the epileptogenic process. Other studies analyzed the effectiveness of acute deep brain stimulation as a means of treatment (5). In individuals with drug-resistant epilepsy, oftentimes, the seizures are in or near a critical part of the brain, making surgery too great a risk. Pacemakers implanted in the brain may help control or eliminate epileptic seizures with programmed or responsive stimulation. Perhaps in the future, researchers can use this method developed by Dr. Cressman and his team to more fully understand how seizures are generated. By utilizing the model and these methods, would it be possible for researchers to detect pathology in brain dynamics, intervene, and prevent epileptic seizures from occurring?


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References:

1. Cressman, Dr. Robert. "Controlling Seizures Through Stimulation Induced Ionic Modulation", Department of Physics and Astronomy, Krasnow Institute for Advanced Study. 29 November 2012. Seminar.
2. Barreto, E., Cressman, J. 2011. Ion Concentration Dynamics as a Mechanism for Neuronal Bursting. Biophys. J. 37(3):361-373.
3. Jensen, M. S., Yaari, Y. 1997. Role of Intrinsic Burst Firing, Potassium Accumulation, and Electrical Coupling in the Elevated Potassium Model of Hippocampal Epilepsy. Neurophysiol. J. 77(3):1224-33.
4. Bikson, M., et al. 2003. Depolarization Block of Neurons During Maintenance of Electrographic Seizures. Neurophysiol. J. 90(4):2402-8.
5. Boon, P., et al. 2009. Electrical Stimulation for the Treatment of Epilepsy. Neurotherapeutics. 6(2):218-27.

Catch Your Zzz's Before You Age

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Sleep is an obvious necessity. With it we are able to rest our tired brains, restore the vigor to our bodies, and prepare ourselves for the labors of the coming day. Sleep, although universally considered a blessing, is a mysterious thing. Many individuals have difficulty falling and staying asleep and this may often be the result of a serious underlying disorder. Dr. Kathy C. Richards, Assistant Dean of the Doctoral Division and Research Development at the School of Nursing at George Mason University, presented the research she is currently working on with numerous faculty from varying universities. The focus of her research involves making sense of the relationship between sleep and cognitive function (1).

Dr. Richards began by introducing a concept known as 'sundowning'. This psychological phenomenon, known to affect some dementia patients, results in periods of increased confusion and agitation when the sun goes down, and sometimes all through the night. Sundowning not only prevents these patients from sleeping well, but also makes them more likely to wander and is a common cause of caregiver burnout (2). Although the cause of this syndrome is still unknown, Dr. Richards makes a correlation between two sleep disorders (RLS and PLMD) and sundowning. She explained that these disorders may be considered precursors of sundowning, and that sundowning itself may be a form of relief for patients suffering from these disorders (1). 

Restless leg syndrome (RLS) (sometimes referred to as 'elvis legs') is a disorder in which there is an urge to move, accompanied by or caused by uncomfortable sensations in the legs. The urge to move or the unpleasant sensations begin or worsen during periods of rest or inactivity, often at sleep onset. Partial or complete relief symptoms is achieved by movement such as walking or stretching. RLS occurs in 10% of the general population. Another form of RLS,  known as secondary RLS, is associated with certain conditions that older people have (1). These conditions include renal failure, iron deficiency, diabetes mellitus, Parkinson's disease, neuropathy. The use of dopamine antagonists and antidepressants as form of treatment have been shown to aggravate the condition. Dr. Richards stressed the importance of understanding the pathophysiology of RLS. In people suffering from RLS, there is a dysfunction of dopamine cells in certain areas of the brain. Iron is a necessary cofactor in the brain for dopamine synthesis and in RLS patients, iron stores are abnormally low in the cerebrospinal fluid (1). Treatment of RLS includes iron replacement therapy, as well as the use of anticonvulsants and general lifestyle changes to improve symptoms. 

Periodic limb movement disorder (PLMD) is a condition that also occurs in approximately 80% of people suffering from RLS (3). While the movements of RLS are a voluntary response to uncomfortable feelings in limbs when the person is awake, the movements of PLMD occur when a person is asleep and are involuntary (4). This condition occurs more commonly in older adults. Treatment for PLMD is the same as with RLS patients. PLMD movements are characterized by rhythmic extensions of the big toe and dorsiflexions of the ankle with occasional flexions of the knee and hip. Dr. Richards went into further detail about how a diagnosis of PLMD is made. Polysomnography (PSG) (also known as sleep study) tests are used as a diagnostic tool. In a study conducted on nursing home patients, muscle tension was measured by use of electrodes. They found that short awakening results in greater muscle tension. Electrodes placed on legs also shows flexion of both feet during sleep in PLMD patients (1). 

http://www.advancedsleepdisorderscenter.com/images/sleepstudypolysomnogram_main.gif

Dr. Richards and her team conducted a study to better understand sleep and behavioral disturbances in dementia. They hypothesized that nighttime behavioral disturbances may be associated with with obstructive sleep apnea syndrome (OSA) as well as with PLMD and RLS. The study was conducted on 60 patients with dementia residing at home. It consisted of 2 nights of PSG monitoring, and 3 nights of behavioral observations done every 5 minutes, using the Cohen-Mansfield Agitation Inventory (CMAI) for direct observation (of a 19 hour duration) to calculate the behavioral disturbance index. Patients were categorized as having probable RLS or no RLS by the diagnoses of two world experts (1). They made these diagnoses by examining different factors including the chief sleep complaint, RLS diagnostic interview per the caregiver, research assistant observations of RLS signs and symptoms, and finally, polysomnography data including apnea hypopnea index (AHI) and periodic limb movement index (PLMI). 

The results of the study were analyzed through different means including electroencephalography (EEG). EEG measures voltage change and in dementia patients, voltage change will be low and there will be slowing in the wave forms. The frequency and shape of EEG wave forms changes in people with cognitive impairment. The sleep stages of people with dementia are different. Dr. Richards and her team developed guidelines with which to score dementia patients' sleep reliably in order to determine whether they were asleep or awake, and what stage they were in. In this study, they found that 24% of dementia patients have probable RLS, while the remaining have no RLS. They also found that OSA was not a predictor of nighttime behavioral problems (1). The lower the apnea index (AHI) and the mini-mental state examination scores (MMSE), the more likely dementia patients were to have nighttime behavioral disturbances. Additionally, it was found that PLMD was a significant predictor of RLS and more nighttime behavioral disturbances. 

Dr. Richards concluded by briefly explaining the work that she is involved in currently.  Obstructive sleep apnea (OSA) is the most common form of sleep apnea and is caused by obstruction of the upper respiratory pathway. It is characterized by repeated cessation of breathing during sleep and results in a reduction of oxygen saturation in the blood. Cognitive effects of OSA include impairment in attention-vigiliance, memory, and executive functioning. Neuroimaging studies have shown evidence of hippocampal atrophy, reduced grey matter, and reduced cerebral blood flow in OSA patients. Mild cognitive impairment (MCI) is a form of memory impairment with little or no decline in everyday function. OSA is widely associated with increased risk of developing MCI or dementia. Dr. Richards and her team are currently exploring methods in which OSA can be treated and cognitive decline can be delayed. They are looking into the use of continuous positive airway pressure (CPAP) as a means of treatment and therapy (1).

CPAP therapy uses a machine to help a person with OSA breathe more easily during sleep.
http://www.mayoclinic.com/images/image_popup/r7_cpap.jpg

The research that Dr. Richards and her team are undertaking is vital in developing a better understanding of sleep disorders and how they are related to patients suffering from dementia. It lays the groundwork on which future research can build upon. The clinical approach that Dr. Richards has taken with respect to this topic of study is important in that it opens doors for exploration of other means by which sleep disorders can be treated. She mentioned the need for an effective RLS behavioral diagnostic tool and this can possibly be a next step in her research. Dr. Richards also pointed out that RLS is commonly seen in autistic children. Perhaps her efforts will allow for a bridge between translational sleep and research aging and neuropsychopharmacology. With collaborative efforts from these two fields of research, would it be possible to develop a single drug that targets these sleeping disorders? Would it be possible to maintain a balance in the dopaminergic, serotonergic, and cholinergic systems of these patients through the use of a single drug? Other non-pharmacological means may be explored such as lifestyle changes that would make a difference. Recent discoveries in science have come a long way and have greatly increased our understanding of sleep disorders and we are on the path towards breakthrough treatment. 

Sources:

1. Richards, Dr. Kathy. "Sleep: A Key to Healthy Aging", School of Nursing: Doctoral Division and Research Development. 8 November 2012. Seminar.
2. "Sundowning: Causes, Symptoms, and Treatment." WebMD. WebMD, n.d. Web. 11. Nov. 2012. <http://www.webmed.com/alzheimers/guide/sundowning-causes-symptoms-treatments>.
3. "Restless Legs Syndrome." Harvard Health Publications. Harvard Medical School, n.d. Web. 11 Nov. 2012. <http://www.health.harvard.edu/newsweek/Restless-legs-syndrome.htm>.
4. "Restless Legs Syndrome and Periodic Limb Movement Disorder." MetroHealth. Center For Sleep Medicine, n.d. Web. 11 Nov. 2012. <http://www.metrohealth.org/body.cfm?id=2080>.

Functional Features of Gene Expression

Functional linkages between genes.
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The Human Genome Project initiative provided researchers with an incredibly detailed blueprint for the building of each cell in the human body. The ultimate goal of scientists is to determine how genes (and the proteins they encode), function in the intact organism (1). This connection, from gene to function, is one that is studied in many different branches of science. Dr. Eswar Iyer, a member of the Cox Lab at George Mason University's Krasnow Institute for Advanced Study, and the numerous other faculty and lab members he works with take a systems neuroscience approach to better understand the concept.

Dr. Iyer presented part of the research he is currently involved in at Dr. Daniel Cox's lab. He began by clarifying exactly what is meant by a systems approach. The basic idea involves the use of reductionist methods while keeping the holistic view in mind.  This is all done without losing sight of the ultimate goal of the research - understanding gene function and determining how it fits into the bigger picture (2).

Dendrites are central to neuronal function.
http://labs.biology.ucsd.edu/halpain/MNeuron1Asmall.JPG

Neurons are highly polarized in their structure, having both axons and dendrites projecting outwards. Dr. Iyer and others at the Cox Lab focus mainly on dendrite morphology. Dendrites are the hallmark of neuronal identity and are central to neuronal function. They are also the primary site of synaptic and sensory input. They play a functional role in the establishment and maintenance of proper neuronal circuitry in a number of neuropathological disease states including autism and down syndrome (2). Dendrites have very unique and reproducible branching morphologies across species. This confirms that there are instructions being sent to the neurons that dictate its neuronal circuitry and branching morphologies. Understanding the mechanisms that control the acquisition and maintenance of neuronal class-specific dendritic morphology is a crucial part of the research being conducted at the Cox lab (2).

In order to attempt to make sense of this, a model system was needed. Dendritic arborization (da) neurons of the Drosophila Melanogaster (more commonly known as fruit flies) peripheral nervous system were used, as they provide an excellent model system for investigating class specific dendrite morphogenesis as well as sensory function (2, 3). Fruit flies are the perfect intermediate; they are a complex whole organism, yet simple enough for study. They possess about 85% of the genes of all the diseases studied in humans and thus, provide a fantastic system for studying a varying number of processes. Four classes of da neuron (Class I-IV), ordered by increasing dendritic complexity, are studied. Each class is involved in varying sensory modalities and behavioral studies can be conducted on these neurons. These neurons provide Dr. Iyer and others with the ability to analyze how neuronal diversity arises (2).

Development of different morphological classes of da neurons.
http://ars.els-cdn.com/content/image/1-s2.0-S0092867403001600-gr1.jpg

Magnetic bead sorting.
http://ars.els-cdn.com/content/image/1-s2.0-S1380293398000104-gr3.gif

It was important to use a specific method to identify novel candidates involved in dendrite morphogenesis. Previously, the forward genetic screen method was used. This method proved to be slow, laborious, and random. A new approach known as reverse genetics was found to be more efficient. The reverse genetics method, when used alongside functional genomic analyses, provides a  faster and more directed approach for investigation of dendrite morphogenesis. Dr. Iyer, after explaining the specifics of this method, went on to outline the process. It begins with purification and isolation of da neuronal classes using an efficient technique known as 'magnetic bead sorting'. Gene expression profiling of classes is performed, followed by bioinformatics analyses to identify statistically enriched gene sets (2). The results of these analyses are functionally validated via a large scale in-vivo RNAi screen. Finally, the data provided by the RNAi screen is analyzed to identify the specific molecules involved in regulation of dendrite development (1). This process resulted in the team narrowing down approximately 750 transcription factors to a single gene that was found to have a perfect phenotype. The gene, named 'Bedwarfed', was analyzed by Dr. Iyer and his team in order to learn more about its function, behavior, and underlying molecular mechanisms (2).

A schematic association of forward and reverse genetic approaches for genetic association of phenotypes.
http://www.hindawi.com/journals/jtm/2012/829210/fig1/

Bedwarfed gene, after performing systemic characterization involving loss-of-function (LOF) and gain-of-function (GOF) analyses, was found to be essential in dendritic growth. It results in the shrinkage of dendritic branches, with no change in the total number of dendrites per neuron. Bedwarfed was also found to interact with a unique homeodomain transcription factor known as 'Cut' to regulate proper dendritic branching. The LOF and GOF studies conducted resulted in simplification of dendritic arbors. The knockdown (LOF) of the gene resulted in dwarfing and shrinking of dendrites. Dr. Iyer and his team expected overexpression (GOF) of the gene to result in a more complex morphology. However, the results of the findings were that the gene still simplified the neuron by removing fine dendritic branching (2). It was found that Bedwarfed plays a role in Cut-mediated dendritic branching. Turning down Cut in neurons was found to have similar effects as overexpression of Bedwarfed and a direct correlation was made between the two. Although Bedwarfed and Cut enhance each other's expression, they are not necessarily dependent on one another in order to be expressed. Bedwarfed also  interacts with ribosomal proteins to control growth and differentially regulate cytoskeletal proteins. The effect of Bedwarfed on the main cytoskeletal constituents of dendritic branches was also studied. It was found that the gene restricted tubulin levels while enhancing actin levels (2).

The research being conducted at the Cox lab is vital in developing a better understanding of the importance of dendritic morphogenesis and neuronal diversity. The work that has been done lays the groundwork for future research. Dr. Iyer mentioned the fact that the Bedwarfed gene is highly expressed in the human brain, retina, and in the nucleus and cytoplasm. A homolog of the gene is also involved in schizophrenia. Future work involves attempting to understand the underlying mechanism as well as testing the same hypothesis in the brain of rats and mice to see whether it is conserved across species. Mice and humans both have about 30,000 genes and share approximately 99% of them (4). Studying the genomic sequence of mice provides researchers with a powerful tool to improve their understanding of the role that genes play in human diseases. A relatively new area of study (and one that I am very interested in) is that of pharmacogenomics. This field involves the study of an individual's genetic inheritance to determine how that individual will respond to a certain drug. By better understanding dendrite morphogenesis and specific genes with a certain phenotype, would it be possible to determine the genes that play a role in alteration of drug metabolism and response? Pharmacogenomics is a promising field in that it might one day be possible to tailor drugs for the needs of each individual and adapted to each person's genetic makeup.

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References:

1. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Studying Gene Expression and Function. Available from: http://www.ncbi.nlm.nih.gov/books/NBK26818/

2. Iyer, Dr. Eswar. "From Gene to Function: A Systems Approach to Neuroscience", Cox Lab: Molecular Neuroanatomy and Developmental Neurogenetics, Krasnow Institute For Advanced Study. 25 October 2012. Seminar.

3. Jan, Y., Jan, L. Branching Out: Mechanisms of Dendritic Arborization. Nat Rev Neurosci. 2010 May;11(5):316-28. PMCID: PMC3079328. 

4. "Of Mice and Men - Striking Similarities at the DNA Level Could Aid Research." SFGate. Web. 28 Oct. 2012. 

<http://www.sfgate.com/news/article/of-mice-and-men-striking-similarities-at-the-2748350.php>.

Marching to the Beat of Calcium

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Calcium is one of the most important minerals found in our bodies and comprises approximately 1.5 to 2% of our body weight (1). Single-atom calcium ions are of the most versatile biological messengers known. Rapid, transient changes in calcium concentration directly control muscle contraction, cell locomotion, and neural transmission, among other things. Sustained, elevation of calcium signals is pivotal for numerous biological processes ranging from gene expression, to fertilization, to apoptosis or programmed cell death (2). Did you know that there is a functional linkage between intracellular calcium levels and cardiac arrhythmias? A better understanding of this relationship can very well lead to therapeutic prevention of life-threatening arrhythmias.

Dr. Saleet Jafri, a bioinformatics professor at George Mason University and a member of the Krasnow Institute of Advanced Study, has worked closely with faculty at GMU as well as at other universities. Their research efforts have culminated in the construction of a three-dimensional model simulation of the rat ventricular myocyte. The use of this stochastic model would allow them to make a connection between aberration in normal calcium homeostasis and how this can result in cardiac arrhythmias (3). In order to efficiently use this model, a numerical method was to be developed. Dr. Jafri and his team went on to develop the Ultrafast Monte Carlo Method, which was used to calculate the open probability of ryanodine receptors and the occurrence of a calcium leak. This GPU-enabled method is less expensive and more computationally efficient than other methods previously used for stochastic stimulations. The Ultrafast Monte Carlo Method employs the use of the Euler method, which is important for solving differential equations. By building this model, Dr. Jafri and his team attempt to answer fundamental questions regarding the mechanisms underlying arrhythmias that could not be answered with previous modeling efforts (2).

Process of excitation-contraction coupling in the cardiomyocte.
http://heart.bmj.com/content/89/4/371/F1.large.jpg

Dr. Jafri clearly stressed the importance of understanding calcium dynamics and the mechanisms underlying it prior to understanding arrhythmias. Calcium acts as a signaling molecule in the excitation-contraction coupling of cardiac muscle. This physiological process relies predominantly on a mechanism known as calcium-induced calcium release (CICR). Central to this process are the calcium release units (CRUs). CRUs, consisting of t-tubules of cardiac muscle and the sarcoplasmic reticulum (SR) contain ryanodine receptors (RyRs) that, after detecting an influx of calcium, activate and result in the release of calcium from the SR to the cytoplasm (4). The release of calcium from the SR by activation of RyRs is triggered by the opening of L-type calcium channels or by the stochastic opening of a single RyR. These synchronized stochastic openings are referred to as calcium sparks (4).

Calcium sparks are the elementary release events that sum to produce a calcium transient, which is a term used to describe the increase in cytosolic calcium. Calcium sparks are visualized using confocal microscopy techniques. With regards to the termination of calcium release, many different elements come into play. According to Dr. Jafri, calcium sparks terminate because of the influence of three specific factors on RyRs gating: a large number of RyRs, coupled gating of RyRs, and finally, calcium concentration in the SR lumenal (2). Calcium sparks are important in maintaining calcium homeostasis via a mechanism known as 'calcium leak'. This calcium leak balances the SR calcium-ATPase flux. Increases in SR calcium means an increase in calcium leak (3). This results in calcium overload which causes membrane depolarization and leads to an arrhythmia. There is also an 'invisible leak', a certain amount of leak that has not been measured or accounted for. Dr. Jafri and his team address this issue using the 'sticky cluster model' (2).

Peaks of a calcium transient, action potential , and cardiac muscle contraction.
http://www1.imperial.ac.uk/resources/C33D8D76-1C29-41B2-82F3-BB0F43E8354F/

Calcium sparks can be seen in this image as yellow and red spots. This cell was loaded with Fluo-3, a fluorescent  calcium indicator.
http://admin.qol.qub.ac.uk/my_research/user_uploads/QL3gHQpz9YM=/Figure%203.gif

Dr. Jafri and the team have implemented their three-dimensional stochastic model of calcium dynamics to better understand the primary mechanism underlying calcium wave generation. They examined the resting and individual calcium spark behavior using their 3D model and the Ultrafast Monte Carlo Method. They also simulated a SR calcium leak experiment in which caffeine was used. In addition, they examined the effects of phosphorylation on calcium spark generation. They have come to learn that the activation of a single RyR of the calcium release units would result in neighboring RyRs to become active as well, generating a synchronized influx of calcium from the SR to the cytoplasm (2). Once 6 or more RyRs open, the remaining channels open as well, resulting in a calcium spark. As for calcium release termination, it occurs by reduced calcium concentration in the SR which then results in stochastic closure, coupled gating, and reduced opening of RyRs (5).

The research that has been conducted by Dr. Jafri and others is pivotal in better understanding calcium entrained cardiac arrhythmias. Their work is invaluable in that it lays the groundwork on which future research can be built upon. Perhaps by using this model, in the future, researchers would be able to understand abnormalities in ryanodine receptors for example, or mutations associated with these receptors. New pharmacological or genetic strategies can be developed to treat disorders associated with the heart. There are certain rate and rhythm control medications that have been developed to help treat arrhythmias. Calcium channel blockers have been used as anti-arrhythmiac agents, but are associated with dangerous side effects and even death. Would it be possible to employ the Ultrafast Monte Carlo Method to simulate the effectiveness of medications to treat different heart conditions? Can the basic idea of stochastic stimulations be used in the treatment of other disorders?

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References:

1. http://www.crcnetbase.com/doi/abs/10.1201/9780203912393.ch6
2. Jafri, Dr. Saleet. "Understanding the Molecular Basis of Calcium-Entrained Cardiac Arrhythmia by GPU-Enabled Monte Carlo Simulation", Department of Molecular Neuroscience, Krasnow Institute For Advanced Study. 4 October 2012. Seminar.
3. Hoang-Trong, M. T., G. S. B. Williams, A. C. Chikando, E. A. Sobie, W. J. Lederer, and M. S. Jafri. 2011. Stochastic Simulation of Cardiac Calcium Dynamics and Waves.Conf Proc IEEE Eng Med Biol Soc. 2011: 4677-4680.
4. Williams, G. S. B., A. C. Chikando, T. M. Hoang-Trong, E. A. Sobie, W. J. Lederer, and M. S. Jafri. 2011. Dynamics of Calcium Sparks and Calcium Leak in Heart. Biophys. J.101:1287-1296.
5. Sobie, E. A., K. W. Dilly, J. d. S. Cruz, W. J. Lederer, and M. S. Jafri. 2002.Termination of cardiac of Ca²⁺ sparks: an investigative mathematical model of calcium-induced calcium release. Biophys. J. 83:59-78

Brain Aging: What's Rise of Nations Got To Do With It?

The brain is a profoundly interconnected organ. It is made up of approximately 60% white matter and 40% gray matter (1). The white matter, which makes up the central core of the brain, is widely responsible for interneuron communication at different locations. In the human lifespan, the brain undergoes a lot of morphological changes including aging and atrophy. This atrophy includes decline in white matter integrity as well as in cortical thickness.

Dr. Maren Strenziok, a post-doctoral fellow at George Mason University's Arch Lab presented the research that she and numerous other faculty and students are currently involved in. The backbone of their research consists of conducting training and longitudinal studies in healthy aging. These studies are vital as they attempt to make sense of why the brain undergoes decline with age. Decline begins at the age of 30-40 years and is steady in terms of brain tissue integrity. On average, cognitive function and fluid abilities and intelligence decline, but this does not occur in everyone. About 30-50% of people show no decline in cognitive function. Different factors including diet, exercise, education, and genetic and social factors are studied for any correlation and to help explain this phenomenon (2).

This image is of a diffusion tensor imaging scan. DTI scans of
a healthy brain add color to its white matter.
http://www.dana.org/news/brainwork/detail.aspx?id=5322

Brain aging has been studied using magnetic resonance imaging (MRI). Dr. Strenziok introduced the techniques used and focused mainly on two types of MRI techniques: diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI). DTI is an MRI technique that allows for the measurement of fractional anisotropy, the random diffusion of water molecules in the brain. Higher fractional anisotropy (FA) reflects better white matter fiber integrity while a decline in FA is indicative of decreasing white matter health. Functional MRI is a technique that helps in mapping the specific regions of the brain engaged in certain tasks, processes or emotions. It works by detecting changes in blood flow related to neural activity of brain cells. It was used to measure the functional connectivity of the brain when in default mode network (DMN).
                        

This image depicts four fMRI brain scans obtained during a visual memory task.
http://berkeley.edu/news/media/releases/2000/11/20_mri.html

In the study conducted at the Arch Lab, a video game known as 'Rise of Nations' was used. This video game was previously shown to have benefited older people and an increase in white matter integrity and improved intellectual ability have been noted. Training was conducted in individuals over the age of 60 and the study lasted 8 weeks. Participants trained 6 times a week; 3 times were supervised in the lab and 3 times were at home. Each session lasted for 1 hour. There were 10 trained subjects and 8 control subjects. Experimenters engaged in motivational speech with the participants. A fixed order of games was used and an emphasis was placed on using a variety of strategies. Pre and post-training performance differences were measured across participants (2).

Rise of Nations: Rise of Legends Preview
http://pcmedia.gamespy.com/pc/image/article/685/685658/rise-of-nations-rise-of-legends-20060203034016276-000.jpg

The results of the experiment were not as expected. Corpus callosum FA was lower post-training in trained individuals. This was a surprise as white matter integrity is expected to increase and a greater FA should mean better performance. This is not always the case however as was found in a study in which Williams Syndrome patients were tested. Although these participants were found to have higher FA post-training, they did worse on tests. It can be concluded therefore, that FA can decrease with expertise, as well as with age. In functional connectivity tests, superior parietal connectivity was higher post-training in trained individuals. It was noted that participants exhibited more reliance on intrahemispheric integration and less reliance on interhemispheric integration. A correlation was also made between lower FA and higher functional connectivity in the same participants. In the future, the team at Arch lab hope to create an index to measure improvement over time in game performance (2). They also hope to further analyze cortical thickness and how it degenerates with age.

Overall, I found Dr. Strenziok's lecture to be informative and thought-provoking and her presentation style was also effective. The research that is being conducted at the Arch lab is vital and can help in better understanding abnormalities of the brain associated with different psychiatric disorders such as obsessive compulsive disorder and depression. By providing insight into the abnormalities and faulty neural connections associated with such disorders, techniques such as fMRI and DTI can provide clues to recovery. By employing these techniques in people at risk but not yet suffering from a developmental disorder, it might possibly enable treatment before the onset of symptoms (3). Patients with traumatic brain injuries (TBI) have symptoms that manifest themselves in different ways. Would it be possible to use fMRI scans to predict how patients with TBI will respond to different rehabilitation strategies?







References:

1. http://www.nursingassistantcentral.com/blog/2008/100-fascinating-facts-you-never-knew-about-the-human-brain/
2. Strenziok, Dr. Maren. "Brain Connectivity: Neural Substrates of Cognitive Function in Healthy Aging", Arch Lab/Cognitive Genetics Research Group – Psychology. 20 September 2012. Lecture.
3. http://www.dana.org/news/brainwork/detail.aspx?id=5322&p=1
4. http://www.dana.org/news/publications/detail.aspx?id=14442