Neonatal Epilepsy

Concussions are minor traumatic brain injuries caused by bumping the head. The action taking place that causes a concussion is when the brain bounces around in the skull causing minor to major bruising. This causes chemical changes in the brain and leaves the damaged areas in the brain vulnerable to permanent damage if injured again. Symptoms involve “impairments of memory and attention, headache, and alteration of mental status, are the result of neuronal dysfunction mostly caused by functional rather than structural abnormalities” ( Signoretti, 2011). According to Signoretti, the symptoms occur because of the trauma causes the neurons to fall out of homeostasis causing a chain reaction of metabolic events such as temporary

action potentials in the brain and spinal cord due to areas of inflammation, demyelination and

Within the foetus, embryonic nerve cells grow exponentially, then migrate to their destinations and develop into a vast collection of distinctive neuronal cell categories unique to their specific function. In prearranged patterns, the cells later form networks with other brain cells. The metabolic process of alcohol instigates makes the cells vulnerable to cell damage by free radicals (harmful substances). Research has suggested that “free radical damage can kill sensitive populations of brain cells at critical times of development in the first trimester of pregnancy (Cartwright, M.M).” Additional experiments have suggested that the third trimester is a particularly susceptible stage for damage to brain cells linked to FASD. The metabolic breakdown of alcohol interferes with brain development through the alteration of the function or production of natural regulatory substances that assist in the promotion of the differentiation and orderly growth of

Any type of brain disease can cause epilepsy; it also can develop as a result of brain damage from other disorders. For example, brain tumors, alcoholism, and Alzheimer's disease often cause epilepsy because they change the way brain usually works. Strokes, heart attacks, and other conditions that deprive the brain of oxygen also can sometimes cause epilepsy. Other more rare causes of epilepsy are prenatal injuries that come about from poor nutrition or maternal infections; poisoning by lead or carbon monoxide; or overdose of prescription antidepressants or street drugs. There are still many patients for whom the cause of their epilepsy cannot be identified (idiopathic epilepsy).

Inflammation is a reaction of tissues in response to any injury the human or vertebrae sustains. Neuroinflammation is the inflammatory response by the glial cells that are present in the nervous system along with neurons. It is an immune response to pathogen invasion or tissue damage most likely to be caused by Infectious bacteria, Traumatic brain injury (TBI), or toxic metabolites. The nervous system contains neurons and glial cells composed of astrocytes, microglia, oligodendrocytes, ependymal cells in the Central nervous system (CNS), and Schwann cells, satellite cells in Peripheral nervous system (PNS). The glial cells are non-neuronal cells that help to form myelin, maintain homeostasis, provide support for neurons with nutrients, destroy

Pediatric epilepsy is a common condition in the United States. Around 326,000 children experience epilepsy under the age of 15, and there are around 200,000 new diagnoses yearly (“What Happens during a Seizure”, 2014). The age of onset can begin as early as infancy and is most common during childhood. In some cases, there is no specific cause for epilepsy. However, the most common cause is a birth defect or developmental disorder. Those that have experienced head trauma, brain infections, or a minor brain injury can also lead to seizures, or epilepsy. The developing brain is more prone to seizures therefor there is a higher incidence in the pediatric population (“Pediatric Epilepsy & Seizures”, 2016).

Bases on Finke and colleagues [22] in the long term, LGI1 associated LE will cause structural damage in the hippocampal system and produces various degrees of cognitive impairment.[22] Hence rapid diagnosis and early effective treatment is warranted to decrease long term brain damages. Considering good prognosis after immunotherapy, neurologists should be vigilant about the possibility of LE when a rapidly progressive cognitive disorder is associated with epileptic seizure.[10]

Traumas to the brain are a major risk factor for the development of epilepsy and within the following years after such an injury they are considered high risk for epilepsy. In a study done on the risk of epilepsy after head trauma the following statistics were discovered regarding the rate of development:

At adult normal physiological condition, microglial display surveillance or so-called ‘resting’ phenotypes gauged by small cell body with extensively ramifying processes that actively surveying the CNS microenvironment. In this steady state, the turnover processes is primarily confined and well-maintained through local self-renewal of the long-lived resident microglial. Anomalies in the CNS such as infections, tissues damage, and accumulation of abnormal protein or biochemical can trigger microglial activation and in turn cause inflammation in CNS. Different from steady state, inflammatory condition may have disrupted the integrity of blood brain barrier and allowed recruitment of circulating myeloid cells and promotes their differentiation into microglial with more potent inflammatory properties and resulting heterogeneity of microglial . Activated microglial rapidly proliferate undergo phenotypic transition where they will exit from the ‘resting’ or ‘surveying’ form and mounted inflammatory effectors functions. Evidences showed that activated microglial capable of upregulated its phagocytose properties and secrete of inflammatory mediators chemokines, cytokines, nitrite, reactive oxygen species, and free radicals to execute repair

Neuronal messages are transmitted by electrical impulses called the Action Potential. This is actually a net positive inward ion flux that leads to depolarization or voltage change in the neuronal membrane. The ions involved include sodium, potassium, calcium and chloride. Normally brain tissues prevent hyper excitability by several inhibitory mechanisms involving negative ions like chloride ions.

The homeostasis of the brain depends heavily on efficient energy metabolism. A number of studies have shown the role of inflammatory mediators such as nitric oxide, NF-κB, and proinflammatory cytokines play a key role in the impairment central nervous system function, thereby leading to the development of several neuroinflammatory and neurodegenerative disorders. Although not much emphasizes has been made in understanding the role of neural-immune aspect of inflammatory mediators and leukocytes infiltration in the development of glioblastoma. Therefore, understanding the role of choroid plexus and leukocytes infiltration and its association with energy metabolism in cancer will lead us in understanding the role of neural-immune interaction in the development of glioblastoma. Dr. Ellora Sen’s research work has caught my attention with her work on neuroinflammation and metabolism in glioblastoma. I believe my previous research experience in working in the area of neuroimmunology, metabolism and cancer make me a suitable candidate for this position and I would enjoy the opportunity to work in this project

HMGB1 is a prototypic damage-associated molecular pattern (DAMP) protein highly secreted by activated macrophages and monocytes as a cytokine mediator of inflammation. This DNA-binding nuclear protein is released both passively during cell death and actively following cytokine stimulation. It is also implicated in both infectious and sterile inflammatory disorders [32-36] affecting the central nervous system (CNS) such as in Parkinson's disease (PD) [37], multiple sclerosis (MS) [38,39], ischemic stroke [40], traumatic brain injury (TBI) [41] and Alzheimer’s disease - AD [42-44]. HMGB1 activates cells by differential engagement of several membrane receptors including advanced glycation end products (RAGE), toll-like receptor 2 (TLR2), and TLR4 which are primarily responsible for HMGB1 pro-inflammatory activity and BBB impairment [45,46]. Specific to the proposed work, several studies have clearly outlined the role of OS in the development of microvascular and cardiovascular complications of 2DM [47].

Intellectual Merit: The innovativeness of this project stems from the integration of a NIR Ca2+ indicator and a transcranial PAI system to target the activity of astroglial cells in awake rats.

Once spontaneous seizures have developed, they will continue for the rest of the animal’s lifetime. The model is simple to establish and does not require any specialist equipment, as kindling does, which minimises costs. Induction of SE as the original precipitating injury closely resembles human TLE (similar to the kainate model) and is easier to model in animals than trauma or febrile seizures 27. However, most precipitating injuries in humans occur in the first few years of childhood 33, and as the optimum time for establishing SE with pilocarpine is PN21, the model is not completely homologous with human epilepsy. The pilocarpine model has the potential to be refractory to AEDs, as TLE often presents with pharmacoresistant seizures, however this is yet to be determined. The model is most suited to investigating biomarkers and fundamental mechanisms of epileptogenesis, or testing newly emergent drugs from high-throughput screening

P-glycoprotein in drug resistant epilepsy- The exact cause for drug resistance in epilepsy is not fully understood. One theory is that the mRNA of ABCB1 the gene encoding for the drug efflux transporter P-glycoprotein is significantly upregulated at the blood brain barrier of patients with drug resistant epilepsy. P-glycoprotein acts as a gate-keeper and limits a large number of drugs from crossing the blood brain barrier (BBB) and therefore from entering the brain [20].This upregulation of P-glycoprotein at the BBB could prevent antiepileptic drugs from accessing the brain and cause drug resistance in epilepsy [20].Recent data from in vivo studies show that P-glycoprotein limits antiepileptic drugs from penetrating the brain [20].It was shown