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GABA as a Biomarker of Stroke

Illustration showing ischemic stroke

What is Stroke?

Stroke is the leading cause of disability in the United States. The condition causes rapid plasticity within various cortical connections in the brain, essentially causing a remap of neural circuiting in affected areas. When remapping occurs, it forces area of the cortex to form new connections, also known as long-term potentiation. This diminishes responsiveness in certain areas of the brain. In human stroke patients, the damage manifests itself in decreased language, motor, and sensory transfers of information caused by changes in neuronal excitation, which are primarily localized in the somatosensory and primary motor cortices of the brain. 1,2

The heterogeneity of stroke can make it difficult to diagnose, determine prognosis trajectories, and determine an appropriate treatment plan, making the identification of biomarkers8 an imperative tool to determine the level of changes in neural circuitry. However, as far as current research goes, there are no established biomarkers for stroke patients, especially within the context of hemodynamic and neurochemical activity. Whole brain analysis provides significant evidence to suggest a negatively correlative relationship of GABA localized within the primary motor cortex9, indicating that GABA may be a viable biomarker for stroke.1 Additionally, multiple studies have linked decreased levels of GABA in the primary cortex after various non-invasive brain stimulation techniques (NIBS).1,5,8,10

What has previous research shown?

In previous studies, NIBS and PETs techniques were used in order to monitor and record GABAergic activity, however, these do not measure GABA levels directly.1 Magnetic resonance spectroscopy (MRS) has been useful non-invasive techniques have been useful in measuring GABAergic synaptic activity.7 Magnetic resonance imaging (fMRI) performed at baseline and after NIBS patients show that decreases in GABA are associated with motor recovery in chronic settings as well.1 While the relationship is between GABA and motor learning is apparent, further research is necessary on how total concentrations GABA within larger volumes of cortical tissue relate to the synaptic activity10, and establish which mechanisms decrease GABA and are responsible for neural remapping.8

Identifying Biomarkers

Pairing NIBS with MRS and fMRI addresses many technical problems associated with using the techniques separately. Data are collected at the same point in time, rather separately, increasing reliability and strengthening the relationship between NIBS techniques and changes before, during, and after interventions2. fMRI-MRS techniques are shown to provide information on neural activity and neurochemical concentrations of various brain states, respectively.4 Physiological and cognitive variables are then easier to identify, and support link between the motor cortex and its chemical milieu.6 This comparability is especially important when trying to link hemodynamic and neurochemical responses, the former of which ceases after prolonged periods of stimulation. 4

What does this help us understand?

This research should help inform future rehabilitative techniques that aim to promote neural plasticity and at least partial restoration of motor functioning in post-stroke patients and assist in the stratification of patient treatment and help isolate which behavioral changes and interventions will most benefit any given patient8, in addition to determining the neuro-metabolic mechanisms responsible for learning, regaining motor-functioning, and specific for task encoding.3

References

  1. Blicher, J., Near, J., Næss-Schmidt, E., Stagg, C., Johansen-Berg, H., & Nielsen, J. et al. (2014). GABA Levels Are Decreased After Stroke and GABA Changes During Rehabilitation Correlate With Motor Improvement. Neurorehabilitation And Neural Repair, 29(3), 278-286. http://dx.doi.org/10.1177/1545968314543652
  2. Carmichael, S. (2012). Brain Excitability in Stroke. Archives Of Neurology, 69(2), 161. http://dx.doi.org/10.1001/archneurol.2011.1175
  3. Floyer-Lea, A. (2006). Rapid Modulation of GABA Concentration in Human Sensorimotor Cortex During Motor Learning. Journal Of Neurophysiology, 95(3), 1639-1644. http://dx.doi.org/10.1152/jn.00346.2005
  4. Ip, I., Berrington, A., Hess, A., Parker, A., Emir, U., & Bridge, H. (2017). Combined fMRI-MRS acquires simultaneous glutamate and BOLD-fMRI signals in the human brain. Neuroimage, 155, 113-119. http://dx.doi.org/10.1016/j.neuroimage.2017.04.030
  5. Koch, G., Ponzo, V., Di Lorenzo, F., Caltagirone, C., & Veniero, D. (2013). Hebbian and Anti-Hebbian Spike-Timing-Dependent Plasticity of Human Cortico-Cortical Connections. Journal Of Neuroscience, 33(23), 9725-9733. http://dx.doi.org/10.1523/jneurosci.4988-12.2013
  6. Kolasinski, J., Logan, J., Hinson, E., Manners, D., Divanbeighi Zand, A., & Makin, T. et al. (2017). A Mechanistic Link from GABA to Cortical Architecture and Perception. Current Biology, 27(11), 1685-1691.e3. http://dx.doi.org/10.1016/j.cub.2017.04.055
  7. Mullins, P., McGonigle, D., O’Gorman, R., Puts, N., Vidyasagar, R., Evans, C., & Edden, R. (2014). Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA. Neuroimage, 86, 43-52. http://dx.doi.org/10.1016/j.neuroimage.2012.12.004
  8. Sato, S., Bergmann, T., & Borich, M. (2015). Opportunities for concurrent transcranial magnetic stimulation and electroencephalography to characterize cortical activity in stroke. Frontiers In Human Neuroscience, 9. http://dx.doi.org/10.3389/fnhum.2015.00250
  9. Stagg, C. (2014). Magnetic Resonance Spectroscopy as a tool to study the role of GABA in motor-cortical plasticity. Neuroimage, 86, 19-27. http://dx.doi.org/10.1016/j.neuroimage.2013.01.009
  10. Stagg, C., Bestmann, S., Constantinescu, A., Moreno Moreno, L., Allman, C., & Mekle, R. et al. (2011). Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex. The Journal Of Physiology, 589(23), 5845-5855. http://dx.doi.org/10.1113/jphysiol.2011.216978
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Looking at Reception History of the Psalms through the Ages

Westminster_Psalter_David_Psalms

My research looks at Jewish influences on (Christian) translations of the Psalms into English in the Middle Ages. To begin, I took a broad look at various reception histories of the Psalms: ancient Israelite, Karaite, rabbinic, early Christian, lay Christian, monastic Christian, and interfaith reception. The media of reception ranged from written texts (Masoretic Text, Qumran scrolls) to musical psalters to illuminated manuscripts to poetic interpretations to theological exegesis. My tour of the reception history gave me a number of fun glimpses of ongoing research on the Psalms, including modern attempts at understanding how the Psalms may have been sung in their ancient conception.*

Here are the books I flipped through for this preliminary research:

My main goals in taking this survey on the Psalms through the ages include:
1. Glean a general understanding of the arc of the history of the Psalms
2. Understand the state of current scholarship on the Psalms
3. See how much research has been done on my specific research topic
4. Find leads as starting points to look deeper into for my research

To my delight, I found that there has been a recent increase in scholarship on Psalms reception history, seemingly coming out of nowhere. At Oxford University, a gathering of scholars from all over the world has formed a community of sorts for such research.

Looking at my specific topic, I found some points of interest. The first English translations of the Psalms appear in the 9th C. Later, starting at the turn of the 11th C., medieval scholars became more and more interested in the literal meaning of Biblical texts, leading them to care for its original linguistic integrity. A number of medieval English scholars worked in Paris, where some interchanged knowledge with the Jewish community there. These interchanges often produced glosses–mostly in Latin–of the Psalms. Following the glosses came a resurgence of full translations of the Psalms into the English vernacular. A significant portion of these translators (many of them figures who planted the seeds of the Reformation) preferred to translate straight from the Hebrew.

In further research, I am thinking to look deeper into the interchanges between Anglo-Norman scholars and Jewish rabbis. I am also hoping to find some interfaith interchange that may have affected the earlier (9th-C.) translations, although I am not betting on the existence of such interchange. I will be speaking with my adviser this Thursday to decide on my direction from here on.

*David C. Mitchell, How Can We Sing the Lord’s Song?: Deciphering the Masoretic Cantillation explains modern efforts at understanding the actual musical implications of the Trope symbols that are found on the Masoretic Text’s copy of the Psalms.

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Who am I???

Hi y’all!

Me

My name is Ryan and I am a 4th year Mathematics major with a minor in Applied Math. I have background in the health sciences and do research in the Department of Anesthesiology in Emory SOM. Our research encompasses topics within neuroscience such as stroke, TBI, and novel therapies. I have an individual project which was spun off a novel idea a fellow PhD from our lab presented in her dissertation. I currently have one other undergraduate training under me who helps on my project.

What project???

Our project is investigating the efficacy of direct conversion therapy in juvenile rats post-traumatic brain injury (TBI). Essentially, it has been shown that a mixture of drugs can reprogram somatic cells in the brain into neuronal cells to assist in post-TBI recovery. I am using a specific transcription factor, NeuroD1, encased within a viral vector (lentivirus) which is injected into the post-ischemic area a few days after TBI is induced. We can observe supportive glial cells converting into neurons. This therapy is novel since it uses the host’s cells, thus reducing the emphasis of immuno-suppression. Furthermore, it appears to be relatively harmless and easily translated to other species. We can further improve our mechanism by finding a way to have NeuroD1 or a similar activator target specific types of cells within the local injury region.

Update

This week, I have to do some surgeries inducing TBI on rats. I have some preliminary data but I need a higher n group number to have some conclusions regarding the highest rate of cell proliferation within the first two weeks following TBI. Thus, I can then determine the best time to inject the lentivirus. Once I do the surgeries, I will sacrifice the animals depending on the time point and study cell proliferation or migration via immunohistochemistry staining, microscopy, imaging, and cell counting. The data analysis will likely take me at least a month.

Where is my future???

I hope to attend medical school and become a pediatrician. I hope that one day I can be a leader in pediatric clinical trials studying TBI, since young children and adults have the highest rates of TBI. Much of the work I do now today, I hope becomes the same therapy methods I translate to human therapy within the next two decades.

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Welcome to SIRE299/RPP Blog

Dear all,

Welcome to our blog for SIRE299/RPP.  You will be expected to complete blogging assignments here by making new posts. I will go through the basics of how to make a post here on the day the blogs are due. Until that time work on your blog post in microsoft word, only publish completely finished blogs here and not works in progress.

 

If you have any questions feel free to comment with them here.

 

Cheers,

Michael