TBI Treatment Development Meeting February 19, 2015 Washington, DC
Research at FDA on TBI Pathophysiology and Biomarker
Development
Cristin Welle, Ph.D.
Center for Devices and Radiological HealthOffice of Science and Engineering LaboratoriesDivision of Biomedical Physics
TBI Treatment Development Meeting February 19, 2015
Development of Therapeutics for TBI
No approved therapeutic devices or pharmaceuticals
Lack of reliable biomarkers • Diagnosis • Monitoring of the condition
Gold Standard: Clinical exam + CT scan
No approved diagnostic devices2 approved diagnostic assessment aid device
TBI Treatment Development Meeting February 19, 2015
Regulatory science at FDA for TBI
• Medical Countermeasures Initiative (MCMi): FDA-wide initiative to coordinate medical countermeasure development, preparedness, and response.
• The goal of the MCMi regulatory science program is to develop the tools, standards, and approaches to assess medical countermeasure safety, efficacy, quality, and performance and to help translate cutting-edge science and technology into innovative, safe, and effective medical countermeasures (MCMs).
• Neural Interfaces Lab in CDRH has been funded to explore TBI biomarker development
TBI Treatment Development Meeting February 19, 2015
Landscape of potential TBI Biomarkers
Potential neuroimaging biomarkers
• Magnetic resonance imaging (MRI)
• Diffusion tensor imaging (DTI)
• Positron emission tomography (PET)
Potential biofluid biomarkers
• Blood serum markers, S-100B, GFAP, Neuron specific enolase, Myelin basic protein, C-Tau, cytokine…etc
Potential electrophysiological biomarkers
• Electroencephalography (EEG)
(Leung et al. MCB 2008; Svetlov et al. J Neurotrauma2009; Gao and Chen J neuropathol Exp Neurol 2011)
!
Diffusion Tensor Imaging
Psychiatry Neuroimaging Laboratory
• At each location, the diffusion behavior of water is modeled as an ellipsoid. • In medical imaging this ellipsoid is called a diffusion tensor.
Slide 7
Diffusion tensor MRI
TBI Treatment Development Meeting February 19, 2015
Potential Electroencephalography (EEG) Biomarker
… the recording of electrical activity on the scalp
‘brain waves’Advantages:
• Noninvasive
• Inexpensive
• Fast
• Portable
• Field-deployable
TBI Treatment Development Meeting February 19, 2015
• Diagnostic assessment aid:
: First FDA-Cleared TBI EEG Device
“indicated for use as an adjunct to standard clinical practice to aid in the evaluation of patients who are being considered for a head CT, but should not be used as a substitute for a CT scan.”
TBI Treatment Development Meeting February 19, 2015
Investigations of electrophysiological biomarkers of brain injury
• EEG signals at acute and chronic timepointsfollowing injury
– Invasive and non-invasive detection sensors
– Multiple quantitative metrics – spontaneous and evoked qEEG
– Non-invasive, calibrated, localized brain injury model
TBI Treatment Development Meeting February 19, 2015
Non-invasive, calibrated, spatially localized brain injury model
Modified from Mahab RA et al. 2012 Med. Phys.
High-intensity focused ultrasound brain injury
TBI Treatment Development Meeting February 19, 2015
Neuroinflammatory Responses to HIFU Brain Injury – 24 hours post-exposure
Control/CC/Iba1
Control/CC/GFAP
HIFU/CC/Iba1 HIFU/CC/GFAP
Control/Cortex/Iba1 Control/Cortex/GFAP
Co
ntr
ol
24
hr
po
st in
jury
HIFU/Cortex/Iba1 HIFU/Cortex/GFAP
Corpus CallosumCortex
TBI Treatment Development Meeting February 19, 2015
Impaired Locomotor Ability of the Mouse Following HIFU Exposure
TBI Treatment Development Meeting February 19, 2015
Invasive ECoG Recordings from mouse primary motor cortex
11
Contralateral HIFU Injury Control
TBI Treatment Development Meeting February 19, 2015
Delta
Theta
Alpha
Beta
Gamma
Injury alters the spontaneous qEEG
TBI Treatment Development Meeting February 19, 2015
Somatosensory evoked potentials (SSEP) reflect brain injury
Median nerve stimulation produces robust SSEPLocal brain injury reduces SSEP amplitude
TBI Treatment Development Meeting February 19, 2015Amplitude variance
Signal entropy
Reduced amplitude variability, but increased signal entropy
TBI Treatment Development Meeting February 19, 2015
Non-invasive flexible scalp electrodes for SSEP detection
TBI Treatment Development Meeting February 19, 2015
TBI Treatment Development Meeting February 19, 2015
Non-invasive electrodes are sensitive to damage severity
TBI Treatment Development Meeting February 19, 2015
Electrophysiological biomarkers
• Potential qEEG markers at acute and chronictimepoints following injury
– qEEG changes in the spontaneous EEG at multiple timepoints
– Acute SSEP changes
– Detectable with invasive and non-invasive sensors
• Pipeline for rapid, portable EEG diagnostic devices for brain injury
===> Development of therapeutics
Thank you!
Neural Interfaces LabEEG
Meijun Ye, PhD
SSEP
Stanley Huang, PhD
Jonathan Fisher, PhD (current faculty at New York Medical College)
Victor Krauthamer, PhD
Division Director, Biomedical Physics
Ultrasound Engineering LabMatthew Myers, PhD
HIFU and Histology
Marjan Nabili
Uniformed Services University of the Health Sciences
Joseph McCabe, PhD
FDA Medical Countermeasures Initiative