research at fda on tbi pathophysiology and …...no approved diagnostic devices 2 approved...

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


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

http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/default.htm

http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/default.htm

http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/AboutMCMi/ucm431268.htm


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


Potential Electroencephalography (EEG) Biomarker

… the recording of electrical activity on the scalp

‘brain waves’Advantages:

• Noninvasive

• Inexpensive

• Fast

• Portable

• Field-deployable


• 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.”


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


Non-invasive, calibrated, spatially localized brain injury model

Modified from Mahab RA et al. 2012 Med. Phys.

High-intensity focused ultrasound brain injury


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


Impaired Locomotor Ability of the Mouse Following HIFU Exposure


Invasive ECoG Recordings from mouse primary motor cortex

11

Contralateral HIFU Injury Control


Delta

Theta

Alpha

Beta

Gamma

Injury alters the spontaneous qEEG


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


Non-invasive flexible scalp electrodes for SSEP detection


Non-invasive electrodes are sensitive to damage severity


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

research at fda on tbi pathophysiology and …...no approved diagnostic devices 2 approved...

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