Jonathan M. Kracht

Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model

Blast exposure is associated with chronic traumatic encephalopathy, impaired neuronal function, and persistent cognitive deficits in blast-exposed military veterans and experimental animals. Blast Brain: An Invisible Injury Revealed Traumatic brain injury (TBI) is the “signature” injury of the conflicts in Afghanistan and Iraq and is associated with psychiatric symptoms and long-term cognitive disability. Recent estimates indicate that TBI may affect 20% of the 2.3 million U.S. servicemen and women deployed since 2001. Chronic traumatic encephalopathy (CTE), a tau protein–linked neurodegenerative disorder reported in athletes with multiple concussions, shares clinical features with TBI in military personnel exposed to explosive blast. However, the connection between TBI and CTE has not been explored in depth. In a new study, Goldstein et al. investigate this connection in the first case series of postmortem brains from U.S. military veterans with blast exposure and/or concussive injury. They report evidence for CTE neuropathology in the military veteran brains that is similar to that observed in the brains of young amateur American football players and a professional wrestler. The investigators developed a mouse model of blast neurotrauma that mimics typical blast conditions associated with military blast injury and discovered that blast-exposed mice also demonstrate CTE neuropathology, including tau protein hyperphosphorylation, myelinated axonopathy, microvascular damage, chronic neuroinflammation, and neurodegeneration. Surprisingly, blast-exposed mice developed CTE neuropathology within 2 weeks after exposure to a single blast. In addition, the neuropathology was accompanied by functional deficits, including slowed axonal conduction, reduced activity-dependent long-term synaptic plasticity, and impaired spatial learning and memory that persisted for 1 month after exposure to a single blast. The investigators then showed that blast winds with velocities of more than 330 miles/hour—greater than the most intense wind gust ever recorded on earth—induced oscillating head acceleration of sufficient intensity to injure the brain. The researchers then demonstrated that blast-induced learning and memory deficits in the mice were reduced by immobilizing the head during blast exposure. These findings provide a direct connection between blast TBI and CTE and indicate a primary role for blast wind–induced head acceleration in blast-related neurotrauma and its aftermath. This study also validates a new blast neurotrauma mouse model that will be useful for developing new diagnostics, therapeutics, and rehabilitative strategies for treating blast-related TBI and CTE. Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein–linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.

Sparsity driven ultrasound imaging.

An image formation framework for ultrasound imaging from synthetic transducer arrays based on sparsity-driven regularization functionals using single-frequency Fourier domain data is proposed. The framework involves the use of a physics-based forward model of the ultrasound observation process, the formulation of image formation as the solution of an associated optimization problem, and the solution of that problem through efficient numerical algorithms. The sparsity-driven, model-based approach estimates a complex-valued reflectivity field and preserves physical features in the scene while suppressing spurious artifacts. It also provides robust reconstructions in the case of sparse and reduced observation apertures. The effectiveness of the proposed imaging strategy is demonstrated using experimental data.

Linear hydrophone arrays for measurement of shock wave lithotripter acoustic fields

Lithotripter acoustic field characterization is based on single-element hydrophone measurements even though many clinical lithotripters do not have highly repeatable sound fields. Here, linear hydrophone arrays composed of 20 elements, each measuring 0.5 by 0.5 mm and spaced 1.25 mm center to center, are described and characterized. The arrays were fabricated by bonding a 9 µm piezopolymer film to a flex circuit on which an array pattern had been formed using standard printed circuit board etching techniques. After bonding, the devices were backed with an epoxy plug in order to provide structural support. The sensitivity of each hydrophone element was measured at 41 mm axial distance with a pressure of 4.5 kPa using a 5.25 MHz, 14-cycle tone burst. The resulting sensitivities were normalized across each array. The normalized RMS voltages were quite uniform across each array, and between arrays, with an ≈ 6% variation in voltage. The arrays were also placed in a piezoelectric lithotripter in order to determine the shot-to-shot repeatability for peak positive pressures of 60 MPa. The array elements withstood about 500 shock waves before slowly losing sensitivity.

Single-shot measurements of the acoustic field of an electrohydraulic lithotripter using a hydrophone array.

Piezopolymer-based hydrophone arrays consisting of 20 elements were fabricated and tested for use in measuring the acoustic field from a shock-wave lithotripter. The arrays were fabricated from piezopolymer films and were mounted in a housing to allow submersion into water. The motivation was to use the array to determine how the shot-to-shot variability of the spark discharge in an electrohydraulic lithotripter affects the resulting focused acoustic field. It was found that the dominant effect of shot-to-shot variability was to laterally shift the location of the focus by up to 5 mm from the nominal acoustic axis of the lithotripter. The effect was more pronounced when the spark discharge was initiated with higher voltages. The lateral beamwidth of individual, instantaneous shock waves were observed to range from 1.5 mm to 24 mm. Due to the spatial variation of the acoustic field, the average of instantaneous beamwidths were observed to be 1 to 2 mm narrower than beamwidths determined from traditional single-point measurements that average the pressure measured at each location before computing beamwidth.

Acoustic stone localization during lithotripsy.

It is desirable to mitigate damage to kidney tissue induced by shock waves administered during lithotripsy. Stone movement due to patient respiration causes a fraction of the shock waves to miss the stone. The goal here is to ensure that shock waves are delivered to the kidney only when the kidney stone is in the focal region of the lithotripter. We present the design of a collar with an array of ultrasound transducers that can be retrofitted to a clinical lithotripter. The transducers are used in a pulse‐echo mode and a hybrid technique combining numeric time‐reversal and MUSIC (MUltiple‐SIgnal‐Classification) is employed to determine the location of a kidney stone relative to the focus of the lithotripter. A model of the acoustic collar was used to select system parameters including the transducer count, center frequency, and transducer placement. The performance of the collar was assessed by translating artificial kidney stones in water and using porcine body wall as an aberrating layer. Performance wi...

Hydrophone array for instantaneous measurement of lithotripter fields.

Electrohydraulic lithotripters employ a spark placed within a hemi‐ellipsoidal reflector to generate shock waves (SWs). The shot‐to‐shot jitter in the spark location results in variability in acoustic measurements, e.g., 50% variation in peak positive pressure. Field measurements with a single‐element hydrophone therefore only provide average field properties over many SWs. The ability to obtain an instantaneous “snapshot” of the sound field would have broad implications for advancing the understanding of how lithotripters fragment stones and damage kidney tissue. Here linear hydrophone arrays consisting of 20 elements were created by bonding a piezopolymer film to copper‐clad polyimide. An array pattern was etched on the copper to provide individual connections to the 20 elements. Failure testing of the hydrophone array was conducted in a piezoelectric lithotripter that generated 60 MPa peak pressure. The sensitivity of the hydrophone remained relatively constant through the first 500 SWs and then gradua...

Hydrophone arrays for instantaneous measurement of high-pressure acoustic fields

Electrohydraulic lithotripter acoustic fields are measured with single‐element hydrophones even though the acoustic fields are not highly repeatable. The ability to obtain an instantaneous “snapshot” of the sound field would have broad implications for advancing the understanding of how lithotripters fragment stones and damage kidney tissue. To better characterize the acoustic field of lithotripters, linear hydrophone arrays were fabricated by bonding a 9 μm piezopolymer film to a copper‐clad polyimide which had an array pattern etched on the copper layer. After bonding, the devices were backed with an epoxy plug in order to provide structural support. The array elements were each 0.5 by 0.5 mm, spaced 1.25 mm center to center, and there were 20 elements. The relative sensitivity of each hydrophone element was measured at 5.25 MHz for an acoustic pressure of 4.5 kPa and the elements were found to vary by ≈ 6%. The arrays were then placed in the focus of a piezoelectric lithotripter and were found to maint...

Kidney stone tracking in vitro using an acoustic triangulation paradigm.

During shock wave lithotripsy, stones undergo motion which can place them outside the focal zone of the lithotripter. This results in shock waves being delivered that do not impact the stone but may injure tissue. Tracking stones using diagnostic ultrasound imaging (∼4 MHz) has proven to be challenging. Here we employed an array of seven relatively low‐frequency (∼600 kHz) elements to detect scattered signals from an artificial kidney stone in the presence of a tissue phantom. Using an optimization routine, the time of flight to each element and array geometry were used to determine the most likely location of the stone. A comparison of threshold crossing and cross‐correlation for detecting signal arrival indicated that while the former yielded faster computation time, the latter was more robust to noise. Stone position was determined to within 2 mm for locations within 10 mm of the focus. For distances beyond 10 mm, the optimization routine was not able to reliably predict stone location but could indica...

Kidney stone localization in vitro using multiple‐signal‐classification.

During shock wave lithotripsy, respiration and patient movement result in motion of a kidney stone. It has been estimated that 50% of the shock waves miss the stone. The misshots result in damage to the tissue with no therapeutic benefit. Here we employed a ring array of seven piezo‐electric elements with center frequency of ∼600 kHz to track stones in vitro. Each element was used to transmit in turn, and the individual waveforms received on all elements were recorded. The Fourier transform of these data gives the multistatic response matrix, whose largest eigenvalues represent the dominant scatterers in the medium. The associated eigenvectors were employed by the multiple‐signal‐classification (MUSIC) method to generate a scattering indicator image from which scatterer locations were determined. We tested MUSIC’s applicability to track artificial kidney stones in water or with a tissue phantom. Single targets were tracked with an accuracy of 4 mm. A single stone resulted in three eigenvalues and therefor...