Correction: Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain.

[This corrects the article DOI: 10.1371/journal.pgen.1005591.].

In vivo acoustoelectric imaging for high-resolution visualization of cardiac electric spatiotemporal dynamics.

Acoustoelectric cardiac imaging (ACI) is a hybrid modality that exploits the interaction of an ultrasonic pressure wave and the resistivity of tissue to map current densities in the heart. This study demonstrates for the first time in vivo ACI in a swine model. ACI measured beat-to-beat variability (n=20) of the peak of the cardiac activation wave at one location of the left ventricle as 5.32±0.74µV, 3.26±0.54mm below the epicardial surface, and 2.67±0.56ms before the peak of the local electrogram. Cross-sectional ACI images exhibited propagation velocities of 0.192±0.061m/s along the epicardial-endocardial axis with an SNR of 24.9 dB. This study demonstrates beat-to-beat and multidimensional ACI, which might reveal important information to help guide electroanatomic mapping procedures during ablation therapy.

Rostral lumbar segments are the key controllers of hindlimb locomotor rhythmicity in the adult spinal rat.

The precise location and functional organization of the spinal neuronal locomotor-related networks in adult mammals remain unclear. Our recent neurophysiological findings provided empirical evidence that the rostral lumbar spinal cord segments play a critical role in the initiation and generation of the rhythmic activation patterns necessary for hindlimb locomotion in adult spinal rats. Since added epidural stimulation at the S1 segments significantly enhanced the motor output generated by L2 stimulation, these data also suggested that the sacral spinal cord provides a strong facilitory influence in rhythm initiation and generation. However, whether L2 will initiate hindlimb locomotion in the absence of S1 segments, and whether S1 segments can facilitate locomotion in the absence of L2 segments remain unknown. Herein, adult rats received complete spinal cord transections at T8 and then at either L2 or S1. Rats with spinal cord transections at T8 and S1 remained capable of generating coordinated hindlimb locomotion when receiving epidural stimulation at L2 and when ensembles of locomotor related loadbearing input were present. In contrast, minimal locomotion was observed when S1 stimulation was delivered after spinal cord transections at T8 and L2. Results were similar when the nonspecific serotonergic agonists were administered. These results demonstrate in adult rats that rostral lumbar segments are essential for the regulation of hindlimb locomotor rhythmicity. In addition, the more caudal spinal networks alone cannot control locomotion in the absence of the rostral segments around L2 even when loadbearing rhythmic proprioceptive afferent input is imposed.NEW & NOTEWORTHY The exact location of the spinal neuronal locomotor-related networks in adult mammals remains unknown. The present data demonstrate that when the rostral lumbar spinal segments (~L2) are completely eliminated in thoracic spinal adult rats, hindlimb stepping is not possible with neurochemical modulation of the lumbosacral cord. In contrast, eliminating the sacral cord retains stepping ability. These observations highlight the importance of rostral lumbar segments in generating effective mammalian locomotion.

Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain.

Dyshomeostasis of both ceramides and sphingosine-1-phosphate (S1P) in the brain has been implicated in aging-associated neurodegenerative disorders in humans. However, mechanisms that maintain the homeostasis of these bioactive sphingolipids in the brain remain unclear. Mouse alkaline ceramidase 3 (Acer3), which preferentially catalyzes the hydrolysis of C18:1-ceramide, a major unsaturated long-chain ceramide species in the brain, is upregulated with age in the mouse brain. Acer3 knockout causes an age-dependent accumulation of various ceramides and C18:1-monohexosylceramide and abolishes the age-related increase in the levels of sphingosine and S1P in the brain; thereby resulting in Purkinje cell degeneration in the cerebellum and deficits in motor coordination and balance. Our results indicate that Acer3 plays critically protective roles in controlling the homeostasis of various sphingolipids, including ceramides, sphingosine, S1P, and certain complex sphingolipids in the brain and protects Purkinje cells from premature degeneration.

Acoustoelectric Time-Reversal for Ultrasound Phase-Aberration Correction.

Acoustoelectric imaging (AEI) is a technique that combines ultrasound (US) with radio frequency recording to detect and map local current source densities. This study demonstrates a new method called acoustoelectric time reversal (AETR), which uses AEI of a small current source to correct for phase aberrations through a skull or other US-aberrating layers with applications to brain imaging and therapy. Simulations conducted at three different US frequencies (0.5, 1.5, and 2.5 MHz) were performed through media layered with different sound speeds and geometries to induce aberrations of the US beam. Time delays of the acoustoelectric (AE) signal from a monopole within the medium were calculated for each element to enable corrections using AETR. Uncorrected aberrated beam profiles were compared with those after applying AETR corrections, which demonstrated a strong recovery (29%-100%) of lateral resolution and increases in focal pressure up to 283%. To further demonstrate the practical feasibility of AETR, we further conducted bench-top experiments using a 2.5 MHz linear US array to perform AETR through 3-D-printed aberrating objects. These experiments restored lost lateral restoration up to 100% for the different aberrators and increased focal pressure up to 230% after applying AETR corrections. Cumulatively, these results highlight AETR as a powerful tool for correcting focal aberrations in the presence of a local current source with applications to AEI, US imaging, neuromodulation, and therapy.

Acoustoelectric imaging of deep dipoles in a human head phantom for guiding treatment of epilepsy.

OBJECTIVE: This study employs a human head model with real skull to demonstrate the feasibility of transcranial acoustoelectric brain imaging (tABI) as a new modality for electrical mapping of deep dipole sources during treatment of epilepsy with much better resolution and accuracy than conventional mapping methods. APPROACH: This technique exploits an interaction between a focused ultrasound (US) beam and tissue resistivity to localize current source densities as deep as 63 mm at high spatial resolution (1 to 4 mm) and resolve fast time-varying currents with sub-ms precision. MAIN RESULTS: Detection thresholds through a thick segment of the human skull at biologically safe US intensities was below 0.5 mA and within range of strong currents generated by the human brain. SIGNIFICANCE: This work suggests that 4D tABI may emerge as a revolutionary modality for real-time high-resolution mapping of neuronal currents for the purpose of monitoring, staging, and guiding treatment of epilepsy and other brain disorders characterized by abnormal rhythms.

High resolution transcranial acoustoelectric imaging of current densities from a directional deep brain stimulator.

OBJECTIVE: New innovations in deep brain stimulation (DBS) enable directional current steering-allowing more precise electrical stimulation of the targeted brain structures for Parkinson's disease, essential tremor and other neurological disorders. While intra-operative navigation through MRI or CT approaches millimeter accuracy for placing the DBS leads, no existing modality provides feedback of the currents as they spread from the contacts through the brain tissue. In this study, we investigate transcranial acoustoelectric imaging (tAEI) as a new modality to non-invasively image and characterize current produced from a directional DBS lead. tAEI uses ultrasound (US) to modulate tissue resistivity to generate detectable voltage signals proportional to the local currents. APPROACH: An 8-channel directional DBS lead (Infinity 6172ANS, Abbott Inc) was inserted inside three adult human skulls submerged in 0.9% NaCl. A 2.5 MHz linear array delivered US pulses through the transtemporal window and focused near the contacts on the lead, while a custom amplifier and acquisition system recorded the acoustoelectric (AE) interaction used to generate images. MAIN RESULTS: tAEI detected monopolar current with stimulation pulses as short as 100 µs with an SNR ranging from 10-27 dB when using safe US pressure (mechanical indices <0.78) and injected current of ~2 mA peak amplitude. Adjacent contacts were discernable along the length and within each ring of the lead with a mean radial separation between contacts of 2.10 and 1.34 mm, respectively. SIGNIFICANCE: These results demonstrate the feasibility of tAEI for high resolution mapping of directional DBS currents using clinically-relevant stimulation parameters. This new modality may improve the accuracy for placing the DBS leads, guide calibration and programming, and monitor long-term performance of DBS for treatment of Parkinson's disease.

Selective Mapping of Deep Brain Stimulation Lead Currents Using Acoustoelectric Imaging.

We describe a new application of acoustoelectric imaging for non-invasive mapping of the location, magnitude and polarity of current generated by a clinical deep brain stimulation (DBS) device. Ultrasound at 1MHz was focused near the DBS device as short current pulses were injected across different DBS leads. A recording electrode detected the high-frequency acoustoelectric interaction signal. Linear scans of the US beam produced time-varying images of the magnitude and polarity of the induced current, enabling precise localization of the DBS leads within 0.70mm, a detection threshold of 1.75mA at 1 MPa and a sensitivity of 0.52 ± 0.07 µV/(mA*MPa). Monopole and dipole configurations in saline were repeated through a human skullcap. Despite 13.8-dB ultrasound attenuation through bone, acoustoelectric imaging was still >10dB above background with a sensitivity of 0.56 ± 0.10 µV/(mA*MPa). This proof-of-concept study indicates that selective mapping of lead currents through a DBS device may be possible using non-invasive acoustoelectric imaging.