Traumatic spinal cord injury (SCI) affects over 300 000 people in the United States alone and is a source of significant morbidity and disability worldwide. Outcomes after SCI have largely remained unchanged in the past 3 decades despite advances in neurocritical care and surgical management. Currently, there are no FDA-approved therapies to improve outcome after traumatic SCI. Also lacking is real-time direct spinal cord monitoring or SCI biomarkers to guide clinical management and prognostication. Therefore, clinicians primarily rely on indirect parameters, such as blood pressures and magnetic resonance imaging (MRI), to treat SCI patients. Novel therapeutics, such as stem cell technology, hold great potential but have yet to demonstrate clinically meaningful improvement in SCI patients.
Therefore, there is an urgent need for novel diagnostic and interventional modalities that can dramatically improve outcomes after SCI through injury stabilization, regeneration, and functional restoration. In this regard, ultrasound is a versatile medical platform technology that can lead to the development of viable diagnostic and therapeutic options for SCI patients through real-time SCI biomarker monitoring, focal pharmaceutical delivery, and neuromodulation for functional restoration. In this article, we provide a brief overview of the pathophysiology of traumatic SCI and the fundamentals of ultrasound. We also conduct a review of the literature and present the current state of diagnostic and focused ultrasound (FUS) in the context of SCI and discuss future directions and challenges.
Traumatic SCI divides into primary and secondary phases. The primary phase begins
immediately after a traumatic event and involves the destruction of neurons and impaired local blood flow due to concurrent vascular injuries. The secondary phase is triggered by the primary phase and can last several weeks to months. During the secondary phase, an inflammatory response exacerbates hypoxia, edema, and microhemorrhage through a vicious cycle, often leading to irrevocable functional loss, reduced regenerative potential, and prolonged recovery. SCI management typically aims to minimize irreversible tissue damage by modifying the secondary phase. Specifically, impaired tissue perfusion and inflammation are promising targets of monitoring and intervention. There are currently no practical, cost-effective, real-time methods to detect and monitor biomarkers, modulate local vascular permeability for the delivery of therapeutics, modulate perfusion and inflammation, or conduct neuromodulation of surviving neurons to enhance functional recovery after SCI. The following section will review the fundamentals of ultrasound and discuss how it can address many of the key limitations in SCI management.
Ultrasound consists of sound waves with frequencies greater than 20 kHz. Ultrasonics technology utilizes a transducer that typically consists of piezoelectric crystals, through which electrical energy is converted into mechanical sound energy and vice versa. Ultrasound propagation through biological tissue is influenced by acoustic parameters of the sound beam itself, such as spatial and temporal frequency, transmission duration mode (eg, continuous vs pulsed), power, angle of transmission, as well as tissue properties like acoustic impedance. Ultrasound imaging in clinical settings generally utilizes a frequency of 3 to 15 MHz. Although frequencies above 20 MHz can be used to obtain higher spatial resolution, this requires specialized ultrafine transducers that are not available for clinical use.
Diagnostic ultrasound, or imaging, is the most widely available and best understood capability of ultrasound. In anatomic imaging, an ultrasound transducer emits sound waves through a medium and quantifies the reflection to compile an image based on the time it takes the pulse to return as an echo. Ultrasound can also perform real-time monitoring of physiological parameters through functional imaging, such as the quantification of vascular fluid dynamics by detecting frequency shifts related to the Doppler effect.
FUS works on the basis of interference of the sound beams at a preplanned focus. Similar to the way a burning lens focuses sunrays, FUS uses acoustic lenses or electronic focusing to noninvasively focus ultrasound waves into a single point to deliver concentrated energy. FUS is generally classified as either high intensity focused ultrasound (HIFU) or low intensity focused ultrasound (LIFU) based on the intensity of the focused acoustic waves. There are no clearly defined ranges but HIFU has high enough intensity (typically > 100 W/cm) to permanently damage tissue through mechanical destruction or thermal coagulation, while LIFU produces functionally reversible lesions. LIFU has shown potential for applications in reversible neuromodulation and disruption of the blood-brain and blood-spinal cord barriers. We will review both preclinical and clinical studies that have evaluated these capabilities of ultrasound in traumatic SCI. Relevant non-SCI studies are discussed when no SCI-specific information is available.
We performed a comprehensive search of ClinicalTrials.gov and PubMed databases on September 21, 2020 (Figure 1). No limits on publication year were used. In order to identify studies on novel application of ultrasound for SCI, we searched ClinicalTrials.gov using the search criteria “spinal cord injuries” and “ultrasound” which returned 47 studies. We also searched PubMed using the terms (“spinal cord” and (“SCI”, “injur*”, or “trauma*”)) and (“ultraso*” or “sonogra*”), which identified 947 additional studies. Titles and abstracts of the 994 total studies were reviewed to determine relevant studies. A total of 964 studies were excluded (Figure 1). Due to the novelty of the subject, studies were re-screened to include those on FUS, perfusion imaging, or biomarker imaging in SCI (n = 13) and 2 additional studies were identified outside our search. Full texts were reviewed to determine the study methodology, ultrasound parameters, and ultrasound applications. The following sections summarize the final 32 studies selected for the review (Table 1).
At present, clinical application of ultrasound is primarily limited to intraoperative visualization of intrathecal structures in patients undergoing surgery after traumatic SCI. However, diagnostic and therapeutic capabilities of ultrasound can extend far beyond simple anatomic scanning during surgery, namely with perfusion imaging, biomarker imaging, and FUS (Figure 2).
Perfusion is critical to the survival and recovery of traumatized spinal cord tissue. The autoregulatory mechanisms that maintain optimal spinal cord blood flow (SCBF) in healthy individuals can become impaired in traumatic SCI, leading to ischemia and infarct at the injury site. Current clinical management guidelines recommend maintaining a mean arterial pressure (MAP) of 85 to 90 mmHg to optimize the SCBF to salvage the penumbra and reduce secondary injuries. However, it is technically not feasible to directly measure the SCBF in clinical settings. Also, MAP is a practical surrogate parameter of SCBF, but it does not reliably reflect one's SCBF status.
Several nonultrasound-based techniques have been developed for SCBF and spinal cord perfusion pressure (SCPP) measurement, including optical monitoring, laser Doppler flowmetry, and MRI. However, these methods either do not translate well to human (eg, hydrogen clearance), do not allow for real-time measurement (eg, MRI), or fail to provide adequate penetration depth needed for meaningful data collection (eg, laser). Real-time monitoring of SCPP with a lumbar intrathecal catheter after SCI is promising, but this approach cannot precisely localize and monitor the perfusion status of the injury site.
Ultrasound can help overcome the limitations of these existing modalities by enabling real-time In Vivo spinal cord monitoring with high spatiotemporal resolution. For example, intraoperative contrast-enhanced ultrasound (CEUS) was used to visualize microcirculatory SCBF after acute SCI in rhesus monkeys. CUES has also been used to demonstrate hypoperfusion in the epicenter of SCI and concurrent abnormal perfusion of adjacent areas in preclinical settings. Ultrasound was additionally able to characterize the extent of cord contusion and blood-spinal cord barrier (BSCB) breakdown in acute SCI. Importantly, SCBF in the SCI epicenter was predictive of neurological outcomes in a porcine SCI model, suggesting that SCBF quantification with ultrasound may hold prognostic value in patients undergoing decompressive surgery.
Several human studies have investigated the application of ultrasound for intraoperative SCBF monitoring. Yang et al described an ultrasound-based technique to perform intraoperative monitoring of SCBF signals and observed an association between CEUS-based SCBF and neurological outcome. The clinical utility of intraoperative CEUS for monitoring spinal cord perfusion during surgical intervention of traumatic SCI is currently being investigated in a clinical trial (NCT04056988). Thus, ultrasound has the potential to provide novel actionable biomarkers in real time to help clinicians make treatment decisions, fine-tune interventions, and prognosticate to improve outcome after traumatic SCI.
Another promising capability of ultrasound is molecular imaging. Ultrasound molecular imaging (UMI) utilizes protein-specific micro- and nanocontrast agents to perform real-time In Vivo biomarker detection and quantification. As a proof of concept, Volz et al used UMI to assess inflammatory biomarkers following SCI in mice. Using microbubbles augmented to target P-selectin, a potent mediator of acute inflammation, the authors successfully characterized the biomarker expression levels up to 42 d after SCI. Diagnostic and prognostic utility of UMI will grow as more biomarkers of SCI and recovery become available. Photoacoustic imaging is another novel technique in which pulsed lasers generate sound waves in tissue that are detected by an ultrasound transducer, with imaging data often overlaid on co-registered structural ultrasound images. Photoacoustic imaging has been used to monitor white matter loss in rat models of traumatic SCI by imaging with a wavelength indicative of CH bonds which are abundant in myelin. Additionally, Kubelick et al employed combined photoacoustic-ultrasound imaging to track the distribution of nanoparticle-labeled stem cells in both In Vivo and Ex Vivo models of SCI, and provided evidence that ultrasound can further enhance the development of stem cell therapy for SCI by addressing current technological gaps.
HIFU-based ablation therapy is FDA-approved for the treatment of essential tremor and tremor-predominant Parkinson disease, with ongoing investigation into the treatment of brain tumor, depression, stroke, obsessive compulsive disorder, and neuropathic pain. However, to date, there is no clinical study on HIFU in the setting of traumatic SCI. Application of HIFU in the spinal cord is at a nascent stage, and experimental protocols are being developed to replicate the levels of precision and accuracy seen with cranial applications. Available preclinical studies involving HIFU and SCI have been limited to peripheral nerve conduction blockade for the treatment of spasticity following SCI and induction of traumatic cord contusion. Nevertheless, HIFU has several cranial applications that may translate to traumatic SCI. For example, neuropathic pain is common after traumatic SCI and could be treated with HIFU ablation. Ablation targets may include HIFU-based central lateral thalomotomy or areas of the spinal cord or peripheral nerves with HIFU-based rhizotomy. HIFU has been used to create ventriculostomies to treat hydrocephalus and it may similarly help treat the complications of traumatic SCI such as syringomyelia. HIFU has been used to improve the permeability of therapeutic particles across the blood-brain barrier (BBB) and it may also help improve drug delivery following SCI. Overall, further studies are needed to address HIFU delivery to the human spinal cord and the impact on tissues before its utility in SCI can be defined.
There is no clinical study on the safety and efficacy of LIFU therapy in human SCI. Furthermore, LIFU has been investigated primarily in the brain and its potential role in SCI remains unclear. Nevertheless, LIFU’s diverse effects on the central nervous system (CNS) including vascular permeability modulation, neuromodulation, neuroprotection, and local therapeutics delivery are directly applicable to SCI.
LIFU can trigger transient physiological changes in neurons without detectable histological alterations. Therefore, LIFU is increasingly being considered as a safe and effective method to perform reversible neuromodulation. One advantage of LIFU delivery is its submillimeter accuracy to affect focal neuromodulation without the unpredictable current spread seen with electrical stimulation. Both thermal (eg, temperature-induced alterations in neuronal membrane potentials) and nonthermal (eg, mechanical acoustic energy alteration of mechanosensitive ion channel activities) mechanisms have been proposed, and investigation is ongoing.
LIFU-induced neuromodulation has been studied primarily in the brain, such as transcranial LIFU for neuroprotection following traumatic brain injury (TBI). Zheng et al showed that 10 min of daily transcranial LIFU therapy to injured cortex was associated with significantly improved behavioral and histopathological outcomes. Su et al also used transcranial low intensity pulsed ultrasound (LIPUS) to improve BBB permeability, promote neuroprotective cytokine release, attenuate cerebral edema, improve neuronal survival, and improve functional behavioral recovery following TBI. Wu et al found that pre-ictal transcranial LIPUS applied to animals prior to a middle cerebral artery stroke improved histopathological sequela and prevented reperfusion injury. Pretreatment with LIPUS was associated with higher brain-derived neurotrophic factor (BDNF) expression, which may have decreased neuronal apoptosis and cell death signaling. These findings suggest that it is possible for LIFU therapy to have similarly beneficial effects in the spinal cord after traumatic injury.
Modulation of BBB permeability with LIFU through induction of microbubble cavitation in the cerebral microvasculature has recently been demonstrated. Additionally, LIFU can be combined with MR thermometry to monitor alterations in vascular permeability under direct visual feedback. Payne et al demonstrated that MR-guided FUS can generate permeability of the BSCB in rats without inducing gross tissue damage. The BSCB opening can be combined with LIFU’s ability to release drug or plasmid-loaded microbubbles with tight spatiotemporal control, making LIFU-induced focal therapeutics delivery a highly promising paradigm in SCI. For example, in a recent study, Song et al used LIFU and nanobubbles to deliver genes coding for BDNF and nerve growth factor directly to the SCI site and successfully demonstrated gene expressions, which correlated with improved neuronal survival, improved vascular permeability, attenuated histological SCI severity, and functional motor scores. Transfection of genes into the spinal cord mediated by ultrasound and microbubbles has also been supported by several other studies. Although early in development, LIFU-based focal drug delivery holds significant promise in facilitating the development and testing of novel therapies in the spinal cord.
LIFU has also been shown to cause cellular stimulation that may enhance the efficacy of stem cell therapies in SCI. For instance, LIFU can induce the production of osteogenic and neurotrophic factors, and enhance cell viability. Using LIFU, Ning et al reported improved functional outcomes in rats injected with mesenchymal stem cells that were stimulated with ultrasound. LIFU has also been shown to improve nerve function and inflammation after injury. In mice with a crush injury to the sciatic nerve, LIFU led to up to 90% recovery of the nerve function. LIFU has also demonstrated improved neuropathic pain when applied to the spinal cord in rats with SCI and to rat peripheral nerves, potentially by modulating inflammatory molecules like IL-6, Iba1, substance p, neurokinin-1 receptor, and tumor necrosis factor-α.
Ultrasound has several highly attractive advantages: low cost, noninvasiveness, compatibility with other imaging and neuromodulation systems, and versatility (real-time imaging, permanent and transient neuromodulation, vascular permeability modulation, targeted therapeutics delivery). Also, ultrasound systems can be readily configured to deliver adaptive (eg, ultrasound imaging combined with epidural electrical stimulation or pharmaceuticals), multifocal (multiple targets either simultaneously or in sequence), and dual-mode (ultrasound imaging combined with FUS) therapies. Despite ever-growing indications of the technology for CNS disorders, the role of diagnostic and FUS in spinal cord disorders remains at a nascent stage. This is evidenced by the absence of active clinical trials on FUS and the spinal cord compared to more than 20 for disorders affecting the brain. The slow progress has largely been due to technical challenges of working with the spinal cord, deep location within the body, circumferential enclosure of the vertebrae that have high sonic impedance, and continuous movement of the spinal cord and the neighboring structures that have presented challenges in designing and deploying ultrasound transducers. Nevertheless, continued advances in neurosurgical technology, biomedical engineering, and material sciences will enable the field to overcome these hurdles.
In diagnostic imaging, clinical adoption of ultrasound for continuous perfusion and inflammatory biomarker monitoring currently face 2 major challenges. First, current Doppler techniques are better suited for assessing high velocity flows of large caliber arteries rather than low velocity flows in the arteries and microvasculature of the spinal cord. Second, commercial transducers are bulky, handheld devices that are ill-suited for SCI patients who are often in strict bed rest or on spine precaution for prolonged periods of time. Nevertheless, advances in acoustics technology and flexible electronics will soon enable ultrasound-based continuous biomarker tracking in the form of wearable percutaneous ultrasound or implantable transdural ultrasound to salvage penumbral tissues and enhance functional restoration in SCI patients.
Ultrasound imaging can serve as a powerful adjunct to other developing therapies for SCI. For instance, Song et al used preclinical models to demonstrate that epidural electrical stimulation is associated with hemodynamic changes in the spinal cord and that In Vivo ultrasound can monitor the spinal cord's response to stimulation with higher sensitivity than electromyography. These findings support the possibility of a novel paradigm of adaptive electrical neuromodulation and underscore the value of ultrasound in advancing spinal cord research and therapeutics development. UMI is another imaging capability that could aid research of SCI pathophysiology and may provide a means for accurate assessment of treatment efficacy in future clinical trials of novel drugs.
LIFU has numerous potential applications in SCI and is positioned to be a highly innovative application of ultrasound. BSCB opening combined with micro- and nanobubble-mediated delivery of pharmaceuticals and gene therapy agents under direct visual feedback can enable precise and reliable administration of treatment. Frequency-specific In Situ release of therapeutics will also allow multiple therapeutics to be co-administered with simultaneous titration. LIFU-mediated neuromodulation may improve axonal growth, mitigate toxic hyperexcitability, and promote neuroprotection following SCI, with resolution and steerability beyond the current limitations of electrical neuromodulation. Low intensity ultrasound and piezoelectric neurostimulators have been used to restore movement in rats following SCI, thereby raising the possibility of ultrasound-based next-generation spinal cord neuromodulation. Potential application of HIFU in SCI is still being defined but may mirror its development and indications in the brain including permanent neuromodulation (ie, lesioning of functionally pathological regions of the spinal cord) as well as posttraumatic syringomyelia (ie, assessment of cerebrospinal fluid flow and targeted lesioning of adhesions or blockage for improved circulation), and pain syndromes.
Overall, perfusion monitoring is the most frequently studied area of novel ultrasound applications in traumatic SCI, with studies in preclinical, clinical, and clinical trial phases of research. Other ultrasound applications like HIFU and LIFU have been limited to preclinical studies thus far (Figure 3 and Table 2). Early studies show promise for these modalities to aid diagnostic and therapeutic intervention of traumatic SCI. Thus, the future of ultrasound in SCI is bright and there has not been a better time to explore this wide-open field.
This study did not receive any funding or financial support.
The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Dr Theodore receives royalties from Globus Medical and DePuy Synthes, has stock ownership in Globus Medical, and does consulting for Globus Medical. Dr Anderson is a compensated consultant for Globus Medical and a member of the Advisory Board for NeuroLogic and Longeviti NeuroSolutions.