Hubert H. Lim

Neuromodulation for Brain Disorders: Challenges and Opportunities

The field of neuromodulation encompasses a wide spectrum of interventional technologies that modify pathological activity within the nervous system to achieve a therapeutic effect. Therapies including deep brain stimulation, intracranial cortical stimulation, transcranial direct current stimulation, and transcranial magnetic stimulation have all shown promising results across a range of neurological and neuropsychiatric disorders. While the mechanisms of therapeutic action are invariably different among these approaches, there are several fundamental neuroengineering challenges that are commonly applicable to improving neuromodulation efficacy. This paper reviews the state-of-the-art of neuromodulation for brain disorders and discusses the challenges and opportunities available for clinicians and researchers interested in advancing neuromodulation therapies.

Electrical stimulation of the midbrain for hearing restoration: Insight into the functional organization of the human central auditory system

The cochlear implant can restore speech perception in patients with sensorineural hearing loss. However, it is ineffective for those without an implantable cochlea or a functional auditory nerve. These patients can be implanted with the auditory brainstem implant (ABI), which stimulates the surface of the cochlear nucleus. Unfortunately, the ABI has achieved limited success in its main patient group [i.e., those with neurofibromatosis type 2 (NF2)] and requires a difficult surgical procedure. These limitations have motivated us to develop a new hearing prosthesis that stimulates the midbrain with a penetrating electrode array. We recently implanted three patients with the auditory midbrain implant (AMI), and it has proven to be safe with minimal movement over time. The AMI provides loudness, pitch, temporal, and directional cues, features that have shown to be important for speech perception and more complex sound processing. Thus far, all three patients obtain enhancements in lip reading capabilities and environmental awareness and some improvements in speech perception comparable with that of NF2 ABI patients. Considering that our midbrain target is more surgically exposable than the cochlear nucleus, this argues for the use of the AMI as an alternative to the ABI. Fortunately, we were able to stimulate different midbrain regions in our patients and investigate the functional organization of the human central auditory system. These findings provide some insight into how we may need to stimulate the midbrain to improve hearing performance with the AMI.

Auditory Midbrain Implant: A Review

The auditory midbrain implant (AMI) is a new hearing prosthesis designed for stimulation of the inferior colliculus in deaf patients who cannot sufficiently benefit from cochlear implants. The authors have begun clinical trials in which five patients have been implanted with a single shank AMI array (20 electrodes). The goal of this review is to summarize the development and research that has led to the translation of the AMI from a concept into the first patients. This study presents the rationale and design concept for the AMI as well a summary of the animal safety and feasibility studies that were required for clinical approval. The authors also present the initial surgical, psychophysical, and speech results from the first three implanted patients. Overall, the results have been encouraging in terms of the safety and functionality of the implant. All patients obtain improvements in hearing capabilities on a daily basis. However, performance varies dramatically across patients depending on the implant location within the midbrain with the best performer still not able to achieve open set speech perception without lip-reading cues. Stimulation of the auditory midbrain provides a wide range of level, spectral, and temporal cues, all of which are important for speech understanding, but they do not appear to sufficiently fuse together to enable open set speech perception with the currently used stimulation strategies. Finally, several issues and hypotheses for why current patients obtain limited speech perception along with several feasible solutions for improving AMI implementation are presented.

The auditory midbrain implant: Effects of electrode location

The auditory midbrain implant (AMI) is a new hearing prosthesis designed for stimulation of the inferior colliculus in patients who do not receive sufficient benefit from cochlear or brainstem prostheses. We have begun clinical trials in which three patients have been implanted with the AMI. Although the intended target was the central nucleus of the inferior colliculus (ICC), the electrode array was implanted into different locations across patients (i.e., ICC, dorsal cortex of inferior colliculus, lateral lemniscus). In this paper, we will summarize the effects of electrical stimulation of these different midbrain regions on various psychophysical properties and speech perception performance. The patient implanted within the intended target, the ICC, exhibited the greatest improvements in hearing performance. However, this patient has not yet achieved open-set speech perception to the performance level typically observed for cochlear implant patients, which we believe is partially due to the location of the array within the ICC. We will present findings from previous AMI studies in guinea pigs demonstrating the existence of spatially distinct functional output regions within the ICC and suggesting that further improvements in performance may be achieved by stimulating within a rostral-ventral region. Remaining questions include if a similar organization exists in the human ICC and if stimulation of its rostral-ventral region with currently available strategies (i.e., those designed for cochlear implants) can restore sufficient speech perception.

Effects of phase duration and pulse rate on loudness and pitch percepts in the first auditory midbrain implant patients: Comparison to cochlear implant and auditory brainstem implant results

The auditory midbrain implant (AMI), which is designed for stimulation of the inferior colliculus (IC), is now in clinical trials. The AMI consists of a single shank array (20 contacts) and uses a stimulation strategy originally designed for cochlear implants since it is already approved for human use and we do not yet know how to optimally activate the auditory midbrain. The goal of this study was to investigate the effects of different pulse rates and phase durations on loudness and pitch percepts because these parameters are required to implement the AMI stimulation strategy. Although each patient was implanted into a different region (i.e. lateral lemniscus, central nucleus of IC, dorsal cortex of IC), they generally exhibited similar threshold versus phase duration, threshold versus pulse rate, and pitch versus pulse rate curves. In particular, stimulation with 100 mus/phase, 250 pulse per second (pps) pulse trains achieved an optimal balance among safety, energy, and current threshold requirements while avoiding rate pitch effects. However, we observed large differences across patients in loudness adaptation to continuous pulse stimulation over long time scales. One patient (implanted in dorsal cortex of IC) even experienced complete loudness decay and elevation of thresholds with daily stimulation. Comparing these results with those of cochlear implant and auditory brainstem implant patients, it appears that stimulation of higher order neurons exhibits less and even no loudness summation for higher rate stimuli and greater current leakage for longer phase durations than that of cochlear neurons. The fact that all midbrain regions we stimulated, which includes three distinctly different nuclei, exhibited similar loudness summation effects (i.e. none for pulse rates above 250 pps) suggests a possible shift in some coding properties that is affected more by which stage along the auditory pathway rather than the types of neurons are being stimulated. However, loudness adaptation occurs at multiple stages from the cochlea up to the midbrain.

Spatially Distinct Functional Output Regions within the Central Nucleus of the Inferior Colliculus: Implications for an Auditory Midbrain Implant

The inferior colliculus central nucleus (ICC) has potential as a new site for an auditory prosthesis [i.e., auditory midbrain implant (AMI)] for deaf patients who cannot benefit from cochlear implants (CIs). We have previously shown that ICC stimulation achieves lower thresholds, greater dynamic ranges, and more localized, frequency-specific primary auditory cortex (A1) activation than CI stimulation. However, we also observed that stimulation location along the caudorostral (isofrequency) dimension of the ICC affects thresholds and frequency specificity in A1, suggesting possible differences in functional (output) organization within the ICC. In this study, we electrically stimulated different regions along the isofrequency laminas of the ICC and recorded the corresponding A1 activity in ketamine-anesthetized guinea pigs using multisite probes to systematically assess ICC stimulation location effects. Our results indicate that stimulation of more rostral and somewhat ventral regions within an ICC lamina achieves lower thresholds, smaller discriminable level steps, and larger evoked potentials in A1. We also observed longer first spike latencies, which correlated with reduced spiking precision, when stimulating in more caudal and dorsal ICC regions. These findings suggest that at least two spatially distinct functional output regions exist along an ICC lamina: a caudal–dorsal region and a rostral–ventral region. The AMI will be implanted along the tonotopic axis of the ICC to achieve frequency-specific activation. However, stimulation location along the ICC laminas affects response properties that have shown to be important for speech perception performance, and needs to be considered when implanting future AMI patients.

Auditory midbrain implant: a combined approach for vestibular schwannoma surgery and device implantation.

Hypothesis: The lateral suboccipital approach is a well-established route for safe removal of vestibular schwannomas in neurofibromatosis Type 2 (NF2) patients. The goal of this study was to assess if this approach can be extended to a lateral supracerebellar infratentorial approach to enable insertion of an auditory midbrain implant (AMI) penetrating array along the tonotopic gradient of the inferior colliculus central nucleus (ICC). Background: The AMI is a new auditory prosthesis designed for penetrating stimulation of the ICC in patients with neural deafness. The initial candidates are NF2 patients who, because of the growth and/or surgical removal of bilateral acoustic neuromas, develop neural deafness and are unable to benefit from cochlear implants. The ideal surgical approach in NF2 patients must first enable safe removal of vestibular schwannomas and then provide sufficient exposure of the midbrain for AMI implantation. Methods: This study was performed on formalin-fixed and fresh cadaver specimens. Computed tomography scan and magnetic resonance imaging were used to study the heads of the specimens and for surgical navigation. Results: The lateral suboccipital craniotomy enabled sufficient exposure of the cerebellopontine angle and internal auditory canal for tumor removal. It could then be extended to a lateral supracerebellar infratentorial approach that provided good exposure of the dorsolateral aspect of the tentorial hiatus and mesencephalon for implantation of the AMI along the tonotopic gradient of the ICC. This approach did not endanger the trochlear nerve or any major midline venous structures in the quadrigeminal cistern. Conclusion: This modified lateral suboccipital approach ensures safe removal of large vestibular schwannomas and provides sufficient exposure of the inferior colliculus for ideal AMI implantation.

Green laser light activates the inner ear

The hearing performance with conventional hearing aids and cochlear implants is dramatically reduced in noisy environments and for sounds more complex than speech (e. g. music), partially due to the lack of localized sensorineural activation across different frequency regions with these devices. Laser light can be focused in a controlled manner and may provide more localized activation of the inner ear, the cochlea. We sought to assess whether visible light with parameters that could induce an optoacoustic effect (532 nm, 10-ns pulses) would activate the cochlea. Auditory brainstem responses (ABRs) were recorded preoperatively in anesthetized guinea pigs to confirm normal hearing. After opening the bulla, a 50-microm core-diameter optical fiber was positioned in the round window niche and directed toward the basilar membrane. Optically induced ABRs (OABRs), similar in shape to those of acoustic stimulation, were elicited with single pulses. The OABR peaks increased with energy level (0.6 to 23 microJ/pulse) and remained consistent even after 30 minutes of continuous stimulation at 13 microJ, indicating minimal or no stimulation-induced damage within the cochlea. Our findings demonstrate that visible light can effectively and reliably activate the cochlea without any apparent damage. Further studies are in progress to investigate the frequency-specific nature and mechanism of green light cochlear activation.

Life and Death Cell Labeling in the Microcirculation of the Spontaneously Hypertensive Rat

Spontaneously hypertensive rats (SHRs) have elevated numbers of apoptotic cells. However, the extent and pattern of cell death at the microvascular level is unexplored. We developed a technique to determine early forms of cell death in vivo in the mesentery by use of the life/death indicator ethidium bromide (EB). The mesenteric microvasculature was superfused with 5 µM EB for a period of 3 min, rinsed and immediately viewed by digital fluorescence microscopy. EB-positive cell structures were observed both in the wall of microvessels as well as in the tissue parenchyma. The microvessels had about 2–4 EB-positive cell structures per 100 µm of vessel length. Larger arterioles (>25 µm) in the SHR had an increased EB-positive structure density. After normalization of the blood pressure in the SHR with adrenalectomy, no significant differences remained between Wistar-Kyoto (WKY) rats and SHRs. After dexamethasone treatment, the adrenalectomized SHRs had a higher EB-positive cell density in the smaller class of microvessels than the WKY rats. In addition, EB-positive cell fragments (0.5–2 µm) were observed in the mesentery microvessel wall, and with TUNEL labeling, they were demonstrated to represent DNA fragments. The percentage of microvessels with EB-positive fragments was higher in the SHR arterioles and capillaries. Capillaries and larger venules (>30 µm) in the SHR had higher levels of cell fragments per vessel length. After adrenalectomy, no significant differences remained between WKY rats and SHRs in any of the mcirovessel categories. When adrenalectomized rats were treated with dexamethasone, a higher number of EB-positive fragments was detected in the wall of SHR capillaries. These results indicate that the mesentery microcirculation in both strains is subject to an early and nonuniform pattern of cell death, as detected by EB, but is enhanced in selected individual microvascular segments of the SHR by a glucocorticoid-driven mechanism.

Electrophysiological Validation of a Human Prototype Auditory Midbrain Implant in a Guinea Pig Model

The auditory midbrain implant (AMI) is a new treatment for hearing restoration in patients with neural deafness or surgically inaccessible cochleae who cannot benefit from cochlear implants (CI). This includes neurofibromatosis type II (NF2) patients who, due to development and/or removal of vestibular schwannomas, usually experience complete damage of their auditory nerves. Although the auditory brainstem implant (ABI) provides sound awareness and aids lip-reading capabilities for these NF2 patients, it generally only achieves hearing performance levels comparable with a single-channel CI. In collaboration with Cochlear Ltd. (Lane Cove, Australia), we developed a human prototype AMI, which is designed for electrical stimulation along the well-defined tonotopic gradient of the inferior colliculus central nucleus (ICC). Considering that better speech perception and hearing performance has been correlated with a greater number of discriminable frequency channels of information available, the ability of the AMI to effectively activate discrete frequency regions within the ICC may enable better hearing performance than achieved by the ABI. Therefore, the goal of this study was to investigate if our AMI array could achieve low-threshold, frequency-specific activation within the ICC, and whether the levels for ICC activation via AMI stimulation were within safe limits for human application. We electrically stimulated different frequency regions within the ICC via the AMI array and recorded the corresponding neural activity in the primary auditory cortex (A1) using a multisite silicon probe in ketamine-anesthetized guinea pigs. Based on our results, AMI stimulation achieves lower thresholds and more localized, frequency-specific activation than CI stimulation. Furthermore, AMI stimulation achieves cortical activation with current levels that are within safe limits for central nervous system stimulation. This study confirms that our AMI design is sufficient for ensuring safe and effective activation of the ICC, and warrants further studies to translate the AMI into clinical application.