Neuromod (Ireland)

Brain tumor treatment presents challenges for patients and clinicians, with prognosis for many of the most common brain tumors being poor. Focused ultrasound (FUS) can be deployed in several ways to circumvent these challenges, including the need to penetrate the blood-brain barrier and spare healthy brain tissue. This article reviews current FUS applications within neuro-oncology, emphasizing ongoing or recently completed clinical trials. Most clinical interest in FUS for neuro-oncology remains focused on exploring BBB disruption to enhance the delivery of standard-of-care therapeutics. More recently, the application of FUS for radiosensitization, liquid biopsy, and sonodynamic therapy is garnering increased clinical attention to assist in tumor ablation, early detection, and phenotypic diagnosis. Preclinical studies show encouraging data for the immunomodulatory effects of FUS, but these findings have yet to be tested clinically. FUS is a burgeoning area of neuro-oncology research. Data from several forthcoming large clinical trials should help clarify its role in neuro-oncology care.

Bimodal neuromodulation is emerging as a nonsurgical treatment for tinnitus. Bimodal treatment combining sound therapy with electrical tongue stimulation using the Lenire device is evaluated in a controlled pivotal trial (TENT-A3, NCT05227365) consisting of 6-weeks of sound-only stimulation (Stage 1) followed by 6-weeks of bimodal treatment (Stage 2) with 112 participants serving as their own control. The primary endpoint compares the responder rate observed in Stage 2 versus Stage 1, where a responder exceeds 7 points in the Tinnitus Handicap Inventory. In participants with moderate or more severe tinnitus, there is a clinically superior performance of bimodal treatment (58.6%; 95% CI: 43.5%, 73.6%; p = 0.022) compared to sound therapy alone (43.2%; 95% CI: 29.7%, 57.8%), which is not observed in the full cohort across all severity groups. Consistent results are observed for the secondary endpoint based on the Tinnitus Functional Index (bimodal treatment: 45.5%; 95% CI: 31.7%, 59.9%; sound-only stimulation: 29.6%; 95% CI: 18.2%, 44.2%; p = 0.010), where a responder exceeds 13 points. There are no device related serious adverse events. These positive outcomes led to FDA De Novo approval of the Lenire device for tinnitus treatment.

Tinnitus subtypes are proposed to lie on a continuum of different symptom dimensions rather than be categorical. However, there is no comprehensive empirical data showing this complex relationship between different tinnitus symptoms. The objective of this study is to provide empirical evidence for the dimensional nature of tinnitus and how different auditory and non-auditory symptoms interact with each other through complex interactions. We do this using graph theory, a mathematical tool that empirically maps this complex interaction. This way, graph theory can be utilised to highlight a new and possibly important outlook on how we can understand the heterogeneous nature of tinnitus. In the current study, we use the screening databases of the Treatment Evaluation of Neuromodulation for Tinnitus-Stage A1 (TENT-A1) and A2 (TENT-A2) randomised trials to delineate the dimensional relationship between different clinical measures of tinnitus as a secondary data analysis. We first calculate the empirical relationship by computing the partial correlation. Following this, we use different measures of centrality to describe the contribution of different clinical measures to the overall network. We also calculate the stability of the network and compare the similarity and differences between TENT-A1 and TENT-A2. Components of the auditory subnetwork (loudness discomfort level, sound sensitivity, average hearing loss and high frequency hearing loss) are highly inter-connected in both networks with sound sensitivity and loudness discomfort level being highly influential with high measures of centrality. Furthermore, the relationship between the densely connected auditory subnetwork with tinnitus-related distress seems to vary at different levels of distress, hearing loss, duration and age of the participants. Our findings provide first-time evidence for tinnitus varying in a dimensional fashion illustrating the heterogeneity of this phantom percept and its ability to be perceptually integrated, yet behaviourally segregated on different symptomatic dimensions.

Bluetooth Low Energy (BLE) offers an inexpensive low-power technology for precise indoor positioning. However, multipath propagation and signal scattering deteriorate localization performances. Machine learning methods were previously demonstrated to significantly improve BLE direction finding estimates over classical signal processing methods in several studies. Performances as well as memory and computing requirements of on-device inference approaches were however not evaluated with respect to embedded hardware. We developed a computational framework to validate storage size, inference time and performances of different previously proposed machine learning and deep learning architectures within a ray-tracing indoor positioning dataset. We highlight that gradient-boosted decision tree methods outperformed deep learning approaches, met embedded hardware requirements, and generalized well when indoor environment changes were introduced. Additionally, we compared static multi-channel features with BLE protocol compliant single random channel features and found a minor single channel performance deterioration, but still significant performance benefit over signal processing methods. Our study therefore provides a validated framework to assess machine learning performances for indoor positioning in embedded hardware.

Low-frequency (<200 Hz), subperception spinal cord stimulation (SCS) is a novel modality demonstrating therapeutic efficacy for treating chronic neuropathic pain. When stimulation parameters were carefully titrated, patients experienced rapid onset (seconds–minutes) pain relief without paresthesia, but the mechanisms of action are unknown. Using an integrated computational model and in vivo measurements in urethane-anesthetized rats, we quantified how stimulation parameters (placement, pulse width, frequency, and amplitude) influenced dorsal column (DC) axon activation and neural responses in the dorsal horn (DH). Both modeled and recorded DC axons responded with irregular spiking patterns in response to low-amplitude SCS. Maximum inhibition of DH neurons occurred at ∼80% of the predicted sensory threshold in both modeled and recorded neurons, and responses were strongly dependent on spatially targeting of stimulation, i.e., the complement of DC axons activated, and on stimulation parameters. Intrathecal administration of bicuculline shifted neural responses to low-amplitude stimulation in both the model and experiment, suggesting that analgesia is dependent on segmental GABAergic mechanisms. Our results support the hypothesis that low-frequency subperception SCS generates rapid analgesia by activating a small number of DC axons which inhibit DH neuron activity via surround inhibition.

Previously we showed that the vitamin A metabolite all-trans retinoic acid (atRA) induces synaptic plasticity in acute brain slices prepared from the mouse and human neocortex (Lenz et al., 2021). Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata-a brain region implicated in memory acquisition. No major changes in synaptic transmission were observed in the ventral hippocampus while a significant increase in both spontaneous excitatory postsynaptic current frequencies and synapse numbers were evident in the dorsal hippocampus 6 hr after atRA administration. The intrinsic properties of hippocampal dentate granule cells were not significantly different and hippocampal transcriptome analysis revealed no essential neuronal changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, that is, for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic strength. Indeed, in vivo long-term potentiation (LTP) experiments demonstrated that systemic atRA treatment improves the ability of dentate granule cells to express LTP. The plasticity-promoting effects of atRA were not observed in synaptopodin-deficient mice, therefore, extending our previous results regarding the relevance of synaptopodin in atRA-mediated synaptic strengthening in the mouse prefrontal cortex. Taken together, our data show that atRA mediates synaptopodin-dependent metaplasticity in mouse dentate granule cells.