Systematic Review on Intra- and Extracochlear Electrical Stimulation for Tinnitus

Several electrical stimulation patterns of the auditory nerve have been described for tinnitus relief, but there is no consensus on the most effective stimulation pattern. Therefore, we aim to systematically review the literature on the effect of intra- and extracochlear electrical stimulation patterns as a treatment option for patients with tinnitus. Only studies on intra- and extracochlear electrical stimulation for patients with tinnitus were included if the stimulation used did not concern standardized CI stimulation patterns to primarily rehabilitate hearing loss as intervention. A total of 34 studies met the inclusion criteria, with 10 studies (89 patients) on intracochlear electrical stimulation and 25 studies on extracochlear electrical stimulation (1109 patients). There was a high to medium risk of bias in 22 studies, especially due to lack of a non-exposed group and poor selection of the exposed group. All included studies showed subjective tinnitus improvement during or after electrical stimulation, using different stimulation patterns. Due to methodological limitations and low reporting quality of the included studies, the potential of intra- and extracochlear stimulation has not been fully explored. To draw conclusions on which stimulation patterns should be optimized for tinnitus relief, a deeper understanding of the mechanisms involved in tinnitus suppression is needed.

A Pathogen Mimetic Molecule Induces Highly Amplified Synergistic Immune Activation to Vaccination via Activation of Multiple Signaling Pathways

We developed a small-molecule trimeric PRR agonist-based adjuvant inspired by the stimulation pattern of a pathogen. This molecule generated by covalently linking TLR2/6 agonist, NOD2 agonist, and NLRP3 inflammasome activator, stimulates multiple subfamilies of PRRs in a spatially defined manner resulting in an amplified innate immune response <i>in vitro.</i> Moreover, it elicits both stronger humoral and cellular immune responses <i>in vivo</i>.

A Pathogen Mimetic Molecule Induces Highly Amplified Synergistic Immune Activation to Vaccination via Activation of Multiple Signaling Pathways

We developed a small-molecule trimeric PRR agonist-based adjuvant inspired by the stimulation pattern of a pathogen. This molecule generated by covalently linking TLR2/6 agonist, NOD2 agonist, and NLRP3 inflammasome activator, stimulates multiple subfamilies of PRRs in a spatially defined manner resulting in an amplified innate immune response <i>in vitro.</i> Moreover, it elicits both stronger humoral and cellular immune responses <i>in vivo</i>.

Entraining stepping movements of Parkinson’s patients to alternating subthalamic nucleus deep brain stimulation

Patients with advanced Parkinson’s can be treated by deep brain stimulation of the subthalamic nucleus (STN). This affords a unique opportunity to record from this nucleus and stimulate it in a controlled manner. Previous work has shown that activity in the STN is modulated in a rhythmic pattern when Parkinson’s patients perform stepping movements, raising the question whether the STN is involved in the dynamic control of stepping. To answer this question, we tested whether an alternating stimulation pattern resembling the stepping-related modulation of activity in the STN could entrain patients’ stepping movements as evidence of the STN’s involvement in stepping control. Group analyses of ten Parkinson’s patients (one female) showed that alternating stimulation significantly entrained stepping rhythms. We found a remarkably consistent alignment between the stepping and stimulation cycle when the stimulation speed was close to the stepping speed in the five patients that demonstrated significant individual entrainment to the stimulation cycle. Our study provides evidence that the STN is causally involved in dynamic control of step timing, and motivates further exploration of this biomimetic stimulation pattern as a basis for the development of specific deep brain stimulation strategies to ameliorate gait impairments.

Analytical study of flexible stimulation waveforms in muscle fatigue reduction

This paper presents the analytical study of flexible stimulation waveforms in muscle fatigue reduction for functional electrical stimulator (FES)-assisted hemiplegic muscle activities. The major challenge of muscle contraction induced by FES is early muscle fatigue which greatly limits activities such as FES-assisted standing and walking. The fixed stimulation pattern applied on a same motor unit has resulted the motor unit to be overworked and fatigue easily. Therefore, in this work, the stimulus parameters, which include the pulse width duration and the frequency were varied to create a few flexible stimulation waveforms using MATLAB/Simulink. The pulse width duration was modulated from 100µs – 500µs to generate five types of flexible stimulation waveforms such as Rectangular, Trapezoidal, Ramp Up, Ramp Down and Triangular. Concurrently, a few ranges of stimulus frequency were also used, which include 20Hz, 30Hz and 50Hz. The generated flexible stimulation waveforms were applied onto a humanoid muscle model to investigate and analyse the muscle output response and early muscle fatigue reduction. From the conducted simulation results and analyses, it was observed that flexible stimulation waveforms such as Triangular, Ramp Up and Ramp Down could reduce early muscle fatigue phenomenon by having lower average of negative slope, in the range of 0.012 to 0.013 for the muscle fitness. In contrast, the Rectangular and Trapezoidal shapes were found to have higher negative slope of muscle fitness in the range of 0.028 to 0.031. The Ramp Down shape was found to have the lowest average of negative slope (0.012) while Rectangular was found to have the highest average of negative slope (0.031). Therefore, it can be concluded that flexible stimulation waveforms such Ramp Down, Ramp Up and Triangular shapes could reduce early muscle fatigue phenomenon with Ramp Down shape having the highest muscle fatigue reduction.

Multi-Structure Cortical States Deduced from Intracellular Representations of Fixed Tactile Input Patterns

The brain has a never-ending internal activity, whose spatiotemporal evolution interacts with external inputs to define how we perceive them. We used reproducible touch-related spatiotemporal inputs and recorded intracellularly from rat neocortical neurons to characterise this interaction. The synaptic responses, or the summed input of the networks connected to the neuron, varied greatly to repeated presentations of the same tactile input pattern delivered to the tip of digit 2. Surprisingly, however, these responses sorted into a set of specific response types, unique for each neuron. Further, using a set of eight such tactile input patterns, we found each neuron to exhibit a set of specific response types for each input provided. Response types were not determined by global cortical state, but instead likely depended on the time-varying state of the specific subnetworks connected to each neuron. The fact that some types of responses were recurrent, i.e. more likely than others, indicates that the cortical network had a non-continuous landscape of solutions for these tactile inputs. Therefore, our data suggests that sensory inputs combine with the internal dynamics of the brain networks, thereby causing them to fall into one of multiple possible perceptual attractor states. The neuron-specific instantiations of response types we observed suggest that the subnetworks connected to each neuron represent different components of those attractor states. Our results indicate that the impact of cortical internal states on external inputs is substantially more richly resolvable than previously shown.Key points summaryIt is known that the internal state of the neocortical network profoundly impacts cortical neuronal responses to sensory input.Little is known of how the internal neocortical activity combines with a given sensory input to generate the response.We used eight reproducible patterns of skin sensor activation and made intracellular recordings in neocortical neurons to explore the response variations in the specific subnetworks connected to each recorded neuron.We found that each neuron exhibited multiple, specific recurring response types to the exact same skin stimulation pattern and that each given stimulation pattern evoked a unique set of response types.The findings indicate a multi-structure internal state that combines with peripheral information to define cortical responses; we suggest this mechanism is a prerequisite for the formation of perception (and illusions) and indicates that the cortical networks work according to attractor dynamics.