Topical fibroblast growth factor-2 for treatment of chronic tympanic membrane perforations.

OBJECTIVE: To determine the efficacy of fibroblast growth factor-2 (FGF-2) in treating chronic nonhealing tympanic membrane (TM) perforations. METHOD: Double-blinded, randomized placebo controlled phase 2 clinical trial for patients with chronic TM perforations of more than 3 months duration with a cross-over arm. Patients received either FGF-2 or placebo (sterile water) saturated gelatin sponge in the perforation after rimming the perforation under topical anesthesia. The perforation was then covered with Tisseel fibrin glue. The primary endpoint was complete closure of the TM perforation. Secondary end points included change in hearing and partial TM closure rates. The TM was examined every 3 weeks with otoendoscopy for closure. The treatment was repeated if there was incomplete closure every 3 weeks up to a total of three treatments per arm. RESULTS: Seventy four patients were recruited for the study. Fifty seven met eligibility criteria and fifty four completed the study. Ten of 14 perforations closed completely in the placebo group (71.4%) and 23 of 40 perforations closed completely in the FGF-2 treatment group (57.5%), P value = .36. Pure tone averages and word recognition scores were not statistically significantly different between study groups post-treatment. After initial complete closure, re-perforation occurred in seven FGF-2 treated patients and two placebo patients making the effective final closure rate 40% for FGF and 57% for placebo, respectively. CONCLUSION: No statistically significant difference in tympanic membrane perforation closure rate was found between the FGF-2 and placebo groups. There were no differences in hearing outcomes between the groups. LEVEL OF EVIDENCE: 1b.

The natural progression of low-frequency hearing loss in patients who meet hybrid implant system candidacy criteria.

OBJECTIVES/HYPOTHESIS: To investigate the natural progression of hearing loss in patients with high-frequency hearing loss whose audiograms met the criteria for a hybrid cochlear implant (CI). STUDY DESIGN: Retrospective database review. METHODS: We retrospectively identified patients who met the criteria for a hybrid CI from our audiometric database. We also recorded the etiology of hearing loss in each patient and excluded patients with retrocochlear etiologies, those age <6 years, duration of observation <1 year, or those with a mixed or conductive hearing loss. We calculated the pre-CI progression of residual low-frequency (LF) hearing level in decibels per year and investigated the risk factor of the progression of hearing loss. RESULTS: A total of 1,083 ears of 944 patients were included in this study. The average rate of hearing loss progression for all etiologies was 1.70 ± 0.10 dB/yr at an average of 250 Hz, 500 Hz, and 1 kHz in the affected ear(s). The progression of hearing loss was 5.0 ± 0.93 dB/yr in patients with Meniere's disease and 3.5 ± 0.76 dB/yr in those with autoimmune disease, both of which were significantly faster than progression rates in other etiologies. In patients with idiopathic, genetic/hereditary, and congenital hearing loss, the progression of hearing loss was 1.46 ± 0.10 dB/yr. Patients with steeply sloping hearing loss experienced significantly faster progression in the ipsilateral ear compared to patients with another audiometric type. CONCLUSIONS: It is suggested that Meniere's disease, autoimmune-mediated inner ear disease, and steeply sloping hearing loss in the ipsilateral ear are risk factors for faster progression of residual LF hearing level. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:1299-1303, 2020.

Stochastic modeling of mouse motor activity under deep brain stimulation: the extraction of arousal information.

In the present paper, we quantify, with a rigorous approach, the nature of motor activity in response to Deep Brain Stimulation (DBS), in the mouse. DBS is currently being used in the treatment of a broad range of diseases, but its underlying principles are still unclear. Because mouse movement involves rapidly repeated starting and stopping, one must statistically verify that the movement at a given stimulation time was not just coincidental, endogenously-driven movement. Moreover, the amount of activity changes significantly over the circadian rhythm, and hence the means, variances and autocorrelations are all time varying. A new methodology is presented. For example, to discern what is and what is not impacted by stimulation, velocity is classified (in a time-evolving manner) as being zero-, one- and two-dimensional movement. The most important conclusions of the paper are: (1) (DBS) stimulation is proven to be truly effective; (2) it is two-dimensional (2-D) movement that strongly differs between light and dark and responds to stimulation; and, (3) stimulation in the light initiates a manner of movement, 2-D movement, that is more commonly seen in the (non-stimulated) dark. Based upon these conclusions, it is conjectured that the above patterns of 2-D movement could be a straightforward, easy to calculate correlate of arousal. The above conclusions will aid in the systematic evaluation and understanding of how DBS in CNS arousal pathways leads to the activation of behavior.

Temporally-patterned deep brain stimulation in a mouse model of multiple traumatic brain injury.

We report that mice with closed-head multiple traumatic brain injury (TBI) show a decrease in the motoric aspects of generalized arousal, as measured by automated, quantitative behavioral assays. Further, we found that temporally-patterned deep brain stimulation (DBS) can increase generalized arousal and spontaneous motor activity in this mouse model of TBI. This arousal increase is input-pattern-dependent, as changing the temporal pattern of DBS can modulate its effect on motor activity. Finally, an extensive examination of mouse behavioral capacities, looking for deficits in this model of TBI, suggest that the strongest effects of TBI in this model are found in the initiation of any kind of movement.

Quantitative descriptions of generalized arousal, an elementary function of the vertebrate brain.

We review a concept of the most primitive, fundamental function of the vertebrate CNS, generalized arousal (GA). Three independent lines of evidence indicate the existence of GA: statistical, genetic, and mechanistic. Here we ask, is this concept amenable to quantitative analysis? Answering in the affirmative, four quantitative approaches have proven useful: (i) factor analysis, (ii) information theory, (iii) deterministic chaos, and (iv) application of a Gaussian equation. It strikes us that, to date, not just one but at least four different quantitative approaches seem necessary for describing different aspects of scientific work on GA.

Temporal patterning of pulses during deep brain stimulation affects central nervous system arousal.

Regulation of CNS arousal is important for a wide variety of functions, including the initiation of all motivated behaviors. Usually studied with pharmacological or hormonal tools, CNS arousal can also be elevated by deep brain stimulation (DBS), in the human brain and in animals. The effectiveness of DBS is conventionally held to depend on pulse width, frequency, amplitude and stimulation duration. We demonstrate a novel approach for testing the effectiveness of DBS to increase arousal in intact female mice: all of the foregoing parameters are held constant. Only the temporal patterning of the pulses within the stimulation is varied. To create differentially patterned pulse trains, a deterministic nonlinear dynamic equation was used to generate a series of pulses with a predetermined average frequency. Three temporal patterns of stimulation were defined: two nonlinear patterns, Nonlinear1 (NL1) and Nonlinear2 (NL2), and the conventional pattern, Fixed Frequency (FF). Female mice with bilateral monopolar electrodes were observed before, during and after hippocampal or medial thalamic stimulation. NL1 hippocampal stimulation was significantly more effective at increasing behavioral arousal than either FF or NL2; however, FF and NL2 stimulation of the medial thalamus were more effective than NL1. During the same experiments, we recorded an unpredicted increase in the spectral power of slow waves in the cortical EEG. Our data comprise the first demonstration that the temporal pattern of DBS can be used to elevate its effectiveness, and also point the way toward the use of nonlinear dynamics in the exploration of means to optimize DBS.