On-Off and Proportional Closed-Loop Adaptive Deep Brain Stimulation Reduces Motor Symptoms in Freely Moving Hemiparkinsonian Rats.

OBJECTIVES: Closed-loop adaptive deep brain stimulation (aDBS) continuously adjusts stimulation parameters, with the potential to improve efficacy and reduce side effects of deep brain stimulation (DBS) for Parkinson's disease (PD). Rodent models can provide an effective platform for testing aDBS algorithms and establishing efficacy before clinical investigation. In this study, we compare two aDBS algorithms, on-off and proportional modulation of DBS amplitude, with conventional DBS in hemiparkinsonian rats. MATERIALS AND METHODS: DBS of the subthalamic nucleus (STN) was delivered wirelessly in freely moving male and female hemiparkinsonian (N = 7) and sham (N = 3) Wistar rats. On-off and proportional aDBS, based on STN local field potential beta power, were compared with conventional DBS and three control stimulation algorithms. Behavior was assessed during cylinder tests (CT) and stepping tests (ST). Successful model creation was confirmed via apomorphine-induced rotation test and Tyrosine Hydroxylase-immunocytochemistry. Electrode location was histologically confirmed. Data were analyzed using linear mixed models. RESULTS: Contralateral paw use in parkinsonian rats was reduced to 20% and 25% in CT and ST, respectively. Conventional, on-off, and proportional aDBS significantly improved motor function, restoring contralateral paw use to approximately 45% in both tests. No improvement in motor behavior was observed with either randomly applied on-off or low-amplitude continuous stimulation. Relative STN beta power was suppressed during DBS. Relative power in the alpha and gamma bands decreased and increased, respectively. Therapeutically effective adaptive DBS used approximately 40% less energy than did conventional DBS. CONCLUSIONS: Adaptive DBS, using both on-off and proportional control schemes, is as effective as conventional DBS in reducing motor symptoms of PD in parkinsonian rats. Both aDBS algorithms yield substantial reductions in stimulation power. These findings support using hemiparkinsonian rats as a viable model for testing aDBS based on beta power and provide a path to investigate more complex closed-loop algorithms in freely behaving animals.

Micromotion Derived Fluid Shear Stress Mediates Peri-Electrode Gliosis through Mechanosensitive Ion Channels.

The development of bioelectronic neural implant technologies has advanced significantly over the past 5 years, particularly in brain-machine interfaces and electronic medicine. However, neuroelectrode-based therapies require invasive neurosurgery and can subject neural tissues to micromotion-induced mechanical shear, leading to chronic inflammation, the formation of a peri-electrode void and the deposition of reactive glial scar tissue. These structures act as physical barriers, hindering electrical signal propagation and reducing neural implant functionality. Although well documented, the mechanisms behind the initiation and progression of these processes are poorly understood. Herein, in silico analysis of micromotion-induced peri-electrode void progression and gliosis is described. Subsequently, ventral mesencephalic cells exposed to milliscale fluid shear stress in vitro exhibited increased expression of gliosis-associated proteins and overexpression of mechanosensitive ion channels PIEZO1 (piezo-type mechanosensitive ion channel component 1) and TRPA1 (transient receptor potential ankyrin 1), effects further confirmed in vivo in a rat model of peri-electrode gliosis. Furthermore, in vitro analysis indicates that chemical inhibition/activation of PIEZO1 affects fluid shear stress mediated astrocyte reactivity in a mitochondrial-dependent manner. Together, the results suggest that mechanosensitive ion channels play a major role in the development of a peri-electrode void and micromotion-induced glial scarring at the peri-electrode region.

Feasibility of pair-housing of rats after cranial implant surgery.

Rat models employing cranial implants are increasingly employed to facilitate neural stimulation and recording in freely moving animals. Due to possible damage to wound, implant or attached devices, rats with cranial implants are traditionally housed singly, and little information is available on group- or pair-housing. Here we describe a protocol for pair-housing rats following cranial implant surgery and describe our experience with pair-housing during post-surgical recovery and up to 16 weeks following surgery.Thirty-six adult Wistar rats of both sexes were implanted with deep brain stimulation electrodes. Ten rats were equipped with an additional wireless headstage. Rats were housed in stable pairs before surgery and re-introduced 0-18 h post-surgery. Rat grimace scores did not indicate pain after conclusion of the analgesia protocol, physiological parameters were in the normal range three days post-surgery and weight loss did not exceed 10%. Rats with a cement cap only were pair-housed continuously without damage to the headcap. Rats carrying an additional fragile headstage had to be separated during lights-off periods to prevent headstage damage but could be pair-housed during lights-on periods.Pair-housing is a feasible and effective method to facilitate the rats' need for social companionship following cranial implant surgery.

The Relationship Between Cortical Activation in Response to Anorectal Stimuli and Continence Behavior in Freely Behaving Rats Before and After Application of Sacral Nerve Stimulation.

BACKGROUND: Changes in anorectal sensation have been reported in patients with fecal incontinence, and there is limited evidence that sacral nerve stimulation can restore normal sensation. OBJECTIVE: The aims of the present study were to investigate changes in the transmission of sensory anorectal stimuli in a rodent model of fecal incontinence and to study the effects of sacral nerve stimulation on defecation behavior. DESIGN: An established model of fecal incontinence was utilized for this study. INTERVENTION: Pudendal nerve stretch and compression were used in 16 adult female Wistar rats and were monitored for 3 weeks: 6 rats received sacral nerve stimulation for 1 week by using an implantable neurostimulator and 10 rats had nonfunctioning "dummy" devices inserted. Five additional rats were sham operated. Anorectal cortical evoked potentials were used as a surrogate marker for anorectal sensory function. MAIN OUTCOME MEASURES: The primary outcomes measured were fecal incontinence index, evoked potential amplitude, and latency. RESULTS: Fifty percent of rats showed behavioral signs of fecal incontinence measured by the Fecal Incontinence Index (>0.20), calculated by using the pellet distribution outside the cage's latrine area. Anorectal evoked potential amplitude was reduced in rats with a Fecal Incontinence Index >0.20 (p = 0.019). The amplitude of forepaw evoked potentials recorded as a control was not different between groups. Chronic sacral nerve stimulation using the fully implantable device and custom rodent lead was safe and stable during this chronic prospective study. Incontinent rats (n = 3) that received sacral nerve stimulation showed an improvement of Fecal Incontinence Index and an increase of evoked potential amplitude to anorectal stimulation compared with the dummy implant controls (n = 5). LIMITATIONS: The main limitation is the small number of animals that received sacral nerve stimulation. CONCLUSIONS: Chronic sacral nerve stimulation is feasible in rats when miniature telemetric devices are used. Behavioral signs of fecal incontinence were positively correlated with the latency of anorectal evoked potentials. See Video Abstract at http://links.lww.com/DCR/B712.RELACIÓN ENTRE LA ACTIVACIÓN CORTICAL EN RESPUESTA A LOS ESTÍMULOS ANORRECTALES Y EL COMPORTAMIENTO DE CONTINENCIA EN RATAS QUE SE COMPORTAN LIBREMENTE ANTES Y DESPUÉS DE LA APLICACIÓN DE ESTIMULACIÓN DEL NERVIO SACRO. ANTECEDENTES: Se han informado cambios en la sensación anorrectal en pacientes con incontinencia fecal y hay evidencia limitada de que la estimulación del nervio sacro puede restaurar la sensación normal. OBJETIVO: Los objetivos del presente estudio fueron investigar los cambios en la transmisión de estímulos anorrectales sensoriales en un modelo de roedor de incontinencia fecal y estudiar los efectos de la estimulación del nervio sacro en la conducta de defecación. DISEO: Un modelo establecido de incontinencia fecal. INTERVENCIN: Se utilizó estiramiento y compresión del nervio pudendo en 16 ratas Wistar hembras adultas y se les realizó un seguimiento durante 3 semanas: seis ratas recibieron estimulación del nervio sacro durante 1 semana utilizando un neuroestimulador implantable y diez ratas tuvieron insertados dispositivos "ficticios" no funcionantes. Se operaron simuladamente cinco ratas adicionales. Los potenciales evocados corticales anorrectales se utilizaron como marcador subrogado de la función sensorial anorrectal. PRINCIPALES MEDIDAS DE RESULTADO: Índice de incontinencia fecal, amplitud de potenciales evocados y latencia. RESULTADOS: El cincuenta por ciento de las ratas mostró signos de comportamiento de incontinencia fecal medidos por el Índice de incontinencia fecal (> 0.20), calculado utilizando la distribución de heces fuera del área de la letrina de la jaula. La amplitud del potencial evocado anorrectal se redujo en ratas con un índice de incontinencia fecal >0.20 (p = 0.019). La amplitud de los potenciales evocados de la pata delantera registrados como control no fue diferente entre los grupos. La estimulación crónica del nervio sacro utilizando un dispositivo totalmente implantable y un cable de roedor personalizado fue segura y estable durante este estudio prospectivo crónico. Las ratas con incontinencia (N = 3) que recibieron estimulación del nervio sacro mostraron una mejora del índice de incontinencia fecal y un aumento de la amplitud del potencial evocado a la estimulación anorrectal en comparación con los controles de implante ficticio (N = 5). LIMITACIONES: La principal limitación es el pequeño número de animales que recibieron estimulación del nervio sacro. CONCLUSIONES: La estimulación crónica del nervio sacro es factible en ratas cuando se utilizan dispositivos telemétricos en miniatura. Los signos conductuales de incontinencia fecal se correlacionaron positivamente con la latencia de los potenciales evocados anorrectales. Consulte Video Resumen en http://links.lww.com/DCR/B712. (Traducción-Dr. Jorge Silva Velazco).

The Active Electrode in the Living Brain: The Response of the Brain Parenchyma to Chronically Implanted Deep Brain Stimulation Electrodes.

BACKGROUND: Deep brain stimulation is an established symptomatic surgical therapy for Parkinson disease, essential tremor, and a number of other movement and neuropsychiatric disorders. The well-established foreign body response around implanted electrodes is marked by gliosis, neuroinflammation, and neurodegeneration. However, how this response changes with the application of chronic stimulation is less well-understood. OBJECTIVE: To integrate the most recent evidence from basic science, patient, and postmortem studies on the effect of such an "active" electrode on the parenchyma of the living brain. METHODS: A thorough and in-part systematic literature review identified 49 papers. RESULTS: Increased electrode-tissue impedance is consistently observed in the weeks following electrode implantation, stabilizing at approximately 3 to 6 mo. Lower impedance values are observed around stimulated implanted electrodes when compared with unstimulated electrodes. A temporary reduction in impedance has also been observed in response to stimulation in nonhuman primates. Postmortem studies from patients confirm the presence of a fibrous sheath, astrocytosis, neuronal loss, and neuroinflammation in the immediate vicinity of the electrode. When comparing stimulated and unstimulated electrodes directly, there is some evidence across animal and patient studies of altered neurodegeneration and neuroinflammation around stimulated electrodes. CONCLUSION: Establishing how stimulation influences the electrical and histological properties of the surrounding tissue is critical in understanding how these factors contribute to DBS efficacy, and in controlling symptoms and side effects. Understanding these complex issues will aid in the development of future neuromodulation systems that are optimized for the tissue environment and required stimulation protocols.

Estimation of dispersive properties of encapsulation tissue surrounding deep brain stimulation electrodes in the rat.

The aim of this study was to estimate the electrical properties of the encapsulation tissue surrounding chronically implanted electrodes for deep brain stimulation in the rat. The impedance spectrum of a concentric bipolar microelectrode implanted in the rat brain was measured immediately following surgery and after 8 weeks of implantation. The experimental impedance data were used in combination with a finite element model of the rat brain using a parametric sweep method to estimate the electrical properties of the tissue surrounding the electrode in acute and chronic conditions. In the acute case, the conductivity and relative permittivity of the peri-electrode space were frequency independent with an estimated conductivity of 0.38 S/m and relative permittivity of 123. The electrical properties of the encapsulation tissue in the chronic condition were fitted to a dispersive Cole-Cole model. The estimated conductivity and relative permittivity in the chronic condition at 1 kHz were 0.028 S/m and 2×105, respectively. The estimated tissue properties can be used in combination with computational modeling as a basis for optimization of chronically implanted electrodes to increase the efficacy of long-term neural recording and stimulation.

Systematic Review of Animal Models Used in Research of Origins and Treatments of Fecal Incontinence.

BACKGROUND: Fecal incontinence is a common disorder, but its pathophysiology is not completely understood. OBJECTIVE: The aim of this review is to present animal models that have a place in the study of fecal incontinence. DATA SOURCES: A literature review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines performed in August 2016 revealed 50 articles of interest. Search terms included fecal/faecal incontinence and animal model or specific species. STUDY SELECTION: Articles not describing an animal model, in vitro studies, veterinary literature, reviews, and non-English articles were excluded. MAIN OUTCOME MEASURES: The articles described models in rats (n = 31), dogs (n = 8), rabbits (n = 7), and pigs (n = 4). RESULTS: Different fecal incontinence etiologies were modeled, including anal sphincter lesions (33 articles) ranging from a single anal sphincter cut to destruction of 50% of the anal sphincter by sharp dissection, electrocautery, or diathermy. Neuropathic fecal incontinence (12 articles) was achieved by complete or incomplete pudendal, pelvic, or inferior rectal nerve damage. Mixed fecal incontinence (5 articles) was modeled either by the inflation of pelvic balloons or an array of several lesions including nervous and muscular damage. Anal fistulas (2 articles), anal sphincter resection (3 articles), and diabetic neuropathy (2 articles) were studied to a lesser extent. LIMITATIONS: Bias may have arisen from the authors' own work on fecal incontinence and the absence of blinding to the origins of articles. CONCLUSIONS: Validated animal models representing the main etiologies of fecal incontinence exist, but no animal model to date represents the whole pathophysiology of fecal incontinence. Therefore, the individual research questions still dictate the choice of model and species.

A review of sacral nerve stimulation parameters used in the treatment of faecal incontinence.

Sacral nerve stimulation (SNS) was originally developed in the field of urinary incontinence. Without adaptation, it was subsequently applied to treat faecal incontinence. SNS has now become a first line therapy for this socially disabling condition, however the mechanism of action is unknown. This review examines the evidence for stimulation parameters currently used for SNS in humans and considers the potential electrophysiological effects of changing these parameters. However, without a proper understanding of the physiology of SNS, changing stimulation parameters remains empirical.

No long-term effects of hormonal therapy preceding brachytherapy on urinary function and health-related quality of life among prostate cancer patients.

OBJECTIVES: To prospectively investigate the influence of 3-month neoadjuvant hormonal therapy (NHT) before brachytherapy (BT) for low-risk prostate cancer (PCa) on urinary function and health-related quality of life (HRQL). METHODS: Between 2003 and 2008, 300 patients with PCa were treated with BT using (125)I stranded seeds, of whom 86 received 3-month NHT to downsize the prostate before treatment. Urinary complaints were measured on all occasions with the International Prostate Symptom Score (n = 134) and European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire PR25 (EORTC-QLQ-PR25 questionnaire; n = 118) and HRQL with the EORTC-QLQ-C30 (n = 120) questionnaire. RESULTS: Post-BT, urinary function became worse over the first 6 weeks and then improved steadily, but did not return to baseline levels at 1 year. At baseline, the NHT group reported worse urinary function compared with the non-NHT group (P < .01). However, the post-BT improvement of urinary function was better in the NHT group at 3 months (P < .05). Global HRQL, physical, role and social functioning decreased over the first 3 months (P < .05) post-BT but returned to baseline levels within 1 year. Emotional function steadily improved over the 1-year follow-up period (P < .001). The NHT group reported better global HRQL, social and emotional functioning 1 year post-BT compared with baseline (P < 05). All results were adjusted for comorbidity. This is a single-center study with a follow-up of 1 year, thereby potentially limiting the general applicability of the results. CONCLUSIONS: Three months of NHT before BT might positively influence urinary function and HRQL up to 1 year post-BT. Therefore, PCa patients should not be dissuaded from considering NHT followed by BT because of prostate size.