Efficacy of Deep Brain Stimulation on the Improvement of the Bladder Functions in Traumatic Brain Injured Rats

Abstract

Objective: Traumatic brain injuries (TBIs) are a prime public health challenge with a high incidence of mortality, and also reflect severe economic impacts. One of their severe symptoms is bladder dysfunction. Conventional therapeutic methods are not effective in managing bladder dysfunction. Henceforth, a research endeavor was attempted to explore a new therapeutic approach for bladder dysfunction through deep brain stimulation (DBS) procedures in a TBI animal model. Methods: TBI in this animal model was induced by the weight-drop method. All rats with an induced TBI were housed for 4 weeks to allow severe bladder dysfunction to develop. Subsequently, an initial urodynamic measurement, the simultaneous recording of cystometric (CMG) and external urethral sphincter electromyography (EUS-EMG) activity was conducted to evaluate bladder function. Further, standard DBS procedures with varying electrical stimulation parameters were executed in the target area of the pedunculopontine tegmental nucleus (PPTg). Simultaneously, urodynamic measurements were re-established to compare the effects of DBS interventions on bladder functions. Results: From the variable combinations of electrical stimulation, DBS at 50 Hz and 2.0 V, significantly reverted the voiding efficiency from 39% to 69% in TBI rats. Furthermore, MRI studies revealed the precise localization of the DBS electrode in the target area. Conclusions: The results we obtained showed an insightful understanding of PPTg-DBS and its therapeutic applications in alleviating bladder dysfunction in rats with a TBI. Hence, the present study suggests that PPTg-DBS is an effective therapeutic strategy for treating bladder dysfunction.

Electrical stimulation methods and protocols for the treatment of traumatic brain injury: a critical review of preclinical research

“…1: 4 and 5 days post-injury, 2x/day; exp. 2 and 3: 5–7 days post-injury, 2x/day Chan et al [ 171 ] Motor recovery with DBS Motor deficits 32 male Long Evans Rats (7 were withdrawn), FPI in motor cortex contralateral to dominant forelimb (severity unclear), awake during DBS 80% of individual motor threshold, 30 Hz, 400 µs pulses, 12 h per day Starting 4 weeks post-injury, for 4 weeks Jen et al [ 172 ] DBS to modulate bladder function in TBI animals Bladder dysfunction 22 female Sprague–Dawley rats, weight drop (450 g from 2 m, severe TBI), anesthetized during DBS and cystometry 1.5 V, 50 Hz, 182 µs pulses One session, 1 week post-injury, during cystometry, triggered by EUS-EMG Praveen Rajneesh et al [ 173 ] DBS to treat bladder dysfunction after TBI Bladder dysfunction 49 male Sprague–Dawley rats, weight drop (450 g from 0.5, 1, 1.5, 2 and 2.25 m, severity unclear), anesthetized during DBS and cystometry 1/1.5/2/2.5 V, 50 Hz, 182 µs biphasic pulses, for 10 s One session, 1 week post-injury, during cystometry when bladder pressure exceeded threshold Praveen Rajneesh et al [ 174 ] DBS to improve bladder function after TBI Bladder dysfunction 28 male Sprague–Dawley rats, weight drop (450 g from 2 m, severe TBI), anesthetized during DBS and cystometry 1/1.5/2/2.5 V (randomized sequence), 50 Hz, 182 µs pulses, for 10 s One session, 1 week post-injury, during cystometry when bladder pressure exceeded threshold Dong et al [ 176 ] DBS to promote wakefulness after TBI DoC 55 Sprague–Dawley rats (28 male, 27 female), weight drop (400 g dropped from 40 to 44 cm, severity unclear), comatose but without anesthesia during DBS 2–4 V, 200 Hz, 0.1 ms pulses, switch between left and right side of lateral hypothalamus every 5 min, for 1 h Once, 2 h post-injury (1 h after electrode implantation) Aronson et al [ 169 ] Task-matched DBS to improve cognitive recovery after TBI ...…”

“…Stimulation frequencies as low as 7.7–8 Hz were applied in the midbrain or medial septal nucleus to treat cognitive deficits [ 166 – 168 ], while 30 Hz stimulation in the lateral cerebellar nucleus was used for a similar purpose [ 170 , 171 ]. All three studies investigating DBS as a treatment for bladder dysfunction in this scope originate from the same research group and used identical stimulation parameters [ 172 – 174 ]. Their triggered approach consists of 10 s of 50 Hz stimulation at amplitudes between 1 and 2.5 V. In their most recent study [ 174 ], they explored simulation of the pedunculopontine tegmental nucleus instead of the rostral pontine reticular nucleus to investigate its neural connectivity with bladder function, resulting in a similar outcome.…”

“…All three studies investigating DBS as a treatment for bladder dysfunction in this scope originate from the same research group and used identical stimulation parameters [ 172 – 174 ]. Their triggered approach consists of 10 s of 50 Hz stimulation at amplitudes between 1 and 2.5 V. In their most recent study [ 174 ], they explored simulation of the pedunculopontine tegmental nucleus instead of the rostral pontine reticular nucleus to investigate its neural connectivity with bladder function, resulting in a similar outcome. Aronson et al applied 130 Hz biphasic pulses in trains of 500 ms in the nucleus accumbens, whenever an animal succeeded a given task, leading to an improved spatial memory in TBI rats [ 169 ].…”

“…Only one group reported that they found no beneficial effects after stimulating the medial septal nucleus at a frequency of 100 Hz [ 168 ]. While one study did undocumented preliminary research to find optimal stimulation parameters [ 166 ], others adopted their parameters from previous studies on different topics [ 171 , 172 , 175 , 176 ] or made the selection and optimization of the stimulation protocols part of their study [ 167 , 168 , 173 , 174 ]. Jen et al found an ideal stimulus length and frequency for effective stimulation for their purpose [ 172 ], only to continue with investigations regarding the optimal stimulation intensity in further studies [ 173 , 174 ].…”

“…While one study did undocumented preliminary research to find optimal stimulation parameters [ 166 ], others adopted their parameters from previous studies on different topics [ 171 , 172 , 175 , 176 ] or made the selection and optimization of the stimulation protocols part of their study [ 167 , 168 , 173 , 174 ]. Jen et al found an ideal stimulus length and frequency for effective stimulation for their purpose [ 172 ], only to continue with investigations regarding the optimal stimulation intensity in further studies [ 173 , 174 ]. Only Aronson et al do not describe how they chose the exact stimulation parameters they use, but mention that phasic stimulation in the nucleus accumbens might be able to promote neural plasticity [ 169 ].…”