ABSTRACT
Symptoms of neurological diseases emerge through the dysfunction of neural circuits whose diffuse and intertwined architectures pose serious challenges for delivering therapies. Deep brain stimulation (DBS) improves Parkinson's disease symptoms acutely but does not differentiate between neuronal circuits, and its effects decay rapidly if stimulation is discontinued. Recent findings suggest that optogenetic manipulation of distinct neuronal subpopulations in the external globus pallidus (GPe) provides long-lasting therapeutic effects in dopamine-depleted (DD) mice. We used synaptic differences to excite parvalbumin-expressing GPe neurons and inhibit lim-homeobox-6expressing GPe neurons simultaneously using brief bursts of electrical stimulation. In DD mice, circuit-inspired DBS provided long-lasting therapeutic benefits that far exceeded those induced by conventional DBS, extending several hours after stimulation. These results establish the feasibility of transforming knowledge of circuit architecture into translatable therapeutic approaches.
Subject(s)
Deep Brain Stimulation/methods , Dopamine/deficiency , Globus Pallidus/physiopathology , Neurons/physiology , Parkinson Disease/therapy , Transcutaneous Electric Nerve Stimulation/methods , Animals , Disease Models, Animal , Dopamine/genetics , Female , Globus Pallidus/cytology , Male , Mice , Mice, Inbred C57BL , Optogenetics , Parkinson Disease/physiopathology , Subthalamic Nucleus/cytology , Subthalamic Nucleus/physiopathology , Synapses/physiologyABSTRACT
We aimed to investigate the terms used to refer to cognitive and fatigue related side effects and their prevalence in phase III add-on clinical trials of anti-epileptic drugs (AEDs). We extracted data from publicly available FDA documents as well as the published literature. Target drug doses were then calculated as drug loads and divided into three categories (low, average, high). The odds ratio of developing the side effects was calculated for each drug load, and the presence of a dose-response effect was also assessed. We found that the cognitive terms used across trials were very variable, and data on discontinuation rates were limited. Placebo rates for cognitive side effects ranged from 0 to 10.6% while those for fatigue ranged from 2.5 to 37.7%. Keeping in mind the variable placebo rates and terminology, the majority of AEDs exhibited a clear dose response effect and significant odds ratios at high doses except brivaracetam and zonisamide for the cognitive side effects and tiagabine, topiramate, and zonisamide for the fatigue side effects. Due to their clinical relevance and impact on quality of life, new trials should make data related to the prevalence and discontinuation rates of these side effects publicly available. Given the clear dose response effect, physicians should consider aiming for lower drug loads and adjusting doses to improve tolerability.
