Neural selectivity,efficiency, and dose equivalence in deep brain stimulation through pulse width tuning and segmented electrodes

BackgroundAchieving deep brain stimulation (DBS) dose equivalence is challenging, especially with pulse width tuning and directional contacts. Further, the precise effects of pulse width tuning are unknown, and recent reports of the effects of pulse width tuning on neural selectivity are at odds with classic biophysical studies.MethodsWe created multicompartment neuron models for two axon diameters and used finite element modeling to determine extracellular influence from standard and segmented electrodes. We analyzed axon activation profiles and calculated volumes of tissue activated.ResultsWe find that long pulse widths focus the stimulation effect on small, nearby fibers, suppressing distant white matter tract activation (responsible for some DBS side effects) and improving battery utilization when equivalent activation is maintained for small axons. Directional leads enable similar benefits to a greater degree. Reexamining previous reports of short pulse stimulation reducing side effects, we explore a possible alternate explanation: non-dose equivalent stimulation may have resulted in reduced spread of neural activation. Finally, using internal capsule avoidance as an example in the context of subthalamic stimulation, we present a patient-specific model to show how long pulse widths could help increase the biophysical therapeutic window.DiscussionWe find agreement with classic studies and predict that long pulse widths may focus the stimulation effect on small, nearby fibers and improve power consumption. While future pre-clinical and clinical work is necessary regarding pulse width tuning, it is clear that future studies must ensure dose equivalence, noting that energy- and charge-equivalent amplitudes do not result in equivalent spread of neural activation when changing pulse width.     

Specific statistical considerations relevantto the design and analysis of gingivitis trials demonstrating

Simulation studies were conducted to address specific statistical issues which arise in the design and analysis of gingivitis studies whose principal aim is the demonstration of superiority or equivalence of one product to another. The effects of measurement scale, using differences or ratios of group means, particular statistical test produces and specific rules demonstrating superiority or equivalence were investigated. An alternative concept to equivalence—denoted “least as good”—was also defined and evaluated. For a wide class of possible distributions of gingivitis scores, characterized by specific gamma distributions, the student-t test applied to means of subject GI gingivitis scores proved to be the most powerful of the test produces considered, having statistical properties quite similar to the randomization or permutation test procedure. Transformations of subject GI mean gingivitis scores did not produce an advantage in demonstrating either superiority or equivalence, and in some cases made it more difficult. Little difference was observed in test results when using the difference in group means as compared with using the ratio of group means for demonstrating either equivalence or superiority. The clinically significant rule produced the lowest false-positive rates for products slightly better than the active control, and similar false-positive and -negative rates as the statistically significant rule for products clearly superior to the active control. Demonstration of product equivalence will require more subjects per group than demonstrating product superiority, the size of this difference being a function of the definition of superiority that is accepted. Showing that the 90% confidence interval for 100*R is completely contained within the [90%, 110%] interval is the preferred method of demonstrating equivalence today, although much more research needs to be done to improve methods for demonstrating product equivalence. The “least as good” alternative to “equivalence” makes it easier to demonstrate “equivalence” for products slightly better than the active control product, but both experience great difficulty in demonstrating equivalence for lest products not quite as good as the active control.     

Variant and invariant characteristics of speech movements

Summary Upper lip, lower lip, and jaw kinematics during select speech behaviors were studied in an attempt to identify potential invariant characteristics associated with this highly skilled motor behavior. Data indicated that speech motor actions are executed and planned presumably in terms of relatively invariant combined multimovement gestures. In contrast, the individual upper lip, lower lip, and jaw movements and their moment-to-moment coordination were executed in a variable manner, demonstrating substantial motor equivalence. Based on the trial-to-trial variability in the movement amplitudes, absolute positions, and velocities of the upper lip, lower lip, and jaw, it appears that speech motor planning is not formulated in terms of spatial coordinates. Seemingly, object-level planning for speech may be encoded in relation to the acoustic consequences of the movements and ultimately with regard to listener's auditory perceptions. In addition, certain temporal parameters among the three movements (relative times of movement onsets and velocity peaks) were related stereotypically, reflecting invariances characteristic of more automatic motor behaviors such as chewing and locomotion. These data thus appear to provide some additional insights into the hierarchy of multimovement control. At the top of the motor control hierarchy, the overall plan appears to be generated with explicit specification of certain temporal parameters. Subsequently, based upon the plan and within that stereotypic temporal framework, covariable adjustments among the individual movements are implemented. Given the results of previous perturbation studies, it is hypothesized that these covariable velocity and amplitude adjustments reflect the action of sensorimptor mechanisms.     

等效试验的基本概念及其在溶栓药物试验中的应用

近年来等效试验越来越普及，其目的是为了证实2种治疗效果相等。以溶栓药物的临床试验为例，说明在优效试验、等效试验及非劣效试验中疗效相等的基本概念。     

非虚假设非中心法及其临床应用

目的本文提出一种非虚假设非中心法,并说明其临床应用.方法以非虚假设取代虚假设将经典非中心法加以扩展,以Monte Carlo方法展示其行为.结果当最小临床承认差量取零时,它还原为经典方法.其观测功效与预定功效吻合.结论这种方法适用于以治疗-对照差临床意义研究或临床等效性为目的临床试验的设计.     

黄芩苷胶囊的人体生物等效性研究

目的:建立人血浆中黄芩苷浓度的高效液相-紫外(HPLC-UV)测定方法,测定志愿者口服黄芩苷胶囊后的血药浓度,估算其药动学参数并对供试制剂与参比制剂的生物等效性进行评价。方法:18名健康志愿者随机单剂量交叉口服黄芩苷试验胶囊和参比片750mg,血浆样品采用固相萃取法处理后,进行HPLC-UV测定。结果:受试及参比制剂中药物主要药动学参数如下:cmax分别为(91±s33)μg·L-1和(86±29)μg·L-1,tmax分别为(7.4±1.3)h和(7.4±1.0)h,AUC0~24分别为(586±233)μg·h·L-1和(579±173)μg·h·L-1,AUC0~∞分别为(616±249)μg·h·L-1和(613±180)μg·h·L-1。黄芩苷试验胶囊的相对生物利用度为(101±18)%。结论:本方法操作简单,专属性强,灵敏度高,准确性好。试验胶囊与参比片生物等效。     

盐酸雷尼替丁咀嚼片剂的人体药动学及相对生物利用度

目的:研究盐酸雷尼替丁咀嚼片剂的人体药动学和生物等效性.方法:20名健康受试者采用双周期随机交叉、单剂量口服盐酸雷尼替丁咀嚼片剂与盐酸雷尼替丁片剂,服药剂量均为150mg.用HPLC法测定血浆中雷尼替丁经时过程的血药浓度,使用3P97软件对试验数据进行处理.结果:盐酸雷尼替丁咀嚼片剂和盐酸雷尼替丁片剂的雷尼替丁Cmax分别为(425.5±119.1),(479.6±135.1)μg·L-1;Tmax分别为(3.0±1.0),(2.9±1.2)h;AUC0-12分别为(2707.0±572.1),(2699.7±544.5)μg·h·L-1,AUG0～∞分别为(3155.2±700.8),(3026.4±612.0)μg·h·L-1,盐酸雷尼替丁咀嚼片剂相对于盐酸雷尼替丁片剂的生物利用度为(102.0±20.6)%.结论:盐酸雷尼替丁咀嚼片剂和盐酸雷尼替丁片剂具有生物等效性.     

ON SAMPLE SIZE CALCULATION BASED ON ODDS RATIO IN CLINICAL TRIALS

Sample size calculation formulas for testing equality, noninferiority, superiority, and equivalence based on odds ratio were derived under both parallel and one-arm crossover designs. An example concerning the study of odds ratio between a test compound (treatment) and a standard therapy (control) for prevention of relapse in subjects with schizophrenia and schizoaffective disorder is presented to illustrate the derived formulas for sample size calculation for various hypotheses under both a parallel design and a crossover design. Simulations were performed to assess the adequacy of the sample size calculation formulas. Simulation results were given at the end of the paper.     

Clinical use of the Kessler psychological distress scales with culturally diverse groups

The Kessler 10 (K10) and embedded Kessler 6 (K6) was developed to screen for non‐specific psychological distress and serious mental illness in mental health surveys of English‐speaking populations, but has been adopted in Western and non‐Western countries as a screening and outcome measure in primary care and mental health settings. This review examines whether the original K6/K10's validity for culturally diverse populations was established, and whether the cultural equivalence, and sensitivity to change of translated or culturally adapted K6/K10s, has been demonstrated with culturally diverse client groups. Evidence for the original K6/K10's validity for culturally diverse populations is limited. Questions about the conceptual and linguistic equivalence of translated/adapted K6/K10s arise from reports of changes in item connotation and differential item functioning. Evidence for structural equivalence is inconsistent, as is support for criterion equivalence, with the majority of studies compromising on accuracy in case prediction. Research demonstrating sensitivity to change with culturally diverse groups is lacking. Inconsistent evidence for the K6/K10's cultural appropriateness in clinical settings, and a lack of clinical norms for either majority or culturally diverse groups, indicate the importance of further research into the psychological distress construct with culturally diverse clients, and the need for caution in interpreting K6/K10 scores. Copyright © 2014 John Wiley & Sons, Ltd.