Huperzine A for the treatment of cognitive, mood, and functional deficits after moderate and severe TBI (HUP-TBI): results of a Phase II randomized controlled pilot study: implications for understanding the placebo effect.

Objective: To investigate the effect of Huperzine A on memory and learning in individuals with moderate-severe traumatic brain injury (TBI).Design: Randomized, double-blind, placebo-controlled Phase II clinical trial.Methods: Subjects were randomly assigned to receive Huperzine A or placebo for 12 weeks and were assessed during in-person visits at screening/baseline, and 6, 12, 24, and 52 weeks post-injury. Changes in memory and learning scores on the California Verbal Learning Test - 2nd Edition (CVLT-II) from baseline to week 12 were assessed using permutation tests and regression analyses.Results: There was no difference between the Huperzine A and placebo groups in memory performance after 12 weeks of treatment. In the placebo group, significant improvements were noted in learning and memory scores. Both groups showed clinically important improvements in depression on the Beck Depression Index.Conclusions: The clinically important improvements in cognitive and emotional outcomes observed in both the placebo and active treatment arms of this clinical trial of Huperzine A are best understood in the context of a placebo effect. Future trials involving patients with moderate-severe TBI in the subacute to chronic phases of recovery should be designed to account for placebo effects as failure to do so may lead to spurious conclusions.

"Discrete peaks" of excitability and map overlap reveal task-specific organization of primary motor cortex for control of human forearm muscles.

The primary motor cortex (M1) presents a somatotopic organization of body parts, but with overlap between muscle/movement representations. This distinct but overlapping M1 organization is believed to be important for individuated control and movement coordination, respectively. Discrete peaks of greater excitability observed within M1 might underpin organization of cortical motor control. This study aimed to examine interactions between M1 representations of synergist and antagonist forearm muscles, compare regions of greater excitability during different functional tasks, and compare characteristics of M1 representation recorded using surface and fine-wire (fw ) electrodes. Transcranial magnetic stimulation (TMS) was applied over M1 for mapping the representation of 4 forearm muscles (extensor carpi radialis brevis [ECRB], extensor digitorum communis, flexor carpi radialis, and flexor digitorum superficialis) during three tasks: rest, grip, and wrist extension in 14 participants. There are three main findings. First, discrete areas of peak excitability within the M1 representation of ECRBfw were identified during grip and wrist extension suggesting that different M1 areas are involved in different motor functions. Second, M1 representations of synergist muscles presented with greater overlap of M1 representations than muscles with mainly antagonist actions, which suggests a role in muscle coordination. Third, as larger normalized map volume and overlap were observed using surface than fine-wire electrodes, data suggest that cross-talk from adjacent muscles compromised interpretation of recordings made with surface electrodes in response to TMS. These results provide a novel understanding of the spatial organization of M1 with evidence of "functional somatotopy." This has important implications for cortical control of movement. Hum Brain Mapp 38:6118-6132, 2017. © 2017 Wiley Periodicals, Inc.

Does movement variability increase or decrease when a simple wrist task is performed during acute wrist extensor muscle pain?

PURPOSE: The goal of complex tasks can be maintained despite variability in the movements of the multiple body segments involved in the task (VAR(elements)). This variability increases in acute pain and may enable the nervous system to search for less painful/injurious movement options. It is unclear whether VAR(elements) increases when pain challenges simple tasks with fewer movement options, yet maintain successful attainment of the goal. We hypothesised that during acute pain related to a simple movement: (1) the task goal would be maintained; (2) VAR(elements) would be increased; and (3) if VAR(elements) increased during pain, it would decrease over time. METHODS: Movements of the right wrist/forearm were recorded with a three-dimensional motion analysis system and during a repetitive radial-ulnar deviation task between two target angle ranges (the task goal). We measured success of attaining the goal (repetitions that reached the target range and total absolute error in degrees), and variability in the motion of wrist flexion-extension and forearm pronation-supination (VAR(elements)). Fourteen healthy participants performed the task in one session before, during, and after wrist extensor muscle pain induced with hypertonic saline, and in another session without pain. RESULTS: The task goal was maintained during acute pain. However, VAR(elements) in other motion planes either reduced (pronation-supination) or did not change (flexion-extension). Thus, variability of task elements is constrained, rather than increased, in simple tasks. CONCLUSIONS: These data suggest the nervous system adapts simple tasks with limited degrees of freedom by reduction of VAR(elements) rather than the increase observed for more complex tasks.

An evidence-based methodology for systematic evaluation of clinical outcome assessment measures for traumatic brain injury.

INTRODUCTION: The high failure rate of clinical trials in traumatic brain injury (TBI) may be attributable, in part, to the use of untested or insensitive measurement instruments. Of more than 1,000 clinical outcome assessment measures (COAs) for TBI, few have been systematically vetted to determine their performance within specific "contexts of use (COU)." As described in guidance issued by the U.S. Food and Drug Administration (FDA), the COU specifies the population of interest and the purpose for which the COA will be employed. COAs are commonly used for screening, diagnostic categorization, outcome prediction, and establishing treatment effectiveness. COA selection typically relies on expert consensus; there is no established methodology to match the appropriateness of a particular COA to a specific COU. We developed and pilot-tested the Evidence-Based Clinical Outcome assessment Platform (EB-COP) to systematically and transparently evaluate the suitability of TBI COAs for specific purposes. METHODS AND FINDINGS: Following a review of existing literature and published guidelines on psychometric standards for COAs, we developed a 6-step, semi-automated, evidence-based assessment platform to grade COA performance for six specific purposes: diagnosis, symptom detection, prognosis, natural history, subgroup stratification and treatment effectiveness. Mandatory quality indicators (QIs) were identified for each purpose using a modified Delphi consensus-building process. The EB-COP framework was incorporated into a Qualtrics software platform and pilot-tested on the Glasgow Outcome Scale-Extended (GOSE), the most widely-used COA in TBI clinical studies. CONCLUSION: The EB-COP provides a systematic methodology for conducting more precise, evidence-based assessment of COAs by evaluating performance within specific COUs. The EB-COP platform was shown to be feasible when applied to a TBI COA frequently used to detect treatment effects and can be modified to address other populations and COUs. Additional testing and validation of the EB-COP are warranted.

Forearm Muscle Activity in Lateral Epicondylalgia: A Systematic Review with Quantitative Analysis.

BACKGROUND: Lateral epicondylalgia (LE) refers to pain at the lateral elbow and is associated with sensory and motor impairments that may impact on neuromuscular control and coordination. OBJECTIVE: This review aimed to systematically identify and analyse the literature related to the comparison of neuromuscular control of forearm muscles between individuals with and without LE. METHODS: A comprehensive search of electronic databases and reference lists using keywords relating to neuromuscular control and LE was undertaken. Studies that investigated electromyography (EMG) measures of forearm muscles in individuals with symptoms of LE were included if the study involved comparison with pain-free controls. The Epidemiological Appraisal Instrument was used to assess study quality. Data extracted from each study were used to calculate the standardised mean difference and 95 % confidence intervals to investigate differences between groups. RESULTS: The search revealed a total of 1920 studies, of which seven were included from 44 that underwent detailed review. Due to differences in outcome measures and tasks assessed, meta-analysis was not possible. The seven included studies used 60 different EMG outcomes, of which 16 (27 %) revealed significant differences between groups. Two were properties of motor unit potentials during wrist extension. Four were measures of increased time between recruitment of wrist extensor muscles and onset of grip force. Seven were measures of amplitude of EMG during tennis strokes. Three were measures of motor cortex organisation. CONCLUSION: Features of neuromuscular control differ between individuals with LE and pain-free controls. This implies potential central nervous system involvement and indicates that rehabilitation may be enhanced by consideration of neuromuscular control in addition to other treatments.

Effects of Prolonged and Acute Muscle Pain on the Force Control Strategy During Isometric Contractions.

UNLABELLED: Musculoskeletal pain is associated with multiple adaptions in movement control. This study aimed to determine whether changes in movement control acquired during acute pain are maintained over days of pain exposure. On day 0, the extensor carpi radialis brevis muscle of healthy participants was injected with nerve growth factor (NGF) to induce persistent movement-evoked pain (n = 13) or isotonic saline as a control (n = 13). On day 2, short-lasting pain was induced by injection of hypertonic saline into extensor carpi radialis brevis muscles of all participants. Three-dimensional force components were recorded during submaximal isometric wrist extensions on day 0, day 4, and before, during, and after saline-induced pain on day 2. Standard deviation (variation of task-related force) and total excursion of center of pressure (variation of force direction) were assessed. Maximal movement-evoked pain was 3.3 ± .4 (0-10 numeric scale) in the NGF-group on day 2 whereas maximum saline-induced pain was 6.8 ± .3 cm (10-cm visual analog scale). The difference in centroid position of force direction relative to day 0 was greater in the NGF group than in the control group (P < .05) on day 2 (before saline-induced pain) and day 4, reflecting changes in tangential force direction used to achieve the task. During saline-induced pain in both groups, tangential and task-related force variation was greater than before and after saline-induced pain (P < .05). PERSPECTIVE: Persistent movement-evoked pain changes force direction from the pain-free direction. Acute pain leads to increased variation in force direction irrespective of persistent movement-evoked pain preceding the acutely painful event. These differences provide novel insight into the search for and consolidation of new motor strategies in the presence of pain.

Functional differences between anatomical regions of the anconeus muscle in humans.

This study sought to resolve a longstanding debate of the function of anconeus. Intramuscular and surface electromyography electrodes recorded muscle activity from two regions of anconeus and from typical elbow flexion and extension muscles. Eleven participants performed pronation-supination around the medial and lateral axes of the forearm, elbow flexion-extension in pronation, supination and neutral positions of the forearm, and gripping. Maximal voluntary contractions (MVC) and submaximal (10% MVC) force-matching tasks were completed. Activity varied between longitudinal (AL) and transverse (AT) segments of anconeus. Although both muscle regions were active across multiple directions (including opposing directions), AL was more active during pronation than supination, whereas AT showed no such difference. During pronation, activity of AL and AT was greatest about the lateral forearm axis. AT was more active during elbow extension with the forearm in pronation, whereas AL did not differ between pronated and neutral forearm alignment. These findings are consistent with the proposal that AL makes a contribution to control of abduction of the ulna during forearm pronation. Different effects of forearm position on AL and AT activity during elbow extension may be explained by the anatomical differences between the regions. These data suggest anconeus performs multiple functions at the elbow and forearm and this varies between anatomically distinct regions of the muscle.