Effect of expectancy and personality on cortical excitability in Parkinson's disease.

Our previous studies in Parkinson's disease have shown that both levodopa and expectancy of receiving levodopa reduce cortical excitability. We designed this study to evaluate how degree of expectancy and other individual factors modulate placebo response in Parkinson's patients. Twenty-six Parkinson's patients were randomized to 1 of 3 groups: 0%, 50%, and 100% expectancy of receiving levodopa. All subjects received placebo regardless of expectancy group. Subjects completed the NEO-Five Factor Inventory, General Perceived Self-Efficacy Scale, and Perceived Stress Scale. Cortical excitability was measured by the amplitude of motor-evoked potential (MEP) evoked by transcranial magnetic stimulation. Objective physical fatigue of extensor carpi radialis before and after placebo levodopa was also measured. Responders were defined as subjects who responded to the placebo levodopa with a decrease in MEP. Degree of expectancy had a significant effect on MEP response (P < .05). Subjects in the 50% and 100% expectancy groups responded with a decrease in MEP, whereas those in the 0% expectancy group responded with an increase in MEP (P < .05). Responders tended to be more open to experience than nonresponders. There were no significant changes in objective physical fatigue between the expectancy groups or between responders and nonresponders. Expectancy is associated with changes in cortical excitability. Further studies are needed to examine the relationship between personality and placebo effect in Parkinson's patients. © 2013 Movement Disorder Society.

Centella asiatica triterpenes for diabetic neuropathy: a randomized, double-blind, placebo-controlled, pilot clinical study.

BACKGROUND: Diabetic neuropathy (DN), a common complication of diabetes mellitus, results from hyperglycemia, poor microcirculation and attendant nerve damage. Currently available treatments relieve symptoms, but do not modify the neurodegeneration underlying DN. Centella asiatica (CA) triterpenes improved microcirculation in earlier clinical studies, and showed neurotropic effects in preclinical models suggesting a potential disease modifying effect in DN. This 52-week, randomized, double-blind, placebo-controlled trial examined the effects of CAST, a standardized CA extract containing triterpenes, on neuropathy symptoms in Type II diabetic subjects. PATIENTS AND METHODS: The study enrolled patients with a history of Type II diabetes, with evidence of symptomatic symmetrical DN with total symptom score (TSS) ≥4, and stable HbA1c level <8. The primary outcome measure was TSS, which assessed intensity and frequency of parasthesia, numbness, pain and burning symptoms self-reported by patients. Secondary measures were nerve conduction, neurological impairment score, and quantitative sensory testing. RESULTS: Comparing CAST (n=21) and Placebo (n=22) groups, significant reductions from baseline for TSS (p<0.01) and paresthesia (p<0.01) were seen only in CAST treated groups. Numbness increased from baseline only in the Placebo group (p<0.05) and was significantly higher than for the CAST group (p<0.001). Burning sensation was reduced in both groups (p<0.01). Plasma triterpene levels in patients treated with CAST mirrored neurotropic concentrations in vitro. CONCLUSIONS: CAST is a potential oral treatment for diabetic neuropathy, as it is well tolerated and effective in reducing the severity of DN symptoms in patients with Type II diabetes.

Extraocular connective tissues: a role in human eye movements?

PURPOSE: This study presents a detailed anatomic analysis of the undisturbed connective tissues that surround the horizontal extraocular muscles (EOMs) of humans. Emphasis is placed on those EOM orbital side tissues that, in previous MRI studies, were assumed to couple the muscle to the pulley. METHODS: Serial 5-mum sections were prepared from paraffin-embedded blocks of the lateral and medial rectus muscles and their surrounding connective tissues. The sections were treated with Masson's trichrome stain for light microscopic examination of muscle fibers (red) and surrounding connective tissues (blue). RESULTS: Rectus muscle sections demonstrated the orbital connective tissues to be a collagenous bridge between the distal third of the muscle and the orbital periosteum (i.e., check ligament [CL]). The CL attaches to the muscle by investing itself around orbital muscle fibers whereas, at the point of attachment, those fibers remain aligned with the remainder of the muscle. The CL on the orbital side and the reflected bulbar fascia on the global side of the muscle constitute a tubelike sheath. The posterior border of the sheath insinuates into the muscle belly and its anterior aspect blends into the sides of the portal through Tenon's capsule. CONCLUSIONS: All rectus EOM fibers participate in eye rotation. The CL is the band of tissue present on the MRI images, but was previously described as the orbital layer insertion for the active pulley hypothesis (APH). The APH should now be questioned. Alternate theories incorporating accepted neurophysiological, anatomic, and ophthalmological principles of EOM movement are discussed.

Lateral rectus muscle changes after bilateral neonatal labyrinthectomy in the ferret.

The vestibular system is essential to the coordination of eye movements during head movements. Exercise, such as the eye movements mediated by the vestibular system, is a major factor in the development of muscle fiber types and the strength of muscle. In this study, the contents of the inner ear were removed (labyrinthectomy) from (LAB) ferrets at postnatal day 10 (P10) and raised with control (SHAM) animals. At P30, the lateral rectus muscles (LR) were removed to analyze the expression of myosin heavy chain (MHC) isoforms and to measure the least diameter of the developmental, slow and fast type muscle fibers. Another set of animals were sacrificed at P120 to analyze MHC isoform expression and muscle fiber diameters, as well as the contractile characteristics of the LR were measured prior to sacrifice. The average LAB LR was significantly stronger than the SHAM LR and the muscle fibers of the LAB animals were larger in diameter. The LAB animals expressed more type IIx and less slow type MHC. These results support the hypothesis that input from the inner ear influence the development of strength and muscle diameter in the ferret extraocular muscles.

Polyneuronal innervation of single muscle fibers in cat eye muscle: inferior oblique.

Single muscle fibers with multiple axonal endplates (multiply innervated fibers) are normally present in adult extraocular muscles (EOMs), while most other mammalian skeletal muscles contain fibers with a single myoneural junction. Recent findings by others led us to investigate for the presence of polyneuronal innervation (innervation of a single muscle fiber by >1 motoneuron) in the inferior oblique (IO) muscle of pentobarbital anesthetized cats. The IO muscle nerve branches, as they coursed through the orbit, were further divided for independent or simultaneous electrical stimulation with bipolar electrodes. Four of five established tests for polyneuronal innervation gave positive results. The sum of the twitch (1) and tetanic (2) tensions in response to individual nerve branch stimulation was greater than that for simultaneous (whole) nerve stimulation. The summed electromyographic (EMG) responses (3) gave a similar positive result. The result for crossed tetanic potentiation (4) was negative for polyneuronal innervation while the crossed fatigue (5) test was positive. These results are consistent with recent studies. That the EOMs exhibit polyneuronal innervation further explains the eye-movement system's functional integrity during some neuromuscular disorders as well as its ability to operate with precision after the loss of numerous motoneurons.

Using modafinil to treat fatigue in Parkinson disease: a double-blind, placebo-controlled pilot study.

BACKGROUND: Fatigue is a major nonmotor symptom in Parkinson disease(PD). It is associated with reduced activity and lower quality of life. OBJECTIVE: To determine if modafinil improves subjective fatigue and physical fatigability in PD. METHODS: Nineteen PD patients who reported significant fatigue in the Multidimensional Fatigue Inventory (MFI) participated in this 8-week study. Subjects took their regular medications and were randomly assigned to the treatment group (9 subjects, modafinil 100-mg capsule BID) or placebo group (10 subjects). We used the MFI to measure subjective fatigue and used finger tapping and intermittent force generation to evaluate physical fatigability. Subjects also completed the Epworth Sleepiness Scale (ESS) and the Center of Epidemiological Study-Depression Scale. RESULTS: There were no significant differences at baseline and at 1 month in finger tapping and ESS between the modafinil and placebo groups. At 2 months, the modafinil group had a higher tapping frequency (P<0.05), shorter dwell time (P<0.05), and less fatigability in finger tapping and tended to have lower ESS scores (P<0.12) than the placebo group. However, there was no difference between groups over time for any dimension of the MFI . CONCLUSIONS: This small study demonstrated that although modafinil may be effective in reducing physical fatigability in PD, it did not improve fatigue symptoms.

Can stooped posture explain multidirectional postural instability in patients with Parkinson's disease?

To determine the effects of the stooped posture of patients with Parkinson's disease (PD) on postural stability, we compared the kinetic, kinematic, and electromyographic responses of seven subjects with PD and 11 control subjects to eight directions of surface translations. Control subjects were studied in an upright posture and in a stooped posture that mimicked the posture of the PD subjects. When control subjects adopted a stooped posture, peak center of pressure displacements slowed and decreased, reducing stability margins toward values observed in PD subjects. Stooped control subjects, however, responded to translations with large joint angle displacements, whereas PD subjects exhibited small joint angle displacements. Stooping in control subjects did not lead to abnormally directed horizontal forces under each foot or antagonistic muscle co-activation at the hip and trunk, as seen in PD subjects. Upright and stooped control subjects never fell during the trials, whereas PD subjects fell in 16% of the trials. We conclude that stooped posture is a destabilizing posture, but it does not account for abnormal postural responses in PD.

Extraocular motor unit and whole-muscle contractile properties in the squirrel monkey. Summation of forces and fiber morphology.

In order to understand the neural control of movement, many investigations have examined the contractile properties of single motor units contracting in isolation, and a great majority of those studies have been done in the cat. Fewer studies, again primarily in the cat, have examined motor units acting in concert in both hind-limb and extraocular muscles. It has been shown, in general, that when individual motor unit forces are added together they do not always add linearly, which makes our understanding of motor control somewhat more complicated. In addition, complex neuronal firing patterns can yield unexpected force outputs or muscle positions whether those patterns occur naturally or are induced through motoneuron stimulation. The current investigation extends these findings of nonlinearity to the primate extraocular system. In studies of the squirrel monkey lateral rectus muscle and its motor units, we show that individual units lose an average of 45% of their force output when they fire in concert with a small number of other motor units. Also, when individual motor units are stimulated at a constant rate of 100 Hz, the force output is most often dramatically different if that constant 100-Hz stimulation is preceded by brief (25 ms), high-frequency stimulation burst or pulse, as occurs during saccades. The force at 100 Hz is usually significantly higher than when no pulse is delivered. However, we now show that an identical stimulation pattern applied to a number of motor units simultaneously does not always yield these force differences. These "nonlinearities" are addressed in terms of the complex muscle architecture that we show in the squirrel monkey lateral rectus muscle. Muscle fibers do not always run in parallel from tendon to tendon. Instead, they may branch or attach to each other laterally or end to end, serially.

Stimulation-evoked eye movements with and without the lateral rectus muscle pulley.

Recent studies have suggested that extraocular muscle (EOM) pulleys, composed of collagen, elastin, and smooth muscle, are among the tissues surrounding the eye. High-resolution magnetic-resonance imaging appears to indicate that the pulleys serve to both constrain and alter the pulling paths of the EOMs. The active pulley hypothesis suggests that the orbital layer of the EOMs inserts on the pulley and serves to control it. Based on anatomical data, the active pulley hypothesis also suggests that the orbital layer does not rotate the eye within the orbit; this is done by the global layer of the muscle. However, no physiological data exist to confirm this hypothesis. Here we used stimulation-evoked eye movements in anesthetized monkeys and cats before and after destruction of the lateral rectus muscle pulley by removal of the lateral bony orbit and adjacent orbital tissue. The absence of these structures resulted in increased lateral, in the primate, and medial, in the cat, eye-movement amplitude and velocity. Vertical eye movements in the cat were not significantly affected. The results indicate that these increases, confined to horizontal eye-movement amplitude and velocity, may be attributed to passive properties within the orbit. In relation to the active pulley hypothesis, we could discern no clear impact (in terms of amplitude or velocity profile of the movements) of lateral eye exposure that could be directly attributable to the active lateral pulley system.

Short-term effects of botulinum toxin on the lateral rectus muscle of the cat.

Botulinum toxin type A (BTX) is often used as an alternative to surgery for the treatment of strabismus and many other motor or cosmetic problems. Although numerous studies established BTX as a powerful transmission-blocking agent at the neuromuscular junction, no evaluation of extraocular muscle (EOM) contractile properties after administration of BTX exists. Some anatomical studies on EOM fiber types suggested a long-term preferential effect of BTX on orbital layer, singly innervated muscle fibers. In this study, we examined the short-term effects of BTX on the contractile properties of normal lateral rectus muscle to determine the functional effect of BTX on muscle-force output over time. Measurements of muscle tension and the corresponding EMG evoked by stimulation of nerve VI were made hourly for up to 18 h following BTX administration. An intramuscular BTX injection of 2 U caused a dramatic decrease in maximum twitch and tetanic tension of the muscle in response to different frequencies of stimulation. This suppression developed gradually over time, with a concomitant reduction of EMG amplitude. No significant changes in muscle-speed-related characteristics (e.g., twitch contraction time, fusion frequency) were found. The results suggest a functional effect of BTX on all muscle fiber types, although, with the dose used, we did not observe complete muscle paralysis within the time of recording. The time course of muscle tension suppression by BTX also was frequency dependent, with the lower stimulation frequencies being more affected, suggesting that implementation of higher frequencies could still produce adequate eye movements.