Study protocol: EXERcise and cognition in sedentary adults with early-ONset dementia (EXERCISE-ON).

BACKGROUND: Although the development of early-onset dementia is a radical and invalidating experience for both patient and family there are hardly any non-pharmacological studies that focus on this group of patients. One type of a non-pharmacological intervention that appears to have a beneficial effect on cognition in older persons without dementia and older persons at risk for dementia is exercise. In view of their younger age early-onset dementia patients may be well able to participate in an exercise program. The main aim of the EXERCISE-ON study is to assess whether exercise slows down the progressive course of the symptoms of dementia. METHODS/DESIGN: One hundred and fifty patients with early-onset dementia are recruited. After completion of the baseline measurements, participants living within a 50 kilometre radius to one of the rehabilitation centres are randomly assigned to either an aerobic exercise program in a rehabilitation centre or a flexibility and relaxation program in a rehabilitation centre. Both programs are applied three times a week during 3 months. Participants living outside the 50 kilometre radius are included in a feasibility study where participants join in a daily physical activity program set at home making use of pedometers. Measurements take place at baseline (entry of the study), after three months (end of the exercise program) and after six months (follow-up). Primary outcomes are cognitive functioning; psychomotor speed and executive functioning; (instrumental) activities of daily living, and quality of life. Secondary outcomes include physical, neuropsychological, and rest-activity rhythm measures. DISCUSSION: The EXERCISE-ON study is the first study to offer exercise programs to patients with early-onset dementia. We expect this study to supply evidence regarding the effects of exercise on the symptoms of early-onset dementia, influencing quality of life. TRIAL REGISTRATION: The present study is registered within The Netherlands National Trial Register (ref: NTR2124).

Comparison of trigeminal and spinal modulation of pain and nociception.

Modulation of pain and nociception by noxious counterstimulation, also called "diffuse noxious inhibitory controls" or DNIC-like effect, is often used in studies of pain disorders. It can be elicited in the trigeminal and spinal innervation areas, but no study has previously compared effects in both innervation areas. Therefore, we performed a study comparing DNIC-like effects on the nociceptive flexion reflex (NFR) and the nociceptive blink reflex as well as the respective pain sensations. In 50 healthy volunteers, the blink reflex elicited with a concentric electrode and the NFR were recorded before and after immersion of the contralateral hand in cold water. Responses were recorded as the subjective pain sensation and the reflex size. The cold water immersion of the contralateral hand elicited a reduction of both subjective pain sensation and reflex amplitude following the stimulation of both reflexes. However, there were no strong correlations between the individual reductions of both subjective pain sensation and reflex amplitude for both reflexes, and neither when results of the two reflexes were compared with each other. The dissociation between DNIC-like effects on pain and on nociception, which had been found previously already for the NFR, implies that both effects need to be studied separately.

Investigation of threshold and magnitude criteria of the nociceptive blink reflex.

OBJECTIVE: The nociceptive blink reflex is a trigeminofacial brain-stem reflex which is used in pain research to evaluate the modulation of pain processing. To standardize the analysis of the reflex we investigated which electromyographic parameters show the best correlation with subjective pain ratings and should therefore be used for scoring blink reflex magnitude. Furthermore we investigated which parameters show the highest accuracy and reliability to define the blink reflex threshold. METHODS: Forty-six subjects each received 54 electrical stimuli to the supraorbital nerve at nine different stimulus intensities, which corresponded to pain ratings between 0 and 70 (scale 0-100). Multilevel modeling was performed to determine which electromyographic blink reflex parameter showed the best correlation with subjective pain ratings. To define the blink reflex threshold ROC analyses were performed, comparing different electromyographic blink reflex parameters with the judgment of expert raters for 2500 blink reflex recordings from this study and 1400 from another. RESULTS: The baseline-adjusted area under the curve showed the best correlation with subjective pain ratings. Seventy-six percent of the residual variance of the pain ratings could be explained by this parameter. The peak z score showed the highest accuracy in defining the blink reflex threshold and also the highest cut-point stability. CONCLUSIONS: We recommend the baseline-adjusted area under the curve for scoring the magnitude of the nociceptive blink reflex and the peak z score to define the nociceptive blink reflex threshold. SIGNIFICANCE: The here defined standardized criteria to score blink reflex magnitude and threshold improve the comparability and validity of blink reflex studies.

Intrinsic properties of the knee extensor muscles after subacute stroke.

UNLABELLED: Horstman AM, Gerrits KH, Beltman MJ, Koppe PA, Janssen, TW, de Haan A. Intrinsic properties of the knee extensor muscles after subacute stroke. OBJECTIVE: To characterize muscle properties of paretic lower-limb (PL) and nonparetic lower-limb (NL) knee extensors in patients with subacute stroke. DESIGN: Case-control study. SETTING: Rehabilitation center research laboratory. PARTICIPANTS: Patients with subacute stroke (n=14) and able-bodied age-matched control subjects (n=12). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Half relaxation times (HRTs) and maximal rates of torque development (MRTDs) were assessed as indicators of contractile speed using both voluntary and electrically evoked contractions. Moreover, changes in torque were measured during a fatigue protocol (35 electrically evoked intermittent contractions; 1.5s on, 2s off) and recovery. RESULTS: No differences among groups were found for normalized MRTDs during electrically evoked contractions (P=.117). However, during voluntary contractions both PLs (53% of control, P=.022) and NL (71% of control, P<.001) had significantly lower MRTD compared with control. Both PL (134% of control, P=.001) and NL (123% of control, P=.032) had significantly higher HRTs than control, indicating muscle slowing in patients with subacute stroke. PLs fatigued more and faster than control (P=.011) and both PL and NL recovered slower (P<.001). CONCLUSIONS: The changes in HRTs and fatigue suggest adaptations in muscle properties toward slower, more fatigable muscle shortly after stroke. The inability to make use of contractile speed because of impaired neural activation seems the most limiting factor during the initial phase of torque development in PL. Thus, besides strengthening, muscle endurance and speed should also be addressed during rehabilitation.

Comparing unilateral and bilateral upper limb training: the ULTRA-stroke program design.

BACKGROUND: About 80% of all stroke survivors have an upper limb paresis immediately after stroke, only about a third of whom (30 to 40%) regain some dexterity within six months following conventional treatment programs. Of late, however, two recently developed interventions--constraint-induced movement therapy (CIMT) and bilateral arm training with rhythmic auditory cueing (BATRAC)--have shown promising results in the treatment of upper limb paresis in chronic stroke patients. The ULTRA-stroke (acronym for Upper Limb TRaining After stroke) program was conceived to assess the effectiveness of these interventions in subacute stroke patients and to examine how the observed changes in sensori-motor functioning relate to changes in stroke recovery mechanisms associated with peripheral stiffness, interlimb interactions, and cortical inter- and intrahemispheric networks. The present paper describes the design of this single-blinded randomized clinical trial (RCT), which has recently started and will take several years to complete. METHODS/DESIGN: Sixty patients with a first ever stroke will be recruited. Patients will be stratified in terms of their remaining motor ability at the distal part of the arm (i.e., wrist and finger movements) and randomized over three intervention groups receiving modified CIMT, modified BATRAC, or an equally intensive (i.e., dose-matched) conventional treatment program for 6 weeks. Primary outcome variable is the score on the Action Research Arm test (ARAT), which will be assessed before, directly after, and 6 weeks after the intervention. During those test sessions all patients will also undergo measurements aimed at investigating the associated recovery mechanisms using haptic robots and magneto-encephalography (MEG). DISCUSSION: ULTRA-stroke is a 3-year translational research program which aims (1) to assess the relative effectiveness of the three interventions, on a group level but also as a function of patient characteristics, and (2) to delineate the functional and neurophysiological changes that are induced by those interventions.The outcome on the ARAT together with information about changes in the associated mechanisms will provide a better understanding of how specific therapies influence neurobiological changes, and which post-stroke conditions lend themselves to specific treatments. TRIAL REGISTRATION: The ULTRA-stroke program is registered at the Netherlands Trial Register (NTR, http://www.trialregister.nl, number NTR1665).

Relationship among shoulder proprioception, kinematics, and pain after stroke.

OBJECTIVE: To identify a possible relationship among chronic poststroke shoulder pain (PSSP), scapular resting pose, and shoulder proprioception. DESIGN: Case-control study. SETTING: Rehabilitation center. PARTICIPANTS: A total of 21 inpatients with stroke and 10 healthy control subjects. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Orientations of both the contralateral and ipsilateral (ie, paretic and nonparetic) shoulders during rest in degrees, angular displacement (degrees) for threshold to detection of passive motion (TDPM) tests, and absolute error (degrees) for passive reproduction of joint position (PRJP) tests. RESULTS: The contralateral shoulder of patients with PSSP showed more scapular lateral rotation and larger TDPM and PRJP scores than both patients without PSSP and control subjects. Additionally, the contralateral shoulder of patients with deteriorated proprioception showed more scapular lateral rotation than control subjects, whereas their ipsilateral shoulder showed more scapular lateral rotation than both control subjects and patients with good proprioception. CONCLUSIONS: A clear relation among affected shoulder kinematics, affected proprioception, and PSSP was found. In determining the risk of developing PSSP, attention should be paid to a patients shoulder proprioception and kinematics. If both are altered after stroke, this could worsen the initial pathology or cause secondary pathologies and thus initiate a vicious circle of repetitive soft tissue damage leading to chronic PSSP. Additionally, more attention should be paid to the ipsilateral (ie, nonparetic) shoulder because it could be used in determining the risk of developing PSSP in the contralateral (ie, paretic) shoulder.

Isometric muscle function of knee extensors and the relation with functional performance in patients with stroke.

OBJECTIVE: (1) To examine the isometric strength, speed, and fatigue resistance of the knee extensors of the paretic limb and nonparetic limb in patients with stroke and compare these with able-bodied subjects. (2) To relate the contractile properties with different indices of functional performance. DESIGN: Case-control study. SETTING: Rehabilitation center research laboratory. PARTICIPANTS: Eighteen stroke patients and 10 able-bodied controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Maximal voluntary torque (MVT), maximal rate of torque development, time to maximal rate of torque development, half relaxation time ((1/2)RT), and fatigue index. Scores on the Functional Ambulation Category scale, Berg Balance Scale, and Rivermead Mobility Index as well as distance walked during the six-minute walk test were obtained. RESULTS: MVT of the paretic leg was lower than of the nonparetic leg (P<.05), and both limbs had lower MVT than controls (P<.05). Both the paretic and the nonparetic leg showed longer (1/2)RT compared with controls (P<.05). The fatigue index was reduced in the paretic leg (P<.05) but not in the nonparetic leg compared with controls. MVT and fatigue index of the paretic leg were related to indices of functional performance (r=0.49-0.64; P<.05). CONCLUSIONS: Apart from bilateral weakness, knee extensors in patients with stroke showed a lower rate of torque development and relaxation (both paretic and nonparetic leg) and lower fatigue resistance (paretic leg only) than controls, which in part may be a consequence of changes within the muscles. Strength and fatigue resistance relate to functional performance, indicating that these muscle properties should be addressed during rehabilitation. However, future research is needed to elucidate the efficacy of exercise programs.

Kinematics of the contralateral and ipsilateral shoulder: a possible relationship with post-stroke shoulder pain.

OBJECTIVE: Post-stroke shoulder pain is a common phenomenon in hemiplegia and impedes rehabilitation. The aim of this study was to identify a possible relationship between post-stroke shoulder pain, scapula resting position and shoulder motion. METHODS: Shoulder kinematics of 27 patients after stroke (17 men) were compared with 10 healthy age-matched control subjects. Using an electromagnetic tracking device, the kinematics of both the contralateral and ipsilateral (i.e. paretic and non-paretic) arm during active and passive abduction and forward flexion were measured and expressed in Euler angles. RESULTS: Scapular lateral rotation relative to the thorax was increased in patients with post-stroke shoulder pain compared with both patients without post-stroke shoulder pain and control subjects at rest as well as during arm abduction and forward flexion. Additionally, glenohumeral elevation was decreased in patients with post-stroke shoulder pain during passive abduction. No differences were found regarding scapula position (displacement relative to the thorax). CONCLUSION: In patients with post-stroke shoulder pain a particular kinematical shoulder pattern was established, characterized by enhanced scapular lateral rotation and diminished glenohumeral mobility.

Intrinsic muscle strength and voluntary activation of both lower limbs and functional performance after stroke.

The objective of this study was to assess the nature of muscle weakness in both legs after stroke compared with able-bodied control individuals and to examine whether there is a relationship between the degree of muscle weakness and coactivation of knee extensors and flexors as well as voluntary activation capacity of knee extensors of both paretic and non-paretic legs and indices of functional performance. Maximal voluntary isometric torques of knee extensors (MVCe) and flexors (MVCf) were determined in 14 patients (bilaterally) and 12 able-bodied controls. Simultaneous measurements were made of torque and surface EMG from agonist and antagonist muscles. Coactivation was calculated. Supramaximal triplets were evoked with electrical stimulation to estimate maximal torque capacity and degree of voluntary activation of knee extensors. MVCs, activation and coactivation parameters were correlated to scores of seven functional performance tests. MVCe, MVCf and voluntary activation were lower in paretic lower limb (PL) compared with both non-paretic lower limb (NL) and control. Besides, all these parameters of NL were also lower than control. Electrically evoked torque capacity of knee extensors of PL was about 60% of both NL and control, which were not significantly different from each other. Strong significant correlations between strength, as well as voluntary activation, and functional performance were found. Coactivation did not correlate well with functional performance. Thus, whereas for NL activation failure can explain weakness, for PL both activation failure and reduced intrinsic torque capacity are responsible for the severe weakness. Activation capacity and muscle strength correlated strongly to functional performance, while coactivation did not.

Effects of electric stimulation-assisted cycling training in people with chronic stroke.

OBJECTIVE: To evaluate whether leg cycling training in subjects with chronic stroke can improve cycling performance, aerobic capacity, muscle strength, and functional performance and to determine if electric stimulation (ES) to the contralateral (paretic) leg during cycling has additional effects over cycling without ES. DESIGN: A randomized controlled trial, with a partial double-blind design. SETTING: A rehabilitation center. PARTICIPANTS: Twelve stroke patients (range, 18-70 y), more than 5 months poststroke, with lower-extremity hemiparesis. INTERVENTION: Subjects were randomly assigned to groups that performed cycling exercise, one with ES evoking muscle contractions and a control group with ES not evoking muscle contractions. Subjects, blinded for group assignment, trained twice a week for 6 weeks. MAIN OUTCOME MEASURES: Changes in aerobic capacity and maximal power output, functional performance, and lower-limb muscle strength. RESULTS: Aerobic capacity and maximal power output significantly increased by 13.8%+/-19.1% and 38.1%+/-19.8%, but muscle strength was not significantly enhanced after training. Functional performance improved (ie, scores on the Berg Balance Scale increased by 6.9%+/-5.8% (P=.000) and the six-minute walk test improved by 14.5%+/-14.1% (P=.035). There was no significant effect on the Rivermead Mobility Index (P=.165). Training-induced changes were not significantly different between the 2 groups. Changes in cycling performance and aerobic capacity were not significantly related to changes in functional performance. CONCLUSIONS: This study showed that a short cycling training program on a semirecumbent cycle ergometer can markedly improve cycling performance, aerobic capacity, and functional performance of people with chronic stroke. The use of ES had no additional effects in this specific group of subjects with chronic stroke.

Proprioception of the shoulder after stroke.

OBJECTIVE: To investigate position sense and kinesthesia of the shoulders of stroke patients. DESIGN: Case-control study. SETTING: A rehabilitation center. PARTICIPANTS: A total of 22 inpatients with stroke and 10 healthy control subjects. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Angular displacement (in degrees) for threshold to detection of passive motion (TDPM) tests and absolute error (in degrees) for passive reproduction of joint position tests. RESULTS: For patients, the TDPM for internal and external rotation was significantly higher for both the contralateral (paretic) side (internal, 7.92 degrees +/-7.19 degrees ; external, 8.46 degrees +/-8.87 degrees ) and the ipsilateral (nonparetic) side (internal, 4.86 degrees +/-5.03 degrees ; external, 6.09 degrees +/-9.15 degrees ) compared with the control group (internal, 1.83 degrees +/-1.09 degrees ; external, 1.71 degrees +/-.85 degrees ). Also, for internal rotation, TDPM was significantly higher for patients on the contralateral side compared with the ipsilateral side. For passive reproduction of joint position tests, no differences were found. CONCLUSIONS: Both the contralateral and ipsilateral shoulders of stroke patients showed impaired TDPM. Passive reproduction of joint position does not seem to be affected as a result of a stroke. The control of the muscle spindles and central integration or processing problems of the afferent signals provided by muscle spindles might cause these effects.

Kinematic alterations in the ipsilateral shoulder of patients with hemiplegia due to stroke.

OBJECTIVE: To evaluate the assumption that shoulder kinematic patterns of the ipsilateral, nonparetic shoulder in hemiplegia are similar to kinematics recorded in a healthy population. DESIGN: Case control study of a convenience sample of ten patients with hemiplegia due to stroke in the subacute phase compared with a control group of similar age. Three-dimensional positions of the scapula and humerus were measured and expressed in Euler angles as a function of active arm elevation in the frontal and sagittal plane and during passive humeral internal/external rotation at an elevation angle of 90 degrees in the frontal and sagittal plane. RESULTS: Compared with controls, in the ipsilateral shoulder of patients, we found both a statistically significant diminished scapular protraction during elevation in the sagittal plane (35 +/- 5 vs. 51 +/- 8 degrees at 110 degrees of humeral elevation) and humeral external rotation during arm elevation in the frontal plane (51 +/- 7 vs. 69 +/- 14 degrees at 110 degrees of humeral elevation). Maximal passive humeral external rotation was found to be impaired in the frontal (64 +/- 13 vs. 98 +/- 14 degrees) and sagittal planes (65 +/- 11 vs. 94 +/- 12 degrees). In addition, there was significantly diminished anterior spinal tilt during humeral internal rotation (-5 +/- 10 vs. -20 +/- 9 degrees) and diminished posterior spinal tilt during external rotation in the frontal plane (-14 +/- 8 vs. -3 +/- 6 degrees). Maximal thoracohumeral elevation in patients was significantly impaired (126 +/- 12 vs. 138 +/- 8 degrees). CONCLUSION: Clear kinematic changes in the ipsilateral shoulder in patients with hemiplegia were found, indicating underlying alterations in muscle contraction patterns. The cause remains speculative. These results suggest that the ipsilateral shoulder should not be considered to function normally beforehand.

Single- and multiple-dose pharmacokinetics of linezolid and co-amoxiclav in healthy human volunteers.

In an open, randomized, two-period crossover study the pharmacokinetics of linezolid and co-amoxiclav were investigated after single- and multiple-dose administration in 12 healthy volunteers (six females and six males). Linezolid was given in tablets of 600 mg twice a day for 7 days and co-amoxiclav in tablets of 1000 mg (875 + 125 mg) once a day for 7 days. The wash-out period was 4 weeks between the administration of the two antibacterial agents. Blood and urine samples were collected on days 1 and 7 before and at different time points up to 24 h after medication. The concentrations of the antibiotics in serum and urine were measured by validated high-performance liquid chromatography methods. Linezolid exhibited a mean C(max) of 14.5 +/- 4.6 mg/L after T(max) of 47.5 +/- 20.1 min on day 1, with a significant increase to 24.0 +/- 6.9 mg/L on day 7 (P < 0.01). The AUD(tot) (total area under the data) revealed a significant increase from 140.5 +/- 28.3 mg.h/L on day 1 to 220.2 +/- 42.6 mg.h/L on day 7 (P < 0.01). There were no significant differences in terminal elimination half-life between days 1 and 7 (9.53 +/- 2.87 versus 7.97 +/- 3.08 h) or in total clearance (71.6 +/- 17.6 versus 81.5 +/- 14.7 ml/min.1.73 m(2)). Results are in agreement with the assumption of a limited accumulation of linezolid under the dosage regimen given. Serum linezolid concentrations in females were always higher than those in males. The volume of distribution V(ss)/f differed significantly between females and males (41.6 +/- 4.2 versus 52.2 +/- 3.3 L/70 kg; P < 0.01). Pharmacokinetic parameters of amoxicillin and clavulanic acid found in this study were similar to previously published data. No accumulation was found with co-amoxiclav. No serious adverse event was observed with the study drugs.