Ultrasonography for quantitative assessment of knee joint effusions-useful tool for objective evaluation of rehabilitation progress?

PURPOSE: We sought to externally validate ultrasonography (US) for quantification of suprapatellar effusion size to improve diagnosis and individualised rehabilitation strategies in knee rehabilitation after anterior cruciate ligament reconstruction (ACLR) surgery. METHODS: US was performed on 35 patients as part of the ongoing CAMOPED study. Data were collected in ACLR and post surgery in defined intervals up to one year post-operation. The palpatory assessment was graded using the International Knee Documentation Committee (oIKDC). RESULTS: In a total of 164 sonographies, a strong correlation between palpatory and US effusion (r = 0.83, p < 0.01) with lower deviations in US quantification compared to palpatory quantification Y = 1.15 + 0.15* x was seen. Threshold values could be determined for the detection of effusions by palpation and for the differentiation between mild and moderate/severe effusions (effusion depth: 2.6 mm and resp. 5.8 mm, respectively). CONCLUSIONS: As demonstrated in this multicenter study, the size of suprapatellar effusions can be easily quantified with high accuracy using standardised bedside ultrasound. Especially in moderate to severe effusions, US provides a practical and reliable tool for outcome measurement superior to palpatory assessment with the goal of optimising individual recommendations during the rehabilitation course. Furthermore, for the first time, it has been possible to define sonographic threshold values for the detection of effusion and differentiation of mild vs. moderate/severe effusion by means of palpation.

Dynamic Standing Exercise using the Innowalk Device in Patients with Genetic and Acquired Motor Impairments.

OBJECTIVE: For individuals with motor impairments, dynamic standing has been proposed as an opportunity for regular daily physical activity. The aim of this study was to analyse patient characteristics, indications, intensity of usage, desired objectives and outcomes of dynamic standing in daily clinical practice in order to form the basis for research regarding this treatment option. SETTING: Data were analysed from standardized questionnaires completed prospectively before supply of a home-based medical device for dynamic standing (Innowalk; Made for Movement GmbH, Langenhagen, Germany) and at the time of individual adaptations. PARTICIPANTS: In a retrospective chart analysis, records of 46 patients (50% cerebral palsy; 50% diverse syndromes) were evaluated. INTERVENTION: The Innowalk had been prescribed for either home-based use (n = 31), in therapeutic institutions (n = 8), or other settings (n = 7). Dynamic standing was performed for 10-30 min as a single session (n = 8) or for 20-60 min 11 [4-21] weeks in 36 patients. RESULTS: Improvements were found for: passive assisted motion (79%), stimulation of intestinal functions (71%), body stability (64%), joint mobility (56%), secure means of allowing supine position (52%), and revision of abnormal motion patterns (48%). CONCLUSION: Thus, this systematic approach shows usage patterns, indications, desired goals and clinical outcome of dynamic standing in daily clinical practice and forms the basis for the design of a prospective, randomized controlled trial.

Effect of assisted walking-movement in patients with genetic and acquired neuromuscular disorders with the motorised Innowalk device: an international case study meta-analysis.

People with physical disabilities (PD) suffer from consequences due to lack of physical activity and consequently, are at increased risk of chronic diseases. We aimed to evaluate the ability of a motorised assistive device for dynamic standing with weight-bearing in addition to standard state-of-the-art therapy to improve clinical outcome in a meta-analysis of available studies. A total of 11 studies were identified from different European countries analysing the effect of the dynamic device Innowalk. Raw data of nine studies were pooled including a total of 31 patients observed between 2009 and 2017. Standardised questionnaires and physical outcomes were examined in this exploratory meta-analysis. We recorded patients' characteristics, duration, intensity, and location of usage as well as general clinical outcomes and improvement of passive range of motion (PROM). The analysed population consisted in 90% cases of patients younger than 18 years of age. Patients were severely disabled individuals (aged 8 (6-10) years; 58% male; 67% non-ambulatory, 86% cerebral palsy). A total of 94% used the Innowalk in a home-based or day-care setting. For nearly all individuals (94%), improvements were recorded for: walking or weight-bearing transfer (n = 13), control/strength of the trunk or head (n = 6), joint mobility (n = 14), sleep (n = 4 out of 6/67%), or muscle strength (n = 17), vital functions (n = 16), bowel function (n = 10), attention/orientation (n = 2). PROM of the hip (flexion, abduction, and adduction) significantly (p < 0.001 for multiple comparisons) increased after 1 month (p < 0.05 flexion, adduction) and further after 5 months (p < 0.05 each) in contrast (p < 0.05 each) to a control group with state-of-the-art therapy. Similarly, PROM showed a trend towards improvement in dorsal extension of the ankle (p = 0.07). In summary, this is the first report of a novel device with additional benefit to standard therapy for severe PD. These intriguing results warrant the planned prospective randomised controlled trial to prove the concept and mechanism of action of this device.

Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation.

Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA), leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC) activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease.

Dopaminergic projections from midbrain to primary motor cortex mediate motor skill learning.

The primary motor cortex (M1) of the rat contains dopaminergic terminals. The origin of this dopaminergic projection and its functional role for movement are obscure. Other areas of cortex receive dopaminergic projections from the ventral tegmental area (VTA) of the midbrain, and these projections are involved in learning phenomena. We therefore hypothesized that M1 receives a dopaminergic projection from VTA and that this projection mediates the learning of a motor skill by inducing cellular plasticity events in M1. Retrograde tracing from M1 of Long-Evans rats in conjunction with tyrosine hydroxylase immunohistochemistry identified dopaminergic cell bodies in VTA. Electrical stimulation of VTA induced expression of the immediate-early gene c-fos in M1, which was blocked by intracortical injections of D(1) and D(2) antagonists. Destroying VTA dopaminergic neurons prevented the improvements in forelimb reaching seen in controls during daily training. Learning recovered on administration of levodopa into the M1 of VTA-lesioned animals. Lesioning VTA did not affect performance of an already learned skill, hence, left movement execution intact. These findings provide evidence that dopaminergic terminals in M1 originate in VTA, contribute to M1 plasticity, and are necessary for successful motor skill learning. Because VTA dopaminergic neurons are known to signal rewards, the VTA-to-M1 projection is a candidate for relaying reward information that could directly support the encoding of a motor skill within M1.

Motor skill learning depends on protein synthesis in the dorsal striatum after training.

Functional imaging studies in humans and electrophysiological data in animals suggest that corticostriatal circuits undergo plastic modifications during motor skill learning. In motor cortex and hippocampus circuit plasticity can be prevented by protein synthesis inhibition (PSI) which can interfere with certain forms learning. Here, the hypothesis was tested that inducing PSI in the dorsal striatum by bilateral intrastriatal injection of anisomycin (ANI) in rats interferes with learning a precision forelimb reaching task. Injecting ANI shortly after training on days 1 and 2 during 4 days of daily practice (n = 14) led to a significant impairment of motor skill learning as compared with vehicle-injected controls (n = 15, P = 0.033). ANI did not affect the animals' motivation as measured by intertrial latencies. Also, ANI did not affect reaching performance once learning was completed and performance reached a plateau. These findings demonstrate that PSI in the dorsal striatum after training impairs the acquisition of a novel motor skill. The results support the notion that plasticity in basal ganglia circuits, mediated by protein synthesis, contributes to motor skill learning.

Dopamine in motor cortex is necessary for skill learning and synaptic plasticity.

Preliminary evidence indicates that dopamine given by mouth facilitates the learning of motor skills and improves the recovery of movement after stroke. The mechanism of these phenomena is unknown. Here, we describe a mechanism by demonstrating in rat that dopaminergic terminals and receptors in primary motor cortex (M1) enable motor skill learning and enhance M1 synaptic plasticity. Elimination of dopaminergic terminals in M1 specifically impaired motor skill acquisition, which was restored upon DA substitution. Execution of a previously acquired skill was unaffected. Reversible blockade of M1 D1 and D2 receptors temporarily impaired skill acquisition but not execution, and reduced long-term potentiation (LTP) within M1, a form of synaptic plasticity critically involved in skill learning. These findings identify a behavioral and functional role of dopaminergic signaling in M1. DA in M1 optimizes the learning of a novel motor skill.

FasL (CD95L/APO-1L) resistance of neurons mediated by phosphatidylinositol 3-kinase-Akt/protein kinase B-dependent expression of lifeguard/neuronal membrane protein 35.

The contribution of Fas (CD95/APO-1) to cell death mechanisms of differentiated neurons is controversially discussed. Rat cerebellar granule neurons (CGNs) express high levels of Fas in vitro but are resistant to FasL (CD95L/APO-1L/CD178)-induced apoptosis. We here show that this resistance was mediated by a phosphatidylinositol 3-kinase (PI 3-kinase)-Akt/protein kinase B (PKB)-dependent expression of lifeguard (LFG)/neuronal membrane protein 35. Reduction of endogenous LFG expression by antisense oligonucleotides or small interfering RNA lead to increased sensitivity of CGNs to FasL-induced cell death and caspase-8 cleavage. The inhibition of PI 3-kinase activity sensitized CGNs to FasL-induced caspase-8 and caspase-3 processing and caspase-dependent fodrin cleavage. Pharmacological inhibition of PI 3-kinase, overexpression of the inhibitory protein IkappaB, or cotransfection of an LFG reporter plasmid with dominant-negative Akt/PKB inhibited LFG reporter activity, whereas overexpression of constitutively active Akt/PKB increased LFG reporter activity. Overexpression of LFG in CGNs interfered with the sensitization to FasL by PI 3-kinase inhibitors. In contrast to CGNs, 12 glioma cell lines, which are sensitive to FasL, did not express LFG. Gene transfer of LFG into these FasL-susceptible glioma cells protected against FasL-induced apoptosis. These results demonstrate that LFG mediated the FasL resistance of CGNs and that, under certain circumstances, e.g., inhibition of the PI 3-kinase-Akt/PKB pathway, CGNs were sensitized to FasL.