Effective connectivity between deep brain stimulation targets in individuals with treatment-resistant depression.

The therapeutic effect of deep brain stimulation on patients with treatment-resistant depression is strongly dependent on the connectivity of the stimulation region with other regions associated with depression. The aims of this study are to characterize the effective connectivity between the brain regions playing important roles in depression and further investigate the underlying pathophysiological mechanisms of treatment-resistant depression and the mechanisms involving deep brain stimulation. Thirty-three individuals with treatment-resistant depression and 29 healthy control subjects were examined. All subjects underwent resting-state functional MRI scanning. The coupling parameters reflecting the causal interactions among deep brain stimulation targets and medial prefrontal cortex were estimated using spectral dynamic causal modelling. Our results showed that compared to the healthy control subjects, in the left hemisphere of treatment-resistant depression patients, the nucleus accumbens was inhibited by the inferior thalamic peduncle and excited the ventral caudate and the subcallosal cingulate gyrus, which in turn excited the lateral habenula. In the right hemisphere, the lateral habenula inhibited the ventral caudate and the nucleus accumbens, both of which inhibited the inferior thalamic peduncle, which in turn inhibited the cingulate gyrus. The ventral caudate excited the lateral habenula and the cingulate gyrus, which excited the medial prefrontal cortex. Furthermore, these effective connectivity links varied between males and females, and the left and right hemispheres. Our findings suggest that intrinsic excitatory/inhibitory connections between deep brain stimulation targets are impaired in treatment-resistant depression patients, and that these connections are sex dependent and hemispherically lateralized. This knowledge can help to better understand the underlying mechanisms of treatment-resistant depression, and along with tractography, structural imaging, and other relevant clinical information, may assist to determine the appropriate region for deep brain stimulation therapy in each treatment-resistant depression patient.

Contribution of altered corticospinal microstructure to gait impairment in children with cerebral palsy.

OBJECTIVE: Corticospinal tract (CST) injury may lead to motor disorders in children with Cerebral Palsy (CP). However, the precise underlying mechanisms are still ambiguous. We aimed to characterize the CST structure and function in children with CP and determine their contributions to balance and gait impairments. METHOD: Twenty-six children with spastic CP participated. Transcranial magnetic stimulation (TMS) and diffusion tensor imaging (DTI) were utilized to characterize CST structure and function. Common clinical measures were used to assess gait speed, endurance and balance, and mobility. RESULTS: CST structure and function were significantly altered in children with CP. Different abnormal patterns of CST structure were identified as either abnormal appearance of brain hemispheres (Group-1) or semi-normal CST appearance (Group-2). We found significant correlations between the DTI parameters of the more affected CST and gait features only in Group-1. CONCLUSION: CST structure and function are abnormal in children with CP and these abnormalities may contribute to balance and gait impairment in some children with CP. SIGNIFICANCE: Our findings may lead to the development of further investigations on the mechanisms underlying gait impairment in children with CP and on decision-making for more effective rehabilitation.

Effective connectivity between emotional and motor brain regions in people with psychogenic nonepileptic seizures (PNES).

OBJECTIVE: To characterize the effective connectivity (EC) between the emotion and motor brain regions in patients with psychogenic nonepileptic seizures (PNES), based on resting-state spectral dynamic causal modeling (spDCM). METHODS: Twenty-three patients with PNES and twenty-five healthy control (HC) subjects underwent resting-state fMRI scanning. The coupling parameters indicating the causal interactions between eight brain regions associated with emotion, executive control, and motion were estimated for both groups, using resting-state fMRI spDCM. RESULTS: Compared to the HC subjects, in patients with PNES: (i) the left insula (INS) and left and right inferior frontal gyri (IFG) are more inhibited by the amygdala (AMYG), anterior cingulate cortex (ACC), and precentral gyrus (PCG); (ii) the left AMYG has greater inhibitory effects on the INS, IFG, dorsolateral prefrontal cortex (DLPFC), PCG, and supplementary motor area (SMA); (iii) the left ACC has more inhibitory effects on the INS and IFG; (iv) the right ACC is more inhibited by the INS and IFG, and has a less inhibitory effect on the SMA and PCG; and (v) the left caudate (CAU) had increased inhibitory effects on the AMYG and IFG and a more excitatory effect on the SMA. CONCLUSION: Our results suggest that in patients with PNES, the emotion-processing regions have inhibitory effects on the executive control areas and motor regions. Our findings may provide further insight into the influence of emotional arousal on functional movements and the underlying mechanisms of involuntary movements during functional seizures. Furthermore, they may suggest that emotion regulation through cognitive behavioral psychotherapies can be a potentially effective treatment modality.

Characterization of brain functional connectivity in treatment-resistant depression.

OBJECTIVE: To characterize the functional connectivity (FC) of target brain regions for deep brain stimulation (DBS) in patients with treatment-resistant depression (TRD), and to evaluate its gender and brain lateralization dependence. METHODS: Thirty-one TRD patients and twenty-nine healthy control (HC) subjects participated. FC of subcallosal cingulate gyrus (SCG), ventral caudate (VCa), nucleus accumbens (NAc), lateral habenula (LHb), and inferior thalamic peduncle (ITP) were evaluated using resting-state fMRI. FC was characterized by calculating the nodal 'degree', a major feature of the graph theory. RESULTS: The degree measures of the left and right VCa, the left LHb, and the left ITP were significantly greater in the TRD than in the HC group. The degree was greater in females with TRD in all these regions except the right LHb. Finally, the left hemisphere was generally more affected by depression and presented significant degrees in LHb and ITP regions of the patients. CONCLUSION: Our findings demonstrate the ability of degree to characterize brain FC and identify the regions with abnormal activities in TRD patients. This implies that the degree may have the potential to be used as an important graph-theoretical feature to further investigate the mechanisms underlying TRD, and consequently along with other diagnostic markers, to assist in the determination of the appropriate target region for DBS treatment in TRD patients.

Brain functional connectivity in individuals with psychogenic nonepileptic seizures (PNES): An application of graph theory.

OBJECTIVE: To determine brain functional connectivity (FC), based on the graph theory, in individuals with psychogenic nonepileptic seizures (PNES), in order to better understand the mechanisms underlying this disease. METHODS: Twenty-three patients with PNES and twenty-five healthy control subjects were examined. Alterations in FC within the whole brain were examined using resting-state functional magnetic resonance imaging (MRI). We calculated measures of the nodal degree, a major feature of the graph theory, for all the cortical and subcortical regions in the brain. Pearson correlation was performed to determine the relationship between nodal degree in abnormal brain regions and patient characteristics. RESULTS: The nodal degrees in the right caudate (CAU), left orbital part of the left inferior frontal gyrus (ORBinf), and right paracentral lobule (PCL) were significantly greater (i.e. hyper-connectivity) in individuals with PNES than in healthy control subjects. On the other hand, a lesser nodal degree (i.e. hypo-connectivity) was detected in several other brain regions including the left and right insula (INS), as well as the right putamen (PUT), and right middle occipital gyrus (MOG). CONCLUSION: Our findings suggest that the FC of several major brain regions can be altered in individuals with PNES. Areas with hypo-connectivity may be involved in emotion processing (e.g., INS) and movement regulation (e.g., PUT), whereas areas with hyper-connectivity may play a role in the inhibition of unwanted movements and cognitive processes (e.g., CAU).

Therapeutic effects of robotic rehabilitation on Neural and Muscular Abnormalities associated with the Spastic Ankle in Stroke Survivors.

Spasticity is a common ailment following stroke, which can cause pain, contracture, abnormal limb posture and functional limitation. Early management of post-stroke spasticity is vital to reduce these complications, and improve function and help patients become independent. We propose a therapeutic program based on applying a series of vibrations to the ankle joints at specific ankle position as well as over the range of motion using a rehabilitation robotic system to reduce the neural and muscular abnormalities associated with spasticity. We provided a 30-minute perturbation training, 3 times a week for 10 sessions for 8 stroke survivor subjects. Ankle stiffness was calculated using the hysteresis curves. Other kinematic and kinetic parameters were also used to evaluate the mechanical abnormalities. We evaluated participants before starting the therapeutic program, immediately after first session of training and after 10 sessions of training.Our results showed that all subjects had substantial improvements in stiffness, max voluntary contraction, energy loss, passive range of motion, and voluntary movement after both short- and long-term therapeutic program. Surprisingly, for most of these measures the maximum improvement obtained at short-term training. Interestingly, these improvements became persistent over the long-term training. These findings suggest that vibration therapy can be considered as an effective rehabilitation intervention to reduce neuromuscular abnormalities associated with the spasticity in stroke.

Graph theory application with functional connectivity to distinguish left from right temporal lobe epilepsy.

OBJECTIVE: To investigate the application of graph theory with functional connectivity to distinguish left from right temporal lobe epilepsy (TLE). METHODS: Alterations in functional connectivity within several brain networks - default mode (DMN), attention (AN), limbic (LN), sensorimotor (SMN) and visual (VN) - were examined using resting-state functional MRI (rs-fMRI). The study accrued 21 left and 14 right TLE as well as 17 nonepileptic control subjects. The local nodal degree, a feature of graph theory, was calculated foreach of the brain networks. Multivariate logistic regression analysis was performed to determine the accuracy of identifying seizure laterality based on significant differences in local nodal degree in the selected networks. RESULTS: Left and right TLE patients showed dissimilar patterns of alteration in functional connectivity when compared to control subjects. Compared with right TLE, patients with left TLE exhibited greater nodal degree' (i.e. hyperconnectivity) with right superomedial frontal gyrus (in DMN), inferior frontal gyrus pars triangularis (in AN), right caudate and left superior temporal gyrus (in LN) and left paracentral lobule (in SMN), while showing lesser nodal degree (i.e. hypoconnectivity) with left temporal pole (in DMN), right insula (in LN), left supplementary motor area (in SMN), and left fusiform gyrus (in VN). The LN showed the highest accuracy of 82.9% among all considered networks in determining laterality of the TLE. By combinations of local degree attributes in the DMN, AN, LN, and VN, logistic regression analysis demonstrated an accuracy of 94.3% by comparison. CONCLUSION: Our study demonstrates the utility of graph theory application to brain network analysis as a potential biomarker to assist in the determination of TLE laterality and improve the confidence in presurgical decision-making in cases of TLE.

Evolution of Graph Theory in Dynamic Functional Connectivity for Lateralization of Temporal Lobe Epilepsy.

Resting-state functional magnetic resonance imaging (rsfMRI) has described the functional architecture of the human brain in the absence of any task or stimulus. Since the functional connectivity (FC), has non-stationary nature, it is evidenced to be varying over time. Using dynamic functional connectivity, six graph theoretical characteristics were measured and compared between left and right temporal lobe epilepsy (TLE). We also obtain a trend for each characteristic in the time course of experiments. The results demonstrated that the static connectivity analysis failed to fully separate the left and right TLE patients for some characteristics, whereby the dynamic analysis has been shown capable of identifying the laterality. Furthermore, the results suggest that the temporal trend of some graph theoretical characteristics can be exploited as a novel marker for TLE laterality.

Therapeutic Effects of repetitive Transcranial Magnetic Stimulation on Corticospinal Tract Activities and Neuromuscular Properties in Children with Cerebral Palsy.

The objective of this research was to study the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on corticospinal tract (CST) activities, reflex hyper-excitability, muscle stiffness, and the clinical status of children with spastic hemiplegic cerebral palsy (CP). Three children participated in this study. The treatment lasted for 6 weeks. Two of the patients, the experimental group, received rTMS therapy 4 days a week during the first 3 weeks, and then received typical occupational therapy (OT) after each rTMS session during the second 3 weeks. One patient, the control group, received the same treatment except that a sham coil was used. Each rTMS session lasted for 20 minutes and each OT session lasted for 45 minutes. We evaluated CST activities by transcranial magnetic stimulation (TMS), reflex hyperexcitability by H-reflex response, and muscle stiffness by sonoelastography images. The tests were taken before and after the treatment. Major TMS parameters (i.e., motor evoked potential (MEP) latency, MEP p-p amplitude, cortical silent period (cSP), and intensity of pulse) for experimental patients were improved in comparison with the control patient. H response latency and max H response on max M-wave (H/M) were improved for the experimental group compared to the control group. Two parameters of texture analysis of the sonoelastography images (i.e., entropy and contrast) were improved for the experimental group. Clinical evaluations such as 10 meter walk test (10MWT), timed up and go (TUG), and 6 minute walk test (6MWT) were performed before and after the course of treatment and were improved for the experimental group compared to the control group. These results indicated that rTMS therapy can improve CST activities, reflexes, muscle stiffness, and walking capacity of spastic hemiplegic CP. Therefore, it can be considered as an effective therapeutic tool for enhancing neuromuscular abnormalities resulting from CP.

The Impact of Repetitive Transcranial Magnetic Stimulation on Affected and Unaffected Sides of a Child with Hemiplegic Cerebral Palsy.

The purpose of this study was to investigate the therapeutic effects of neuro-navigated repetitive transcranial magnetic stimulation (rTMS) combined with occupational therapy (OT) on gait impairment of a child (male, age: 13.2) with spastic hemiplegic cerebral palsy (CP). The treatment included 4 days a week of rTMS sessions for 3 weeks and 4 days of rTMS and OT sessions per week for 3 weeks. Transcranial magnetic stimulation (TMS) was used to evaluate corticospinal tract (CST) activities and H-reflex test was used to assess reflex hyper-excitability. Common clinical tests demonstrate the clinical status of the patient. Evaluations were performed in 4 time steps: baseline, 3 weeks after the beginning of the treatment, at the end of the treatment, and 1 month after the end of the treatment. The patient did not receive any specific treatment after the end of the treatment up to the follow up evaluations. The tests' results were compared between the affected and unaffected legs of the patient. Four parameters of the TMS test were calculated (motor evoked potential (MEP) latency, MEP peak-to-peak amplitude, cortical silent period (cSP), and stimulation intensity). These parameters were all improved for the affected side and cSP improved for the unaffected side, but MEP p-p amplitude and intensity got worse slightly for the unaffected side. Recruitment curves of H response and M-wave of the H-reflex test for both sides were obtained. Improvements could be seen after the treatment for both sides. Max H response on max M-wave (H/M) and H response latency got better after the treatment for both sides. Walking speed for self and fast velocity, timed up and go, and walking endurance improved during and after the treatment. All the improvements persisted after one month of the end of the treatment in the follow up evaluations. These findings indicate that rTMS combined with OT can have effective and long-lasting impact on neuromuscular impairments in spastic CP children.

Robotic-assisted locomotor training enhances ankle performance in adults with incomplete spinal cord injury.

OBJECTIVE: Ankle joint control plays an important role in independent walking. This study investigated the effects of robotic-assisted locomotor training on impaired ankle joint control in individuals with chronic incomplete spinal cord injury. METHODS: Sixteen individuals with incomplete spinal cord injury underwent 12 one-h sessions of robotic-assisted locomotor training for 4 weeks, while 16 individuals with incomplete spinal cord injury served as inactive controls. Changes in ankle control measures, torque and co-activation were evaluated during maximal voluntary contractions in dorsi- and plantar-flexion. Changes in walking performance measures using Timed Up and Go (TUG), 10-m walk (10MWT) and 6-min walk (6MWT) tests were evaluated at 2 time points: baseline and after 4 weeks. RESULTS: Maximal voluntary contractions torque during both dorsi- and plantar-flexion contractions improved markedly in the robotic-assisted locomotor training group compared with baseline. Furthermore, after the training, co-activation during the dorsi-flexion maximal voluntary contractions decreased in the training group compared with controls. In addition, the training group significantly improved walking mobility (TUG) and speed (10MWT) compared with baseline. Finally, correlation analysis indicated a significant linear relationship between maximal voluntary contraction torques and walking performance measures. CONCLUSION: These findings provide evidence that robotic-assisted locomotor training improves ankle joint control, which may translate into enhanced walking performance in individuals with chronic incomplete spinal cord injury.

Differences in white matter microstructure between Parkinson's disease patients with and without REM sleep behavior disorder.

REM sleep behavior disorder (RBD) is characterized by increased muscle tone and violent limb movements and usually occurs during the early stages of Parkinson disease (PD). PD patients with RBD represent faster motor progression and cognitive dysfunction. We used diffusion imaging to assess which regions are involved in this phenomenon. In the current study, we computed Quantitative Anisotropic (QA), which is based on spin distribution function (SDF) that quantifies the density of diffusing water and is more sensitive to psychological differences between groups and also diffusion MRI connectometry to conduct group analysis between age and gender matched PD patients with and without RBD. The major regions with significantly reduced QA in PD patients with RBD were left and right cingulum and left and left inferior occipital fasciculus.

Structural brain network analysis in schizophrenia using minimum spanning tree.

Schizophrenia is a mental disorder in which functional and structural brain networks are disrupted. Classical network analysis has been used by many researchers to quantify brain networks and to study the network changes in schizophrenia, but unfortunately metrics used in this classical method highly depend on the networks' density and weight; the comparisons made by this method are biased. The minimum spanning tree (MST) is an alternative method to solve this problem, but its usefulness in studying the schizophrenic brain network has not been examined yet. In the present study, we quantified structural brain networks using MST metrics to conduct group analysis between age and sex matched schizophrenic patients and healthy controls. Many MST metrics including Kappa, gamma, max, Betweenness centrality (BC), leaf number, and diameter were found to have significantly changed between two groups that implied a disruption in the whole brain integrity. This was unlike the brain segregation, which was not altered in the schizophrenia group. These results have consistency with Classical network analysis works and demonstrate the MST potential as a powerful method to be used in researches, studying schizophrenic brain connectome.

Facilitatory effects of anti-spastic medication on robotic locomotor training in people with chronic incomplete spinal cord injury.

BACKGROUND: The objective of this study was to investigate whether an anti-spasticity medication can facilitate the effects of robotic locomotor treadmill training (LTT) to improve gait function in people with incomplete spinal cord injury (SCI). METHODS: Individuals with chronic incomplete SCI were recruited and carried out a 4 week intervention of either locomotor treadmill training (LTT) alone (n = 26) or LTT combined with Tizanidine (TizLTT), an anti-spasticity medication (n = 22). Gait function was evaluated using clinical outcome measures of gait, speed and endurance. To better understand the underlying mechanisms of the therapeutic effects, maximal strength, active range of motion (AROM) and peak velocity (Vp) of ankle dorsi- and planter-flexor muscles were also measured. Differences were assessed using two-way mixed design analysis of variance. The number of subjects that achieved the minimal important difference (MID) for clinical scores was also measured for each group, and the results of those that did attain the MID were compared with those that did not. RESULTS: Both LTT and TizLTT resulted in significant improvements in walking speed and dorsiflexion maximum strength, with no significant differences between them, using group-averaging analysis. However, using the MID analysis, a higher proportion of subjects in the TizLTT group achieved the MID for walking speed (40%) compared with LTT alone (13%). Those that achieved the MID for walking speed were significantly higher functioning at baseline than those that did not in the TizLTT group, and the change in walking speed was associated with the change in dorsiflexion peak velocity (R(2) = 0.40; P < 0.05). CONCLUSION: Tizanidine appears to facilitate the effects of LTT on gait function in individuals with chronic SCI that are higher functioning at baseline. We speculate that this may be due to restoration of inhibitory mechanisms by Tizanidine, resulting in greater stretch in the planterflexor muscles during the LTT.

Comparison between the therapeutic effects of robotic-assisted locomotor training and an anti-spastic medication on spasticity.

We studied the effects of robotic-assisted locomotor (LOKOMAT) training or an anti-spastic medication (tizanidine) on neuromuscular abnormality associated with spasticity in persons with incomplete Spinal Cord Injury (SCI). Subjects were randomly divided to three groups: Lok, Tiz, and Cont. LOKOMAT training was performed 3 days/week for 4 weeks, with up to 45 minutes of training per session. Tizanidine (2mg) was administered (4\day), for 4 weeks. Subjects in Cont group received no intervention. The participants were evaluated before and after 4 weeks of training, and the effects of training on the intrinsic (muscular) and reflexive components of the neuromuscular properties were quantified over the ankle range-of-motion. A parallel-cascade system identification technique was used to determine the reflex and intrinsic stiffness of the ankle joint as a function of ankle position at each time point. The intercept and slope of the stiffness vs. joint angle curve were then calculated and tracked over the four-week period. The number of subjects that achieved the minimally important difference (MID) for the intercepts and slopes, and levels of changes were compared. Both Lokomat and tizanidine resulted in significant reduction in both intercept and slope of reflex and intrinsic stiffness. However, a higher proportion of subjects in Lok group achieved the MID for the reflex (>90%) and intrinsic (65-78%) parameters compared with Tiz group (up to 63% and 25% for reflex and intrinsic parameters, respectively). The levels of reduction were also higher in the Lok than the Tiz group. No one in the Cont group achieved the MID. Our findings demonstrate that LOKOMAT training can be more efficient in modifying neuromuscular abnormalities associated with spasticity than tizanidine.

Effects of robotic-locomotor training on stretch reflex function and muscular properties in individuals with spinal cord injury.

OBJECTIVE: We sought to determine the therapeutic effect of robotic-assisted step training (RAST) on neuromuscular abnormalities associated with spasticity by characterization of their recovery patterns in people with spinal cord injury (SCI). METHODS: Twenty-three motor-incomplete SCI subjects received one-hour RAST sessions three times per week for 4 weeks, while an SCI control group received no training. Neuromuscular properties were assessed using ankle perturbations prior to and during the training, and a system-identification technique quantified stretch reflex and intrinsic stiffness magnitude and modulation with joint position. Growth-mixture modeling classified subjects based on similar intrinsic and reflex recovery patterns. RESULTS: All recovery classes in the RAST group presented significant (p<0.05) reductions in intrinsic and reflex stiffness magnitude and modulation with position; the control group presented no changes over time. Subjects with larger baseline abnormalities exhibited larger reductions, and over longer training periods. CONCLUSIONS: Our findings demonstrate that RAST can effectively reduce neuromuscular abnormalities, with greater improvements for subjects with higher baseline abnormalities. SIGNIFICANCE: Our findings suggest, in addition to its primary goal of improving locomotor patterns, RAST can also reduce neuromuscular abnormalities associated with spasticity. These findings also demonstrate that these techniques can be used to characterize neuromuscular recovery patterns in response to various types of interventions.

Interventions to Reduce Spasticity and Improve Function in People With Chronic Incomplete Spinal Cord Injury: Distinctions Revealed by Different Analytical Methods.

BACKGROUND: Spinal cord injury (SCI) results in impaired function, and ankle joint spasticity is a common secondary complication. Different interventions have been trialed with variable results. OBJECTIVE: We investigated the effects of pharmacological and physical (locomotor training) interventions on function in people living with incomplete motor function loss caused by SCI and used different analytical techniques to understand whether functional levels affect recovery with different interventions. METHODS: Participants with an incomplete SCI were assigned to 3 groups: no intervention, Lokomat, or tizanidine. Outcome measures were the 10-m walk test, 6-minute walk test, and the Timed Up and Go. Participants were classified in 2 ways: (1) based on achieving an improvement above the minimally important difference (MID) and (2) using growth mixture modeling (GMM). Functional levels of participants who achieved the MID were compared and random coefficient regression (RCR) was used to assess recovery in GMM classes. RESULTS: Overall, walking speed and endurance improved, with no difference between interventions. Only a small number of participants achieved the MID. Both MID and GMM-RCR analyses revealed that tizanidine improved endurance in high-functioning participants. GMM-RCR classification also showed that speed and mobility improved after locomotor training. CONCLUSIONS: Improvements in function were achieved in a limited number of people with SCI. Using the MID and GMM techniques, differences in responses to interventions between high-and low-functioning participants could be identified. These techniques may, therefore, have potential to be used for characterizing therapeutic effects resulting from different interventions.

Ankle voluntary movement enhancement following robotic-assisted locomotor training in spinal cord injury.

BACKGROUND: In incomplete spinal cord injury (iSCI), sensorimotor impairments result in severe limitations to ambulation. To improve walking capacity, physical therapies using robotic-assisted locomotor devices, such as the Lokomat, have been developed. Following locomotor training, an improvement in gait capabilities-characterized by increases in the over-ground walking speed and endurance-is generally observed in patients. To better understand the mechanisms underlying these improvements, we studied the effects of Lokomat training on impaired ankle voluntary movement, known to be an important limiting factor in gait for iSCI patients. METHODS: Fifteen chronic iSCI subjects performed twelve 1-hour sessions of Lokomat training over the course of a month. The voluntary movement was qualified by measuring active range of motion, maximal velocity peak and trajectory smoothness for the spastic ankle during a movement from full plantar-flexion (PF) to full dorsi-flexion (DF) at the patient's maximum speed. Dorsi- and plantar-flexor muscle strength was quantified by isometric maximal voluntary contraction (MVC). Clinical assessments were also performed using the Timed Up and Go (TUG), the 10-meter walk (10MWT) and the 6-minute walk (6MWT) tests. All evaluations were performed both before and after the training and were compared to a control group of fifteen iSCI patients. RESULTS: After the Lokomat training, the active range of motion, the maximal velocity, and the movement smoothness were significantly improved in the voluntary movement. Patients also exhibited an improvement in the MVC for their ankle dorsi- and plantar-flexor muscles. In terms of functional activity, we observed an enhancement in the mobility (TUG) and the over-ground gait velocity (10MWT) with training. Correlation tests indicated a significant relationship between ankle voluntary movement performance and the walking clinical assessments. CONCLUSIONS: The improvements of the kinematic and kinetic parameters of the ankle voluntary movement, and their correlation with the functional assessments, support the therapeutic effect of robotic-assisted locomotor training on motor impairment in chronic iSCI.

Prediction of gait recovery in spinal cord injured individuals trained with robotic gait orthosis.

BACKGROUND: Motor impairment is a major consequence of spinal cord injury (SCI). Earlier studies have shown that robotic gait orthosis (e.g., Lokomat) can improve an SCI individual's walking capacity. However, little is known about the differential responses among different individuals with SCI. The present longitudinal study sought to characterize the distinct recovery patterns of gait impairment for SCI subjects receiving Lokomat training, and to identify significant predictors for these patterns. METHODS: Forty SCI subjects with spastic hypertonia at their ankles were randomly allocated to either control or intervention groups. Subjects in the intervention group participated in twelve 1-hour Lokomat trainings over one month, while control subjects received no interventions. Walking capacity was evaluated in terms of walking speed, functional mobility, and endurance four times, i.e. baseline, 1, 2, and 4 weeks after training, using the 10-Meter-Walking, Timed-Up-and-Go, and 6-Minute-Walking tests. Growth Mixture Modeling, an analytical framework for stratifying subjects based on longitudinal changes, was used to classify subjects, based on their gait impairment recovery patterns, and to identify the effects of Lokomat training on these improvements. RESULTS: Two recovery classes (low and high walking capacity) were identified for each clinical evaluation from both the control and intervention groups. Subjects with initial high walking capacity (i.e. shorter Timed-Up-and-Go time, higher 10-Meter-Walking speed and longer 6-Minute-Walking distance) displayed significant improvements in speed and functional mobility (0.033 m/s/week and-0.41 s/week respectively); however no significant change in endurance was observed. Subjects with low walking capacity exhibited no significant improvement. The membership in these two classes-and thus prediction of the subject's gait improvement trajectory over time-could be determined by the subject's maximum voluntary torque at the ankle under both plantar-and dorsi-flexion contractions determined prior to any training. CONCLUSION: Our findings demonstrate that subjects responded to Lokomat training non-uniformly, and should potentially be grouped based on their likely recovery patterns using objective criteria. Further, we found that the subject's ankle torque can predict whether he/she would benefit most from Lokomat training prior to the therapy. These findings are clinically significant as they can help individualize therapeutic programs that maximize patient recovery while minimizing unnecessary efforts and costs.

Variability in responsiveness to interventions in people with spinal cord injury: Do some respond better than others?

Spinal cord injury (SCI) results in significant impairments in function and ankle joint spasticity is a common secondary complication. Various interventions have been trialed to improve function and reduce spasticity after SCI, with variable results. We investigated the effects of a pharmacological (an anti-spastic medication - tizanidine) and a physical intervention (robotic-assisted locomotor training - Lokomat) on function in people with incomplete SCI over 4-week of training. The outcome measures were walking speed, endurance and mobility. Subjects were randomized into one of three groups; no intervention (control), Lokomat (Lok) and tizanidine (Tiz). To account for variability, we used growth mixture modelling (GMM) to class subjects based on their recovery patterns. GMM identified two classes of recovery: high and low function. Significant improvements were seen in walking speed and mobility in high and low functioning subjects in the Lok group, and in walking endurance in high functioning subjects in the Tiz group. However, changes with training were clinically important only for approximately 10% of subjects, who achieved a minimal important difference (MID) in functional outcomes as a result of the training. We used mixed model ANOVAs to compare the group effects. Improvements with training were seen in both classes, however no differences between interventions were found. The GMM had classed all subjects that achieved the MID as high functioning. GMM can be used to successfully class subjects; however larger subject numbers and longer interventions are required to fully utilize this technique. Our results demonstrate that both interventions have potential to improve walking capacity, but more intense training for a longer period may need to achieve MID.