John L K Kramer

University of Zurich, Zürich, Zurich, Switzerland

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Publications (26)72.13 Total impact

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    ABSTRACT: Study design:This is a review article.Objectives:This study discusses the following: (1) concepts and constraints for the determination of minimal clinically important difference (MCID), (2) the contrasts between MCID and minimal detectable difference (MDD), (3) MCID within the different domains of International Classification of Functioning, disability and health, (4) the roles of clinical investigators and clinical participants in defining MCID and (5) the implementation of MCID in acute versus chronic spinal cord injury (SCI) studies.Methods:The methods include narrative reviews of SCI outcomes, a 2-day meeting of the authors and statistical methods of analysis representing MDD.Results:The data from SCI study outcomes are dependent on many elements, including the following: the level and severity of SCI, the heterogeneity within each study cohort, the therapeutic target, the nature of the therapy, any confounding influences or comorbidities, the assessment times relative to the date of injury, the outcome measurement instrument and the clinical end-point threshold used to determine a treatment effect. Even if statistically significant differences can be established, this finding does not guarantee that the experimental therapeutic provides a person living with SCI an improved capacity for functional independence and/or an increased quality of life. The MDD statistical concept describes the smallest real change in the specified outcome, beyond measurement error, and it should not be confused with the minimum threshold for demonstrating a clinical benefit or MCID. Unfortunately, MCID and MDD are not uncomplicated estimations; nevertheless, any MCID should exceed the expected MDD plus any probable spontaneous recovery.Conclusion:Estimation of an MCID for SCI remains elusive. In the interim, if the target of a therapeutic is the injured spinal cord, it is most desirable that any improvement in neurological status be correlated with a functional (meaningful) benefit.Spinal Cord advance online publication, 16 December 2014; doi:10.1038/sc.2014.232.
    Spinal Cord 12/2014; 53(2). · 1.70 Impact Factor
  • John Kramer, Patrick Freund, Armin Curt
    Quantitative techniques for MRI of the human spinal cord, 1st edited by Julien Cohen-Adad, Claudia A.M. Wheeler-Kingshott, 05/2014: chapter 1.3B Traumatic Spinal Cord Injury, Chronic SCI and Recovery; Elsevier., ISBN: 9780123972828
  • J Haefeli, J L K Kramer, J Blum, A Curt
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    ABSTRACT: Within an area, habituation and sensitization represent well-established modulatory effects to repetitive noxious input. Less is known regarding the nociceptive conditioning effects between body sites - i.e., how stimulating one site may affect another. Therefore, we investigated the effects of nociceptive stimulation of anatomically distinct locations (shoulder and hand) on pain rating and evoked potentials (i.e., contact heat-evoked potentials). The effect of stimulation order was assessed in eight healthy subjects. The shoulder was examined before the hand or the hand before the shoulder. All subjects underwent both conditions (shoulder before hand and hand before shoulder) on separate days. In an additional 30 subjects (total n = 38), between retesting the shoulder or the hand, conditioning stimulation in the respective other location (i.e., hand or shoulder) was applied. Both analyses focused upon changes in the magnitude of evoked pain responses in relation to the respective area being conditioned by heterotopic stimulation. When the shoulder was stimulated before the hand, N2P2 amplitude was significantly reduced. In contrast, stimulating the hand before the shoulder resulted in significant response increments (shorter N2 latency). Additionally, conditioning stimulation of the hand resulted in increased pain rating to shoulder stimulation. Overall, these findings indicate that response modulation to noxious contact heat stimulation depends upon conditioning stimulus location. These effects represent changes beyond conventional habituation due to repeated stimulation in the same area.
    European journal of pain (London, England) 01/2014; · 3.37 Impact Factor
  • Jenny Haefeli, John L K Kramer, Julia Blum, Armin Curt
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    ABSTRACT: . Although a mainstay of clinical sensory examination after damage in the spinal cord, pinprick sensation represents only one afferent modality conveyed in the spinothalamic tract. As an objective outcome, complementary information regarding spinothalamic tract conduction may be elucidated by measuring contact heat evoked potentials (CHEPs). . To assess the value of CHEPs to measure spinothalamic tract function in spinal cord disorders compared with pinprick scoring. . CHEPs were examined using a standard (35°C) and increased baseline (42°C) contact heat temperature. Pinprick sensation was rated as absent, impaired, or normal according to the International Standards for the Neurological Classification of Spinal Cord Injury. . Fifty-nine dermatomes above, at, and below the sensory level of impairment were analyzed in 37 patients with defined spinal cord disorder. In dermatomes with absent or impaired pinprick sensation, CHEPs using a standard baseline temperature were mainly abolished (3/16 and 8/35, respectively). However, when applying an increased baseline temperature, CHEPs became recordable (absent: 11/16; impaired: 31/35). Furthermore, CHEPs with increased baseline temperature allowed discerning between dermatomes with absent, impaired, and normal pinprick sensation when using an objective measure (ie, N2P2 amplitude). In contrast, the pain perception to contact heat stimulation was independent of pinprick scores. . Applying pinprick testing is of limited sensitivity to assess spinothalamic tract function in spinal cord disorders. The application of CHEPs (using standard and increased baseline temperatures) as an objective readout provides complementary information of spinothalamic tract functional integrity beyond pinprick testing.
    Neurorehabilitation and neural repair 12/2013; · 4.62 Impact Factor
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    ABSTRACT: : After spinal cord injury, contact heat evoked potentials (CHEPs) may represent a means to refine the clinical assessment of sensory function from each spinal cord segment by quantifying nociception, including conduction along the spinothalamic tract. : The influence of stimulation site (i.e., dermatomes) on CHEPs and thermal thresholds in 19 healthy subjects (mean age, 45.2 ± 18.3 years) divided into 2 age classes (younger subjects, n = 10; mean age, 28.8 ± 5.2 years; older subjects, n = 9; mean age, 63.4 ± 3.4 years) at 5 different dermatomes (C4, C5, C6, C8, and T4) was assessed. : In terms of distance from the body midline (i.e., spinal cord entry), there was a reduction in CHEP amplitudes from proximal (C4 and T4) to distal (C6 and C8) dermatomes with a corresponding reduction in nociceptive perception (i.e., pain threshold and rating). Within primary and secondary cortical sensory areas, including areas associated with affective noxious processing, the cortical source density analysis showed a similar current density distribution between C4 and C8 dermatomes but consistent higher current densities for C4. : The study supports CHEPs as a feasible tool for assessing discrete dermatomes corresponding to spinal cord segments. The results suggest that the proximodistal pattern in the intensity of perceived pain and CHEP amplitudes is likely attributable to the distribution of heat nociceptors and the increase in conduction distance from proximal to distal dermatomes. The present findings emphasize on the importance that if patients are assessed segment by segment, the underlying topographical differences need to be accounted for.
    Journal of clinical neurophysiology: official publication of the American Electroencephalographic Society 06/2013; 30(3):291-8. · 1.47 Impact Factor
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    ABSTRACT: Imaging studies have identified a wide network of brain areas activated by nociceptive stimuli and revealed differences in somatotopic representation of highly distinct stimulation sites (foot vs. hand) in the primary (S1) and secondary (S2) somatosensory cortices. Somatotopic organization between adjacent dermatomes and differences in cortical coding of similarly perceived nociceptive stimulation are less well studied. Here, cortical processing following contact heat nociceptive stimulation of cervical (C4, C6, and C8) and trunk (T10) dermatomes were recorded in 20 healthy subjects using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Stimulation of T10 compared with the C6 and C8 revealed significant higher response intensity in the left S1 (contralateral) and the right S2 (ipsilateral) even when the perceived pain was equal between stimulation sites. Accordingly, contact heat evoked potentials following stimulation of T10 showed significantly higher N2P2 amplitudes compared to C6 and C8. Adjacent dermatomes did not reveal a distinct somatotopical representation. Within the assessed cervical and trunk dermatomes, nociceptive cortical processing to heat differs significantly in magnitude even when controlling for pain perception. This study provides evidence that controlling for pain perception is not sufficient to compare directly the magnitude of cortical processing [blood oxygen level dependence (BOLD) response and amplitude of evoked potentials] between body sites. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
    Human Brain Mapping 03/2013; · 6.92 Impact Factor
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    ABSTRACT: Following nociceptive heat or laser stimulation, an early contralateral and later vertex potential can be recorded. Although more indicative of the nociceptive input, the acquisition of the contralateral N1 after contact heat stimulation (contact heat-evoked potentials [CHEPs]) remains difficult. An advantage of contact heat is that the baseline skin temperature preceding peak stimulation can be controlled. Increasing the baseline temperature may represent a novel strategy to improve the acquisition of CHEPs without resulting in more subjective pain to stimulation. A study was undertaken in 23 healthy subjects to examine the effects of increasing the baseline temperature but not the perceived intensity of contact heat stimulation. A combined standard averaging and single-trial analysis was performed to disclose how changes in averaged waveforms related to latency jitter and individual trial amplitudes. By increasing the baseline temperature, the acquisition of N1 was improved among subjects with a low-amplitude response (greater than -4μV) following 35°C baseline temperature stimulation (P<.05). Based on standard averaging, N2/P2 amplitudes were also significantly increased with and without an accompanying change in the rating of perceived pain when the baseline temperature was increased (P<.05). In contrast, automated single-trial averaging revealed no significant difference in N2 amplitude when the baseline temperature was increased to 42°C and the peak temperature reduced. These findings suggest that 2 mechanisms underlie the improved acquisition of CHEPs: increased synchronization of afferent volley, yielding larger-amplitude evoked potentials in response to the same rating of intensity; and reduced inter-trial variability.
    Pain 11/2012; · 5.64 Impact Factor
  • Journal of Neuroscience 09/2012; 32(38):12981-2. · 6.75 Impact Factor
  • John L K Kramer, Armin Curt
    Brain 09/2012; · 10.23 Impact Factor
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    ABSTRACT: For therapeutics directed to the injured spinal cord, a change in neurological impairment has been proposed as a relevant acute clinical study end point. However, changes in neurological function, even if statistically significant, may not be associated with a functional impact, such as a meaningful improvement in items within the self-care subscore of the Spinal Cord Independence Measure (SCIM). The authors examined the functional significance associated with spontaneously recovering upper-extremity motor function after sensorimotor-complete cervical spinal cord injury (SCI). Using the European Multi-center Study about Spinal Cord Injury (EMSCI) data set, a retrospective analysis was undertaken of individuals with cervical sensorimotor-complete SCI (initial motor level, C4-C7). Specifically, changes in upper-extremity motor score (UEMS), motor level, and SCIM (total and self-care subscore) were assessed between approximately 1 and 48 weeks after injury (n = 74). The initial motor level did not significantly influence the total UEMS recovered or number of motor levels recovered. SCIM self-care subscore recovery was significantly greater for those individuals regaining 2 motor levels compared with those recovering only 1 or no motor levels. However, the recovery in the SCIM self-care subscore was not significantly different between individuals recovering only 1 motor level and those individuals who showed no motor-level improvement. A 2 motor-level improvement indicates a clinically meaningful change and might be considered a primary outcome in acute and subacute interventional trials enrolling individuals with cervical sensorimotor-complete SCI.
    Neurorehabilitation and neural repair 05/2012; 26(9):1064-71. · 4.62 Impact Factor
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    ABSTRACT: Sensory and/or motor function sparing, including the S4-S5 spinal cord segment, is central to classifying neurologic impairment after spinal cord injury (SCI) using the American Spinal Injury Association Impairment Scale (AIS) grades within the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). Within the ISNCSCI protocol, which is essential for both clinical and research purposes, assessing sacral sparing requires an anorectal and S4-S5 examination. However, in situations where these data are incomplete, the relationships between anorectal/S4-S5 examinations and functional preservation at more rostral sacral segments may be useful. To evaluate whether slightly more rostral sensory and motor outcomes of the ISNCSCI can accurately predict caudal sacral sparing (S4-S5 dermatome sensation, "deep pressure" anal sensation [AS], and voluntary anal contraction [AC]). Retrospective analysis of the European Multicenter Study about Spinal Cord Injury database. One thousand four hundred sixty-seven AIS-A, AIS-B, and AIS-C subjects. International Standards for Neurological Classification of Spinal Cord Injury examinations. The value of six factors (sensory preservation at S1, S2, and S3; motor preservation at S1; motor function at more than three segments below the motor level; and sensory function at more than three segments below the neurologic level) for predicting ISNCSCI sacral sparing measures (AS, S4-S5 dermatome sensation, AC) was evaluated. Combinations of the most promising factors were then evaluated for their ability to accurately predict the AIS grade. Preserved sensation at the first sacral segment (S1S) provided good prediction (90.5%) of caudal sacral sensory sparing (ie, AS or S4-S5 sensation). Voluntary anal contraction was accurately predicted by preserved motor function within the first sacral segment (S1M) in 85.4% of cases. The alternate classification schemes evaluated for accurately predicting the AIS classification grade were S1S+S1M and S1S+motor preservation more than three segments below the motor level. The ability of these schemes to accurately predict AIS grades was stable over time but varied with the rostrocaudal level of spinal injury. For the initial baseline examination, the alternate classification schemes were accurate in ~95% of cases for T2-T9 SCI, with slightly lower accuracy for cervical SCI (~80%). There are close relationships between functional sparing at different sacral segments. These relationships can be used to estimate AIS grades when complete information about the anorectal and S4-S5 examination is not available. The accuracy of the classification remains stable over time, while the increased variability in lower levels of SCI, that is, lumbar injuries, emphasizes the importance of careful sacral examinations. The highly reliable predictive values of S1-S3 segments can complement conclusions from anorectal examinations if the latter are considered to be confounded or incomplete.
    The spine journal: official journal of the North American Spine Society 05/2012; 12(5):389-400.e3. · 2.90 Impact Factor
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    ABSTRACT: The purpose of this study was to investigate the test-retest reliability of contact heat-evoked potentials (CHEPs) in neurologically healthy subjects from cervical dermatomes (C4-C8). Seventeen individuals underwent test-retest examination of cervical CHEPs. Peak latencies and peak-to-peak amplitude of N2-P2 and ratings of perceived intensity were analyzed using test-retest reliability statistics (intraclass correlation coefficients [ICCs] and Bland-Altman confidence parameters). For comparison, a group of similar age and gender was also examined with dermatomal somatosensory-evoked potentials (dSSEPs, n = 17). The ICC values for CHEP latency and amplitude parameters were significant (P < 0.05) and corresponded to at least "fair" reliability, while peak-to-peak amplitude demonstrated "substantial" (≥0.81) reliability for all dermatomes. The coefficients of repeatability (i.e., 2SD of the difference between examinations) confirm that CHEPs and dSSEPs are reliable according to measures of latency. Superior peak-to-peak amplitude test-retest reliability was found for CHEPs. In conclusion, the test-retest reliability of dSSEP and CHEP parameters supports the fact that these outcomes can be used to objectively track changes in spinal conduction in the dorsal column and spinothalamic tract, respectively. The reliable acquisition of CHEPs may depend on the intensity of the sensation reported by the subject for a given area of skin stimulated.
    Journal of clinical neurophysiology: official publication of the American Electroencephalographic Society 02/2012; 29(1):70-5. · 1.47 Impact Factor
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    ABSTRACT: Effective treatment after cervical spinal cord injury (SCI) is imperative as so many activities of daily living (ADLs) are dependent on functional recovery of arm and hand actions. We focus on defining and comparing neurological and functional endpoints that might be used during acute or subacute Phase 2 clinical trials involving subjects with cervical sensorimotor complete SCI (ASIA Impairment Scale [AIS-A]). For the purposes of this review, the trial would examine the effects of a pharmaceutical small molecule, drug, biologic, or cell transplant on spinal tissue. Thus, neurological improvement is the intended consequence and is most directly measured by assessing neurological impairment (eg, motor aspects of the International Standards Neurological Classification of Spinal Cord Injury [ISNCSCI]). However, changes in neurological function, even if statistically significant, may not be associated with a clear functional impact (ie, a meaningful improvement in individual activity, such as independent self-care ADLs). The challenge is to measure improvement as precisely as possible (change in impairment), but to define a clinically meaningful response in the context of functional improvement (impact on activity limitations). The principal comparisons focused on elements of the ISNCSCI assessment, including upper extremity motor score and motor level. Personal activity capabilities were also examined at various time points. The data suggest that an improvement of 2 or more motor levels after cervical sensorimotor complete SCI may be a clinically meaningful endpoint threshold that could be used for acute and subacute Phase 2 trials with subjects having sensorimotor complete cervical SCI.
    Topics in Spinal Cord Injury Rehabilitation 01/2012; 18(1):1-14.
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    John D Steeves, John L K Kramer, Jose Zariffa
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    ABSTRACT: The principles of spinal cord injury clinical trial programs are briefly reviewed as one example of the challenge faced by most human studies of neurologically directed therapeutic interventions, including rehabilitation strategies. Different trial protocols are reviewed, as are inclusion/exclusion criteria for study subjects, the choice of clinical endpoints, and the statistical approaches that might be used in a trial program. Potential factors that might confound the accurate interpretation of trial data are also identified. Regardless of the specific therapeutic target or the rehabilitation strategy to be evaluated, there are many unresolved issues that will have to be answered before specific and effective prescriptions can be delivered.
    Topics in Spinal Cord Injury Rehabilitation 01/2012; 18(1):79-84.
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    ABSTRACT: Upper limb robotic rehabilitation devices can collect quantitative data about the user's movements. Identifying relationships between robotic sensor data and manual clinical assessment scores would enable more precise tracking of the time course of recovery after injury and reduce the need for time-consuming manual assessments by skilled personnel. This study used measurements from robotic rehabilitation sessions to predict clinical scores in a traumatic cervical spinal cord injury (SCI) population. A retrospective analysis was conducted on data collected from subjects using the Armeo Spring (Hocoma, AG) in three rehabilitation centers. Fourteen predictive variables were explored, relating to range-of-motion, movement smoothness, and grip ability. Regression models using up to four predictors were developed to describe the following clinical scores: the GRASSP (consisting of four sub-scores), the ARAT, and the SCIM. The resulting adjusted R(2) value was highest for the GRASSP "Quantitative Prehension" component (0.78), and lowest for the GRASSP "Sensibility" component (0.54). In contrast to comparable studies in stroke survivors, movement smoothness was least beneficial for predicting clinical scores in SCI. Prediction of upper-limb clinical scores in SCI is feasible using measurements from a robotic rehabilitation device, without the need for dedicated assessment procedures.
    IEEE transactions on neural systems and rehabilitation engineering: a publication of the IEEE Engineering in Medicine and Biology Society 12/2011; 20(3):341-50. · 2.42 Impact Factor
  • J. Steeves, J. Kramer, J. Zariffa
    Annals of Physical and Rehabilitation Medicine 10/2011; 54.
  • J L K Kramer, J Haefeli, A Curt, J D Steeves
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    ABSTRACT: To investigate the effect of increasing the skin surface baseline temperature for contact heat evoked potentials (CHEPs). CHEPs were studied in healthy subjects and subjects with chronic cervical spinal cord injury (SCI) using a conventional 35°C (condition 1) or increased 42-45°C baseline temperature (condition 2). A third condition was used to standardize the contact heat stimulus duration from the different baseline temperatures. Changes in peak latency and N2P2 amplitude of the CHEPs and rating of perceived intensity were examined between conditions. In healthy subjects, increasing the baseline temperature for contact heat stimulation significantly increased the rating of perceived intensity (conditions 2 and 3), as well as the amplitude of CHEPs (condition 2 only). Following SCI, an increased baseline temperature facilitated perception of contact heat stimulation and evoked potentials could be recorded from dermatomes that were insensitive to contact heat from a conventional baseline temperature. Enhancing the acquisition of CHEPs can be achieved by increasing the baseline temperature. This effect can be attributed, in part, to shortening the stimulation duration. After SCI, increasing the baseline temperature for CHEPs in dermatomes with absent or diminished sensation improved the neurophysiological resolution of afferent sparing.
    Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 09/2011; 123(3):582-9. · 3.12 Impact Factor
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    ABSTRACT: Multi-center pilot study. To investigate the use of an upper limb robotic rehabilitation device (Armeo Spring, Hocoma AG, Switzerland) in a subacute cervical spinal cord injury (SCI) population. Two Canadian inpatient rehabilitation centers. Twelve subjects (motor level C4-C6, ASIA Impairment Scale A-D) completed the training, which consisted of 16.1±4.6 sessions over 5.2±1.4 weeks. Two types of outcomes were recorded: (1) feasibility of incorporating the device into an inpatient rehabilitation program (compliance with training schedule, reduction in therapist time required and subject questionnaires) and (2) efficacy of the robotic rehabilitation for improving functional outcomes (Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP), action research arm test, grip dynamometry and range of motion). By the end of the training period, the robot-assisted training was shown to require active therapist involvement for 25±11% (mean±s.d.) of the total session time. In the group of all subjects and in a subgroup composed of motor-incomplete subjects, no statistically significant differences were found between intervention and control limbs for any of the outcome measures. In a subgroup of subjects with partial hand function at baseline, the GRASSP-Sensibility component showed a statistically significant increase (6.0±1.6 (mean±s.e.m.) point increase between baseline and discharge for the intervention limbs versus 1.9±0.9 points for the control limbs). The pilot results suggest that individuals with some preserved hand function after SCI may be better candidates for rehabilitation training using the Armeo Spring device.
    Spinal Cord 09/2011; 50(3):220-6. · 1.70 Impact Factor
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    John D Steeves, Jose Zariffa, John L K Kramer
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    ABSTRACT: In this review, several aspects surrounding the choice of a therapeutic intervention and the conduct of clinical trials are discussed. Some of the background for why human studies have evolved to their current state is also included. Specifically, the following questions have been addressed: 1) What criteria should be used to determine whether a scientific discovery or invention is worthy of translation to human application? 2) What recent scientific advance warrants a deeper understanding of clinical trials by everyone? 3) What are the different types and phases of a clinical trial? 4) What characteristics of a human disorder should be noted, tracked, or stratified for a clinical trial and what inclusion /exclusion criteria are important to enrolling appropriate trial subjects? 5) What are the different study designs that can be used in a clinical trial program? 6) What confounding factors can alter the accurate interpretation of clinical trial outcomes? 7) What are the success rates of clinical trials and what can we learn from previous clinical trials? 8) What are the essential principles for the conduct of valid clinical trials?
    Yonsei medical journal 09/2011; 52(5):701-16. · 0.77 Impact Factor
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    ABSTRACT: Robotic rehabilitation devices have been suggested as a tool to increase the amount of rehabilitation delivered after a neurological injury. Clinical robotic rehabilitation studies of the upper extremity have generally focused on stroke survivors. We present the results of a multi-center pilot study where an upper-limb robotic rehabilitation device (Armeo Spring®, Hocoma AG) was incorporated into the rehabilitation program of 12 subjects with sub-acute cervical spinal cord injury (motor level C4-C6, AIS A-D). Outcomes were measured using two tests of upper extremity function: ARAT and GRASSP. The change in scores for the arm receiving the Armeo training were not statistically significant when compared to the arm not receiving the Armeo training at discharge from therapy and over follow up assessments (8.7 +/- 2.9 compared to 7.4 +/- 2.5 for ARAT at discharge, p = 0.98, and 13.0 +/- 3.2 compared to 13.3 +/- 3.3 for GRASSP at discharge, p = 0.69). Nevertheless, subjects with some minimal (partial) hand function at baseline had a significantly larger increase in GRASSP scores than subjects with no minimal hand function preserved at baseline (19.3 +/- 2.4 compared to 6.6 +/- 4.7, p = 0.02). This suggests that the initial functional capabilities of patients can influence the benefits measured after robotic rehabilitation training and heterogeneous subject populations should be avoided in early phase studies.
    IEEE ... International Conference on Rehabilitation Robotics : [proceedings]. 06/2011; 2011:5975400.

Publication Stats

155 Citations
72.13 Total Impact Points


  • 2012–2014
    • University of Zurich
      • Balgrist Spinal Cord Injury Center - SCI
      Zürich, Zurich, Switzerland
  • 2011–2012
    • Vancouver General Hospital
      • International Collaboration on Repair Discoveries Research Centre [ICORD]
      Vancouver, British Columbia, Canada
    • University of Toronto
      Toronto, Ontario, Canada
  • 2009–2012
    • University of British Columbia - Vancouver
      • International Collaboration on Repair Discoveries (ICORD)
      Vancouver, British Columbia, Canada