The main finding from this study is that the extent of injury to specific motor tracts is useful for predicting behavioral gains from therapy in subjects with chronic stroke. Tract-specific injury was stronger than infarct volume or baseline behavioral status at predicting gains; note that baseline behavioral status is often an entry criterion in stroke trials, suggesting that measures of tract injury could be useful to some clinical trials, such as for patient stratification. Tract-specific injury is a relatively simple measure to determine, and is useful to identify subjects who have sufficient biological substrate to improve from therapy.
The current results suggest that the tracts studied are important resources for deriving treatment-induced behavioral gains. The findings emphasize the value of white matter survival for achieving such gains, and so complement prior studies that focused on the role of gray matter structures to treatment-induced motor gains after stroke5, 15, 16
. Tract-specific injury performed better than infarct volume did at predicting treatment gains, underscoring the importance of lesion location as a determinant of rehabilitation therapy effects. Tract-specific injury also predicted gains better than baseline behavior predicted gains did. A given behavioral phenotype can arise from many different brain states, but only some of these are likely to improve with therapy. The current study suggests that measures of tract-specific injury are useful for identifying treatment responders, beyond that provided by baseline behavior, and so might be useful for patient selection in clinical trials.
The current results are in general agreement with a prior study that found tract-specific injury to be a useful predictor of treatment gains17
. In that study, Stinear et al17
found best prediction by measuring a combination of white matter integrity via DTI and neurophysiology via transcranial magnetic stimulation. Such multimodal assessment allows for more detailed classification of tract injury. However, the current approach also has its advantages, including assessment of injury to several specific tracts and simplicity of data analysis methodology. A prior study18
that used the tract/injury overlap approach to study gait found a limited relationship between tract injury and therapy-related gains. The reason for this disparity with current results might reflect fundamental differences in cerebral organization between hand movements () and gait18
, or that these authors examined corticospinal tract with only zero subdivisions, which was found to perform less well than with the current approach of using 16 subdivisions (Table 4, Supplement
The constellation of findings () provides some insight into the relative contributions that the four motor tracts make to motor gains during post-stroke motor therapy. Injury to the tract descending from PMv predicted treatment gains less often than injury to the other descending tracts did, suggesting a smaller role of this tract in supporting gains from a robotic therapy targeting the distal arm. Injury to the tracts descending from M1 and from PMd each had approximately equal predictive power, which was of some surprise given the predominance of M1 in issuing pyramidal and corticospinal fibers, though possibly related to the fact that the majority of fibers overlapped between these two tracts (). Together, the results do suggest that all four tracts play a role in mediating gains from motor therapy in chronic stroke, though their inter-relationships makes challenging a precise estimate of each tract’s role. The reason for the incomplete concordance of findings across the three behavioral scales, in particular the lack of prediction of ARAT score gains, is unclear but might reflect differences in extent to which content of each scale corresponded to content of the therapy. Further insight might be gained in future studies that use of assessments more aligned with the specific behaviors supported by each motor area, such as assessment of internal movement triggering for SMA and of external movement triggering for PMd19
The current analysis did not find a threshold whereby a certain level of tract injury was clearly associated with total loss of distal arm motor function at baseline, or with inability to derive gains from therapy. For example, some subjects with >90% tract injury had good baseline function and good treatment gains, whereas some had poor baseline function/gains (). This current finding regarding white matter tract injury
contrasts with a prior study that examined motor cortex injury
, which did find such a threshold; in that study, injury to >37% of the hand motor map was associated with total loss of hand motor function20
. With severe injury to motor cortex, recovery does not occur, but with severe injury to the white matter tract descending from motor cortex, recovery occurs in some patients. Together, these findings suggest that behavioral effects of large white matter injuries might be reduced by forms of plasticity that are not possible with large cortical injuries.
Strengths of the study included that the findings were robust across varied methodological assumptions such as the threshold used to define injury. All infarcts were in left brain, eliminating variance due to stroke side. There were also limits with the current approach. Clearly, numerous factors besides tract injury, such as injury to other brain structures21
, extent to which brain plasticity is exhausted at baseline22
, or psychosocial factors23
, influence behavioral response to therapy. The stroke masks obtained in the current chronic stroke cohort do not likely reflect the full nature of the acute injury; using the tract/injury overlap approach in the acute phase of stroke might find stronger relationships. The focus on left hemisphere injury does not provide specific information on right brain injury. The reason that the tract descending from M1 had lower volume than the tracts descending from PMd or SMA, despite contributing a larger proportion of axons to the corticospinal tract7
, is unclear but might reflect tract fiber density or topography6, 24
, or perhaps DTI-specific issues such as coherence. Finally, while measures of tract-specific injury correlated with change in behavior across therapy, these measures of injury showed a limited relationship with baseline behavior, in contrast to prior studies25-27
. This is likely due to the pattern of deficits among enrollees--those with moderate-severe tract injury in the current study had a bimodal distribution, with some having mild-moderate and some having severe behavioral deficits (), and so the strength of the behavior/injury correlation varies with enrollee characteristics.
Many therapies are emerging that aim to improve motor function in people with stroke. Measuring the key biological substrate needed to achieve treatment gains will be useful to best match therapies with the right patients. The current report provides a robust and relatively simple method for measuring extent of injury to specific motor tracts, reinforces the importance of lesion location in stroke, and emphasizes the greater predictive value of tract-specific measures as compared to global measures of injury such as infarct volume.