Indirect Structural Connectivity As a Biomarker for Stroke Motor Recovery

In this dissertation project, we demonstrated that diffusion magnetic resonance imaging and measures of indirect structural brain connectivity are sensitive to changes in fiber integrity and connectivity to remote regions in the brain after stroke. Our results revealed new insights into the effects local lesions have on global connectivity—in particular, the cerebellum—and how these changes in connectivity and integrity relate to motor impairment. We tested this methodology on two stroke groups—subacute and chronic—and were able to show that indirect connectivity is sensitive to differences in connectivity during stroke recovery. Our work can inform clinical methods for rehabilitating motor function in stroke individuals. By introducing methodology that extends local damage to remotely connected motor related areas, we can measure Wallerian degeneration in addition to providing the framework to predict improvements in motor impairment score based on structural connectivity at the subacute stage.We used diffusion magnetic resonance imaging (dMRI), probabilistic tractography, and novel graph theory metrics to quantify structural connectivity and integrity after stroke. In the first aim, we improved on a measure of indirect structural connectivity in order to detect remote gray matter regions with reduced connectivity after stroke. In a region-level analysis, we found that indirect connectivity was more sensitive to remote changes in connectivity after stroke than measures of direct connectivity, in particular in cortical, subcortical, and cerebellar gray matter regions that play a central role in sensorimotor function. Adding this information to the integrity of the corticospinal tract (CST) improved our ability to predict motor impairment. In the second aim, we investigated the relationship between white matter integrity, connectivity, and motor impairment by developing a unified measure of white matter structure that extends local changes in white matter integrity along remotely connected fiber tracks. Our measure uniquely identified damaged fiber tracks outside the CST, correlated with motor impairment in the CST better than the FA, and also was able to relate white matter structure in the superior cerebellar peduncle to motor impairment. Our final aim used a novel connectome similarity metric and the measure of indirect structural connectivity in order to identify cross-sectional differences in white matter structure between subacute and chronic stroke. We found more reductions in indirect connectivity in the chronic stroke cerebellar fibers than the subacute group, Additionally, the indirect connectivity of the superior cerebellar peduncle at the subacute stage correlated with the improvement in motor impairment score for the paired participants. In conclusion, indirect connectivity is an important measure of global brain damage and motor impairment after stroke, and can be a useful metric to relate to brain function and stroke recovery

Rehabilitation Outcome Following Acute Stroke: Considering Ideomotor Apraxia

Stroke is a leading cause of death and the leading cause of adult disability in the United States affecting approximately 795,000 people yearly. Stroke sequelae often span multiple domains, including motor, cognitive, and sensory subsystems. Impairments can contribute to difficulty participating in activities of daily living (ADLs) and translate into disability - a concern for patients and occupational therapists alike. The role of ideomotor apraxia (IMA) in stroke rehabilitation is unclear. Thus, the purpose of these two studies is to investigate stroke rehabilitation outcome while considering the presence of ideomotor apraxia. Stroke causes dysfunctional movement patterns arising from an array of potential etiologies. Agreement exists that understanding the patient's functioning serves as the basis for the rehabilitation process and it is insufficient for clinicians simply to determine functional movement problems without knowing how underlying impairments contribute. Stroke-induced paresis is a prevalent impairment and frequent target of traditional rehabilitation. Stroke rehabilitation often addresses paresis narrowly with little consideration for other stroke consequences. Ideomotor apraxia is one such disorder after stroke that could conceivably limit rehabilitation benefit of otherwise efficacious treatment interventions aimed at remediating paresis. This led us to an initial study of a subject who experienced a single left, ischemic stroke with paresis of his right upper extremity and comorbid ideomotor apraxia. The subject participated in combined physical and mental practice for six consecutive weeks to improve use of his right arm. After intervention, the subject demonstrated clinically significant improvements in functional performance of his more-affected right upper extremity and reported greater self-perception of performance. The subject continued to demonstrate improvements after four weeks with no intervention and despite persistent IMA. This single case report highlights the importance of recognizing that ideomotor apraxia does present after stroke, and traditional stroke rehabilitation efforts directed at paresis can be efficacious for subjects with IMA. Traditional beliefs suggested that ideomotor apraxia does not translate to disability in everyday life and that IMA resolves spontaneously. Despite accumulating evidence of the influence of IMA on functional ability, this topic remains relatively neglected. It is unclear how ideomotor apraxia affects the rehabilitation process. The second study reports rehabilitation outcomes of a group of subjects following acute stroke. The Florida Apraxia Battery gesture-to-verbal command test was used to detect IMA in subjects. Level of independence with a set of ADLs and motor impairment of the more-affected upper extremity was documented at admission and discharge. Study subjects participated in standard of care stroke rehabilitation in the inpatient rehabilitation units. A total of fifteen subjects who sustained a left hemisphere stroke participated in this study - ten with IMA and five without IMA. After rehabilitation, subjects with IMA improved ADL independence and displayed decreased motor impairment of their right upper extremity. Subjects with and without IMA exhibited comparable improvements in ADL independence, but subjects with IMA exhibited less ADL independence upon when compared to subjects without IMA. Additional findings suggested that subjects with IMA were not different with respect to motor impairments and length of stay; however, additional studies with larger sample sizes are needed. In summary, these two studies aid to elucidate the implications of ideomotor apraxia on traditional stroke rehabilitation efforts. Study subjects with ideomotor apraxia after acute stroke still derive benefit from traditional rehabilitation. Because traditional rehabilitation interventions narrowly target motor impairment, these findings support the need for considering IMA as a factor in developing interventions tailored to patients with IMA and possibly as a specific focus for interventions. A step toward addressing this need is to assess whether IMA is present after stroke on a regular basis. This work provides a framework for researchers and clinicians to investigate further how ideomotor apraxia translates into disability. These findings are important since consideration of ideomotor apraxia could influence selection and design of rehabilitation interventions to optimize patient daily functioning after stroke

Clinical Effects and Differences in Neural Function Connectivity Revealed by MRI in Subacute Hemispheric and Brainstem Infarction Patients With Dysphagia After Swallowing Therapy

Background: Early detection and intervention for post-stroke dysphagia could reduce the incidence of pulmonary complications and mortality. The aims of this study were to investigate the benefits of swallowing therapy in swallowing function and brain neuro-plasticity and to explore the relationship between swallowing function recovery and neuroplasticity after swallowing therapy in cerebral and brainstem stroke patients with dysphagia.Methods: We collected 17 subacute stroke patients with dysphagia (11 cerebral stroke patients with a median age of 76 years and 6 brainstem stroke patients with a median age of 70 years). Each patient received swallowing therapies during hospitalization. For each patient, functional oral intake scale (FOIS), functional dysphagia scale (FDS) and 8-point penetration-aspiration scale (PAS) in videofluoroscopy swallowing study (VFSS), and brain functional magnetic resonance imaging (fMRI) were evaluated before and after treatment.Results: FOIS (p = 0.003 in hemispheric group and p = 0.039 in brainstem group) and FDS (p = 0.006 in hemispheric group and p = 0.028 in brainstem group) were both significantly improved after treatment in hemispheric and brainstem stroke patients. In hemispheric stroke patients, changes in FOIS were related to changes of functional brain connectivity in the ventral default mode network (vDMN) of the precuneus in brain functional MRI (fMRI). In brainstem stroke patients, changes in FOIS were related to changes of functional brain connectivity in the left sensorimotor network (LSMN) of the left postcentral region characterized by brain fMRI.Conclusion: Both hemispheric and brainstem stroke patients with different swallowing difficulties showed improvements after swallowing training. For these two dysphagic stroke groups with corresponding etiologies, swallowing therapy could contribute to different functional neuroplasticity

DYNAMICS OF FUNCTIONAL CONNECTIVITY WITHIN CORTICAL MOTOR NETWORK DURING MOTOR LEARNING IN STROKE - CORRELATIONS WITH "TRUE" MOTOR RECOVERY

Arm motor recovery after stroke is usually incomplete; six months after onset about two-thirds of patients suffer from arm motor impairment that significantly impacts the individual's activities of daily living. Thus, novel concepts beyond current strategies for arm motor rehabilitation after stroke are needed. An essential approach for this is to better understand whether motor learning-related neural changes in stroke are similar with those in healthy controls and how these neural changes relate to recovery of the pre-morbid movement pattern or "true" recovery. Abnormal task-related activation in primary and non-primary motor cortices has been a consistent finding in functional MRI studies of stroke. Disturbed functional network architecture, e.g., the influence that one motor area exerts over another, also impacts stroke recovery. The outcome measures chosen to evaluate recovery are also important for the interpretation of these brain changes. Thus, the long-range goal of this work was to longitudinally investigate the changes in cortical motor function at two levels, regional (micro-circuitry, regional activation) and network (macro-circuitry, functional connectivity), following an arm-focused motor training in chronic stroke survivors and how these brain changes relate to recovery of the pre-morbid movement pattern or "true" recovery. In the Chapter I, we reviewed the literature concerning the pathophysiology of stroke, neural substrates of motor control, and motor learning principles and neural substrates in healthy and pathological (stroke) brain. In the Chapter II, we examined the relationships between task-related motor activation and clinical and kinematic metrics of arm motor impairment in survivors of subcortical stroke. We found evidence that primary motor activation was significantly correlated to kinematic metrics of arm motor impairment, but not with clinical metrics. In the Chapter III, we longitudinally investigated the regional changes in motor-related activation (functional MRI) in primary and non-primary motor areas following an arm-focused motor training in stroke survivors and age-sex matched healthy controls. We demonstrated that similar changes in the motor areas contralateral to the trained arm were found with training in both stroke and healthy participants. We also demonstrated a significant increase in motor performance in both groups as well as a normalization of the correlations between bilateral motor activation and movement kinematics in participants with stroke. In the Chapter IV, we also investigated the changes in functional connectivity between primary and non-primary motor areas following an arm-focused motor training and how these changes correlate with "true" motor recovery. We demonstrated significant enhanced functional connectivity in motor areas contralateral to the trained hand (or ipsilesional), although no "normalization" of the inter-hemispheric inhibition following training in our survivors. We also showed a "normalization" of the relationships between cortical motor functional connectivity and movement kinematics. In the Chapter V, we concluded that the present dissertation work support the hypotheses that motor system is plastic at different levels, regional and network, even in the chronic stage of stroke and some of these changes are similar with those reported in healthy controls. Further, these changes provide a substrate for "true" recovery. These findings promote the use of neuroimaging and kinematic metrics to improve our understanding of the neural substrates underlying reorganization in remaining intact brain structures after stroke. Such an approach may further enable monitoring recovery or compensation based on this reorganization and evaluating new treatment regimes that assist motor recovery

The role of white matter disconnection in stroke as a predictor of clinical outcome after mechanical thrombectomy.

Rationale: Mechanical thrombectomy is a promising approach to acute treatment in large vessel occlusion (LVO) ischemic stroke. This technique has shown to be safe and effective when performed both in early and late-window trials. Several clinical and mainly volumetric, radiological features are used as prognostic factors for functional outcome and patient eligibility. However, emerging evidence supports the idea that lesion topography is strongly associated with prognosis and functional brain recovery. The aim of this study is to examine the role of clinical (i.e. mRS and NIHSS) vs. standard volume-based lesion (i.e. ASPECTS, core, penumbra and final lesion volume) vs. topological radiological (i.e. white matter structural disconnection) features, in patients eligible for acute mechanical thrombectomy. Materials and methods: We selected a group of patients (n=50) who underwent acute mechanical thrombectomy over 47 months, from January 2018 to November 2021, and occurred at the Stroke Unit and Clinica Neurologica of the Hospital of Padova. They were studied with the modified Rankin Scale (mRS) and the National Institutes of Health Stroke Scale (NIHSS) both at admission (pre) and at discharge (post), then, again with the mRS at 90 days from the acute event. The lesions were manually segmented on structural MRI and CT scans using the program ITK-SNAP. Four models were performed through a linear regression analysis. Specifically, we computed a baseline clinical model (M1) based on demographics, pre-stroke mRS and admission NIHSS. Then we added commonly used (standard) radiological parameters of lesion or perfusion damage (core, penumbra, ASPECTS) (M2). Therefore, we added information about the white matter structural disconnection to clinical variables (M3). Finally, we tested a baseline clinical +early recovery model (M4), which included age, pre-mRS, admission NIHSS, and post-mRS. The lesions were normalized in atlas space and displayed to study their distribution and structural disconnections (SDC). Results: The mean baseline mRS was 0.48±0.90, while the mean 90-day mRS was 2.18±1.81. The linear regression analysis showed a significant positive correlation between 90-day mRS and clinical variables (pre-mRS, NIHSS at presentation, post-mRS), while radiological variables (ASPECTS, core, and penumbra volume) did not seem to be associated with functional outcome. The results of the ANOVA analysis showed that, between the four models tested, M4 (including age, pre-mRS, NIHSS at presentation, and post-mRS as independent variables) was the one providing the highest adjusted R-squared [Adj.R-squared=0.614] and explained 62% of the variance in outcome prediction. At a voxel-wise level, we found a significant positive correlation between brain recovery (Delta 90-day mRS-pre-mRS) and damage, affecting predominantly the left corticospinal tract and the corresponding structural white matter disconnection (SDC), which also extended to the cingulum and, bilaterally, to the callosal commissure. Conclusion: In our sample, acute clinical status represents the most valuable prognostic factor. Interestingly, while radiological (i.e. volumetric and semi-quantitative) features, such as ASPECTS, core, and penumbra volume, did not show any significant correlation with 90-day mRS, structural white matter disconnection and lesion topography, in particular of the left corticospinal tract, were associated with a poorer recovery after endovascular treatment. These results could have important future implications in pre-treatment patients’ selection and in post-treatment post stroke rehabilitation.​Rationale: Mechanical thrombectomy is a promising approach to acute treatment in large vessel occlusion (LVO) ischemic stroke. This technique has shown to be safe and effective when performed both in early and late-window trials. Several clinical and mainly volumetric, radiological features are used as prognostic factors for functional outcome and patient eligibility. However, emerging evidence supports the idea that lesion topography is strongly associated with prognosis and functional brain recovery. The aim of this study is to examine the role of clinical (i.e. mRS and NIHSS) vs. standard volume-based lesion (i.e. ASPECTS, core, penumbra and final lesion volume) vs. topological radiological (i.e. white matter structural disconnection) features, in patients eligible for acute mechanical thrombectomy. Materials and methods: We selected a group of patients (n=50) who underwent acute mechanical thrombectomy over 47 months, from January 2018 to November 2021, and occurred at the Stroke Unit and Clinica Neurologica of the Hospital of Padova. They were studied with the modified Rankin Scale (mRS) and the National Institutes of Health Stroke Scale (NIHSS) both at admission (pre) and at discharge (post), then, again with the mRS at 90 days from the acute event. The lesions were manually segmented on structural MRI and CT scans using the program ITK-SNAP. Four models were performed through a linear regression analysis. Specifically, we computed a baseline clinical model (M1) based on demographics, pre-stroke mRS and admission NIHSS. Then we added commonly used (standard) radiological parameters of lesion or perfusion damage (core, penumbra, ASPECTS) (M2). Therefore, we added information about the white matter structural disconnection to clinical variables (M3). Finally, we tested a baseline clinical +early recovery model (M4), which included age, pre-mRS, admission NIHSS, and post-mRS. The lesions were normalized in atlas space and displayed to study their distribution and structural disconnections (SDC). Results: The mean baseline mRS was 0.48±0.90, while the mean 90-day mRS was 2.18±1.81. The linear regression analysis showed a significant positive correlation between 90-day mRS and clinical variables (pre-mRS, NIHSS at presentation, post-mRS), while radiological variables (ASPECTS, core, and penumbra volume) did not seem to be associated with functional outcome. The results of the ANOVA analysis showed that, between the four models tested, M4 (including age, pre-mRS, NIHSS at presentation, and post-mRS as independent variables) was the one providing the highest adjusted R-squared [Adj.R-squared=0.614] and explained 62% of the variance in outcome prediction. At a voxel-wise level, we found a significant positive correlation between brain recovery (Delta 90-day mRS-pre-mRS) and damage, affecting predominantly the left corticospinal tract and the corresponding structural white matter disconnection (SDC), which also extended to the cingulum and, bilaterally, to the callosal commissure. Conclusion: In our sample, acute clinical status represents the most valuable prognostic factor. Interestingly, while radiological (i.e. volumetric and semi-quantitative) features, such as ASPECTS, core, and penumbra volume, did not show any significant correlation with 90-day mRS, structural white matter disconnection and lesion topography, in particular of the left corticospinal tract, were associated with a poorer recovery after endovascular treatment. These results could have important future implications in pre-treatment patients’ selection and in post-treatment post stroke rehabilitation

Putting the “Sensory” Into Sensorimotor Control: The Role of Sensorimotor Integration in Goal-Directed Hand Movements After Stroke

Integration of sensory and motor information is one-step, among others, that underlies the successful production of goal-directed hand movements necessary for interacting with our environment. Disruption of sensorimotor integration is prevalent in many neurologic disorders, including stroke. In most stroke survivors, persistent paresis of the hand reduces function and overall quality of life. Current rehabilitative methods are based on neuroplastic principles to promote motor learning that focuses on regaining motor function lost due to paresis, but the sensory contributions to motor control and learning are often overlooked and currently understudied. There is a need to evaluate and understand the contribution of both sensory and motor function in the rehabilitation of skilled hand movements after stroke. Here, we will highlight the importance of integration of sensory and motor information to produce skilled hand movements in healthy individuals and individuals after stroke. We will then discuss how compromised sensorimotor integration influences relearning of skilled hand movements after stroke. Finally, we will propose an approach to target sensorimotor integration through manipulation of sensory input and motor output that may have therapeutic implications

White Matter Integrity as a Biomarker for Stroke Recovery: Implications for TMS Treatment

White matter consists of myelinated axons which integrate information across remote brain regions. Following stroke white matter integrity is often compromised leading to functional impairment and disability. Despite its prevalence among stroke patients the role of white matter in development of post-stroke rehabilitation has been largely ignored. Rehabilitation interventions like repetitive transcranial magnetic stimulation (rTMS) are promising but reports on its efficacy have been conflicting. By understanding the role of white matter integrity in post-stroke motor recovery, brain reorganization and TMS efficacy we may be able to improve the development of future interventions. In this dissertation we set out answer these questions by investigating the relationship between white matter integrity and 1) bimanual motor performance following stroke, 2) cortical laterality following stroke and 3) TMS signal propagation (in a group of cocaine users without stroke). We identified white matter integrity of the corpus callosum as a key structure influencing bimanual performance using kinematic measures of hand symmetry (Chapter 2). Second, we found that reduced white matter integrity of corpus callosum was correlated with loss of functional laterality of the primary motor cortex during movement of the affected hand (Chapter 3). Lastly, we found that reduced white matter tract integrity from the site of stimulation to a downstream subcortical target, was correlated to the ability to modulate that target (Chapter 4). Taken together these studies support white matter integrity as a valuable biomarker for future rTMS trials in stroke. To emphasize the implications of these findings, we provide an example of how to incorporate white matter integrity at multiple levels of rTMS study design

Specific patterns of white matter alterations help distinguishing Alzheimer's and vascular dementia

Alzheimer disease (AD) and vascular dementia (VaD) together represent the majority of dementia cases. Since their neuropsychological profiles often overlap and white matter lesions are observed in elderly subjects including AD, differentiating between VaD and AD can be difficult. Characterization of these different forms of dementia would benefit by identification of quantitative imaging biomarkers specifically sensitive to AD or VaD. Parameters of microstructural abnormalities derived from diffusion tensor imaging (DTI) have been reported to be helpful in differentiating between dementias, but only few studies have used them to compare AD and VaD with a voxelwise approach. Therefore, in this study a whole brain statistical analysis was performed on DTI data of 93 subjects (31 AD, 27 VaD and 35 healthy controls - HC) to identify specific white matter patterns of alteration in patients affected by VaD and AD with respect to HC. Parahippocampal tracts were found to be mainly affected in AD, while VaD showed more spread white matter damages associated with thalamic radiations involvement. The genu of the corpus callosum was predominantly affected in VaD, while the splenium was predominantly affected in AD revealing the existence of specific patterns of alteration useful in distinguishing between VaD and AD. Therefore, DTI parameters of these regions could be informative to understand the pathogenesis and support the etiological diagnosis of dementia. Further studies on larger cohorts of subjects, characterized for brain amyloidosis, will allow to confirm and to integrate the present findings and, furthermore, to elucidate the mechanisms of mixed dementia. These steps will be essential to translate these advances to clinical practice