Value-Generating Exploratory Trials in Neurodegenerative Dementias.

Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.

Limited capacity for ipsilateral secondary motor areas to support hand function post-stroke.

KEY POINTS: Ipsilateral-projecting corticobulbar pathways, originating primarily from secondary motor areas, innervate the proximal and even distal portions, although they branch more extensively at the spinal cord. It is currently unclear to what extent these ipsilateral secondary motor areas and subsequent cortical projections may contribute to hand function following stroke-induced damage to one hemisphere. In the present study, we provide both structural and functional evidence indicating that individuals increasingly rely on ipsilateral secondary motor areas, although at the detriment of hand function. Increased activity in ipsilateral secondary motor areas was associated with increased involuntary coupling between shoulder abduction and finger flexion, most probably as a result of the low resolution of these pathways, making it increasingly difficult to open the hand. These findings suggest that, although ipsilateral secondary motor areas may support proximal movements, they do not have the capacity to support distal hand function, particularly for hand opening. ABSTRACT: Recent findings have shown connections of ipsilateral cortico-reticulospinal tract (CRST), predominantly originating from secondary motor areas to not only proximal, but also distal muscles of the arm. Following a unilateral stroke, CRST from the ipsilateral side remains intact and thus has been proposed as a possible backup system for post-stroke rehabilitation even for the hand. We argue that, although CRST from ipsilateral secondary motor areas can provide control for proximal joints, it is insufficient to control either hand or coordinated shoulder and hand movements as a result of its extensive spinal branching compared to contralateral corticospinal tract. To address this issue, we combined magnetic resonance imaging, high-density EEG, and robotics in 17 individuals with severe chronic hemiparetic stroke and 12 age-matched controls. We tested for changes in structural morphometry of the sensorimotor cortex and found that individuals with stroke demonstrated higher grey matter density in secondary motor areas ipsilateral to the paretic arm compared to controls. We then measured cortical activity when participants were attempting to generate hand opening either supported on a table or when lifting against a shoulder abduction load. The addition of shoulder abduction during hand opening increased reliance on ipsilateral secondary motor areas in stroke, but not controls. Crucially, the increased use of ipsilateral secondary motor areas was associated with decreased hand opening ability when lifting the arm as a result of involuntary coupling between the shoulder and wrist/finger flexors. Taken together, this evidence implicates a compensatory role for ipsilateral (i.e. contralesional) secondary motor areas post-stroke, although with no apparent capacity to support hand function.

Upper Extremity Motor Impairments and Microstructural Changes in Bulbospinal Pathways in Chronic Hemiparetic Stroke.

Following hemiparetic stroke, precise, individuated control of single joints is often replaced by highly stereotyped patterns of multi-joint movement, or abnormal limb synergies, which can negatively impact functional use of the paretic arm. One hypothesis for the expression of these synergies is an increased dependence on bulbospinal pathways such as the rubrospinal (RubST) tract and especially the reticulospinal (RetST) tracts, which co-activate multiple muscles of the shoulder, elbow, wrist, and fingers. Despite indirect evidence supporting this hypothesis in humans poststroke, it still remains unclear whether it is correct. Therefore, we used high-resolution diffusion tensor imaging (DTI) to quantify white matter microstructure in relation to severity of arm synergy and hand-related motor impairments. DTI was performed on 19 moderately to severely impaired chronic stroke individuals and 15 healthy, age-matched controls. In stroke individuals, compared to controls, there was significantly decreased fractional anisotropy (FA) and significantly increased axial and radial diffusivity in bilateral corona radiata and body of the corpus callosum. Furthermore, poststroke, the contralesional (CL) RetST FA correlated significantly with both upper extremity (UE) synergy severity (r = -0.606, p = 0.003) and hand impairment (r = -0.609, p = 0.003). FA in the ipsilesional RubST significantly correlated with hand impairment severity (r = -0.590, p = 0.004). For the first time, we separately evaluate RetST and RubST microstructure in chronic stroke individuals with UE motor impairment. We demonstrate that individuals with the greatest UE synergy severity and hand impairments poststroke have the highest FA in the CL RetST a pattern consistent with increased myelination and suggestive of neuroplastic reorganization. Since the RetST pathway microstructure, in particular, is sensitive to abnormal joint coupling and hand-related motor impairment in chronic stroke, it could help test the effects of specific, and novel, anti-synergy neurorehabilitation interventions for recovery from hemiparesis.

Neural Plasticity in Moderate to Severe Chronic Stroke Following a Device-Assisted Task-Specific Arm/Hand Intervention.

Currently, hand rehabilitation following stroke tends to focus on mildly impaired individuals, partially due to the inability for severely impaired subjects to sufficiently use the paretic hand. Device-assisted interventions offer a means to include this more severe population and show promising behavioral results. However, the ability for this population to demonstrate neural plasticity, a crucial factor in functional recovery following effective post-stroke interventions, remains unclear. This study aimed to investigate neural changes related to hand function induced by a device-assisted task-specific intervention in individuals with moderate to severe chronic stroke (upper extremity Fugl-Meyer < 30). We examined functional cortical reorganization related to paretic hand opening and gray matter (GM) structural changes using a multimodal imaging approach. Individuals demonstrated a shift in cortical activity related to hand opening from the contralesional to the ipsilesional hemisphere following the intervention. This was driven by decreased activity in contralesional primary sensorimotor cortex and increased activity in ipsilesional secondary motor cortex. Additionally, subjects displayed increased GM density in ipsilesional primary sensorimotor cortex and decreased GM density in contralesional primary sensorimotor cortex. These findings suggest that despite moderate to severe chronic impairments, post-stroke participants maintain ability to show cortical reorganization and GM structural changes following a device-assisted task-specific arm/hand intervention. These changes are similar as those reported in post-stroke individuals with mild impairment, suggesting that residual neural plasticity in more severely impaired individuals may have the potential to support improved hand function.

Measuring Pain for Patients Seeking Physical Therapy: Can Functional Magnetic Resonance Imaging (fMRI) Help?

In the multidisciplinary fields of pain medicine and rehabilitation, advancing techniques such as functional magnetic resonance imaging (fMRI) are used to enhance our understanding of the pain experience. Given that such measures, in some circles, are expected to help us understand the brain in pain, future research in pain measurement is undeniably rich with possibility. However, pain remains intensely personal and represents a multifaceted experience, unique to each individual; no single measure in isolation, fMRI included, can prove or quantify its magnitude beyond the patient self-report. Physical therapists should be aware of cutting-edge advances in measuring the patient's pain experience, and they should work closely with professionals in other disciplines (eg, magnetic resonance physicists, biomedical engineers, radiologists, psychologists) to guide the exploration and development of multimodal pain measurement and management on a patient-by-patient basis. The primary purpose of this perspective article is to provide a brief overview of fMRI and inform physical therapist clinicians of the pros and cons when utilized as a measure of the patient's perception of pain. A secondary purpose is to describe current known factors that influence the quality of fMRI data and its analyses, as well as the potential for future clinical applications relevant to physical therapist practice. Lastly, the interested reader is introduced and referred to existing guidelines and recommendations for reporting fMRI research.