Kathleen Margaret Friel - US grants

functional ability; psychomotor function; brain injury; motor cortex; hand; caudate nucleus; limb movement; sensory feedback; behavioral /social science research tag; Saimiri; behavior test;

[unreadable] DESCRIPTION (provided by applicant): The goal of the proposed experiments is to understand the role of cortical activity in the development of the corticospinal (CS) system in the cat. The cat CS system is immature at birth and continues to develop during early postnatal life. Neural activity during development appears to play a vital role in determining the topographic organization of the CS system and in establishing specific, functional connections between CS axons and their neuronal targets in the spinal cord. The proposed experiments will determine the topographic distribution of the neurotrophins BDNF and NT-3 during development, with respect to the critical period for CS development. In a second series of experiments, sensory-motor cortex will be silenced early in development. Then, either constraint-induced movement therapy or pyramidal tract stimulation will be implemented for four weeks. This aim will determine the efficacy of the rehabilitation regimens in guiding CS development toward a more normal pattern. Since abnormal CS development in humans often results in permanent disabilities, understanding the factors that cause abnormal CS development, and the efficacy of behavioral interventions in guiding the CS system toward a more normal development, is highly clinically significant. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Activity-dependent competition drives development of the corticospinal (CS) system during early postnatal life. Animal studies have demonstrated that imbalance of activity between the motor cortex (Ml) in the two hemispheres causes aberrant CS circuit formation and motor impairments. Rebalancing Ml activity on the two sides later in development restores normal CS connections and motor function. In human hemiplegic CP, a neurological disorder characterized by poor motor control, motor areas become damaged during perinatal development. The damage tends to have a unilateral predominance. Decreased CS system activity on the affected side is thought to be crucial to development of hemiplegic CP. It is hypothesized that restoring balance between the activity of Ml on each side is essential for restitution of normal CS circuitry and motor skill. One treatment effective in improving motor function in children with hemiplegic CP is training of the affected side with concurrent restraint of the unaffected limb. During treatment, children engage in skilled, repetitive movements with the affective side, while the unaffected side is restrained with a sling. This behavioral treatment balances Ml activity by increasing activity of the affected side through training while decreasing activity of the unaffected side through restraint. The proposed work will also examine how different intensities of skill training influence recovery. The important issue of whether training of movements focusing on precise distal control and shaping of increasing skill difficulty is more effective than repetitive task performance without increasing skill difficulty has not been addressed. Understanding the mechanisms underlying behavioral improvements is an important step towards developing new therapies that can be applied to a broader population of children with hemiplegia, especially those with more debilitating impairments who have the greatest need for an effective treatment. This proposal takes a translational approach to the study of CP rehabilitation, built upon an understanding of the development of the cat motor system. The applicant will obtain training in TMS, human motor skill assessment and analysis, and translating hypotheses between the animal and the human. By understanding the mechanisms of recovery, particularly the interplay between training and CS system plasticity in recovery, the applicant will be in the unique position to translate these mechanisms to improve CP treatment.

DESCRIPTION (provided by applicant): Intensive hand training can improve dexterity in children with hemiplegic cerebral palsy. Two categories of training paradigms have been tested. In constraint-induced movement therapy (CIMT), the less-affected upper extremity (UE) is restrained while the affected UE is trained. Intensive bimanual training (e.g., Hand-arm bimanual intensive training (HABIT)) encourages children to use both UEs in bimanual tasks. However, it has been reported that children whose impaired UE is controlled via ipsilateral corticospinal (CS) connections show less recovery in CIMT than children whose impaired UE is controlled by contralateral CS connections. This raises the interesting possibility that there is a interaction between treatment type and CS connection pattern. Limited use of an UE drives down activity in the contralateral motor cortex (M1). In children with contralateral control of the affected UE, decreasing activity in the healthy M1 gives the affected side a competitive advantage over the other side. In contrast, in children with ipsilateral control of the affected UE the healthy M1 controls the affected UE. Constraining the less-affected UE drives down activity in the healthy M1, which may impede recovery of the impaired UE. The PIs will further investigate this important issue. They will use single-pulse transcranial magnetic stimulation to probe M1 function in children who have previously received HABIT or CIMT. The PIs hypothesize that children with ipsilateral connectivity of the affected hand showed greater improvement in dexterity after HABIT, compared to CIMT. Importantly, they will help determine whether children with ipsilateral CS projections would best benefit from bimanual therapy vs. CIMT.

DESCRIPTION (provided by applicant): Cerebral palsy (CP) is the most common pediatric neurological disorder. CP is caused by damage to brain motor areas during development. CP results in weakness, altered tone and abnormal coordination. Therapies for CP have largely been scaled from adult stroke therapies. However, the motor circuits involved in adult stroke are quite different from those in children with CP. Effective therapies for children with CP should be built on a specific understanding of motor circuit control in children with CP. We propose to identify the neurophysiological underpinnings of hand control in children with CP and will determine predictors of the efficacy of hand therapy. Building an understanding of hand motor control in children with CP fills an important gap and will set the foundation for further development of hand therapies for children with CP. Two types of intensive hand training have shown efficacy in children with unilateral spastic CP (USCP), whose motor deficits are largely restricted to one side of the body. In constraint-induced movement therapy (CIMT), the dominant arm is restrained while the impaired hand is trained in unimanual tasks. In hand-arm intensive bimanual training (HABIT), alternatively, children use both hands together. It has been reported that the efficacy of CIMT is affected by the pattern of corticospinal tract connectivity i children with USCP. The central hypothesis of the proposed research, supported by our pilot data, is that efficacy of hand training is differentially affected by connectivity of motor circuit and type of training. We also hypothesize that neurophysiological biomarkers of motor circuit dysfunction can predict which type of hand training is ideal for an individual. Two important questions remain unanswered: 1) How do motor circuits interact and change in response to intensive hand therapy? 2) Does the efficacy of intensive hand therapy depend on laterality of the corticospinal tract that controls the affected hand? The proposed experiments will answer these questions. Children are not little adults. Therapies for USCP must be built on a strong understanding of motor control in USCP. By identifying the neural circuit effects of CIMT vs. HABIT, we can tailor therapies to children most likely to benefit. This work will also provide a framework for developing new activity-based therapies for USCP.

? DESCRIPTION (provided by applicant): Cerebral palsy (CP) is the most common pediatric neurological disorder. CP is caused by damage to brain motor areas during development. CP results in weakness, altered tone and abnormal coordination. People with unilateral spastic cerebral palsy (USCP) tend to under-use their paretic side, and do not develop robust motor control of the paretic side. As people with USCP age, motor deficits on the paretic side persist due to disuse of the paretic side. Few therapies exist for upper extremity rehabilitation in adults with USCP. The goal of the present study was to determine feasibility and efficacy of upper limb therapy in adults with CP. Upper extremity robotic therapy can improve arm movement deficits in adults after stroke. Transcranial direct current stimulation (tDCS) can augment the efficacy of robotic therapy when delivered immediately before training. We propose to test this same protocol in USCP. We hypothesize that tDCS plus upper extremity robotic training will be a safe, feasible protocol that improved upper extremity function. Participants will receive thirty-six sessions of therapy, three days/week for 12 weeks. During each therapy session, each participant will receive 20 min of real 2mA anodal tDCS or sham tDCS, immediately followed by robotic arm therapy. Anodal (excitatory) tDCS will be applied over the motor map of the paretic hand. During robotic therapy, each participant will use the wrist and upper arm to follow a cursor in a center-out task for 1000 movements. We will measure motor function of the affected upper limb before, after, and six months after the series of therapy sessions. We will also measure kinematics of movements on the robot and side effects of tDCS at each session. We will also measure motor cortex excitability before and after the series of therapy sessions, using single pulse transcranial magnetic stimulation. We hypothesize that therapy will result in improved reaching accuracy and smoothness on the robotic task, improvement in clinical motor measures, and will show an excellent safety profile. We also hypothesize that the therapy will expand the motor map of the paretic hand. Understanding the feasibility, efficacy, and neurophysiological effects of combined tDCS and robotic therapy will be an important step in developing and optimizing effective upper limb therapy for adults with CP.

PROJECT SUMMARY Cerebral palsy (CP) is the most common pediatric neurological disorder. CP is caused by damage to brain areas during development. CP results in weakness, altered tone and abnormal coordination. In unilateral spastic CP (USCP), the damage has a unilateral predominance. Although CP is defined as a motor disability, approximately 80% of people with USCP have deficits in sensation that limit the extent of rehabilitation. There is a poor understanding of how the sensory and motor systems interact in children with USCP. Impairments in motor and sensory function have largely been studied in isolation (rather than together) in children with USCP, even though voluntary movement requires the integration of sensory and motor processing. Moreover, while the motor system is better-characterized, there is still a limited understanding of how the location, type, and size of a child?s lesion impacts sensorimotor processing. There is an urgent need to identify and quantify sensory factors that impair movement in children with USCP. Our long-term goal is to develop evidence-based ways to improve movement in children with USCP. The overall objective for this project is to determine how fine touch sensation and sensation of limb position contribute to movement deficits in children with USCP. To meet our goal, we must not only know how sensory systems impact impairment in movement, but we must determine how a child?s lesion and brain connectivity contributes to these impairments. Our central hypothesis is that sensory dysfunction plays a key role in the ability of children with USCP to engage in functional, skillful movements. We also hypothesize that damage to specific brain regions cause specific kinds of impairments. The rationale for the proposed work is that demonstration of a strong relationship between sensory impairments and movement deficits will steer the development of therapies that engage children in the use of sensory information during meaningful complex tasks, with the goal of boosting motor function. !

PROJECT SUMMARY/ABSTRACT Unilateral spastic cerebral palsy (USCP) is characterized by movement deficits, particularly upper extremity (UE) impairments on one side of the body. Although strides have been made to improve UE rehabilitation approaches, even the best available therapies fail to fully ameliorate UE impairments, are costly, and require large amounts of time. Thus, there is an urgent need to optimize the effectiveness and cost of UE therapies. Our long-term goal is to develop evidence-based strategies to improve movement in children with USCP. Early damage to the developing brain can result in a re-wiring of the direct corticospinal tract (CST) projections innervating UE function. In many children with USCP, there are no CST connections from the damaged hemisphere, and instead ipsilateral (same-sided) CST pathways control movement of the affected UE. Previously, this type of reorganization was believed to be maladaptive and unresponsive to treatment. However, during the first funding period of this R01, we determined that UE therapy efficacy is independent of CST laterality. Importantly, we found that the hemisphere containing CST connectivity to the affected hand showed neuroplastic changes in response to intensive therapy. Nonetheless, this heterogeneity in the brain connectivity means it is unlikely that a one-size-fits-all rehabilitation approach will be suitable. Therefore, our next goal is to leverage these findings using an individualized approach to obtain the same or greater changes using a fraction of the dosage by enhancing the neuroplastic changes with transcranial direct current stimulation (tDCS). Our preliminary results show that tDCS enhances the efficacy of UE training only if it is targeted to an individual?s CST laterality determined with single-pulse transcranial magnetic stimulation (TMS). The overall objective for this renewal is to vertically extend what has been learned under our prior R01 by determining how to optimally target tDCS to enhance the efficacy of UE training in children with USCP. Our central hypothesis is that bimanual training (BT) combined with a tDCS montage targeting the hemisphere with CST connectivity to the impaired UE muscles will improve UE function more than BT plus sham stimulation. We will test this by conducting a randomized clinical trial (RCT) to determine the efficacy of targeted tDCS/BT for improving UE function and interactions between tDCS/BT and motor cortex physiology in children with USCP. Our working hypotheses are that children who receive targeted anodal tDCS will show the most robust changes in hand function and motor cortex physiology. Determination of the synergistic effects of tDCS and BT may substantially reduce the required rehabilitation time and cost necessary to improve UE function. The proposed work is innovative because it may increase accessibility of treatment, particularly for centers that serve families of lower socio-economic status, due to the reduced cost of therapy.