Computational neurorehabilitation: modeling plasticity and learning to predict recovery

Despite progress in using computational approaches to inform medicine and neuroscience in the last 30 years, there have been few attempts to model the mechanisms underlying sensorimotor rehabilitation. We argue that a fundamental understanding of neurologic recovery, and as a result accurate predictions at the individual level, will be facilitated by developing computational models of the salient neural processes, including plasticity and learning systems of the brain, and integrating them into a context specific to rehabilitation. Here, we therefore discuss Computational Neurorehabilitation, a newly emerging field aimed at modeling plasticity and motor learning to understand and improve movement recovery of individuals with neurologic impairment. We first explain how the emergence of robotics and wearable sensors for rehabilitation is providing data that make development and testing of such models increasingly feasible. We then review key aspects of plasticity and motor learning that such models will incorporate. We proceed by discussing how computational neurorehabilitation models relate to the current benchmark in rehabilitation modeling – regression-based, prognostic modeling. We then critically discuss the first computational neurorehabilitation models, which have primarily focused on modeling rehabilitation of the upper extremity after stroke, and show how even simple models have produced novel ideas for future investigation. Finally, we conclude with key directions for future research, anticipating that soon we will see the emergence of mechanistic models of motor recovery that are informed by clinical imaging results and driven by the actual movement content of rehabilitation therapy as well as wearable sensor-based records of daily activity

Brain Activation During Passive and Volitional Pedaling After Stroke

Background: Prior work indicates that pedaling-related brain activation is lower in people with stroke than in controls. We asked whether this observation could be explained by between-group differences in volitional motor commands and pedaling performance. Methods: Individuals with and without stroke performed passive and volitional pedaling while brain activation was recorded with functional magnetic resonance imaging. The passive condition eliminated motor commands to pedal and minimized between-group differences in pedaling performance. Volume, intensity, and laterality of brain activation were compared across conditions and groups. Results: There were no significant effects of condition and no Group × Condition interactions for any measure of brain activation. Only 53% of subjects could minimize muscle activity for passive pedaling. Conclusions: Altered motor commands and pedaling performance are unlikely to account for reduced pedaling-related brain activation poststroke. Instead, this phenomenon may be due to functional or structural brain changes. Passive pedaling can be difficult to achieve and may require inhibition of excitatory descending drive

Transcranial Magnetic Stimulation and Neuroimaging Coregistration

The development of neuroimaging techniques is one of the most impressive advancements in neuroscience. The main reason for the widespread use of these instruments lies in their capacity to provide an accurate description of neural activity during a cognitive process or during rest. This important advancement is related to the possibility to selectively detect changes of neuronal activity in space and time by means of different biological markers. Specifically, functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and nearinfrared spectroscopy (NIRS) use metabolic markers of ongoing neuronal activity to provide an accurate description of the activation of specific brain areas with high spatial resolution. Similarly, electroencephalography (EEG) is able to detect electric markers of neuronal activity, providing an accurate description of brain activation with high temporal resolution. The application of these techniques during a cognitive task allows important inferences regarding the relation between the detected neural activity, the cognitive process involved in an ongoing task, and behaviour: this is known as a \u201ccorrelational approach\u201d

Robot-assisted fMRI assessment of early brain development

Preterm birth can interfere with the intra-uterine mechanisms driving cerebral development during the third trimester of gestation and often results in severe neuro-developmental impairments. Characterizing normal/abnormal patterns of early brain maturation could be fundamental in devising and guiding early therapeutic strategies aimed at improving clinical outcome by exploiting the enhanced early neuroplasticity. Over the last decade the morphology and structure of the developing human brain has been vastly characterized; however the concurrent maturation of brain function is still poorly understood. Task-dependent fMRI studies of the preterm brain can directly probe the emergence of fundamental neuroscientific notions and also provide clinicians with much needed early diagnostic and prognostic information. To date, task-fMRI studies of the preterm population have however been hampered by methodological challenges leading to inconsistent and contradictory results. In this thesis I present a modular and flexible system to provide clinicians and researchers with a simple and reliable solution to deliver computer-controlled stimulation patterns to preterm infants during task-fMRI experiments. The system is primarily aimed at studying the developing sensori-motor system as preterm infants are often affected by neuro-motor dysfunctions such as cerebral palsy. Wrist and ankle robotic stimulators were developed and firstly used to study the emerging somatosensory “homunculus”. The wrist robotic stimulator was then used to characterize the development of the sensori-motor system throughout the mid-to-late preterm period. An instrumented pacifier system was also developed to explore the potential sensorimotor modulation of early sucking activity; however, despite its clear potential to be employed in future fMRI studies, results have not yet been obtained on preterm infants. Functional difficulties associated with prematurity are likely to extend to multi-sensory integration, and the olfactory system currently remains under-investigated despite its clear developmental importance. A custom olfactometer was developed and used to assess its early functionality.Open Acces

An fMRI Study of Command Following and Communication Using Overt and Covert Motor Responses: Implications for Disorders of Consciousness

We used functional magnetic resonance imaging (fMRI) to explore neural mechanisms of command following or communicating using executed or imagined movements, in order to understand why most covertly aware patients cannot communicate. 15 healthy participants executed or imagined arm movements that were either selected by them or pre-determined. We also explored non-volitional motor activity by passively moving participants. Response selection involved greater activity in high-level associative areas in frontal and parietal regions than following commands. Furthermore, there was no interaction between response and modality. Neural activity during passive movement exceeded that of active (volitional) movement in sensorimotor regions. Our results suggest that the ability to select between motor responses is not dependent on how that response is expressed (via motor execution/imagery). They also suggest a potential neural basis of the distinction in cognitive abilities seen in DOCs. Finally, passive movement could be applied to study unresponsive patients’ motor systems

Development of a magnetic resonance compatible wrist device for the analysis of movement encoding in the brain

Tese de mestrado integrado em Engenharia Biomédica e Biofísica, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2016A interação com o mundo é feita através de movimento - desde a locomoção até à comunicação verbal - tornando o controlo de movimento um dos aspectos fundamentais de maior interesse em neurociência. O controlo de movimento tem sido alvo de observação desde cedo em estudos comportamentais e neurofisiológicos, e sabemos hoje que os movimentos voluntários resultam de padrões de impulsos elétricos gerados no sistema nervoso. Contudo, não conhecemos ainda os aspetos mais precisos da geração de padrões de movimento nem a sua relação com parâmetros como direção, velocidade, etc. Uma característica importante do controlo de movimento é a existência de tuning direcional - que consiste numa resposta neuronal preferencial a uma direção de movimento. Ao executar movimentos numa direção preferida, alguns neurónios despolarizam a uma frequência máxima, e a mesma diminui gradualmente à medida que o movimento se afasta da direção preferida. Este fenómeno foi caracterizado em 1982 em áreas motoras (córtex motor primário) ao serem executados movimentos direcionais do braço contralateral. Contudo, estudos recentes mostram a existência de tuning direcional não só para o membro contralateral, mas também para o membro ipsilateral. Estas representações direcionais foram encontradas com medições electrofisiológicas ao nível celular, e também com técnicas modernas de imagiologia que medem sinal proveniente de volumes da ordem de mm3, como ressonância magnética funcional. Com recurso a ambos os tipos de técnicas foram encontradas representações ipsilaterais bem estruturadas para movimentos ao nível do braço bem como dos dedos. Desta forma, ambos os hemisférios cerebrais codificam movimentos direccionais de ambas as mãos. Sabemos também, por experiência quotidiana, que os movimentos bimanuais são bem coordenados, o que sugere que os mesmos são gerados tomando em conta informação de ambas as mãos. No entanto, a relação entre os padrões neuronais de movimentos bimanuais e unimanuais ainda não é clara. Nesta dissertação pretende-se localizar e caracterizar tuning direcional durante movimentos unimanuais e bimanuais no cérebro humano. Desta forma temos como objectivo procurar quais as regiões corticais que codificam movimentos direcionais da mão contralateral, da mão ipsilateral, bem como as representações de movimentos bimanuais e a sua relação com movimentos unimanuais. Para tal, foi desenhada uma experiência motora para testar movimentos direcionais, que foi executada em simultâneo com a aquisição de imagens de ressonância magnética funcional. Foi desenvolvido um dispositivo para monitorizar de forma precisa movimentos da mão. De forma a assegurar compatibilidade com o ambiente em ressonância magnética, foram construídos dois manípulos ergonómicos com recurso a impressão 3D em nylon. Os manípulos foram equipados com sensores de rotação resistivos, e foram montados numa mesa de suporte desenvolvida para o efeito. Afim de treinar os participantes e controlar a experiência, foi desenvolvido um protocolo motor organizado de forma semelhante a um jogo de alvos. Os participantes controlaram a posição de cursores num ecrã utilizando movimentos das mãos, monitorizados pelo dispositivo. O objectivo do protocolo motor foi atingir 6 alvos radiais com os cursores e voltar à posição central, com movimentos de cada uma das mãos, ou as duas (para todas as combinações de 6 alvos para cada mão). No total, a experiência consistiu em 48 condições de movimento – 6 movimentos radiais para a mão esquerda, 6 para a mão direita e 36 combinações bimanuais. A experiência motora foi executada por 7 sujeitos destros saudáveis. Após uma sessão de treino, a experiência decorreu num scanner de ressonância magnética funcional Siemens Trio 3T, onde foram adquiridas imagens funcionais durante 10 repetições da experiência para cada sujeito. Adicionalmente, foram adquiridos dados de cinemática para as duas mãos durante as sessões de treino e de teste. A análise de dados de cinemática consistiu na observação de tempos de reação e de movimento em cada condição. Comparámos condições unimanuais e bimanuais, testámos efeitos de direção, e ainda combinações bimanuais (movimentos simétricos, paralelos ou não relacionados). Para cada uma destas hipóteses foram usados os testes estatísticos aplicáveis. Não foram observados efeitos significativos nos tempos de reação, de forma consistente, para qualquer das condições em estudo. Pelo contrário, os tempos de movimento foram consistentemente sensíveis aos efeitos estudados. As imagens por ressonância magnética funcional foram analisadas numa primeira fase conforme o procedimento tradicional. Este consiste no pré-processamento - envolvendo correções espaciais de efeitos de campo magnético, filtragem temporal, alinhamento com a imagem anatómica e segmentação. De seguida foi aplicado um modelo linear de forma de forma de independente para cada voxel (unidade discreta de volume) nas imagens. O modelo consistiu em 48 variáveis categóricas, correspondentes às condições de movimento em estudo, e 10 variáveis categóricas correspondentes às sessões de repetição da experiência. O objetivo deste modelo é a estimação dos pesos (β) da regressão linear, i.e., para cada condição é estimada a influência da mesma no sinal em cada voxel. De seguida é possível fazer inferência sobre os valores β - sob a hipótese nula de que são, em média, zero. Procedendo desta forma, foi aplicado um teste t aos regressores β associados a movimentos da mão esquerda, direita, e movimentos bimanuais para as regiões: área sensorial somática I (S1), córtex motor primário (M1), córtex pré-motor ventral e dorsal (PMv, PMd), área motora suplementar (AMS), lóbulo parietal superior, anterior e posterior (LPSa, LPSp) e córtex visual (V12). Foram encontrados valores de activação predominantemente associados com movimentos contralaterais e bimanuais, e activação menor em movimentos ipsilaterais. Os resultados coincidem fortemente com a perspetiva clássica de que cada hemisfério está associado a controlo da mão contralateral. Contudo, os métodos univariados testam o quanto os voxels (ou regiões) variam a sua resposta com condições individuais, tornando a comparação entre condições de movimento difícil. Adicionalmente, estes métodos são indicados para o mapeamento de activação perante estímulos, mas não para avaliar a estrutura da representação de condições, i.e., caracterizar respostas neuronais associadas conjunto de estímulos - como é o caso de tuning direcional. Desta forma, foi aplicado um modelo de análise representacional no qual se pressupõe que os estímulos podem ser caracterizados por padrões de activação - neste caso correspondentes aos valores beta para cada voxel quando é executada uma condição. Neste modelo é calculada uma medida de (dis)similaridade entre todos os pares de condições. Neste projecto foi utilizada a distância Euclidiana, sendo que as comparações entre pares das 48 condições foram organizadas em matrizes de distância. Os resultados revelam, qualitativamente, a presença duma estrutura de tuning direcional bem definida para movimentos contralaterais, bem como ipsilaterais. Também os movimentos bimanuais apresentaram uma estrutura de tuning bem definida e diferenciada entre regiões. De forma a quantificar e inferir acerca da presença de codificação direcional, os valores de distância correspondentes às condições contralaterais, ipsilaterais e bimanuais foram testados estatisticamente. Este teste assenta no pressuposto de que, perante a inexistência de codificação, as distâncias são zero (este pressuposto foi confirmado). Os resultados indicam uma forte codificação direcional de movimentos contralaterais para todas as regiões testadas. Este resultado é coincidente com estudos anteriores que encontram tuning direcional contralateral em todas as regiões em que o mesmo foi investigado. Contudo, encontrámos também uma forte codificação de movimentos ipislaterais, excepto na AMS e LPS anterior no hemisfério direito (não dominante). Estes resultados são coerentes com estudos recentes que mostram uma forte presença de codificação de movimentos ipsilaterais. Os movimentos bimanuais estão também caracterizados por uma forte representação. Contudo, existe a hipótese de que estes estejam presentes apenas como consequência da codificação direcional de movimentos da mão contralateral (ou ipsilateral), e não directamente associados à codificação especializada de movimentos bimanuais. Esta hipótese é, contudo, de elevado interesse, já que uma codificação bimanual especializada pode explicar o mecanismo da coordenação bimanual. Desta forma, as matrizes de distância foram reorganizadas em termos de movimentos da mão esquerda e da mão direita. Os mapas resultantes foram comparados qualitativamente com simulações, revelando uma codificação bimanual maioritariamente associada com movimentos contralaterais. Contudo, a AMS e o córtex premotor ventral aparentam codificar movimentos bimanuais de forma não-linear, que poderá indicar alguma especialização em movimentos bimanuais que poderá ser útil para coordenação. Trabalho futuro envolverá avaliar quantitativamente estes mapas de forma a perceber quanta codificação bimanual é gerada de forma especializada. Os resultados deste estudo coincidem com estudos recentes de codificação ipsilateral, e revisitam questões acerca da codificação bimanual. No futuro pretende-se decompor a codificação bimanual, avaliar de forma extensa e continua a superfície cortical, cerebelo e núcleos da base. Adicionalmente, esperamos executar futuras aquisições em novos participantes. Este tipo de estudo pretende responder a questões no âmbito do controlo neural de movimento, que poderão ser úteis futuramente no contexto da reabilitação e controlo robótico. Consideramos também que os métodos de procura de codificação poderão ser utilizados para caracterização do sistema motor de sujeitos saudáveis em comparação com casos patológicos como acidente vascular cerebral, fornecendo um meio de avaliação dos mesmos.We interact with the world by moving our body: legs for locomotion, hands for dexterous tasks, and articulatory muscles to communicate. It is known that these movements result from patterns of electrical impulses in the nervous system. However, it is not yet known how the brain controls the fine aspects of movement. One important characteristic of movement control in the brain is directional tuning - a preferential neuronal response to an executed direction. In this work, we examine where and how the brain encodes movement directions in unimanual and bimanual movements in humans. In order to address this question, we designed a motor experiment for directional movements. A hand device was developed in order to precisely monitor hand movements while 7 right-handed healthy participants executed a motor task. The task was built similarly to a game in which participants reached radial targets using wrist movements of one or both hands. After training, subjects executed the motor task in a magnetic resonance scanner. Functional imaging data were acquired and analysed using novel multivoxel pattern analysis, in which we calculate pairwise dissimilarities of patterns of fMRI voxel activity across movement conditions. We tested for encoding of unimanual (contralateral and ipsilateral) and bimanual movements in cortical regions of interest. Kinematics data were also analysed to test for performance effects of direction and hand combination. We found significant encoding of contralateral and bimanual movements in all tested regions. Ipsilateral movements were strongly represented in both hemispheres, except for right supplementary motor area and anterior-superior parietal lobule. Furthermore, the right (non-dominant) hemisphere encoded contralateral movements more preferentially than ipsilateral ones, when compared with the left hemisphere. These results are in line with recent findings of well-defined ipsilateral movement representations. Future work will involve decomposing bimanual tuning functions in order to find a quantitative relationship between bimanual and unimanual encoding

Sensorimotor experience in virtual environments

The goal of rehabilitation is to reduce impairment and provide functional improvements resulting in quality participation in activities of life, Plasticity and motor learning principles provide inspiration for therapeutic interventions including movement repetition in a virtual reality environment, The objective of this research work was to investigate functional specific measurements (kinematic, behavioral) and neural correlates of motor experience of hand gesture activities in virtual environments stimulating sensory experience (VE) using a hand agent model. The fMRI compatible Virtual Environment Sign Language Instruction (VESLI) System was designed and developed to provide a number of rehabilitation and measurement features, to identify optimal learning conditions for individuals and to track changes in performance over time. Therapies and measurements incorporated into VESLI target and track specific impairments underlying dysfunction. The goal of improved measurement is to develop targeted interventions embedded in higher level tasks and to accurately track specific gains to understand the responses to treatment, and the impact the response may have upon higher level function such as participation in life. To further clarify the biological model of motor experiences and to understand the added value and role of virtual sensory stimulation and feedback which includes seeing one\u27s own hand movement, functional brain mapping was conducted with simultaneous kinematic analysis in healthy controls and in stroke subjects. It is believed that through the understanding of these neural activations, rehabilitation strategies advantaging the principles of plasticity and motor learning will become possible. The present research assessed successful practice conditions promoting gesture learning behavior in the individual. For the first time, functional imaging experiments mapped neural correlates of human interactions with complex virtual reality hands avatars moving synchronously with the subject\u27s own hands, Findings indicate that healthy control subjects learned intransitive gestures in virtual environments using the first and third person avatars, picture and text definitions, and while viewing visual feedback of their own hands, virtual hands avatars, and in the control condition, hidden hands. Moreover, exercise in a virtual environment with a first person avatar of hands recruited insular cortex activation over time, which might indicate that this activation has been associated with a sense of agency. Sensory augmentation in virtual environments modulated activations of important brain regions associated with action observation and action execution. Quality of the visual feedback was modulated and brain areas were identified where the amount of brain activation was positively or negatively correlated with the visual feedback, When subjects moved the right hand and saw unexpected response, the left virtual avatar hand moved, neural activation increased in the motor cortex ipsilateral to the moving hand This visual modulation might provide a helpful rehabilitation therapy for people with paralysis of the limb through visual augmentation of skills. A model was developed to study the effects of sensorimotor experience in virtual environments, and findings of the effect of sensorimotor experience in virtual environments upon brain activity and related behavioral measures. The research model represents a significant contribution to neuroscience research, and translational engineering practice, A model of neural activations correlated with kinematics and behavior can profoundly influence the delivery of rehabilitative services in the coming years by giving clinicians a framework for engaging patients in a sensorimotor environment that can optimally facilitate neural reorganization

Design and Validation of an MR Conditional Upper Extremity Evaluation System to Study Brain Activation Patterns after Stroke

Stroke is the third leading cause of death and second most frequent cause of disability in the United States. Stroke rehabilitation methods have been developed to induce the cortical reorganization and motor-relearning that leads to stroke recovery. In this thesis, we designed and developed an MR conditional upper extremity reach and grasp movement evaluation system for the stroke survivors to study their kinematic performances in reach and grasp movement and the relationship between kinematic metrics and the recovery level measured by clinical assessment methods. We also applied the system into the functional MRI experiments to identify the ability to study motor performance with the system inside the scanner and the reach, grasp and reach-to-grasp movements related brain activation patterns. Our experiments demonstrates that ours system is an MR conditional system in the 3.0 Tesla magnetic field. It is able to measure the stroke survivors\u27 reach and grasp movement in terms of grasp aperture and elbow joint angles. We used the Mann Whitney U test to examine the significant metrics in each tasks and principle component analysis to decide the major metrics that are associated with the outcome. Then we discovered better recovery scores are associated with these major kinematic metrics such as larger maximal velocity, larger mean velocity, larger maximal movement angle, and longer time to peak velocity. Additional to these metrics, time to maximal angle, time to target and time to peak velocity could also be used as additional metrics to help predict the recovery and assess robot-assisted therapy and optimize task-oriented rehabilitation strategy. We also identified the movement related brain activations in the motor and sensory areas as well as cerebellum in both normal and stroke survivors

Force Amplitude Modulation of Tongue and Hand Movements

Rapid, precise movements of the hand and tongue are necessary to complete a wide range of tasks in everyday life. However, the understanding of normal neural control of force production is limited, particularly for the tongue. Functional neuroimaging studies of incremental hand pressure production in healthy adults revealed scaled activations in the basal ganglia, but no imaging studies of tongue force regulation have been reported. The purposes of this study were (1) to identify the neural substrates controlling tongue force for speech and nonspeech tasks, (2) to determine which activations scaled to the magnitude of force produced, and (3) to assess whether positional modifications influenced maximum pressures and accuracy of pressure target matching for hand and tongue movements. Healthy older adults compressed small plastic bulbs in the oral cavity (for speech and nonspeech tasks) and in the hand at specified fractions of maximum voluntary contraction while magnetic resonance images were acquired. Volume of interest analysis at individual and group levels outlined a network of neural substrates controlling tongue speech and nonspeech movements. Repeated measures analysis revealed differences in percentage signal change and activation volume across task and effort level in some brain regions. Actual pressures and the accuracy of pressure matching were influenced by effort level in all tasks and body position in the hand squeeze task. The current results can serve as a basis of comparison for tongue movement control in individuals with neurological disease. Group differences in motor control mechanisms may help explain differential response of limb and tongue movements to medical interventions (as occurs in Parkinson disease) and ultimately may lead to more focused intervention for dysarthria in several conditions such as PD

Characterisation of the Haemodynamic Response Function (HRF) in the neonatal brain using functional MRI

Background: Preterm birth is associated with a marked increase in the risk of later neurodevelopmental impairment. With the incidence rising, novel tools are needed to provide an improved understanding of the underlying pathology and better prognostic information. Functional Magnetic Resonance Imaging (fMRI) with Blood Oxygen Level Dependent (BOLD) contrast has the potential to add greatly to the knowledge gained through traditional MRI techniques. However, it has been rarely used with neonatal subjects due to difficulties in application and inconsistent results. Central to this is uncertainity regarding the effects of early brain development on the Haemodynamic Response Function (HRF), knowledge of which is fundamental to fMRI methodology and analysis. Hypotheses: (1) Well localised and positive BOLD functional responses can be identified in the neonatal brain. (2) The morphology of the neonatal HRF differs significantly during early human development. (3) The application of an age-appropriate HRF will improve the identification of functional responses in neonatal fMRI studies. Methods: To test these hypotheses, a systematic fMRI study of neonatal subjects was carried out using a custom made somatosensory stimulus, and an adapted study design and analysis pipeline. The neonatal HRF was then characterised using an event related study design. The potential future application of the findings was then tested in a series of small experiments. Results: Well localised and positive BOLD functional responses were identified in neonatal subjects, with a maturational tendency towards an increasingly complex pattern of activation. A positive amplitude HRF was identified in neonatal subjects, with a maturational trend of a decreasing time-to-peak and increasing positive peak amplitude. Application of the empirical HRF significantly improved the precision of analysis in further fMRI studies. Conclusions: fMRI can be used to study functional activity in the neonatal brain, and may provide vital new information about both development and pathology