Neurorehabilitation of hand functions using brain computer interface

Introduction: Brain computer interface (BCI) is a promising new technology with possible application in neurorehabilitation after spinal cord injury. Movement imagination or attempted movement-based BCI coupled with functional electrical stimulation (FES) enables the simultaneous activation of the motor cortices and the muscles they control. When using the BCI- coupled with FES (known as BCI-FES), the subject activates the motor cortex using attempted movement or movement imagination of a limb. The BCI system detects the motor cortex activation and activates the FES attached to the muscles of the limb the subject is attempting or imaging to move. In this way the afferent and the efferent pathways of the nervous system are simultaneously activated. This simultaneous activation encourages Hebbian type learning which could be beneficial in functional rehabilitation after spinal cord injury (SCI). The FES is already in use in several SCI rehabilitation units but there is currently not enough clinical evidence to support the use of BCI-FES for rehabilitation. Aims: The main aim of this thesis is to assess outcomes in sub-acute tetraplegic patients using BCI-FES for functional hand rehabilitation. In addition, the thesis explores different methods for assessing neurological rehabilitation especially after BCI-FES therapy. The thesis also investigated mental rotation as a possible rehabilitation method in SCI. Methods: Following investigation into applicable methods that can be used to implement rehabilitative BCI, a BCI based on attempted movement was built. Further, the BCI was used to build a BCI-FES system. The BCI-FES system was used to deliver therapy to seven sub-acute tetraplegic patients who were scheduled to receive the therapy over a total period of 20 working days. These seven patients are in a 'BCI-FES' group. Five more patients were also recruited and offered equivalent FES quantity without the BCI. These further five patients are in a 'FES-only' group. Neurological and functional measures were investigated and used to assess both patient groups before and after therapy. Results: The results of the two groups of patients were compared. The patients in the BCI-FES group had better improvements. These improvements were found with outcome measures assessing neurological changes. The neurological changes following the use of the BCI-FES showed that during movement attempt, the activation of the motor cortex areas of the SCI patients became closer to the activation found in healthy individuals. The intensity of the activation and its spatial localisation both improved suggesting desirable cortical reorganisation. Furthermore, the responses of the somatosensory cortex during sensory stimulation were of clear evidence of better improvement in patients who used the BCI-FES. Missing somatosensory evoked potential peaks returned more for the BCI-FES group while there was no overall change in the FES-only group. Although the BCI-FES group had better neurological improvement, they did not show better functional improvement than the FES-only group. This was attributed mainly to the short duration of the study where therapies were only delivered for 20 working days. Conclusions: The results obtained from this study have shown that BCI-FES may induce cortical changes in the desired direction at least faster than FES alone. The observation of better improvement in the patients who used the BCI-FES is a good result in neurorehabilitation and it shows the potential of thought-controlled FES as a neurorehabilitation tool. These results back other studies that have shown the potential of BCI-FES in rehabilitation following neurological injuries that lead to movement impairment. Although the results are promising, further studies are necessary given the small number of subjects in the current study

Real-time fMRI connectivity neurofeedback for modulation of the motor system

Advances in functional magnetic resonance imaging (fMRI) have enabled an understanding of the neural mechanisms underlying human brain functions such as motor functions. In recent decades fMRI, which is a non-invasive and highresolution technique, has been used to investigate the functions of the human brain using the blood oxygen level dependent (BOLD) response as an indirect measurement of brain neural activities. Real-time fMRI (rt-fMRI) has been used as neurofeedback to enable individuals to regulate their neural activity to achieve improvements in their health and performance, such as their motor performance. Neurofeedback can be defined as the measurement of the neural activity of a participant that is presented to them as visual or auditory signals that enable self-regulation of neural activity. Rt-fMRI has also been used to provide feedback about the connectivity between brain regions. Such connectivity neurofeedback can be a more effective feedback strategy than providing feedback from a single region. Recently, connectivity neurofeedback has been explored to examine how functional connectivity of cortical areas and subcortical areas of the brain can be modulated. Enhancing connectivity between cortical and subcortical regions holds promise for the improvement of performance, particularly motor function performance. The aim of this PhD research was to modulate connectivity neurofeedback by using real-time fMRI neurofeedback (rt-fMRI-NF) between brain regions and to investigate whether any possible enhancement in the activation due to a successful fMRI-NF will translate into changes in behavioural measures. The thesis research began with experimental work to establish the experimental paradigm. This included work, using fMRI, to develop and test localisers for different motor areas such as primary motor cortex (M1), supplementary motor cortex (SMA), the motor cerebellum and the motor thalamus. The results showed that the execution of actions, such as hand clenching, can be used to functionally activate many motor areas including M1, SMA and the cerebellum. The motor thalamus was localised using a motor thalamus mask that was created offline using the Talairach atlas. All localisers tested in this research were feasible and able to be used for applications such as rt-fMRI-NF research to define the regions of interest. The first rt-fMRI connectivity neurofeedback experimental study of this thesis was conducted to determine whether healthy participants can use neurofeedback to enhance the connectivity between M1 and the thalamus using rt-fMRI. It also aimed to investigate whether successful rt-fMRI-NF of M1- thalamus connectivity could translate into changes in behavioural measures. For this purpose, the behavioural tasks were conducted before and after each MRI session. Two behavioural tasks were used in this experiment: Go/No Go and switching tasks. The results of this experiment showed a significant increase in connectivity neurofeedback in the experimental group (M1-thalamus), hence, rt-fMRI-NF is a useful tool to modulate functional connectivity between M1 and the thalamus using motor imagery and it facilitates the learning by participants of new mental strategies to upregulate M1-thalamus connectivity. The behavioural tasks showed a significant reduction in the switching time in the experimental group while Go/No Go task did not show a significant reduction in the reaction time in the experimental group. The second rt-fMRI connectivity neurofeedback experimental study of this thesis was conducted to investigate the ability of neurofeedback to modulate M1-cerebellum connectivity using motor imagery based rt-fMRI-NF. The results of this research showed enhanced connectivity between M1 and the cerebellum in each participant. However, this enhancement was not statistically significant. In summary, this PhD thesis extends and validates the usefulness of connectivity neurofeedback using motor imagery based rt-fMRI to modulate the correlation between cortical and subcortical brain regions. Successful modulation using this technique has the potential to lead to an enhancement in motor functions. Thereby, the results of this PhD research may help to advance connectivity neurofeedback for use as a supplementary treatment for many brain disorders such as stroke recovery and Parkinson’s disease

Development of A Versatile Multichannel CWNIRS Instrument for Optical Brain-Computer Interface Applications

This thesis describes the design, development, and implementation of a versatile multichannel continuous-wave near-infrared spectroscopy (CWNIRS) instrument for brain-computer interface (BCI) applications. Specifically, it was of interest to assess what gains could be achieved by using a multichannel device compared to the single channel device implemented by Coyle in 2004. Moreover, the multichannel approach allows for the assessment of localisation of functional tasks in the cerebral cortex, and can identify lateralisation of haemodynamic responses to motor events. The approach taken to extend single channel to multichannel was based on a software-controlled interface. This interface allowed flexibility in the control of individual optodes including their synchronisation and modulation (AM, TDM, CDMA). Furthermore, an LED driver was developed for custom-made triple-wavelength LEDs. The system was commissioned using a series of experiments to verify the performance of individual components in the system. The system was then used to carry out a set of functional studies including motor imagery and cognitive tasks. The experimental protocols based on motor imagery and overt motor tasks were verified by comparison with fMRI. The multichannel approach identified stroke rehabilitation as a new application area for optical BCI. In addition, concentration changes in deoxyhaemoglobin were identified as being a more localised indicator of functional activity, which is important for effective BCI design. An assessment was made on the effect of the duration of the stimulus period on the haemodynamic signals. This demonstrated the possible benefits of using a shorter stimulus period to reduce the adverse affects of low blood pressure oscillations. i

Development of A Versatile Multichannel CWNIRS Instrument for Optical Brain-Computer Interface Applications

This thesis describes the design, development, and implementation of a versatile multichannel continuous-wave near-infrared spectroscopy (CWNIRS) instrument for brain-computer interface (BCI) applications. Specifically, it was of interest to assess what gains could be achieved by using a multichannel device compared to the single channel device implemented by Coyle in 2004. Moreover, the multichannel approach allows for the assessment of localisation of functional tasks in the cerebral cortex, and can identify lateralisation of haemodynamic responses to motor events. The approach taken to extend single channel to multichannel was based on a software-controlled interface. This interface allowed flexibility in the control of individual optodes including their synchronisation and modulation (AM, TDM, CDMA). Furthermore, an LED driver was developed for custom-made triple-wavelength LEDs. The system was commissioned using a series of experiments to verify the performance of individual components in the system. The system was then used to carry out a set of functional studies including motor imagery and cognitive tasks. The experimental protocols based on motor imagery and overt motor tasks were verified by comparison with fMRI. The multichannel approach identified stroke rehabilitation as a new application area for optical BCI. In addition, concentration changes in deoxyhaemoglobin were identified as being a more localised indicator of functional activity, which is important for effective BCI design. An assessment was made on the effect of the duration of the stimulus period on the haemodynamic signals. This demonstrated the possible benefits of using a shorter stimulus period to reduce the adverse affects of low blood pressure oscillations. i

Creating a new tool for Post-Traumatic Disorder treatment

The first article on real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback was published in 2003 (Weiskopf et al., 2003) with the aim to enable the subject to learn to control activation in rostral-ventral and dorsal anterior cingulate cortex (ACC). Rt-fMRI neurofeedback involves data collection of neural activity, real-time data preprocessing, online statistical analysis, providing the results back to the participant, and active effort of participant in order to either up- and/or down-regulate the target region’s activation. In the last 16 years the topic attracted great attention from different labs around the world and many different brain regions were regulated with the help of rt-fMRI neurofeedback. Nevertheless it had the most distinct impact in the clinical research as it could be used with clinical population in order to normalize their abnormal neural activity. The dissertation focused on the implementation of the rt-fMRI neurofeedback to the Post-Traumatic Stress Disorder (PTSD) patients. PTSD is developed as a result of experiencing a traumatic event in first hand or hearing that a close one experienced it. PTSD has a high prevalence (Kessler et al., 2005) and also high impact on the patient’s life quality (Warshaw et al., 1993). Unfortunately the response rate to the therapy is around 50% (Bradley et al., 2005; Stein et al., 2006). Hence, there is a need for a new treatment tool for PTSD. The neurocircuitry model of PTSD indicate that there is increased activity in amygdala, decreased activity in ventromedial prefrontral cortex (vmPFC)/rostral ACC (rACC) and hippocampus (Rauch et al., 2006). Animal model of PTSD revealed that stimulating rACC led to increase in extinction learning and rats exhibited less PTSD symptoms (Milad & Quirk, 2002). Following these findings, we decided to implement rACC rt-fMRI neurofeedback to PTSD patients. The first study focused to develop a new paradigm to target rACC and tested it with healthy population. We used Ekman faces as functional localizer in order to locate the rACC. Experimental design constituted of four functional runs in one session. The main aim was to assess the methods effectiveness in one session. Surprisingly eight out of sixteen female participants learned to regulate their rACC, whereas only four out of sixteen male participants were able to regulate their rACC at will. Interestingly the learner/non-learners are not widely reported in the rt-fMRI literature and no gender difference has been reported so far. As a result we decided to implement it with only one sex in PTSD group. In the second study we tested the paradigm with the female PTSD patients. Eight out of sixteen PTSD patients gained control over their rACC. We also found that PTSD patients recruited more brain regions, especially multi-sensory brain regions for the upregulation of rACC in comparison to healthy subjects. We failed to find a single factor to predict rACC control success across groups. There is a need for further study to identify the predictor factors. As a result we concluded that the best practice of rt-fMRI with PTSD patients would be to use it as a supportive tool to psychotherapy in order to identify the best working strategy for their treatment. Further research recommendations are discussed below

Spatio-Temporal and Multisensory Integration: the relationship between sleep and the cerebellum

Does the cerebellum sleep? If so, does sleep contribute to cerebellar cognition? In this thesis, the sleep contribution to the consolidation process of spatial-temporal and multisensory integration was investigated in relation to the human cerebellum. Multiple experimental approaches were used to answer research questions addressed in the various chapters. Summarizing the evidence of the electrophysiology and neuroimaging studies, in Chapter1 we present intriguing evidence that the cerebellum is involved in sleep physiology, and that cerebellar-dependent memory formation can be consolidated during sleep. In Chapter 2, using functional neuroimaging in healthy participants during various forms of the Serial interception sequential learning (SISL) task, i.e., predictive timing, motor coordination, and motor imagination, we assessed the cerebellar involvement in spatio-temporal predictive timing; and possible cerebellar interactions with other regions, most notably the hippocampus. In Chapter 3, we add to the findings of Chapter 2 that indicate the cerebellum and hippocampus are involved in the task, by showing that more than simply activated, the cerebellum is a necessary and responsible region for the establishment of the spatio-temporal prediction. This follows from the deficits in behavioral properties of the predictive and reactive timing in the cerebellar ataxia type 6 patients, using the modified version of the SISL task. In Chapter 4, we assessed the subsequent post-interval behavioral performances on the learning of the fixed and random timing sequences in the SISL task, comparing a sleep group and wake group in healthy participants. Our findings show that sleep consolidates the process of cerebellar-dependent spatio-temporal integration. In Chapter 5, we investigated the establishment of visual-tactile integration during sleep through the examination of tactile motion stimulation during sleep and showed that, subsequent to sleep, directional visual motion discrimination i

Analysis of consciousness for complete locked-in syndrome patients

This thesis presents methods for detecting consciousness in patients with complete locked-in syndrome (CLIS). CLIS patients are unable to speak and have lost all muscle movement. Externally, the internal brain activity of such patients cannot be easily perceived, but CLIS patients are considered to be still conscious and cognitively active. Detecting the current state of consciousness of CLIS patients is non-trivial, and it is difficult to ascertain whether CLIS patients are conscious or not. Thus, it is vital to develop alternative ways to re-establish communication with these patients during periods of awareness, and a possible platform is through brain–computer interface (BCI). Since consciousness is required to use BCI correctly, this study proposes a modus operandi to analyze not only in intracranial electrocorticography (ECoG) signals with greater signal-to-noise ratio (SNR) and higher signal amplitude, but also in non-invasive electroencephalography (EEG) signals. By applying three different time-domain analysis approaches sample entropy, permutation entropy, and Poincaré plot as feature extraction to prevent disease-related reductions of brainwave frequency bands in CLIS patients, and cross-validated to improve the probability of correctly detecting the conscious states of CLIS patients. Due to the lack a of 'ground truth' that could be used as teaching input to correct the outcomes, k-Means and DBSCAN these unsupervised learning methods were used to reveal the presence of different levels of consciousness for individual participation in the experiment first in locked-in state (LIS) patients with ALSFRS-R score of 0. The results of these different methods converge on the specific periods of consciousness of CLIS/LIS patients, coinciding with the period during which CLIS/LIS patients recorded communication with an experimenter. To determine methodological feasibility, the methods were also applied to patients with disorders of consciousness (DOC). The results indicate that the use of sample entropy might be helpful to detect awareness not only in CLIS/LIS patients but also in minimally conscious state (MCS)/unresponsive wakefulness syndrome (UWS) patients, and showed good resolution for both ECoG signals up to 24 hours a day and EEG signals focused on one or two hours at the time of the experiment. This thesis focus on consistent results across multiple channels to avoid compensatory effects of brain injury. Unlike most techniques designed to help clinicians diagnose and understand patients' long-term disease progression or distinguish between different disease types on the clinical scales of consciousness. The aim of this investigation is to develop a reliable brain-computer interface-based communication aid eventually to provide family members with a method for short-term communication with CLIS patients in daily life, and at the same time, this will keep patients' brains active to increase patients' willingness to live and improve their quality of life (QOL)

Assessing brain connectivity through electroencephalographic signal processing and modeling analysis

Brain functioning relies on the interaction of several neural populations connected through complex connectivity networks, enabling the transmission and integration of information. Recent advances in neuroimaging techniques, such as electroencephalography (EEG), have deepened our understanding of the reciprocal roles played by brain regions during cognitive processes. The underlying idea of this PhD research is that EEG-related functional connectivity (FC) changes in the brain may incorporate important neuromarkers of behavior and cognition, as well as brain disorders, even at subclinical levels. However, a complete understanding of the reliability of the wide range of existing connectivity estimation techniques is still lacking. The first part of this work addresses this limitation by employing Neural Mass Models (NMMs), which simulate EEG activity and offer a unique tool to study interconnected networks of brain regions in controlled conditions. NMMs were employed to test FC estimators like Transfer Entropy and Granger Causality in linear and nonlinear conditions. Results revealed that connectivity estimates reflect information transmission between brain regions, a quantity that can be significantly different from the connectivity strength, and that Granger causality outperforms the other estimators. A second objective of this thesis was to assess brain connectivity and network changes on EEG data reconstructed at the cortical level. Functional brain connectivity has been estimated through Granger Causality, in both temporal and spectral domains, with the following goals: a) detect task-dependent functional connectivity network changes, focusing on internal-external attention competition and fear conditioning and reversal; b) identify resting-state network alterations in a subclinical population with high autistic traits. Connectivity-based neuromarkers, compared to the canonical EEG analysis, can provide deeper insights into brain mechanisms and may drive future diagnostic methods and therapeutic interventions. However, further methodological studies are required to fully understand the accuracy and information captured by FC estimates, especially concerning nonlinear phenomena