James Sulzer

Real-time fMRI neurofeedback: progress and challenges.

In February of 2012, the first international conference on real time functional magnetic resonance imaging (rtfMRI) neurofeedback was held at the Swiss Federal Institute of Technology Zurich (ETHZ), Switzerland. This review summarizes progress in the field, introduces current debates, elucidates open questions, and offers viewpoints derived from the conference. The review offers perspectives on study design, scientific and clinical applications, rtfMRI learning mechanisms and future outlook.

Closed-loop brain training: the science of neurofeedback

Neurofeedback is a psychophysiological procedure in which online feedback of neural activation is provided to the participant for the purpose of self-regulation. Learning control over specific neural substrates has been shown to change specific behaviours. As a progenitor of brain–machine interfaces, neurofeedback has provided a novel way to investigate brain function and neuroplasticity. In this Review, we examine the mechanisms underlying neurofeedback, which have started to be uncovered. We also discuss how neurofeedback is being used in novel experimental and clinical paradigms from a multidisciplinary perspective, encompassing neuroscientific, neuroengineering and learning-science viewpoints.

A Highly Backdrivable, Lightweight Knee Actuator for Investigating Gait in Stroke

Many of those who survive a stroke develop a gait disability known as stiff-knee gait (SKG). Characterized by reduced knee flexion angle during swing, people with SKG walk with poor energy efficiency and asymmetry due to the compensatory mechanisms required to clear the foot. Previous modeling studies have shown that knee flexion activity directly before the foot leaves the ground, and this should result in improved knee flexion angle during swing. The goal of this research is to physically test this hypothesis using robotic intervention. We developed a device that is capable of assisting knee flexion torque before swing but feels imperceptible (transparent) for the rest of the gait cycle. This device uses sheathed Bowden cable to control the deflection of a compliant torsional spring in a configuration known as a series elastic remote knee actuator (SERKA). In this investigation, we describe the design and evaluation of SERKA, which includes a pilot experiment on stroke subjects. SERKA could supply a substantial torque (12 N middot m) in less than 20 ms, with a maximum torque of 41 N middot m. The device resisted knee flexion imperceptibly when desired, at less than 1 N middot m rms torque during normal gait. With the remote location of the actuator, the user experiences a mass of only 1.2 kg on the knee. We found that the device was capable of increasing both peak knee flexion angle and velocity during gait in stroke subjects. Thus, the SERKA is a valid experimental device that selectively alters knee kinetics and kinematics in gait after stroke.

Neurofeedback-mediated self-regulation of the dopaminergic midbrain

The dopaminergic system is involved in reward encoding and reinforcement learning. Dopaminergic neurons from this system in the substantia nigra/ventral tegmental area complex (SN/VTA) fire in response to unexpected reinforcing cues. The goal of this study was to investigate whether individuals can gain voluntary control of SN/VTA activity, thereby potentially enhancing dopamine release to target brain regions. Neurofeedback and mental imagery were used to self-regulate the SN/VTA. Real-time functional magnetic resonance imaging (rtfMRI) provided abstract visual feedback of the SN/VTA activity while the subject imagined rewarding scenes. Skin conductance response (SCR) was recorded as a measure of emotional arousal. To examine the effect of neurofeedback, subjects were assigned to either receiving feedback directly proportional (n=15, veridical feedback) or inversely proportional (n=17, inverted feedback) to SN/VTA activity. Both groups of subjects were able to up-regulate SN/VTA activity initially without feedback. Veridical feedback improved the ability to up-regulate SN/VTA compared to baseline while inverted feedback did not. Additional dopaminergic regions were activated in both groups. The ability to self-regulate SN/VTA was differentially correlated with SCR depending on the group, suggesting an association between emotional arousal and neurofeedback performance. These findings indicate that SN/VTA can be voluntarily activated by imagery and voluntary activation is further enhanced by neurofeedback. The findings may lead the way towards a non-invasive strategy for endogenous control of dopamine.

Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: How is brain regulation mediated?

An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback-guided control of brain activation, i.e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first- (single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate cortex, the dorsolateral and ventrolateral prefrontal cortex, the temporo-parietal area and the visual association areas including the temporo-occipital junction. In conclusion, we demonstrate that several key regions, such as the anterior insula and the basal ganglia, are consistently activated during self-regulation in real-time fMRI neurofeedback independent of the targeted region-of-interest. Our results imply that if the real-time fMRI neurofeedback studies target regions of this regulation network, such as the anterior insula, care should be given whether activation changes are related to successful regulation, or related to the regulation process per se. Furthermore, future research is needed to determine how activation within this regulation network is related to neurofeedback success.

Real-time Neurofeedback Using Functional MRI Could Improve Down-Regulation of Amygdala Activity During Emotional Stimulation: A Proof-of-Concept Study

AbstractThe amygdala is a central target of emotion regulation. It is overactive and dysregulated in affective and anxiety disorders and amygdala activity normalizes with successful therapy of the symptoms. However, a considerable percentage of patients do not reach remission within acceptable duration of treatment. The amygdala could therefore represent a promising target for real-time functional magnetic resonance imaging (rtfMRI) neurofeedback. rtfMRI neurofeedback directly improves the voluntary regulation of localized brain activity. At present, most rtfMRI neurofeedback studies have trained participants to increase activity of a target, i.e. up-regulation. However, in the case of the amygdala, down-regulation is supposedly more clinically relevant. Therefore, we developed a task that trained participants to down-regulate activity of the right amygdala while being confronted with amygdala stimulation, i.e. negative emotional faces. The activity in the functionally-defined region was used as online visual feedback in six healthy subjects instructed to minimize this signal using reality checking as emotion regulation strategy. Over a period of four training sessions, participants significantly increased down-regulation of the right amygdala compared to a passive viewing condition to control for habilitation effects. This result supports the concept of using rtfMRI neurofeedback training to control brain activity during relevant stimulation, specifically in the case of emotion, and has implications towards clinical treatment of emotional disorders.

Preswing Knee Flexion Assistance Is Coupled With Hip Abduction in People With Stiff-Knee Gait After Stroke

Background and Purpose— Stiff-knee gait is defined as reduced knee flexion during the swing phase. It is accompanied by frontal plane compensatory movements (eg, circumduction and hip hiking) typically thought to result from reduced toe clearance. As such, we examined if knee flexion assistance before foot-off would reduce exaggerated frontal plane movements in people with stiff-knee gait after stroke. Methods— We used a robotic knee orthosis to assist knee flexion torque during the preswing phase in 9 chronic stroke subjects with stiff-knee gait on a treadmill and compared peak knee flexion, hip abduction, and pelvic obliquity angles with 5 nondisabled control subjects. Results— Maximum knee flexion angle significantly increased in both groups, but instead of reducing gait compensations, hip abduction significantly increased during assistance in stroke subjects by 2.5°, whereas no change was observed in nondisabled control subjects. No change in pelvic obliquity was observed in either group. Conclusions— Hip abduction increased when stroke subjects received assistive knee flexion torque at foot-off. These findings are in direct contrast to the traditional belief that pelvic obliquity combined with hip abduction is a compensatory mechanism to facilitate foot clearance during swing. Because no evidence suggested a voluntary mechanism for this behavior, we argue that these results were most likely a reflection of an altered motor template occurring after stroke.

Improvement in precision grip force control with self-modulation of primary motor cortex during motor imagery.

Motor imagery (MI) has shown effectiveness in enhancing motor performance. This may be due to the common neural mechanisms underlying MI and motor execution (ME). The main region of the ME network, the primary motor cortex (M1), has been consistently linked to motor performance. However, the activation of M1 during motor imagery is controversial, which may account for inconsistent rehabilitation therapy outcomes using MI. Here, we examined the relationship between contralateral M1 (cM1) activation during MI and changes in sensorimotor performance. To aid cM1 activity modulation during MI, we used real-time fMRI neurofeedback-guided MI based on cM1 hand area blood oxygen level dependent (BOLD) signal in healthy subjects, performing kinesthetic MI of pinching. We used multiple regression analysis to examine the correlation between cM1 BOLD signal and changes in motor performance during an isometric pinching task of those subjects who were able to activate cM1 during motor imagery. Activities in premotor and parietal regions were used as covariates. We found that cM1 activity was positively correlated to improvements in accuracy as well as overall performance improvements, whereas other regions in the sensorimotor network were not. The association between cM1 activation during MI with performance changes indicates that subjects with stronger cM1 activation during MI may benefit more from MI training, with implications toward targeted neurotherapy.

Design of a wearable perturbator for human knee impedance estimation during gait

Mechanical impedance modulation is the key to natural, stable and efficient human locomotion. An improved understanding of this mechanism is necessary for the development of the next generation of intelligent prosthetic and orthotic devices. This paper documents the design methodologies that were employed to realize a knee perturbator that can experimentally estimate human knee impedance during gait through the application of angular velocity perturbations. The proposed experiment requires a light, transparent, wearable, and remotely actuated device that closely follows the movement of the biological joint. A genetic algorithm was used to design a polycentric hinge whose instantaneous center of rotation is optimized to be kinematically compatible with the human knee. A wafer disc clutch was designed to switch between a high transparency passive mode and a high impedance actuated mode. A remote actuation and transmission scheme was designed to enable high power output perturbations while minimizing the devices mass. Position and torque sensors were designed for device control and to provide data for post-processing and joint impedance estimation. Pending the fabrication and mechanical testing of the device, we expect this knee perturbator to be a valuable tool for experimental investigation of locomotive joint impedance modulation.

WITHDRAWN: Neurofeedback-mediated self-regulation of the dopaminergic midbrain

The publisher regrets due to an error in the publishing process the above articles was accidentally withdrawn and has now been published in (Neuroimage 83C December 2013 https://doi.org/10.1016/j.neuroimage.2013.05.115). The publisher would like to apologize for any inconvenience caused.