Four methods of brain pattern analyses of fMRI signals associated with wrist extension versus wrist flexion studied for potential use in future motor learning BCI.

OBJECTIVE: In stroke survivors, a treatment-resistant problem is inability to volitionally differentiate upper limb wrist extension versus flexion. When one intends to extend the wrist, the opposite occurs, wrist flexion, rendering the limb non-functional. Conventional therapeutic approaches have had limited success in achieving functional recovery of patients with chronic and severe upper extremity impairments. Functional magnetic resonance imaging (fMRI) neurofeedback is an emerging strategy that has shown potential for stroke rehabilitation. There is a lack of information regarding unique blood-oxygenation-level dependent (BOLD) cortical activations uniquely controlling execution of wrist extension versus uniquely controlling wrist flexion. Therefore, a first step in providing accurate neural feedback and training to the stroke survivor is to determine the feasibility of classifying (or differentiating) brain activity uniquely associated with wrist extension from that of wrist flexion, first in healthy adults. APPROACH: We studied brain signal of 10 healthy adults, who performed wrist extension and wrist flexion during fMRI data acquisition. We selected four types of analyses to study the feasibility of differentiating brain signal driving wrist extension versus wrist flexion, as follows: 1) general linear model (GLM) analysis; 2) support vector machine (SVM) classification; 3) 'Winner Take All'; and 4) Relative Dominance. RESULTS: With these four methods and our data, we found that few voxels were uniquely active during either wrist extension or wrist flexion. SVM resulted in only minimal classification accuracies. There was no significant difference in activation magnitude between wrist extension versus flexion; however, clusters of voxels showed extension signal > flexion signal and other clusters vice versa. Spatial patterns of activation differed among subjects. SIGNIFICANCE: We encountered a number of obstacles to obtaining clear group results in healthy adults. These obstacles included the following: high variability across healthy adults in all measures studied; close proximity of uniquely active voxels to voxels that were common to both the extension and flexion movements; in general, higher magnitude of signal for the voxels common to both movements versus the magnitude of any given uniquely active voxel for one type of movement. Our results indicate that greater precision in imaging will be required to develop a truly effective method for differentiating wrist extension versus wrist flexion from fMRI data.

Development of a combined, sequential real-time fMRI and fNIRS neurofeedback system to enhance motor learning after stroke.

BACKGROUND: After stroke, wrist extension dyscoordination precludes functional arm/hand. We developed a more spatially precise brain signal for use in brain computer interface (BCI's) for stroke survivors. NEW METHOD: Combination BCI protocol of real-time functional magnetic resonance imaging (rt-fMRI) sequentially followed by functional near infrared spectroscopy (rt-fNIRS) neurofeedback, interleaved with motor learning sessions without neural feedback. Custom Matlab and Python code was developed to provide rt-fNIRS-based feedback to the chronic stroke survivor, system user. RESULTS: The user achieved a maximum of 71 % brain signal accuracy during rt-fNIRS neural training; progressive focus of brain activation across rt-fMRI neural training; increasing trend of brain signal amplitude during wrist extension across rt-fNIRS training; and clinically significant recovery of arm coordination and active wrist extension. COMPARISON WITH EXISTING METHODS: Neurorehabilitation, peripherally directed, shows limited efficacy, as do EEG-based BCIs, for motor recovery of moderate/severely impaired stroke survivors. EEG-based BCIs are based on electrophysiological signal; whereas, rt-fMRI and rt-fNIRS are based on neurovascular signal. CONCLUSION: The system functioned well during user testing. Methods are detailed for others' use. The system user successfully engaged rt-fMRI and rt-fNIRS neurofeedback systems, modulated brain signal during rt-fMRI and rt-fNIRS training, according to volume of brain activation and intensity of signal, respectively, and clinically significantly improved limb coordination and active wrist extension. fNIRS use in this case demonstrates a feasible/practical BCI system for further study with regard to use in chronic stroke rehab, and fMRI worked in concept, but cost and some patient-use issues make it less feasible for clinical practice.

Shifting Spatial Neglect With Repeated Line Bisections: Possible Role of Lateralized Attentional Fatigue.

BACKGROUND AND OBJECTIVE: Many patients who have signs of neglect immediately after a right hemisphere stroke remain disabled even when they improve on tests of neglect. Few patients are tested for attentional persistence and fatigue despite their importance in many instrumental activities. To investigate whether stimulus repetition might alter the allocation of attention, we repeatedly tested a patient 16 weeks after she developed hemispatial neglect from a right hemisphere stroke. METHODS: During each of three testing sessions given in 1 day, we asked the patient to bisect 90 lines of two lengths, presented in 30-trial blocks in three locations: left, center, and right of her midsagittal plane, partially counterbalanced across sessions. We adjusted multiple regression analyses and analysis of variance as well as post hoc regression and t tests for persistence in the repeated measures using variance-sample size analysis to estimate self-similarity, a measure related to the fractal correlation dimension. RESULTS: In each session, the patient's line bisections revealed transient leftward bias in her left peripersonal space, and constant rightward bias in her right peripersonal space. Her leftward bias shifted to a rightward bias over repeated trials in her left space. CONCLUSIONS: The patient's left-to-right shift with repeated trials suggests either fatigue from an attempted compensation for leftward inattention or habituation of a contralesional spatial attentional attraction, revealing contralesional left-sided neglect in both the left and right spaces. Future studies are needed to learn if other patients show similar or different deficits with repetition, and how best to treat them.

Vestibulo-ocular reflex function in children with high-functioning autism spectrum disorders.

Sensorimotor processing alterations are a growing focus in the assessment and treatment of Autism Spectrum Disorders (ASD). The rotational vestibulo-ocular reflex (rVOR), which functions to maintain stable vision during head movements, is a sensorimotor system that may be useful in understanding such alterations and their underlying neurobiology. In this study, we assessed post-rotary nystagmus elicited by continuous whole body rotation among children with high-functioning ASD and typically developing children. Children with ASD exhibited increased rVOR gain, the ratio of eye velocity to head velocity, indicating a possible lack of cerebellar inhibitory input to brainstem vestibular nuclei in this population. The ASD group also showed less regular or periodic horizontal eye movements as indexed by greater variance accounted for by multiple higher frequency bandwidths as well as greater entropy scores compared to typically developing children. The decreased regularity or dysrhythmia in the temporal structure of nystagmus beats in children with ASD may be due to alterations in cerebellum and brainstem circuitry. These findings could potentially serve as a model to better understand the functional effects of differences in these brain structures in ASD. Autism Res 2017, 10: 251-266. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Oculomotor performance in children with high-functioning Autism Spectrum Disorders.

Sensorimotor issues are of increasing focus in the assessment and treatment of Autism Spectrum Disorders (ASD). The oculomotor system is a sensorimotor network that can provide insights into functional neurobiology and has well-established methodologies for investigation. In this study, we assessed oculomotor performance among children with high functioning ASD and typically developing children, ages 6-12 years. Children with ASD exhibited greater horizontal saccade latency and greater phase lag during vertical smooth pursuit. Saccades and smooth pursuit are mediated by spatially distant brain regions and the long-fiber tracts connecting them, many of which are implicated in ASD. Training paradigms for oculomotor deficits have shown positive outcomes in other clinical populations, and deficits described here may provide useful targets for interventions.

Motor map reliability and aging: a TMS/fMRI study.

This study compared the reliability of motor maps over 3 sessions from both neuronavigated transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) data between younger and older adults. Seven younger (ages 19-31) and seven older (ages 64-76) adults participated in three joint TMS/fMRI assessment sessions separated by 7 or 14 days. Sessions involved mapping of the right first dorsal interosseous muscle using single-pulse TMS immediately followed by block-design fMRI scanning involving volitional right-hand index finger to thumb oppositional squeeze. Intersession reliability of map volume, evaluated by intraclass correlation and Jaccard Coefficient between testing sessions, was more consistent for younger adults in both fMRI and TMS. A positive correlation was evidenced between fMRI and TMS map volumes and Jaccard Coefficients indicating spatial consistency across sessions between the two measures. Comparisons of map reliability between age groups showed that younger adults have more stable motor maps in both fMRI and TMS. fMRI and TMS maps show consistency across modalities. Future interpretation of motor maps should attempt to account for potential increased variability of such mapping in older age groups. Despite these age group differences in reliability, fMRI and TMS appear to offer consistent and complementary information about cortical representation of the first dorsal interosseous muscle.

Physical activity and neural correlates of aging: a combined TMS/fMRI study.

Aerobic exercise has been suggested to ameliorate aging-related decline in humans. Recently, evidence has indicated chronological aging is associated with decreases in measures of interhemispheric inhibition during unimanual movements, but that such decreases may be mitigated by long-term physical fitness. The present study investigated measures of ipsilateral (right) primary motor cortex activity during right-hand movements using functional magnetic resonance imaging and transcranial magnetic stimulation (TMS). Healthy, right-handed participant groups were comprised of 12 sedentary older adults, 12 physically active older adults, and 12 young adults. Active older adults and younger adults evidenced longer ipsilateral silent periods (iSP) and less positive BOLD of ipsilateral motor cortex (iM1) as compared to sedentary older adults. Across groups, duration of iSP from TMS was inversely correlated with BOLD activity in iM1 during unimanual movement. These findings suggest that increased physical activity may have a role in decreasing aging-related losses of interhemispheric inhibition.

Structural connectivity of Broca's area and medial frontal cortex.

Despite over 140 years of research on Broca's area, the connections of this region to medial frontal cortex remain unclear. The current study investigates this structural connectivity using diffusion-weighted MRI tractography in living humans. Our results show connections between Broca's area and Brodmann's areas (BA) 9, 8, and 6 (both supplementary motor area (SMA) in caudal BA 6, and Pre-SMA in rostral BA 6). Trajectories follow an anterior-to-posterior gradient, wherein the most anterior portions of Broca's area connect to BA 9 and 8 while posterior Broca's area connects to Pre-SMA and SMA. This anterior-posterior connectivity gradient is also present when connectivity-based parcellation of Broca's area is performed. Previous studies of language organization suggest involvement of anterior Broca's area in semantics and posterior Broca's area in syntax/phonology. Given corresponding patterns of functional and structural organization of Broca's area, it seems well warranted to investigate carefully how anterior vs. posterior medial frontal cortex differentially affect semantics, syntax and phonology.

Regional changes in word-production laterality after a naming treatment designed to produce a rightward shift in frontal activity.

Five nonfluent aphasia patients participated in a picture-naming treatment that used an intention manipulation (opening a box and pressing a button on a device in the box with the left hand) to initiate naming trials and was designed to re-lateralize word production mechanisms from the left to the right frontal lobe. To test the underlying assumption regarding re-lateralization, patients participated in fMRI of category-member generation before and after treatment. Generally, the four patients who improved during treatment showed reduced frontal activity from pre- to post-treatment fMRI with increasing concentration of activity in the right posterior frontal lobe (motor/premotor cortex, pars opercularis), demonstrating a significant shift in lateraliity toward the right lateral frontal lobe, as predicted. Three of these four patients showed no left frontal activity by completion of treatment, indicating that right posterior lateral frontal activity supported category-member generation. Patients who improved in treatment showed no difference in lateralization of lateral frontal activity from normal controls pre-treatment, but post-treatment, their lateral frontal activity during category-member generation was significantly more right lateralized than that of controls. Patterns of activity pre- and post-treatment suggested increasing efficiency of cortical processing as a result of treatment in the four patients who improved. The one patient who did not improve during treatment showed a leftward shift in lateral frontal lateralization that was significantly different from the four patients who did improve. Neither medial frontal nor posterior perisylvian re-lateralization from immediately pre- to immediately post-treatment images was a necessary condition for significant treatment gains or shift in lateral frontal lateralization. Of the three patients who improved and in whom posterior perisylvian activity could be measured at post-treatment fMRI, all maintained equal or greater amounts of left-hemisphere perisylvian activity as compared to right. This finding is consistent with reviews suggesting both hemispheres are involved in recovery of language in aphasia patients.

Optical head tracking for functional magnetic resonance imaging using structured light.

An accurate motion-tracking technique is needed to compensate for subject motion during functional magnetic resonance imaging (fMRI) procedures. Here, a novel approach to motion metrology is discussed. A structured light pattern specifically coded for digital signal processing is positioned onto a fiduciary of the patient. As the patient undergoes spatial transformations in 6 DoF (degrees of freedom), a high-resolution CCD camera captures successive images for analysis on a computing platform. A high-speed image processing algorithm is used to calculate spatial transformations in a time frame commensurate with patient movements (10-100 ms) and with a precision of at least 0.5 microm for translations and 0.1 deg for rotations.

Assessing a signal model and identifying brain activity from fMRI data by a detrending-based fractal analysis.

One of the major challenges of functional magnetic resonance imaging (fMRI) data analysis is to develop simple and reliable methods to correlate brain regions with functionality. In this paper, we employ a detrending-based fractal method, called detrended fluctuation analysis (DFA), to identify brain activity from fMRI data. We perform three tasks: (a) Estimating noise level from experimental fMRI data; (b) Assessing a signal model recently introduced by Birn et al.; and (c) Evaluating the effectiveness of DFA for discriminating brain activations from artifacts. By computing the receiver operating characteristic (ROC) curves, we find that the ROC curve for experimental data is similar to the curve for simulated data with similar signal-to-noise ratio (SNR). This suggests that the proposed algorithm for estimating noise level is very effective and that Birn's model fits our experimental data very well. The brain activation maps for experimental data derived by DFA are similar to maps derived by deconvolution using a widely used software, AFNI. Considering that deconvolution explicitly uses the information about the experimental paradigm to extract the activation patterns whereas DFA does not, it remains to be seen whether one can effectively integrate the two methods to improve accuracy for detecting brain areas related to functional activity.

Discriminating brain activity from task-related artifacts in functional MRI: fractal scaling analysis simulation and application.

Functional magnetic resonance imaging (fMRI) signal changes can be separated from background noise by various processing algorithms, including the well-known deconvolution method. However, discriminating signal changes due to task-related brain activities from those due to task-related head motion or other artifacts correlated in time to the task has been little addressed. We examine whether three exploratory fractal scaling analyses correctly classify these possibilities by capturing temporal self-similarity; namely, fluctuation analysis, wavelet multi-resolution analysis, and detrended fluctuation analysis (DFA). We specifically evaluate whether these fractal analytic methods can be effective and reliable in discriminating activations from artifacts. DFA is indeed robust for such classification. Brain activation maps derived by DFA are similar, but not identical, to maps derived by deconvolution. Deconvolution explicitly utilizes task timing to extract the signals whereas DFA does not, so these methods reveal somewhat different information from the data. DFA is better than deconvolution for distinguishing fMRI activations from task-related artifacts, although a combination of these approaches is superior to either one taken alone. We also present a method for estimating noise levels in fMRI data, validated with numerical simulations suggesting that Birn's model is effective for simulating fMRI signals. Simulations further corroborate that DFA is excellent at discriminating signal changes due to task-related brain activities from those due to task-related artifacts, under a range of conditions.

Functional MRI of language in aphasia: a review of the literature and the methodological challenges.

Animal analogue studies show that damaged adult brains reorganize to accommodate compromised functions. In the human arena, functional magnetic resonance imaging (fMRI) and other functional neuroimaging techniques have been used to study reorganization of language substrates in aphasia. The resulting controversy regarding whether the right or the left hemisphere supports language recovery and treatment progress must be reframed. A more appropriate question is when left-hemisphere mechanisms and when right-hemisphere mechanisms support recovery of language functions. Small lesions generally lead to good recoveries supported by left-hemisphere mechanisms. However, when too much language eloquent cortex is damaged, right-hemisphere structures may provide the better substrate for recovery of language. Some studies suggest that recovery is particularly supported by homologues of damaged left-hemisphere structures. Evidence also suggests that under some circumstances, activity in both the left and right hemispheres can interfere with recovery of function. Further research will be needed to address these issues. However, daunting methodological problems must be managed to maximize the yield of future fMRI research in aphasia, especially in the area of language production. In this review, we cover six challenges for imaging language functions in aphasia with fMRI, with an emphasis on language production: (1) selection of a baseline task, (2) structure of language production trials, (3) mitigation of motion-related artifacts, (4) the use of stimulus onset versus response onset in fMRI analyses, (5) use of trials with correct responses and errors in analyses, and (6) reliability and stability of fMRI images across sessions. However, this list of methodological challenges is not exhaustive. Once methodology is advanced, knowledge from conceptually driven fMRI studies can be used to develop theoretically driven, mechanism-based treatments that will result in more effective therapy and to identify the best patient candidates for specific treatments. While the promise of fMRI in the study of aphasia is great, there is much work to be done before this technique will be a useful clinical tool.

Asymmetrical alien hands in corticobasal degeneration.

There are several forms of alien limb, but alien limb in corticobasal degeneration (CBD) is not well understood. We studied a patient with CBD who demonstrated two different types of alien limb. With his right hand he demonstrated a tactile avoidance response with levitation. With his left hand, he demonstrated continuous tactile pursuit of the examiner's hand ("tactile mitgehen"). Mitgehen is often associated with frontal dysfunction, but avoidance response and levitation are often associated with parietal dysfunction.

Neural substrates of syntactic mapping treatment: an fMRI study of two cases.

Two patients (G01, J02) with chronic nonfluent aphasia and sentence production deficits received syntactic mapping treatment to improve sentence production. The patients had dramatically different outcomes in that improved syntax production generalized to nontreatment tasks for G01, but not for JO2. To learn how treatment influenced the neural substrates for syntax production, both patients underwent pre- and posttreatment functional magnetic resonance imaging (fMRI) of sentence generation. G01 showed more robust activity posttreatment than pretreatment in Broca's area; ventral temporal activity decreased slightly from pre- to posttreatment. Comparison of J02's pretreatment and posttreatment images revealed little change, although activity was more diffuse pre- than posttreatment. Findings suggest that for G01, rehabilitation led to engagement of an area (Broca's area) used minimally during the pretreatment scan, whereas for J02, rehabilitation may have led to more efficient use of areas already involved in sentence generation during the pretreatment scan. fMRI findings are discussed in the context of sentence-production outcome and generalization.

Role of the right and left hemispheres in recovery of function during treatment of intention in aphasia.

Two patients with residual nonfluent aphasia after ischemic stroke received an intention treatment that was designed to shift intention and language production mechanisms from the frontal lobe of the damaged left hemisphere to the right frontal lobe. Consistent with experimental hypotheses, the first patient showed improvement on the intention treatment but not on a similar attention treatment. In addition, in keeping with experimental hypotheses, the patient showed a shift of activity to right presupplementary motor area and the right lateral frontal lobe from pre- to post-intention treatment functional magnetic resonance imaging (fMRI) of language production. In contrast, the second patient showed improvement on both the intention and attention treatments. During pre-treatment fMRI, she already showed lateralization of intention and language production mechanisms to the right hemisphere that continued into post-intention treatment imaging. From pre- to post-treatment fMRI of language production, both patients demonstrated increased activity in the posterior perisylvian cortex, although this activity was lateralized to left-hemisphere language areas in the second but not the first patient. The fact that the first patient's lesion encompassed almost all of the dominant basal ganglia and thalamus whereas the second patient's lesion spared these structures suggests that the dominant basal ganglia could play a role in spontaneous reorganization of language production functions to the right hemisphere. Implications regarding the theoretical framework for the intention treatment are discussed.

Comparison of hemodynamic response nonlinearity across primary cortical areas.

Hemodynamic responses to auditory and visual stimuli and motor tasks were assessed for the nonlinearity of response in each of the respective primary cortices. Five stimulus or task durations were used (1, 2, 4, 8, and 16 s), and five male subjects (aged 19 +/- 1.9 years) were imaged. Two tests of linearity were conducted. The first test consisted of using BOLD responses to short stimuli to predict responses to longer stimuli. The second test consisted of fitting ideal impulse response functions to the observed responses for each event duration. Both methods show that the extent of the nonlinearity varies across cortices. Results for the second method indicate that the hemodynamic response is nonlinear for stimuli less than 10 s in the primary auditory cortex, nonlinear for tasks less than 7 s in the primary motor cortex, and nonlinear for stimuli less than 3 s in the primary visual cortex. In addition, neural adaptation functions were characterized that could model the observed nonlinearities.

Effects of the Amazonian psychoactive beverage Ayahuasca on binocular rivalry: interhemispheric switching or interhemispheric fusion?

An early theoretical analysis supposed changes in hemispheric integration as the basis of altered state of consciousness induced by psychoactive drugs. Brain imaging studies revealed right cortical activation after administration of hallucinogens. Recent studies on binocular rivalry suggest that interhemispheric switching is the neural substrate of the perceptual oscillations observed during dichoptic stimulus presentation. The current study tested perceptual alternation in ceremonial participants, who ingested the South American hallucinogenic beverage ayahuasca, to examine the claim that there might be changes in interhemispheric function under the influence of hallucinogens. Ingestion of ayahuasca resulted in a decrease of rivalry alternation rates, increased length of one percept and there was evidence of phenomenal fusion. The findings are in line with results of brain activation studies and support the concept of interhemispheric fusion in altered states of consciousness.