Remotely monitored transcranial direct current stimulation in pediatric cerebral palsy: open label trial protocol.

BACKGROUND: Pediatric applications of non-invasive brain stimulation using transcranial direct current stimulation (tDCS) have demonstrated its safety with few adverse events reported. Remotely monitored tDCS, as an adjuvant intervention to rehabilitation, may improve quality of life for children with cerebral palsy (CP) through motor function improvements, reduced treatment costs, and increased access to tDCS therapies. Our group previously evaluated the feasibility of a remotely monitored mock tDCS setup in which families and children successfully demonstrated the ability to follow tDCS instructional guidance. METHODS AND DESIGN: Here, we designed a protocol to investigate the feasibility, safety, and tolerability of at-home active transcranial direct current stimulation in children with CP with synchronous supervision from laboratory investigators. Ten participants will be recruited to participate in the study for 5 consecutive days with the following sessions: tDCS setup practice on day 1, sham tDCS on day 2, and active tDCS on days 3-5. Sham stimulation will consist of an initial 30-second ramp up to 1.5 mA stimulation followed by a 30-second ramp down. Active stimulation will be delivered at 1.0 - 1.5 mA for 20 minutes and adjusted based on child tolerance. Feasibility will be evaluated via photographs of montage setup and the quality of stimulation delivery. Safety and tolerability will be assessed through an adverse events survey, the Box and Blocks Test (BBT) motor assessment, and a setup ease/comfort survey. DISCUSSION: We expect synchronous supervision of at-home teleneuromodulation to be tolerable and safe with increasing stimulation quality over repeated sessions when following a tDCS setup previously determined to be feasible. The findings will provide opportunity for larger clinical trials exploring efficacy and illuminate the potential of remotely monitored tDCS in combination with rehabilitation interventions as a means of pediatric neurorehabilitation. This will demonstrate the value of greater accessibility of non-invasive brain stimulation interventions and ultimately offer the potential to improve care and quality of life for children and families with CP. TRIAL REGISTRATION: October 8, 2021( https://clinicaltrials.gov/ct2/show/NCT05071586 ).

Study Protocol: Multimodal Longitudinal Assessment of Infant Brain Organization and Recovery in Perinatal Brain Injury.

PURPOSE: Perinatal brain injury is a primary cause of cerebral palsy, a condition resulting in lifelong motor impairment. Infancy is an important period of motor system development, including development of the corticospinal tract (CST), the primary pathway for cortical movement control. The interaction between perinatal stroke recovery, CST organization, and resultant motor outcome in infants is not well understood. METHODS: Here, we present a protocol for multimodal longitudinal assessment of brain development and motor function following perinatal brain injury using transcranial magnetic stimulation and magnetic resonance imaging to noninvasively measure CST functional and structural integrity across multiple time points in infants 3 to 24 months of age. We will further assess the association between cortical excitability, integrity, and motor function. DISCUSSION: This protocol will identify bioindicators of motor outcome and neuroplasticity and subsequently inform early detection, diagnosis, and intervention strategies for infants with perinatal stroke, brain bleeds, and related diagnoses.

Neural correlates of lower limbs proprioception: An fMRI study of foot position matching.

Little is known about the neural correlates of lower limbs position sense, despite the impact that proprioceptive deficits have on everyday life activities, such as posture and gait control. We used fMRI to investigate in 30 healthy right-handed and right-footed subjects the regional distribution of brain activity during position matching tasks performed with the right dominant and the left nondominant foot. Along with the brain activation, we assessed the performance during both ipsilateral and contralateral matching tasks. Subjects had lower errors when matching was performed by the left nondominant foot. The fMRI analysis suggested that the significant regions responsible for position sense are in the right parietal and frontal cortex, providing a first characterization of the neural correlates of foot position matching.

The social hippocampus.

The concept of cognitive map has been proposed as a way to organize our experiences and guide behavior across all domains of cognition. The hippocampus has been identified as the neural substrate supporting cognitive maps for navigating physical space. Recent evidence is broadening the role of the hippocampus into mapping other manner of spaces. Here we focus on the case of social space as a candidate for hippocampal representation because it combines multiple continuous dimensions and requires dynamic navigation through social contexts. We present evidence for the role of the hippocampus in (1) supporting social memory, (2) representing different dimensions of social space, (3) tracking dynamic social behavior, (4) maintaining a flexible map allowing adaptation to new social contexts, and (5) maladaptive social behavior across psychiatric disorders. To do so, we explore evidence across species including birds, rodents, nonhuman primates and humans, indicating hippocampal involvement in a range of social processes. Review of previous findings in a manner predicted by the cognitive map supports the existence of systematic mapping of social space by the hippocampus. Evidence for hippocampal social maps complements findings from other abstract domains, such as auditory, temporal and conceptual, allowing successful navigation through many domains of everyday life.

A composite measure to explore visual disability in primary progressive multiple sclerosis.

BACKGROUND: Optical coherence tomography (OCT) and magnetic resonance imaging (MRI) can provide complementary information on visual system damage in multiple sclerosis (MS). OBJECTIVES: The objective of this paper is to determine whether a composite OCT/MRI score, reflecting cumulative damage along the entire visual pathway, can predict visual deficits in primary progressive multiple sclerosis (PPMS). METHODS: Twenty-five PPMS patients and 20 age-matched controls underwent neuro-ophthalmologic evaluation, spectral-domain OCT, and 3T brain MRI. Differences between groups were assessed by univariate general linear model and principal component analysis (PCA) grouped instrumental variables into main components. Linear regression analysis was used to assess the relationship between low-contrast visual acuity (LCVA), OCT/MRI-derived metrics and PCA-derived composite scores. RESULTS: PCA identified four main components explaining 80.69% of data variance. Considering each variable independently, LCVA 1.25% was significantly predicted by ganglion cell-inner plexiform layer (GCIPL) thickness, thalamic volume and optic radiation (OR) lesion volume (adjusted R2 0.328, p = 0.00004; adjusted R2 0.187, p = 0.002 and adjusted R2 0.180, p = 0.002). The PCA composite score of global visual pathway damage independently predicted both LCVA 1.25% (adjusted R2 value 0.361, p = 0.00001) and LCVA 2.50% (adjusted R2 value 0.323, p = 0.00003). CONCLUSION: A multiparametric score represents a more comprehensive and effective tool to explain visual disability than a single instrumental metric in PPMS.

Synchronization and variability imbalance underlie cognitive impairment in primary-progressive multiple sclerosis.

We aimed to investigate functional connectivity and variability across multiple frequency bands in brain networks underlying cognitive deficits in primary-progressive multiple sclerosis (PP-MS) and to explore how they are affected by the presence of cortical lesions (CLs). We analyzed functional connectivity and variability (measured as the standard deviation of BOLD signal amplitude) in resting state networks (RSNs) associated with cognitive deficits in different frequency bands in 25 PP-MS patients (12 M, mean age 50.9 ± 10.5 years) and 20 healthy subjects (9 M, mean age 51.0 ± 9.8 years). We confirmed the presence of a widespread cognitive deterioration in PP-MS patients, with main involvement of visuo-spatial and executive domains. Cognitively impaired patients showed increased variability, reduced synchronicity between networks involved in the control of cognitive macro-domains and hyper-synchronicity limited to the connections between networks functionally more segregated. CL volume was higher in patients with cognitive impairment and was correlated with functional connectivity and variability. We demonstrate, for the first time, that a functional reorganization characterized by hypo-synchronicity of functionally-related/hyper-synchronicity of functionally-segregated large scale networks and an abnormal pattern of neural activity underlie cognitive dysfunction in PP-MS, and that CLs possibly play a role in variability and functional connectivity abnormalities.

Motor Imagery as a Function of Disease Severity in Multiple Sclerosis: An fMRI Study.

Motor imagery (MI) is defined as mental execution without any actual movement. While healthy adults usually show temporal equivalence, i.e., isochrony, between the mental simulation of an action and its actual performance, neurological disorders are associated with anisochrony. Unlike in patients with stroke and Parkinson disease, only a few studies have investigated differences of MI ability in multiple sclerosis (MS). However, the relationship among disease severity, anisochrony and brain activation patterns during MI has not been investigated yet. Here, we propose to investigate MI in MS patients using fMRI during a behavioral task executed with dominant/non-dominant hand and to evaluate whether anisochrony is associated with disease severity. Thirty-seven right-handed MS patients, 17 with clinically isolated syndrome (CIS) suggestive of MS and 20 with relapsing-remitting MS (RR-MS) and 20 right-handed healthy controls (HC) underwent fMRI during a motor task consisting in the actual or imaged movement of squeezing a foam ball with the dominant and non-dominant hand. The same tasks were performed outside the MRI room to record the number of actual and imagined ball squeezes, and calculate an Index of performance (IP) based on the ratio between actual and imagined movements. IP showed that a progressive loss of ability in simulating actions (i.e., anisochrony) more pronounced for non-dominant hand, was found as function of the disease course. Moreover, anisochrony was associated with activation of occipito-parieto-frontal areas that were more extensive at the early stages of the disease, probably in order to counteract the changes due to MS. However, the neural engagement of compensatory brain areas becomes more difficult with more challenging tasks, i.e., dominant vs. non-dominant hand, with a consequent deficit in behavioral performance. These results show a strict association between MI performance and disease severity, suggesting that, at early stages of the disease, anisochrony in MI could be considered as surrogate behavioral marker of MS severity.

Resting-state functional connectivity and motor imagery brain activation.

Motor imagery (MI) relies on the mental simulation of an action without any overt motor execution (ME), and can facilitate motor learning and enhance the effect of rehabilitation in patients with neurological conditions. While functional magnetic resonance imaging (fMRI) during MI and ME reveals shared cortical representations, the role and functional relevance of the resting-state functional connectivity (RSFC) of brain regions involved in MI is yet unknown. Here, we performed resting-state fMRI followed by fMRI during ME and MI with the dominant hand. We used a behavioral chronometry test to measure ME and MI movement duration and compute an index of performance (IP). Then, we analyzed the voxel-matched correlation between the individual MI parameter estimates and seed-based RSFC maps in the MI network to measure the correspondence between RSFC and MI fMRI activation. We found that inter-individual differences in intrinsic connectivity in the MI network predicted several clusters of activation. Taken together, present findings provide first evidence that RSFC within the MI network is predictive of the activation of MI brain regions, including those associated with behavioral performance, thus suggesting a role for RSFC in obtaining a deeper understanding of neural substrates of MI and of MI ability. Hum Brain Mapp 37:3847-3857, 2016. © 2016 Wiley Periodicals, Inc.

Relationship between timed 25-foot walk and diffusion tensor imaging in multiple sclerosis.

OBJECTIVE/BACKGROUND: The majority of multiple sclerosis patients experience impaired walking ability, which impacts quality of life. Timed 25-foot walk is commonly used to gauge gait impairment but results can be broadly variable. Objective biological markers that correlate closely with patients' disability are needed. Diffusion tensor imaging, quantifying fiber tract integrity, might provide such information. In this project we analyzed relationships between timed 25-foot walk, conventional and diffusion tensor imaging magnetic resonance imaging markers. DESIGN/METHODS: A cohort of gait impaired multiple sclerosis patients underwent brain and cervical spinal cord magnetic resonance imaging. Diffusion tensor imaging mean diffusivity and fractional anisotropy were measured on the brain corticospinal tracts and spinal restricted field of vision at C2/3. We analyzed relationships between baseline timed 25-foot walk, conventional and diffusion tensor imaging magnetic resonance imaging markers. RESULTS: Multivariate linear regression analysis showed a statistically significant association between several magnetic resonance imaging and diffusion tensor imaging metrics and timed 25-foot walk: brain mean diffusivity corticospinal tracts (p = 0.004), brain corticospinal tracts axial and radial diffusivity (P = 0.004 and 0.02), grey matter volume (p = 0.05), white matter volume (p = 0.03) and normalized brain volume (P = 0.01). The linear regression model containing mean diffusivity corticospinal tracts and controlled for gait assistance was the best fit model (p = 0.004). CONCLUSIONS: Our results suggest an association between diffusion tensor imaging metrics and gait impairment, evidenced by brain mean diffusivity corticospinal tracts and timed 25-foot walk.

Impact of transcranial direct current stimulation on fatigue in multiple sclerosis.

PURPOSE: Fatigue is a frequent and difficult to treat symptom affecting patients with multiple sclerosis (MS) with a profound negative impact on quality of life. Fatigue has been associated with functional and structural abnormalities of the frontal cortex, including frontal hypo-activation. The aim of this exploratory study was to assess whether fatigue symptoms can be reduced by excitability-enhancing anodal transcranial direct current stimulation (tDCS). METHODS: In this sham-controlled, double-blind intervention study, tDCS was applied over the left prefrontal cortex of MS patients with fatigue for five consecutive days. Symptoms were tracked for 1 month via questionnaires. Lesion load at baseline was calculated for each patient and correlated with fatigue levels and responsiveness to stimulation. RESULTS: In the whole group analysis the scores of the fatigue scales were not altered by tDCS. However, in an exploratory analysis we found a correlation between response to the stimulation regarding subjectively perceived fatigue and lesion load in the left frontal cortex: patients responding positively to anodal tDCS had higher lesion load, compared to non-responding patients. CONCLUSION: We conclude that in patient subgroups discernible by specific morphological alterations, tDCS may be a tool for MS fatigue management.

Transcranial electrical stimulation modifies the neuronal response to psychosocial stress exposure.

Stress is a constant characteristic of everyday life in our society, playing a role in triggering several chronic disorders. Therefore, there is an ongoing need to develop new methods in order to manage stress reactions. The regulatory function of right medial-prefrontal cortex (mPFC) is frequently reported by imaging studies during psychosocial stress situations. Here, we examined the effects of inhibitory and excitatory preconditioning stimulation via cathodal and anodal transcranial direct current stimulation (tDCS) on psychosocial stress related behavioral indicators and physiological factors, including the cortisol level in the saliva and changes in brain perfusion. Twenty minutes real or sham tDCS was applied over the right mPFC of healthy subjects before the performance of the Trier Social Stress Test (TSST). Regional cerebral blood flow (rCBF) was measured during stimulation and after TSST, using pseudo-continuous arterial spin labeling (pCASL). Comparing the effect of the different stimulation conditions, during anodal stimulation we found higher rCBF in the right mPFC, compared to the sham and in the right amygdala, superior PFC compared to the cathodal condition. Salivary cortisol levels showed a decrease in the anodal and increase in cathodal groups after completion of the TSST. The behavioral stress indicators indicated the increase of stress level, however, did not show any significant differences among groups. In this study we provide the first insights into the neuronal mechanisms mediating psychosocial stress responses by prefrontal tDCS.

Safety of 5 kHz tACS.

BACKGROUND: Sinusoidal transcranial alternating current stimulation (tACS) at 5 kHz applied for 10 min at 1 mA intensity over the hand area of the primary motor cortex (M1) results in sustained changes in cortical excitability as previously demonstrated. OBJECTIVE: Here we have assessed safety aspects of this stimulation method by measuring neuron-specific enolase (NSE) levels, examining electroencephalogram (EEG) traces and analyzing anatomical data by using magnetic resonance imaging (MRI). METHODS: Altogether 18 healthy volunteers participated in the study. tACS was applied at 5 kHz for a duration of 10 min over the left M1 at an intensity of 1 mA. RESULTS: After stimulation no significant changes were detected in NSE levels, no structural alterations were observed in the anatomical scans and no pathological changes were found in the EEG recordings. CONCLUSIONS: Our data imply that the application of tACS is safe at least within these parameters and with these applied protocols.

Combining functional magnetic resonance imaging with transcranial electrical stimulation.

Transcranial electrical stimulation (tES) is a neuromodulatory method with promising potential for basic research and as a therapeutic tool. The most explored type of tES is transcranial direct current stimulation (tDCS), but also transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) have been shown to affect cortical excitability, behavioral performance and brain activity. Although providing indirect measure of brain activity, functional magnetic resonance imaging (fMRI) can tell us more about the global effects of stimulation in the whole brain and what is more, on how it modulates functional interactions between brain regions, complementing what is known from electrophysiological methods such as measurement of motor evoked potentials. With this review, we aim to present the studies that have combined these techniques, the current approaches and discuss the results obtained so far.

High-frequency TRNS reduces BOLD activity during visuomotor learning.

Transcranial direct current stimulation (tDCS) and transcranial random noise stimulation (tRNS) consist in the application of electrical current of small intensity through the scalp, able to modulate perceptual and motor learning, probably by changing brain excitability. We investigated the effects of these transcranial electrical stimulation techniques in the early and later stages of visuomotor learning, as well as associated brain activity changes using functional magnetic resonance imaging (fMRI). We applied anodal and cathodal tDCS, low-frequency and high-frequency tRNS (lf-tRNS, 0.1-100 Hz; hf-tRNS 101-640 Hz, respectively) and sham stimulation over the primary motor cortex (M1) during the first 10 minutes of a visuomotor learning paradigm and measured performance changes for 20 minutes after stimulation ceased. Functional imaging scans were acquired throughout the whole experiment. Cathodal tDCS and hf-tRNS showed a tendency to improve and lf-tRNS to hinder early learning during stimulation, an effect that remained for 20 minutes after cessation of stimulation in the late learning phase. Motor learning-related activity decreased in several regions as reported previously, however, there was no significant modulation of brain activity by tDCS. In opposition to this, hf-tRNS was associated with reduced motor task-related-activity bilaterally in the frontal cortex and precuneous, probably due to interaction with ongoing neuronal oscillations. This result highlights the potential of lf-tRNS and hf-tRNS to differentially modulate visuomotor learning and advances our knowledge on neuroplasticity induction approaches combined with functional imaging methods.