Clinical Sensitivity of Fractal Neurodynamics.

Among the significant advances in the understanding of the organization of the neuronal networks that coordinate the body and brain, their complex nature is increasingly important, resulting from the interaction between the very large number of constituents strongly organized hierarchically and at the same time with "self-emerging." This awareness drives us to identify the measures that best quantify the "complexity" that accompanies the continuous evolutionary dynamics of the brain. In this chapter, after an introductory section (Sect. 15.1), we examine how the Higuchi fractal dimension is able to perceive physiological processes (15.2), neurological (15.3) and psychiatric (15.4) disorders, and neuromodulation effects (15.5), giving a mention of other methods of measuring neuronal electrical activity in addition to electroencephalography, such as magnetoencephalography and functional magnetic resonance. Conscious that further progress will support a deeper understanding of the temporal course of neuronal activity because of continuous interaction with the environment, we conclude confident that the fractal dimension has begun to uncover important features of the physiology of brain activity and its alterations.

Fractal Neurodynamics.

The neuronal ongoing electrical activity in the brain network, the neurodynamics, reflects the structure and functionality of generating neuronal pools. The activity of neurons due to their excitatory and inhibitory projections is associated with specific brain functions. Here, the purpose was to investigate if the local ongoing electrical activity exhibits its characteristic spectral and fractal features in wakefulness and sleep across and within subjects. Moreover, we aimed to show that measures typical of complex systems catch physiological features missed by linear spectral analyses. For this study, we concentrated on the evaluation of the power spectral density (PSD) and Higuchi fractal dimension (HFD) measures. Relevant clinical impact of the specific features of neurodynamics identification stands primarily in the potential of classifying cortical parcels according to their neurodynamics as well as enhancing the effectiveness of neuromodulation interventions to cure symptoms secondary to neuronal activity unbalances.

Assessing cortical excitability with electroencephalography: A pilot study with EEG-iTBS.

BACKGROUND: Cortical excitability measures neural reactivity to stimuli, usually delivered via Transcranial Magnetic Stimulation (TMS). Excitation/inhibition balance (E/I) is the ongoing equilibrium between excitatory and inhibitory activity of neural circuits. According to some studies, E/I could be estimated in-vivo and non-invasively through the modeling of electroencephalography (EEG) signals and termed 'intrinsic excitability' measures. Several measures have been proposed (phase consistency in the gamma band, sample entropy, exponent of the power spectral density 1/f curve, E/I index extracted from detrend fluctuation analysis, and alpha power). Intermittent theta burst stimulation (iTBS) of the primary motor cortex (M1) is a non-invasive neuromodulation technique allowing controlled and focal enhancement of TMS cortical excitability and E/I of the stimulated hemisphere. OBJECTIVE: Investigating to what extent E/I estimates scale with TMS excitability and how they relate to each other. METHODS: M1 excitability (TMS) and several E/I estimates extracted from resting state EEG recordings were assessed before and after iTBS in a cohort of healthy subjects. RESULTS: Enhancement of TMS M1 excitability, as measured through motor-evoked potentials (MEPs), and phase consistency of the cortex in high gamma band correlated with each other. Other measures of E/I showed some expected results, but no correlation with TMS excitability measures or strong consistency with each other. CONCLUSIONS: EEG E/I estimates offer an intriguing opportunity to map cortical excitability non-invasively, with high spatio-temporal resolution and with a stimulus independent approach. While different EEG E/I estimates may reflect the activity of diverse excitatory-inhibitory circuits, spatial phase synchrony in the gamma band is the measure that best captures excitability changes in the primary motor cortex.

Fractal Dimension as a discriminative feature for high accuracy classification in motor imagery EEG-based brain-computer interface.

BACKGROUND AND OBJECTIVE: The brain-computer interface (BCI) technology acquires human brain electrical signals, which can be effectively and successfully used to control external devices, potentially supporting subjects suffering from motor impairments in the interaction with the environment. To this aim, BCI systems must correctly decode and interpret neurophysiological signals reflecting the intention of the subjects to move. Therefore, the accurate classification of single events in motor tasks represents a fundamental challenge in ensuring efficient communication and control between users and BCIs. Movement-associated changes in electroencephalographic (EEG) sensorimotor rhythms, such as event-related desynchronization (ERD), are well-known features of discriminating motor tasks. Fractal dimension (FD) can be used to evaluate the complexity and self-similarity in brain signals, potentially providing complementary information to frequency-based signal features. METHODS: In the present work, we introduce FD as a novel feature for subject-independent event classification, and we test several machine learning (ML) models in behavioural tasks of motor imagery (MI) and motor execution (ME). RESULTS: Our results show that FD improves the classification accuracy of ML compared to ERD. Furthermore, unilateral hand movements have higher classification accuracy than bilateral movements in both MI and ME tasks. CONCLUSIONS: These results provide further insights into subject-independent event classification in BCI systems and demonstrate the potential of FD as a discriminative feature for EEG signals.

Auditory Personalization of EMDR Treatment to Relieve Trauma Effects: A Feasibility Study [EMDR+].

According to the WHO (World Health Organization), Eye Movement Desensitization and Reprocessing (EMDR) is an elective therapy to treat people with post-traumatic stress disorders (PTSD). In line with the personalization of therapeutic strategies, through this pilot study, we assessed in people suffering from the effects of trauma the feasibility, safety, acceptance, and efficacy of EMDR enriched with sound stimulation (by administering neutral sounds synchronized with the guided bilateral alternating stimulation of the gaze) and musical reward (musical listening based on the patients' predisposition and personal tastes). Feasibility, quantified by the number of patients who completed the treatment, was excellent as this was the case in 12 out of the 12 enrolled people with psychological trauma. Safety and acceptance, assessed by self-compiled questionnaires, were excellent, with an absence of side effects and high satisfaction. Efficacy, quantified by the number of EMDR treatment sessions required to reach the optimal scores on the Subjective Units of Disturbance (SUD) and Validity of Cognition (VOC) scales typical of EMDR protocols, revealed an average duration of 8.5 (SD 1.2) sessions, which is well below the 12 sessions considered a standard EMDR treatment duration. EMDR+ appears to be a relevant personalization of EMDR, particularly in music-sensitive people, consolidating the therapeutic alliance through a multisensory communicative bond for trauma treatment.

Effects on Corticospinal Tract Homology of Faremus Personalized Neuromodulation Relieving Fatigue in Multiple Sclerosis: A Proof-of-Concept Study.

OBJECTIVES: Fatigue in multiple sclerosis (MS) is a frequent and invalidating symptom, which can be relieved by non-invasive neuromodulation, which presents only negligible side effects. A 5-day transcranial direct-current stimulation, 15 min per day, anodically targeting the somatosensory representation of the whole body against a larger occipital cathode was efficacious against MS fatigue (fatigue relief in multiple sclerosis, Faremus treatment). The present proof-of-concept study tested the working hypothesis that Faremus S1 neuromodulation modifies the homology of the dominant and non-dominant corticospinal (CST) circuit recruitment. METHODS: CST homology was assessed via the Fréchet distance between the morphologies of motor potentials (MEPs) evoked by transcranial magnetic stimulation in the homologous left- and right-hand muscles of 10 fatigued MS patients before and after Faremus. RESULTS: In the absence of any change in MEP features either as differences between the two body sides or as an effect of the treatment, Faremus changed in physiological direction the CST's homology. Faremus effects on homology were more evident than recruitment changes within the dominant and non-dominant sides. CONCLUSIONS: The Faremus-related CST changes extend the relevance of the balance between hemispheric homologs to the homology between body sides. With this work, we contribute to the development of new network-sensitive measures that can provide new insights into the mechanisms of neuronal functional patterning underlying relevant symptoms.

Effective Intracerebral Connectivity in Acute Stroke: A TMS-EEG Study.

Stroke is a major cause of disability because of its motor and cognitive sequelae even when the acute phase of stabilization of vital parameters is overcome. The most important improvements occur in the first 8-12 weeks after stroke, indicating that it is crucial to improve our understanding of the dynamics of phenomena occurring in this time window to prospectively target rehabilitation procedures from the earliest stages after the event. Here, we studied the intracortical excitability properties of delivering transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) of left and right hemispheres in 17 stroke patients who suffered a mono-lateral left hemispheric stroke, excluding pure cortical damage. All patients were studied within 10 days of symptom onset. TMS-evoked potentials (TEPs) were collected via a TMS-compatible electroencephalogram system (TMS-EEG) concurrently with motor-evoked responses (MEPs) induced in the contralateral first dorsal interosseous muscle. Comparison with age-matched healthy volunteers was made by collecting the same bilateral-stimulation data in nine healthy volunteers as controls. Excitability in the acute phase revealed relevant changes in the relationship between left lesioned and contralesionally right hemispheric homologous areas both for TEPs and MEPs. While the paretic hand displayed reduced MEPs compared to the non-paretic hand and to healthy volunteers, TEPs revealed an overexcitable lesioned hemisphere with respect to both healthy volunteers and the contra-lesion side. Our quantitative results advance the understanding of the impairment of intracortical inhibitory networks. The neuronal dysfunction most probably changes the excitatory/inhibitory on-center off-surround organization that supports already acquired learning and reorganization phenomena that support recovery from stroke sequelae.

On the Homology of the Dominant and Non-Dominant Corticospinal Tracts: A Novel Neurophysiological Assessment.

OBJECTIVES: The homology of hemispheric cortical areas plays a crucial role in brain functionality. Here, we extend this concept to the homology of the dominant and non-dominant hemi-bodies, investigating the relationship of the two corticospinal tracts (CSTs). The evoked responses provide an estimate of the number of in-phase recruitments via their amplitude as a suitable indicator of the neuronal projections' integrity. An innovative concept derived from experience in the somatosensory system is that their morphology reflects the recruitment pattern of the whole circuit. METHODS: CST homology was assessed via the Fréchet distance between the morphologies of motor-evoked potentials (MEPs) using a transcranial magnetic stimulation (TMS) in the homologous left- and right-hand first dorsal interosseous muscles of 40 healthy volunteers (HVs). We tested the working hypothesis that the inter-side Fréchet distance was higher than the two intra-side distances. RESULTS: In addition to a clear confirmation of the working hypothesis (p < 0.0001 for both hemi-bodies) verified in all single subjects, we observed that the intra-side Fréchet distance was higher for the dominant than the non-dominant one. Interhemispheric morphology similarity increased with right-handedness prevalence (p = 0.004). CONCLUSIONS: The newly introduced measure of circuit recruitment patterning represents a potential benchmark for the evaluation of inter-lateral mechanisms expressing the relationship between homologous hemilateral structures subtending learning and suggests that variability in recruitment patterning physiologically increases in circuits expressing greater functionality.

Local neurodynamics as a signature of cortical areas: new insights from sleep.

Sleep crucial for the animal survival is accompanied by huge changes in neuronal electrical activity over time, the neurodynamics. Here, drawing on intracranial stereo-electroencephalographic (sEEG) recordings from the Montreal Neurological Institute (MNI), we analyzed local neurodynamics in the waking state at rest and during the N2, N3, and rapid eye movement (REM) sleep phases. Higuchi fractal dimension (HFD)-a measure of signal complexity-was studied as a feature of the local neurodynamics of the primary motor (M1), somatosensory (S1), and auditory (A1) cortices. The key working hypothesis, that the relationships between local neurodynamics preserve in all sleep phases despite the neurodynamics complexity reduces in sleep compared with wakefulness, was supported by the results. In fact, while HFD awake > REM > N2 > N3 (P < 0.001 consistently), HFD in M1 > S1 > A1 in awake and all sleep stages (P < 0.05 consistently). Also power spectral density was studied for consistency with previous investigations. Meaningfully, we found a local specificity of neurodynamics, well quantified by the fractal dimension, expressed in wakefulness and during sleep. We reinforce the idea that neurodynamic may become a new criterion for cortical parcellation, prospectively improving the understanding and ability of compensatory interventions for behavioral disorders.

Functional balance at rest of hemispheric homologs assessed via normalized compression distance.

Introduction: The formation and functioning of neural networks hinge critically on the balance between structurally homologous areas in the hemispheres. This balance, reflecting their physiological relationship, is fundamental for learning processes. In our study, we explore this functional homology in the resting state, employing a complexity measure that accounts for the temporal patterns in neurodynamics. Methods: We used Normalized Compression Distance (NCD) to assess the similarity over time, neurodynamics, of the somatosensory areas associated with hand perception (S1). This assessment was conducted using magnetoencephalography (MEG) in conjunction with Functional Source Separation (FSS). Our primary hypothesis posited that neurodynamic similarity would be more pronounced within individual subjects than across different individuals. Additionally, we investigated whether this similarity is influenced by hemisphere or age at a population level. Results: Our findings validate the hypothesis, indicating that NCD is a robust tool for capturing balanced functional homology between hemispheric regions. Notably, we observed a higher degree of neurodynamic similarity in the population within the left hemisphere compared to the right. Also, we found that intra-subject functional homology displayed greater variability in older individuals than in younger ones. Discussion: Our approach could be instrumental in investigating chronic neurological conditions marked by imbalances in brain activity, such as depression, addiction, fatigue, and epilepsy. It holds potential for aiding in the development of new therapeutic strategies tailored to these complex conditions, though further research is needed to fully realize this potential.

Normalized compression distance to measure cortico-muscular synchronization.

The neuronal functional connectivity is a complex and non-stationary phenomenon creating dynamic networks synchronization determining the brain states and needed to produce tasks. Here, as a measure that quantifies the synchronization between the neuronal electrical activity of two brain regions, we used the normalized compression distance (NCD), which is the length of the compressed file constituted by the concatenated two signals, normalized by the length of the two compressed files including each single signal. To test the NCD sensitivity to physiological properties, we used NCD to measure the cortico-muscular synchronization, a well-known mechanism to control movements, in 15 healthy volunteers during a weak handgrip. Independently of NCD compressor (Huffman or Lempel Ziv), we found out that the resulting measure is sensitive to the dominant-non dominant asymmetry when novelty management is required (p = 0.011; p = 0.007, respectively) and depends on the level of novelty when moving the non-dominant hand (p = 0.012; p = 0.024). Showing lower synchronization levels for less dexterous networks, NCD seems to be a measure able to enrich the estimate of functional two-node connectivity within the neuronal networks that control the body.

Brain electrical microstate features as biomarkers of a stable motor output.

Objective.The aim of the present study was to elucidate the brain dynamics underlying the maintenance of a constant force level exerted during a visually guided isometric contraction task by optimizing a predictive multivariate model based on global and spectral brain dynamics features.Approach.Electroencephalography (EEG) was acquired in 18 subjects who were asked to press a bulb and maintain a constant force level, indicated by a bar on a screen. For intervals of 500 ms, we calculated an index of force stability as well as indices of brain dynamics: microstate metrics (duration, occurrence, global explained variance, directional predominance) and EEG spectral amplitudes in the theta, low alpha, high alpha and beta bands. We optimized a multivariate regression model (partial least square (PLS)) where the microstate features and the spectral amplitudes were the input variables and the indexes of force stability were the output variables. The issues related to the collinearity among the input variables and to the generalizability of the model were addressed using PLS in a nested cross-validation approach.Main results.The optimized PLS regression model reached a good generalizability and succeeded to show the predictive value of microstates and spectral features in inferring the stability of the exerted force. Longer duration and higher occurrence of microstates, associated with visual and executive control networks, corresponded to better contraction performances, in agreement with the role played by the visual system and executive control network for visuo-motor integration.Significance.A combination of microstate metrics and brain rhythm amplitudes could be considered as biomarkers of a stable visually guided motor output not only at a group level, but also at an individual level. Our results may play an important role for a better understanding of the motor control in single trials or in real-time applications as well as in the study of motor control.

Functional Source Separation-Identified Epileptic Network: Analysis Pipeline.

This proof-of-concept (PoC) study presents a pipeline made by two blocks: 1. the identification of the network that generates interictal epileptic activity; and 2. the study of the time course of the electrical activity that it generates, called neurodynamics, and the study of its functional connectivity to the other parts of the brain. Network identification is achieved with the Functional Source Separation (FSS) algorithm applied to electroencephalographic (EEG) recordings, the neurodynamics quantified through signal complexity with the Higuchi Fractal Dimension (HFD), and functional connectivity with the Directed Transfer Function (DTF). This PoC is enhanced by the data collected before and after neuromodulation via transcranial Direct Current Stimulation (tDCS, both Real and Sham) in a single drug-resistant epileptic person. We observed that the signal complexity of the epileptogenic network, reduced in the pre-Real, pre-Sham, and post-Sham, reached the level of the rest of the brain post-Real tDCS. DTF changes post-Real tDCS were maintained after one month. The proposed approach can represent a valuable tool to enhance understanding of the relationship between brain neurodynamics characteristics, the effects of non-invasive brain stimulation, and epileptic symptoms.

Home treatment against fatigue in multiple sclerosis by a personalized, bilateral whole-body somatosensory cortex stimulation.

BACKGROUND: Fatigue in multiple sclerosis (MS) is a highly invalidating symptom with no pharmacological efficacious therapies, which furthermore present frequent severe side effects. In two previous randomized controlled trials we observed the efficacy of a personalized neuromodulation treatment consisting of a personalized transcranial Direct Current Stimulation (tDCS) for 15 min per day for 5 days (Faremus). METHODS: By this medical-device phase II study, we aimed at assessing the feasibility, acceptance, safety and efficacy of Faremus treatment when applied at patients' home. We considered the efficacy as primary outcome assessed by a reduction of fatigue levels measured by Modified Fatigue Impact Scale (mFIS) scored before and after the treatment. Primary outcome determined the sample size estimate. Individual ad-hoc questionnaires quantified the acceptance, safety and side effects during the treatment. RESULTS: All 15 patients completed the treatment, reporting optimal acceptance and safety on using Faremus at their home without side-effects. The treatment ameliorated fatigue symptoms more than 20% of baseline in 10 out of the 15 patients and of 37% on average, with a corresponding effect size 1.21. CONCLUSIONS: Faremus personalized electroceutical intervention, a 5-days anodal tDCS over the bilateral whole-body somatosensory cortex, is well accepted and can be feasibly, safely, and efficaciously applied at patients' home, offering a comfortable treatment by reducing the need to travel when fatigue-related symptoms hamper the quality of life.

Corticomuscular Coherence Dependence on Body Side and Visual Feedback.

Physiological movement develops on the basis of sensorimotor integration through synchronisation between the copy of signals sent to the effector muscles and the incoming flow of sensory information. Our aim is to study corticomuscular coherence (CMC), the most widely used measure of synchronization between brain and muscle electrical activities, in dependence on the level of visual feedback and the executing body side. We analysed CMC in 18 healthy volunteers while performing a weak isometric handgrip of an air bulb with either the right or the left hand, in either the presence or absence of visual feedback on the exerted pressure. The absence of visual feedback decreased the CMC peak frequency from 27 Hz to 23 Hz (p < 0.001), increased the CMC peak amplitude from 0.05 to 0.07 (p = 0.005) and decreased the electroencephalographic beta band power (p = 0.005). None of these measures changed in dependence on the performing hand (p > 0.2 consistently). The lack of dependence of CMC on the controlled hand involved in the movement can be considered in agreement with small hemispheric asymmetries of hand representations in primary sensorimotor cortices. Modulation of visual information changed corticomuscular synchronizations and cortical involvement, reflecting the crucial role of gaze in human behaviour. Given the fundamental role of sensory integration in motor execution, the availability of a simple index sensitive to modulations of perceptual afferents may prove useful in determining the use or the monitoring of the effects of sensory enrichments in personalized rehabilitation.

Neuronal Electrical Ongoing Activity as Cortical Areas Signature: An Insight from MNI Intracerebral Recording Atlas.

The time course of the neuronal activity in the brain network, the neurodynamics, reflects the structure and functionality of the generating neuronal pools. Here, using the intracranial stereo-electroencephalographic (sEEG) recordings of the public Montreal Neurological Institute (MNI) atlas, we investigated the neurodynamics of primary motor (M1), somatosensory (S1) and auditory (A1) cortices measuring power spectral densities (PSD) and Higuchi fractal dimension (HFD) in the same subject (M1 vs. S1 in 16 subjects, M1 vs. A1 in 9, S1 vs. A1 in 6). We observed specific spectral features in M1, which prevailed above beta band, S1 in the alpha band, and A1 in the delta band. M1 HFD was higher than S1, both higher than A1. A clear distinction of neurodynamics properties of specific primary cortices supports the efforts in cortical parceling based on this expression of the local cytoarchitecture and connectivity. In this perspective, we selected within the MNI intracortical database a first set of primary motor, somatosensory and auditory cortices' representatives to query in recognizing ongoing patterns of neuronal communication. Potential clinical impact stands primarily in exploiting such exchange patterns to enhance the efficacy of neuromodulation intervention to cure symptoms secondary to neuronal activity unbalances.

tDCS randomized controlled trials in no-structural diseases: a quantitative review.

The increasing number and quality of randomized controlled trials (RCTs) employing transcranial direct current stimulation (tDCS) denote the rising awareness of neuroscientific community about its electroceutical potential and opening to include these treatments in the framework of medical therapies under the indications of the international authorities. The purpose of this quantitative review is to estimate the recommendation strength applying the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria and PICO (population, intervention, comparison, outcome) model values for effective tDCS treatments on no-structural diseases, and to provide an estimate of Sham effect for future RCTs. Applying GRADE evaluation pathway, we searched in literature the tDCS-based RCTs in psychophysical diseases displaying a major involvement of brain electrical activity imbalances. Three independent authors agreed on Class 1 RCTs (18 studies) and meta-analyses were carried out using a random-effects model for pathologies sub-selected based on PICO and systemic involvement criteria. The meta-analysis integrated with extensive evidence of negligible side effects and low-cost, easy-to-use procedures, indicated that tDCS treatments for depression and fatigue in Multiple Sclerosis ranked between moderately and highly recommendable. For these interventions we reported the PICO variables, with left vs. right dorsolateral prefrontal target for 30 min/10 days against depression and bilateral somatosensory vs occipital target for 15 min/5 days against MS fatigue. An across-diseases meta-analysis devoted to the Sham effect provided references for power analysis in future tDCS RCTs on these clinical conditions. High-quality indications support tDCS as a promising tool to build electroceutical treatments against diseases involving neurodynamics alterations.