Cortical stimulation in aphasia following ischemic stroke: toward model-guided electrical neuromodulation.

The aim of this paper is to integrate different bodies of research including brain traveling waves, brain neuromodulation, neural field modeling and post-stroke language disorders in order to explore the opportunity of implementing model-guided, cortical neuromodulation for the treatment of post-stroke aphasia. Worldwide according to WHO, strokes are the second leading cause of death and the third leading cause of disability. In ischemic stroke, there is not enough blood supply to provide enough oxygen and nutrients to parts of the brain, while in hemorrhagic stroke, there is bleeding within the enclosed cranial cavity. The present paper focuses on ischemic stroke. We first review accumulating observations of traveling waves occurring spontaneously or triggered by external stimuli in healthy subjects as well as in patients with brain disorders. We examine the putative functions of these waves and focus on post-stroke aphasia observed when brain language networks become fragmented and/or partly silent, thus perturbing the progression of traveling waves across perilesional areas. Secondly, we focus on a simplified model based on the current literature in the field and describe cortical traveling wave dynamics and their modulation. This model uses a biophysically realistic integro-differential equation describing spatially distributed and synaptically coupled neural networks producing traveling wave solutions. The model is used to calculate wave parameters (speed, amplitude and/or frequency) and to guide the reconstruction of the perturbed wave. A stimulation term is included in the model to restore wave propagation to a reasonably good level. Thirdly, we examine various issues related to the implementation model-guided neuromodulation in the treatment of post-stroke aphasia given that closed-loop invasive brain stimulation studies have recently produced encouraging results. Finally, we suggest that modulating traveling waves by acting selectively and dynamically across space and time to facilitate wave propagation is a promising therapeutic strategy especially at a time when a new generation of closed-loop cortical stimulation systems is about to arrive on the market.

The use of neurocomputational models as alternatives to animal models in the development of electrical brain stimulation treatments.

Recent publications call for more animal models to be used and more experiments to be performed, in order to better understand the mechanisms of neurodegenerative disorders, to improve human health, and to develop new brain stimulation treatments. In response to these calls, some limitations of the current animal models are examined by using Deep Brain Stimulation (DBS) in Parkinson's disease as an illustrative example. Without focusing on the arguments for or against animal experimentation, or on the history of DBS, the present paper argues that given recent technological and theoretical advances, the time has come to consider bioinspired computational modelling as a valid alternative to animal models, in order to design the next generation of human brain stimulation treatments. However, before computational neuroscience is fully integrated in the translational process and used as a substitute for animal models, several obstacles need to be overcome. These obstacles are examined in the context of institutional, financial, technological and behavioural lock-in. Recommendations include encouraging agreement to change long-term habitual practices, explaining what alternative models can achieve, considering economic stakes, simplifying administrative and regulatory constraints, and carefully examining possible conflicts of interest.

Phase-shifted tACS can modulate cortical alpha waves in human subjects.

In the present study, we investigated traveling waves induced by transcranial alternating current stimulation in the alpha frequency band of healthy subjects. Electroencephalographic data were recorded in 12 healthy subjects before, during, and after phase-shifted stimulation with a device combining both electroencephalographic and stimulation capacities. In addition, we analyzed the results of numerical simulations and compared them to the results of identical analysis on real EEG data. The results of numerical simulations indicate that imposed transcranial alternating current stimulation induces a rotating electric field. The direction of waves induced by stimulation was observed more often during at least 30 s after the end of stimulation, demonstrating the presence of aftereffects of the stimulation. Results suggest that the proposed approach could be used to modulate the interaction between distant areas of the cortex. Non-invasive transcranial alternating current stimulation can be used to facilitate the propagation of circulating waves at a particular frequency and in a controlled direction. The results presented open new opportunities for developing innovative and personalized transcranial alternating current stimulation protocols to treat various neurological disorders. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09997-1.

Delayed and lasting effects of deep brain stimulation on locomotion in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a variety of motor signs affecting gait, postural stability, and tremor. These symptoms can be improved when electrodes are implanted in deep brain structures and electrical stimulation is delivered chronically at high frequency (>100 Hz). Deep brain stimulation (DBS) onset or cessation affects PD signs with different latencies, and the long-term improvements of symptoms affecting the body axis and those affecting the limbs vary in duration. Interestingly, these effects have not been systematically analyzed and modeled. We compare these timing phenomena in relation to one axial (i.e., locomotion) and one distal (i.e., tremor) signs. We suggest that during DBS, these symptoms are improved by different network mechanisms operating at multiple time scales. Locomotion improvement may involve a delayed plastic reorganization, which takes hours to develop, whereas rest tremor is probably alleviated by an almost instantaneous desynchronization of neural activity in subcortical structures. Even if all PD patients develop both distal and axial symptoms sooner or later, current computational models of locomotion and rest tremor are separate. Furthermore, a few computational models of locomotion focus on PD and none exploring the effect of DBS was found in the literature. We, therefore, discuss a model of a neuronal network during DBS, general enough to explore the subcircuits controlling locomotion and rest tremor simultaneously. This model accounts for synchronization and plasticity, two mechanisms that are believed to underlie the two types of symptoms analyzed. We suggest that a hysteretic effect caused by DBS-induced plasticity and synchronization modulation contributes to the different therapeutic latencies observed. Such a comprehensive, generic computational model of DBS effects, incorporating these timing phenomena, should assist in developing a more efficient, faster, durable treatment of distal and axial signs in PD.

Quantitative assessment of neuromotor function in workers with current low exposure to mercury vapor.

Evaluation of neuromotor function has been used in several epidemiological studies of workers with long-term exposure to mercury vapor (Hg 0). Some recent studies indicate adverse effects at relatively low exposure levels. In the present study, we used sensitive quantitative methods, developed specifically to detect subtle effects of exposure to toxins on motor function. After exclusion of individuals with neurological diseases or other conditions that may affect performance, 43 chloralkali workers with current low exposure to Hg 0, and 22 age-matched referents remained for further analysis. The median urinary mercury concentration in exposed workers was 5.9 microg/g (range 1.3-25) creatinine (microg/gC), while that in referents was 0.7 microg/gC (range 0.2-4.1). The mean exposure time was 15 years, and the median cumulative mercury index was 161 years x microg/gC in exposed workers. A eurythmokinesimeter (EKM) was used to quantify eye-hand coordination, and a diadochokinesimeter, to measure rapid alternating rotation of the forearms. In general, the differences in performance between the exposed workers and the referents were small. Age was associated with a decrease in speed, more tremor, and longer contact duration between the stylus and the metal targets in performance of rapid pointing movements. Smokers had significantly more tremor, and more contacts per event in the EKM test, than nonsmokers. Taking age, shift work, and smoking habits into account, no significant associations with current or cumulative mercury exposure were found for the majority of the outcome variables from the quantitative tests. In general, this study indicates no significant adverse effects of Hg 0 on neuromotor function at the exposure levels studied.

Postural sway and effect of levodopa in early Parkinson's disease.

OBJECTIVE: To characterize postural stability control and levodopa responsiveness in early Parkinson's disease (PD). METHODS: Postural sway was studied during quiet stance in ten patients within six years of PD onset, both before (OFF) and after (ON) regular oral levodopa dosing. Postural sway was recorded using a force platform during 30 sec with eyes open, and six dependent variables were examined. RESULTS: Mild baseline subclinical changes in postural sway were recorded in our patients. Clear benefit was observed in five out of six characteristics (mean sway, transversal sway, sagittal sway, sway intensity, and sway area) in the ON condition. CONCLUSION: Postural control mechanisms are affected early in PD and modulated by dopamine.

Statistical determination of the optimal subthalamic nucleus stimulation site in patients with Parkinson disease.

OBJECT: The subthalamic nucleus (STN) is currently recognized as the preferred target for deep brain stimulation (DBS) in patients with Parkinson disease (PD). If there is agreement in the literature that DBS improves motor symptoms significantly, the situation is less clear with respect to the side effects of this procedure. The goal of this study was to correlate the coordinate values of active electrode contacts with the amplitude of residual clinical symptoms and side effects using a mathematical approach. METHODS: In this study the investigators examined a cohort of 41 patients with PD who received clinical benefits from DBS after stimulating electrodes had been implanted bilaterally into the STN. The combined scores of residual clinical symptoms plus side effects, including speech disturbance, postural instability, and weight gain, were fitted by using either inverted ellipsoidal exponefitials or smooth splines. These analyses showed evidence of lower combined scores for stimulating contacts at an x coordinate approximately 12.0 to 12.3 mm lateral to the anterior commissure-posterior commissure (AC-PC) line and at a z coordinate approximately 3.1 to 3.3 mm under the AC-PC line. There was insufficient evidence for a preferred y coordinate location. CONCLUSIONS: The authors propose a "best" therapeutic ellipse area that is centered at an x, z location of 12.5 mm, -3.3 mm and characterized by an extension of 1.85 mm in the x direction and 2.22 mm in the z direction. Therapeutic electrode contacts located within this area are well correlated with the lowest occurrence of residual symptoms and the lowest occurrence of side effects independent of STN anatomical considerations. The lack of a significant result in the y direction remains to be explored further.

Development and validation of a neural population model based on the dynamics of a discontinuous membrane potential neuron model.

The major goal of this study was to develop a population density based model derived from statistical mechanics based on the dynamics of a discontinuous membrane potential neuron model. A secondary goal was to validate this model by comparing results from a direct simulation approach on the one hand and our population based approach on the other hand. Comparisons between the two approaches in the case of a synaptically uncoupled and a synaptically coupled neural population produced satisfactory qualitative agreement in terms of firing rate and mean membrane potential. Reasonable quantitative agreement was also obtained for these variables in performed simulations. The results of this work based on the dynamics of a discontinuous membrane potential neuron model provide a basis to simulate phenomenologically large-scale neuronal networks with a reasonably short computing time.

Individual subject sensitivity to extremely low frequency magnetic field.

It is becoming important to specify the smallest effects of extremely low frequency (ELF) magnetic fields (MF) on human physiology. One difficulty is that some people seem more sensitive and more responsive than others to MF exposure. Consequently, within- and between-subject differences have to be taken into account when evaluating these effects. As shown in previous work, human postural tremor is sensitive to MF exposure. But data about individual responses have not been examined in detail. Thus, postural tremor of 24 subjects was evaluated under ELF MF "on" and "off" conditions in a double-blind real/sham exposure protocol. The direction of the tremor changes was analyzed individually for three tremor characteristics. Results showed that subjects with high amplitude tremor seem to be more responsive to MF exposure. MF had an instantaneous effect (between "on" and "off" conditions) and also a more delayed and persistent one (between real and sham conditions), but differences were small. Moreover, due to the within- and between-subject variability, no statistical analysis could be done. However, these results do not show any potentially harmful effect of domestic or industrial 50 Hz MF on humans. They provide a starting point to orient future studies and should be taken into account in the establishment of new exposure limits.

Quantitative tremor assessment in workers with current low exposure to mercury vapor.

Measurement of tremor has been used in several occupational studies of workers with long-term exposure to mercury vapor (Hg(0)). Recent studies indicate an adverse effect even at relatively low exposure levels. In the present study, we used sensitive quantitative methods to assess tremor in chloralkali workers with current low exposure to Hg(0). Neurological examinations and recordings of tremor using both an accelerometer and a laser-based system were conducted in 43 mercury-exposed workers and 22 age-matched referents. The median urinary mercury concentration in exposed workers was 5.9 (1.3-25) microg/g creatinine (microg/gC), while it was 0.7 (0.2-4.1) microg/gC in referents. The mean exposure time was 15 years, and the median cumulative mercury index was 161 years x microg/gC in exposed workers. There were no differences between the exposed workers and the referents in the clinical evaluation of tremor. In the quantitative tremor tests, no associations were found with current or cumulative mercury exposure for the majority of tremor measures. There were indications that exposure to Hg(0) was associated with a lowering of tremor frequency in the non-dominant hand, and a possible interaction with smoking. The differences were small, however, and overall, this study indicates no significant adverse effects on tremor at these exposure levels.

Is a computational model useful to understand the effect of deep brain stimulation in Parkinson's disease?

A growing number of computational models have been proposed over the last few years to help explain the therapeutic effect of deep brain stimulation (DBS) on motor disorders in Parkinson's disease (PD). However, none of these has been able to explain in a convincing manner the physiological mechanisms underlying DBS. Can these models really contribute to improving our understanding? The model by Rubin and Terman [31] represents one of the most comprehensive and biologically plausible models of DBS published recently. We examined the validity of the model, replicated its simulations and tested its robustness. While our simulations partially reproduced the results presented by Rubin and Terman [31], several issues were raised including the high complexity of the model in its non simplified form, the lack of robustness of the model with respect to small perturbations, the nonrealistic representation of the thalamus and the absence of time delays. Computational models are indeed necessary, but they may not be sufficient in their current forms to explain the effect of chronic electrical stimulation on the activity of the basal ganglia (BG) network in PD.

Transient effect of low-intensity magnetic field on human motor control.

There is no consensus with respect to how extremely low frequency (ELF) magnetic fields (MF) affect biological systems. However, this information is crucial to establishing new guidelines for: (i) the new design of electronic devices, (ii) working conditions of exposed workers (e.g. electric linepersons), and in a general manner (iii) policies for human risk management. This study evaluates the effect of a sinusoidal 50 Hz, 1000 microT MF centered at the level of the head on human postural tremor of the index finger, using the wavelet analysis method. In addition to the detection of transient events in tremor time series linked with MF, this method was used to evaluate the differences between MF "on" and "off" conditions and between real and sham exposure in a counterbalanced protocol. Results indicate that neither transient events nor "off-on" or "on-off" MF transition effects were present in the postural tremor time series. Surprisingly, an unexpected significant time dependent decrease in tremor average power was noted along the 20s recordings. Interestingly, this effect was significantly more pronounced in the presence of MF. These results suggest a relaxing effect of ELF MF on motor control resulting in an attenuation of postural tremor intensity.

Automatic detection of movement disorders using recordings of rapid alternating movements.

The present work assesses the potential of rapid alternating movement analysis for detecting movement disorders like Parkinson's disease. Rapid alternating wrist movements were recorded by a diadochokinesimeter for patients with Parkinson's disease (n=10) and healthy controls (n=20). An index of irregularity was computed for each individual as the density of jerk singularities (i.e. zero-crossings) during the movements. Several scales of analysis (i.e. "coarseness") were used for detecting the jerk events and two methods were compared for all of these scales: (1) automatic classification by means of a threshold that optimally separates the indexes of irregularity of the patients from those of the controls, and (2) statistical decision (normal or abnormal) based upon a distribution of indexes of irregularity obtained from a large population of normal subjects. The results showed that (1) two scales of analysis were sufficient and that (2) both methods presented similar performances (e.g. sensitivity=1.00, specificity=0.85, efficiency=0.90). However, statistical decision should be preferred because of its simplicity. The possibility of automatic detection of movement disorders from alternating movements is discussed.

Standardization of quantitative tests for preclinical detection of neuromotor dysfunctions in pediatric neurotoxicology.

In the neurotoxicology pediatric domain, few neuromotor tests are specifically designed to be sensitive enough for the early detection of subtle deficits in voluntary and involuntary movements. In research and clinical domains, an effort is done to objectify or quantify the qualitative aspects of a movement (pattern of movement) in predicting neurological problems. This study aimed to standardize quantitative motor measures initially developed for adults and adapted to the evaluation of preschoolers. The sample consisted of 110 healthy children aged 4-6. The following quantitative neuromotor tests were selected: alternating movements and pointing movements (DOCO Microsystèmes Inc., Montréal, Canada), postural tremor, postural sway and simple reaction time (Danish Product Development Ltd., Snekkersten, Denmark). Validation measures included global motor tasks and a neurological examination. Results indicate adequate test-retest reliability and complementarities amongst the selected voluntary and involuntary measures. Both the feasibility and relevance of quantitative neuromotor tests in preschool aged children were established. Results also provide a representation of intra-individual and inter-individual variability within this population. Lastly, the results highlight the importance of developmental factors, behavioral factors and testing conditions in the neuromotor evaluation of young children. The proposed tests could help in the early detection of children at risk for motor dysfunctions following neurotoxic exposure. The tests can also be used for the follow up of various conditions relating to motor functions (cerebral palsy, muscular dystrophy, preterm infants) and in the evaluation of the effects of medication.

Neuromotor functions in Inuit preschool children exposed to Pb, PCBs, and Hg.

The aim of this study was to examine the effects of prenatal and postnatal chronic exposure to mercury (Hg), polychlorinated biphenyls (PCBs) and lead (Pb) on the neuromotor development of preschool children. The study population consisted of 110 preschool Inuit children from Nunavik (Canada). Blood Hg, PCBs and Pb concentrations were measured at birth (cord blood) and at the time of testing. Gross motor functions were evaluated and a neurological examination was performed. Fine neuromotor performance was assessed using quantitative measures of postural hand tremor, reaction time, sway oscillations, as well as alternating and pointing movements. Potential covariates were documented including demographic and familial characteristics, other prenatal neurotoxicants (alcohol, tobacco) and nutrients (selenium (Se), Omega-3 polyunsaturated fatty acids (n-3 PUFA)). Hierarchical multivariate regression analyses were performed, controlling for significant covariates. Gross motor development was not linked to prenatal exposures. However, significant associations were observed between blood Pb concentration at testing time and changes in reaction time, sway oscillations, alternating arm movements and action tremor. For some of these outcomes, neuromotor effects of Pb exposure are observed at blood concentrations below 10 microg/dl. Negative effects of PCBs on neuromotor development were not clearly observed, neither were the potential beneficial effects of n-3 PUFA and selenium. Tremor amplitude was related to blood Hg concentrations at testing time, which corroborate an effect already reported among adults.

Event identification in movement recordings by means of qualitative patterns.

We present a pattern-matching technique for detecting events in movement recordings. The events are defined as sequences of qualitative changes in the speed and/or the higher order derivatives (e.g., in a speed peak, the acceleration changes from positive to negative). The technique uses qualitative patterns that are sequences of qualitative states (e.g., negative, infinitesimal, positive...) of the speed and the higher order derivatives. A fast pattern-matching algorithm is presented. Its sensitivity can be tuned by means of a filtering parameter, and a multiscale analysis method is proposed for detecting events of different amplitudes and durations. An application to the assessment of the irregularity of rapid movement in Parkinson's disease is presented.

Optokinetic stimulation and the egocentred midsagittal plane: an fMRI study.

Animal studies and observations of neglect patients suggest that the posterior parietal cortex is part of a system that codes ego-centred space. Few studies show the existence of areas involved in the representation of egocentred space in healthy humans. We investigated with fMRI and a conjunction protocol, the overlap of activity between optokinetic stimulation and a task of midline computation. Results showed that the right posterior parietal and frontal cortices were involved in both tasks (p < 0.0001). The evidence presented in this study provides the neuroanatomical substrate involved in the recovery of neglect during vestibular stimulation. This last point is of clinical interest for the rehabilitation of hemineglect.

Quantifying postural tremor in workers exposed to low levels of manganese.

The aim of this study was: (1) To determine the minimum number of characteristics necessary to discriminate between postural tremor recorded in control subjects (CO), in subjects exposed to manganese (MN), and in patients with Parkinson's disease (PD), and (2) to examine the continuum of changes between the three groups examined. Workers previously exposed to Mn (n = 10), patients with PD (n = 10), and control subjects (CO) (n = 11) underwent a clinical examination. Blood Mn was measured at the end of exposure time for the MN group and 12 months later at the beginning of the experiment for all groups. Postural tremor with visual feedback was recorded in the index finger with a laser system. Statistical criteria were used to reduce computed tremor characteristics to a minimal set of reliable discriminating variables. Two variables were retained namely corrected wobble (CW), describing the morphology of the tremor oscillations, and variability ratio (VR), describing proportional power of tremor. Both variables had an overall correct classification rate of 77.4%. Blood Mn levels at the time of the experiment were similar for all groups and had insignificant correlation with tremor variables. However, blood Mn levels in workers which were also measured at the end of exposure time (i.e., 12 months before) showed significant correlation (Spearman's rank coefficient) with both harmonic index (rho = 0.70, P = 0.03) and first maximum of the autocorrelation function (rho = 0.89, P = 0.001). We conclude that (1) the tremor of workers exposed to Mn could be adequately described with only two variables; (2) a continuum of changes between tremor recorded in control subjects, in subjects exposed to Mn and in patients with PD was observed, with the MN group always found in between the control (CO) and the PD groups; (3) while blood Mn levels in workers were back at control levels at the time of the experiment, the effect of Mn on postural tremor was still detected. Thus our method has the potential to detect the effect of Mn on tremor with only two variables even after Mn level in the blood is back to normal values.

Lack of efficacy of a nicotine transdermal treatment on motor and cognitive deficits in Parkinson's disease.

UNLABELLED: Studies assessing the efficacy of nicotine in Parkinson's disease (PD) have generated contradictory results. The controversy seems to stem from uncontrolled factors including the lack of objective measures, the practice effect in a test-retest design, and the absence of plasmatic dosage. This study aimed at further controlling these factors using transdermal nicotine in PD. METHODS: Twenty-two nonsmoking PD patients received a transdermal nicotine treatment over 25 days in increasing titrated doses. Motor and cognitive assessments were carried out on days 11 and 25 (low-dose and high-dose assessments, respectively) and after a 14-day washout period. RESULTS: Patients tolerated nicotine poorly. Thirteen (59%) withdrew, mostly because of acute side effects. In the remaining nine patients, nicotine neither improved nor worsened motor or cognitive functioning in comparison with 10 age, gender and education matched controls. CONCLUSIONS: Transdermal nicotine is not effective in treating motor and cognitive deficits in PD. The results obtained with our objective measures confirm a recent double-blind, placebo-controlled study that used clinical measures. It is possible that nicotine lacks specificity in targeting critical nicotinic receptors that might be involved in PD pathophysiology. The low tolerability may be related to such a lack of specificity of nicotine, which would directly stimulate the autonomic nervous system.

Quantifying motion in dystonic syndromes: the bare essentials.

Quantifying movement disorders is becoming crucially important in neurosurgery units to evaluate the efficacy of new therapeutic interventions such as deep brain stimulation. Kinematic analysis, available for more than a century, may represent an adequate solution to this problem. However, quantifying movement disorders poses a number of technical problems. To help clinicians quantify movement disorders, the authors present data recorded in patients with dystonic syndromes and explore the question of movement "normality" in these patients when they receive deep brain stimulation of the internal globus pallidus. In particular, they show that when one control group (n = 11) and a group of dystonic patients (n = 11) are compared, it is possible to detect subtle changes in the performance of a double-handed finger to nose test. These differences persist in the absence of differences in the clinical evaluation of these patients. Suggestions regarding the compromises to make and pitfalls to avoid when quantifying movement disorders are discussed.