Using non-invasive brain stimulation to augment motor training-induced plasticity

Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date.     

Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS)

Both resting state functional magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS) are increasingly popular techniques that can be used to non-invasively measure brain connectivity in human subjects. TMS shows additional promise as a method to manipulate brain connectivity. In this review we discuss how these two complimentary tools can be combined to optimally study brain connectivity and manipulate distributed brain networks. Important clinical applications include using resting state fcMRI to guide target selection for TMS and using TMS to modulate pathological network interactions identified with resting state fcMRI. The combination of TMS and resting state fcMRI has the potential to accelerate the translation of both techniques into the clinical realm and promises a new approach to the diagnosis and treatment of neurological and psychiatric diseases that demonstrate network pathology.     

An electrophysiological link between the cerebellum, cognition and emotion: frontal theta EEG activity to single-pulse cerebellar TMS

Early intracranial electrical stimulation studies in animals demonstrated cerebellar connectivity to brain structures involved in cognitive and emotive functions. Human electrophysiological data to support cerebellum involvement in the latter functions are however lacking. In the present study, electrophysiological responses were recorded to single-pulse transcranial magnetic stimulation (TMS) over the vermis in healthy human volunteers. Increased theta activity was observed after single-pulse vermis TMS as compared to sham and occipital TMS. Both animal and human research relate theta activity with the septo-hippocampal complex, an important brain structure involved in cognition and emotion. The present electrophysiological study supports the earlier intracranial electrical stimulation findings by demonstrating cerebellar involvement in the modulation of the core frequencies related to cognitive and emotive aspects of human behavior.     

Modulation of cortical oscillatory activities induced by varying single-pulse transcranial magnetic stimulation intensity over the left primary motor area: a combined EEG and TMS study

Combined transcranial magnetic stimulation/electroencephalography (TMS/EEG) was used to study the activation and interaction of cortical regions to a variety of focused sub- and suprathreshold magnetic pulses over the left primary motor cortex (M1) in ten healthy subjects. Five single-pulse TMS conditions were performed based on the individual resting motor threshold (RMT): (1) 80%; (2) 100%; (3) 120%; (4) 130%; and (5) sham. Simple self-paced movements of the right first finger were also executed. We evaluated the reactions to magnetic stimulation and movement conditions using event-related power and event-related coherence transformations of alpha and beta rhythms. Event-related power reflected regional oscillatory activity of neural assemblies, while event-related coherence reflected the inter-regional functional coupling of oscillatory neural activity. The event-related power transformation revealed that the magnetic pulse modulated cortical oscillations within the first half second for both frequency ranges. For the alpha rhythm, threshold TMS induced a small decrease in the amplitude of EEG oscillations over the stimulation site, while for both rhythms, a progressive synchronization was observed as the intensity of TMS was increased in both hemispheres. Movement onset produced a greater bilateral decrease of power compared with the effects of a magnetic pulse. The event-related coherence revealed that TMS enhanced the electrode connectivity of both hemispheres. Additionally, it was more enhanced within the first 500 ms following stimulation and was seen only for the alpha frequency rhythm. The increase of functional connectivity between cortical areas was minor for magnetic stimulation conditions compared with that for finger movements. The single-pulse TMS over M1 partially modulated the motor cortex generators of oscillatory activity, while a simple active self-paced movement of the right first finger induced greater cortex activation and coupling between cortical regions. We propose that finger movements impose higher functional demands on the motor system compared to artificial magnetic stimulation. These findings are consistent with the possibility that the human motor system may be based on network-like oscillatory cortical activity and might be modulated by brief electromagnetic sub- and suprathreshold pulses applied to M1, suggesting a phenomenon of resetting.     

康复治疗对脑卒中后脑网络运动功能重塑的磁共振研究进展

随着脑卒中后运动功能障碍研究的不断深入,功能磁共振成像(fMRI)受到广泛关注。脑卒中后皮质下病灶影响附近或远端相关脑区,导致运动功能障碍。镜像神经元疗法、重复性经颅磁、经颅电刺激可通过无创方式激活大脑皮质相关区域,恢复大脑半球之间的平衡,对全脑网络环路有调节作用,但经颅电刺激缺乏A级证据。针灸虽能广泛调节全脑功能网络节点的拓扑结构,但由于针刺选穴、手法、时间、经络的差异,不能全面阐释针灸的治疗机制。康复治疗技术与神经影像学的结合成为脑卒中治疗研究的新方向。     

经颅直流电刺激结合功能性电刺激对脑卒中平台期患者上肢运动功能康复影响的研究

目的:将经颅直流电刺激(tDCS)和功能性电刺激(FES)结合,观察这种联合治疗干预方式对脑卒中平台期患者上肢功能的影响。方法:3例脑卒中后平台期偏瘫患者在4周基线期后接受4周的tDCS结合FES治疗干预。干预前后用Fugl-Meyer上肢运动功能评分(U-FMA)、表面肌电图(sEMG)、经颅磁刺激(TMS)进行评定。结果:干预后U-FMA分数较干预前提高。7个主动肌中有5个表面肌电激活性干预前后有明显变化。用TMS成对刺激方法评估受试者健侧大脑短潜伏期皮质内抑制与短潜伏期皮质内易化结果显示部分的干预前后变化。结论:tDCS结合FES治疗干预改善了受试者上肢的运动功能,该方案可能是针对脑卒中平台期患者的一种有前景的干预康复方案。     

Time course and spatial distribution of fMRI signal changes during single-pulse transcranial magnetic stimulation to the primary motor cortex

Simultaneous transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) may advance the understanding of neurophysiological mechanisms of TMS. However, it remains unclear if TMS induces fMRI signal changes consistent with the standard hemodynamic response function (HRF) in both local and remote regions. To address this issue, we delivered single-pulse TMS to the left M1 during simultaneous recoding of electromyography and time-resolved fMRI in 36 healthy participants. First, we examined the time-course of fMRI signals during supra- and subthreshold single-pulse TMS in comparison with those during voluntary right hand movement and electrical stimulation to the right median nerve (MNS). All conditions yielded comparable time-courses of fMRI signals, showing that HRF would generally provide reasonable estimates for TMS-evoked activity in the motor areas. However, a clear undershoot following the signal peak was observed only during subthreshold TMS in the left M1, suggesting a small but meaningful difference between the locally and remotely TMS-evoked activities. Second, we compared the spatial distribution of activity across the conditions. Suprathreshold TMS-evoked activity overlapped not only with voluntary movement-related activity but also partially with MNS-induced activity, yielding overlapped areas of activity around the stimulated M1. The present study has provided the first experimental evidence that motor area activity during suprathreshold TMS likely includes activity for processing of muscle afferents. A method should be developed to control the effects of muscle afferents for fair interpretation of TMS-induced motor area activity during suprathreshold TMS to M1.     

Ethanol modulates cortical activity: direct evidence with combined TMS and EEG

The motor cortex of 10 healthy subjects was stimulated by transcranial magnetic stimulation (TMS) before and after ethanol challenge (0.8 g/kg resulting in blood concentration of 0.77 +/- 0.14 ml/liter). The electrical brain activity resulting from the brief electromagnetic pulse was recorded with high-resolution electroencephalography (EEG) and located using inversion algorithms. Focal magnetic pulses to the left motor cortex were delivered with a figure-of-eight coil at the random interstimulus interval of 1.5-2.5 s. The stimulation intensity was adjusted to the motor threshold of abductor digiti minimi. Two conditions before and after ethanol ingestion (30 min) were applied: (1) real TMS, with the coil pressed against the scalp; and (2) control condition, with the coil separated from the scalp by a 2-cm-thick piece of plastic. A separate EMG control recording of one subject during TMS was made with two bipolar platinum needle electrodes inserted to the left temporal muscle. In each condition, 120 pulses were delivered. The EEG was recorded from 60 scalp electrodes. A peak in the EEG signals was observed at 43 ms after the TMS pulse in the real-TMS condition but not in the control condition or in the control scalp EMG. Potential maps before and after ethanol ingestion were significantly different from each other (P = 0.01), but no differences were found in the control condition. Ethanol changed the TMS-evoked potentials over right frontal and left parietal areas, the underlying effect appearing to be largest in the right prefrontal area. Our findings suggest that ethanol may have changed the functional connectivity between prefrontal and motor cortices. This new noninvasive method provides direct evidence about the modulation of cortical connectivity after ethanol challenge.     

Experimentation with a transcranial magnetic stimulation system for functional brain mapping

We describe functional brain mapping experiments using a transcranial magnetic stimulation (TMS) device. This device, when placed on a subject's scalp, stimulates the underlying neurons by generating focused magnetic field pulses. A brain mapping is then generated by measuring responses of different motor and sensory functions to this stimulation. The key process in generating this mapping is the association of the 3-D positions and orientations of the TMS probe on the scalp to a 3-D brain reconstruction such as is feasible with a magnetic resonance image (MRI). We have developed a registration system which not only generates functional brain maps using such a device, but also provides real-time feedback to guide the technician in placing the probe at appropriate points on the head to achieve the desired map resolution. Functional areas we have mapped are the motor and visual cortex. Validation experiments focus on repeatability tests for mapping the same subjects several times. Applications of the technique include neuroanatomy research, surgical planning and guidance, treatment and disease monitoring, and therapeutic procedures.     

Artifact correction and source analysis of early electroencephalographic responses evoked by transcranial magnetic stimulation over primary motor cortex

Analyzing the brain responses to transcranial magnetic stimulation (TMS) using electroencephalography (EEG) is a promising method for the assessment of functional cortical connectivity and excitability of areas accessible to this stimulation. However, until now it has been difficult to analyze the EEG responses during the several tens of milliseconds immediately following the stimulus due to TMS-induced artifacts. In the present study we show that by combining a specially adapted recording system with software artifact correction it is possible to remove a major part of the artifact and analyze the cortical responses as early as 10 ms after TMS. We used this methodology to examine responses of left and right primary motor cortex (M1) to TMS at different intensities. Based on the artifact-corrected data we propose a model for the cortical activation following M1 stimulation. The model revealed the same basic response sequence for both hemispheres. A large part of the response could be accounted for by two sources: a source close to the stimulation site (peaking approximately 15 ms after the stimulus) and a midline frontal source ipsilateral to the stimulus (peaking approximately 25 ms). In addition the model suggests responses in ipsilateral temporo-parietal junction areas (approximately 35 ms) and ipsilateral (approximately 30 ms) and middle (approximately 50 ms) cerebellum. Statistical analysis revealed significant dependence on stimulation intensity for the ipsilateral midline frontal source. The methodology developed in the present study paves the way for the detailed study of early responses to TMS in a wide variety of brain areas.     

Electrophysiological and functional connectivity of the human supplementary motor area

Neuro-imaging methods for detecting functional and structural inter-regional connectivity are in a rapid phase of development. While reports of regional connectivity patterns based on individual methods are becoming common, studies comparing the results of two or more connectivity-mapping methods remain rare. In this study, we applied transcranial magnetic stimulation during PET imaging (TMS/PET), a stimulation-based method, and meta-analytic connectivity modeling (MACM), a task-based method to map the connectivity patterns of the supplementary motor area (SMA). Further, we drew upon the behavioral domain meta-data of the BrainMap? database to characterize the behavioral domain specificity of two maps. Both MACM and TMS/PET detected multi-synaptic connectivity patterns, with the MACM-detected connections being more extensive. Both MACM and TMS/PET detected connections belonging to multiple behavioral domains, including action, cognition and perception. Finally, we show that the two connectivity-mapping methods are complementary in that, the MACM informed on the functional nature of SMA connections, while TMS/PET identified brain areas electrophysiologically connected with the SMA. Thus, we demonstrate that integrating multimodal database and imaging techniques can derive comprehensive connectivity maps of brain areas.     

Functional electrical therapy for hemiparesis alleviates disability and enhances neuroplasticity

Impaired motor and sensory function is common in the upper limb in humans after cerebrovascular stroke and it often remains as a permanent disability. Functional electrical stimulation therapy is known to enhance the motor function of the paretic hand; however, the mechanism of this enhancement is not known. We studied whether neural plasticity has a role in this therapy-induced enhancement of the hand motor function in 20 hemiparetic subjects with chronic stroke (age 53 ± 6 years; 7 females and 13 males; 10 with cerebral infarction and 10 with cerebral haemorrhage; and time since incident 2.4 ± 2.0 years). These subjects were randomized to functional electrical therapy or conventional physiotherapy group. Both groups received upper limb treatment (twice daily sessions) for two weeks. Behavioral hand motor function and neurophysiologic transcranial magnetic stimulation (TMS) tests were applied before and after the treatment and at 6-months follow-up. TMS is useful in assessing excitability changes in the primary motor cortex. Faster corticospinal conduction and newly found muscular responses were observed in the paretic upper limb in the functional electrical therapy group but not in the conventional therapy group after the intervention. Behaviourally, faster movement times were observed in the functional electrical therapy group but not in the conventionally treated group. Despite the small number of heterogeneous subjects, functional exercise augmented with individualized electrical therapy of the paretic upper limb may enhance neuroplasticity, observed as corticospinal facilitation, in chronic stroke subjects, along with moderate improvements in the voluntary motor control of the affected limb.     

Transcranial magnetic brain stimulation: therapeutic promises and scientific gaps

Since its commercial advent in 1985, transcranial magnetic stimulation (TMS), a technique for stimulating neurons in the cerebral cortex through the scalp, safely and with minimal discomfort, has captured the imaginations of scientists, clinicians and lay observers. Initially a laboratory tool for neurophysiologists studying the human motor system, TMS now has a growing list of applications in clinical and basic neuroscience. Although we understand many of its effects at the system level, detailed knowledge of its actions, particularly as a modulator of neural activity, has lagged, due mainly to the lack of suitable non-human models. Nevertheless, these gaps have not blocked the therapeutic application of TMS in brain disorders. Moderate success has been achieved in treating disorders such as depression, where the U.S. Food and Drug Administration has cleared a TMS system for therapeutic use. In addition, there are small, but promising, bodies of data on the treatment of schizophrenic auditory hallucinations, tinnitus, anxiety disorders, neurodegenerative diseases, hemiparesis, and pain syndromes. Some other nascent areas of study also exist. While the fate of TMS as a therapeutic modality depends on continued innovation and experimentation, economic and other factors may be decisive.     

Alteration of cortical excitability in patients with fibromyalgia

We assessed cortical excitability and intracortical modulation systematically, by transcranial magnetic stimulation (TMS) of the motor cortex, in patients with fibromyalgia. In total 46 female patients with fibromyalgia and 21 normal female subjects, matched for age, were included in this study. TMS was applied to the hand motor area of both hemispheres and motor evoked potentials (MEPs) were recorded for the first interosseous muscle of the contralateral hand. Single-pulse stimulation was used for measurements of the rest motor threshold (RMT) and suprathreshold MEP. Paired-pulse stimulation was used to assess short intracortical inhibition (SICI) and intracortical facilitation (ICF). Putative correlations were sought between changes in electrophysiological parameters and major clinical features of fibromyalgia, such as pain, fatigue, anxiety, depression and catastrophizing. The RMT on both sides was significantly increased in patients with fibromyalgia and suprathreshold MEP was significantly decreased bilaterally. However, these alterations, suggesting a global decrease in corticospinal excitability, were not correlated with clinical features. Patients with fibromyalgia also had lower ICF and SICI on both sides, than controls, these lower values being correlated with fatigue, catastrophizing and depression. These neurophysiological alterations were not linked to medication, as similar changes were observed in patients with or without psychotropic treatment. In conclusion, fibromyalgia is associated with deficits in intracortical modulation involving both GABAergic and glutamatergic mechanisms, possibly related to certain aspects of the pathophysiology of this chronic pain syndrome. Our data add to the growing body of evidence for objective and quantifiable changes in brain function in fibromyalgia.     

In vivo assessment of human visual system connectivity with transcranial electrical stimulation during functional magnetic resonance imaging

Functional magnetic resonance imaging (fMRI) was used to investigate local and distant cerebral activation induced by transcranial electrical stimulation in order to noninvasively map functional connectivity in the human visual system. Stimulation with lateromedially directed currents and the anode 4.5 cm dorsally to the inion over the right visual cortex induced phosphenes extending into the contralateral lower quadrant of the visual field. fMRI showed a focal hemodynamic response underneath the anode in extrastriate cortex and distant coactivation in subcortical (lateral geniculate nucleus), cortical visual (striate and extrastriate), and visuomotor areas (frontal and supplementary eye fields). This pattern of activation resembles a network of presumably interconnected visual and visuomotor areas. Analysis of activation sites supplies new information about cerebral correlates of phosphenes and shows that the cortical region underneath the cranial stimulation site is not necessarily the origin of behavioral and/or perceptual effects of transcranial stimulation. We conclude that combining transcranial electrical stimulation of neural tissue with simultaneous fMRI offers the possibility to study noninvasively cerebral connectivity in the human brain.     

Modulating the brain at work using noninvasive transcranial stimulation

This paper proposes a shift in the way researchers currently view and use transcranial brain stimulation technologies. From a neuroscience perspective, the standard application of both transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) has been mainly to explore the function of various brain regions. These tools allow for noninvasive and painless modulation of cortical tissue. In the course of studying the function of an area, many studies often report enhanced performance of a task during or following the stimulation. However, little follow-up research is typically done to further explore these effects. Approaching this growing pool of cognitive neuroscience literature with a neuroergonomics mindset (i.e., studying the brain at work), the possibilities of using these stimulation techniques for more than simply investigating the function of cortical areas become evident. In this paper, we discuss how cognitive neuroscience brain stimulation studies may complement neuroergonomics research on human performance optimization. And, through this discussion, we hope to shift the mindset of viewing transcranial stimulation techniques as solely investigatory basic science tools or possible clinical therapeutic devices to viewing transcranial stimulation techniques as interventional tools to be incorporated in applied science research and systems for the augmentation and enhancement of human operator performance.     

Examining cortical dynamics and connectivity with simultaneous single-pulse transcranial magnetic stimulation and fast optical imaging

Transcranial magnetic stimulation (TMS) is a widely used experimental and clinical technique that directly induces activity in human cortex using magnetic fields. However, the neural mechanisms of TMS-induced activity are not well understood. Here, we introduce a novel method of imaging TMS-evoked activity using a non-invasive fast optical imaging tool, the event-related optical signal (EROS). EROS measures changes in the scattering of near-infrared light that occur synchronously with electrical activity in cortical tissue. EROS has good temporal and spatial resolution, allowing the dynamics and spatial spread of a TMS pulse to be measured. We used EROS to monitor activity induced in primary motor cortex (M1) by a TMS pulse. Left- and right-hand representations were mapped using standard TMS procedures. Optical sources and detectors mounted on thin rubber patches were then centered on M1 hand representations. EROS was recorded bilaterally from motor cortex while unilateral TMS was simultaneously delivered. Robust ipsilateral EROS activations were apparent within 16 ms of a pulse for TMS delivered to both left and right hemispheres. Clear motor evoked potentials (MEPs) were also elicited by these TMS pulses. Movement artifacts could be excluded as a source of EROS, as no activation was present on short-distance optical channels. For left hemisphere TMS subsequent (40 ms) contralateral activity was also present, presumably due to trans-synaptic propagation of TMS-evoked activity. Results demonstrate that concurrent TMS/EROS is a viable and potentially powerful method for studying TMS-induced activity in the human brain. With further development, this technique may be applied more broadly in the study of the dynamics of causal cortico-cortical connectivity.     

Neural correlates of age-related changes in cortical neurophysiology

Functional imaging studies of cortical motor systems in humans have demonstrated age-related reorganisation often attributed to anatomical and physiological changes. In this study we investigated whether aspects of brain activity during a motor task were influenced not only by age, but also by neurophysiological parameters of the motor cortex contralateral to the moving hand. Twenty seven right-handed volunteers underwent functional magnetic resonance imaging whilst performing repetitive isometric right hand grips in which the target force was parametrically varied between 15 and 55% of each subject's own maximum grip force. For each subject we characterised two orthogonal parameters, B(G) (average task-related activity for all hand grips) and B(F) (the degree to which task-related activity co-varied with peak grip force). We used transcranial magnetic stimulation (TMS) to assess task-related changes in interhemispheric inhibition from left to right motor cortex (IHIc) and to perform measures relating to left motor cortex excitability during activation of the right hand. Firstly, we found that B(G) in right (ipsilateral) motor cortex was greater with increasing values of age(2) and IHIc. Secondly, B(F) in left ventral premotor cortex was greater in older subjects and in those in whom contralateral M1 was less responsive to TMS stimulation. In both cases, neurophysiological parameters accounted for variability in brain responses over and above that explained by ageing. These results indicate that neurophysiological markers may be better indicators of biological ageing than chronological age and point towards the mechanisms by which reconfiguration of distributed brain networks occurs in the face of degenerative changes.     

An event-related optical topography study of cortical activation induced by single-pulse transcranial magnetic stimulation

To visualize cortical activations during transcranial magnetic stimulation (TMS), it is necessary to measure those activations at high spatiotemporal resolution while preventing interference with the magnetic property of a coil. One suitable method that satisfies these demands is optical topography (OT), which has been used in cortical activation studies. In the present study, single-pulse TMS was applied to the left primary motor area, and cortical responses at the stimulation site were measured simultaneously with event-related OT. When TMS was applied at 110% motor threshold (MT), we observed significant oxyhemoglobin increases that were both time-locked and correlated with the hemodynamic basis function. Moreover, when TMS was applied at 90% MT, significant oxyhemoglobin increases were detected even though there were no motor-evoked potentials. These results demonstrate that OT can directly measure cortical responses to subthreshold single-pulse TMS, independent of the afferent feedback from the peripheral neuromuscular activity.     

Transcranial magnetic stimulation and stroke: a computer-based human model study

This paper explores how transcranial magnetic stimulation (TMS) induced currents in the brain are perturbed by electrical and anatomical changes following a stroke in its chronic stage. Multiple MRI derived finite element head models were constructed and evaluated to address the effects that strokes can have on the induced stimulating TMS currents by comparing stroke models of various sizes and geometries to a healthy head model under a number of stimulation conditions. The TMS induced currents were significantly altered for stimulation proximal to the lesion site in all of the models analyzed. The current density distributions were modified in magnitude, location, and orientation such that the population of neural elements that are stimulated will be correspondingly altered. The current perturbations were minimized for conditions tested where the coil was far removed from the lesion site, including models of stimulation contralateral to the lesioned hemisphere. The present limitations of TMS to the peri-lesional cortex are explored, ultimately concluding that conventional clinical standards for stimulation are unreliable and potentially dangerous predictors of the site and degree of stimulation when TMS is applied proximal to infarction site.