The Use of Non-invasive Brain Stimulation Techniques to Facilitate Recovery from Post-stroke Aphasia

Aphasia is a common symptom after left hemispheric stroke. Neuroimaging techniques over the last 10–15 years have described two general trends: Patients with small left hemisphere strokes tend to recruit perilesional areas, while patients with large left hemisphere lesions recruit mainly homotopic regions in the right hemisphere. Non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have been employed to facilitate recovery by stimulating lesional and contralesional regions. The majority of these brain stimulation studies have attempted to block homotopic regions in the right posterior inferior frontal gyrus (IFG) to affect a presumed disinhibited right IFG (triangular portion). Other studies have used anodal or excitatory tDCS to stimulate the contralesional (right) fronto-temporal region or parts of the intact left IFG and perilesional regions to improve speech-motor output. It remains unclear whether the interhemispheric disinhibition model, which is the basis for motor cortex stimulation studies, also applies to the language system. Future studies could address a number of issues, including: the effect of lesion location on current density distribution, timing of the intervention with regard to stroke onset, whether brain stimulation should be combined with behavioral therapy, and whether multiple brain sites should be stimulated. A better understanding of the predictors of recovery from natural outcome studies would also help to inform study design, and the selection of clinically meaningful outcome measures in future studies.     

Introducing Transcranial Magnetic Stimulation (TMS) and its Property of Causal Inference in Investigating Brain-Function Relationships

Transcranial magnetic stimulation (TMS) is a method capable of transiently modulating neural excitability. Depending on the stimulation parameters information processing in the brain can be either enhanced or disrupted. This way the contribution of different brain areas involved in mental processes can be studied, allowing a functional decomposition of cognitive behavior both in the temporal and spatial domain, hence providing a functional resolution of brain/mind processes. The aim of the present paper is to argue that TMS with its ability to draw causal inferences on function and its neural representations is a valuable neurophysiological tool for investigating the causal basis of neuronal functions and can provide substantive insight into the modern interdisciplinary and (anti)reductionist neurophilosophical debates concerning the relationships between brain functions and mental abilities. Thus, TMS can serve as a heuristic method for resolving causal issues in an arena where only correlative tools have traditionally been available.     

Crossmodal visual-tactile extinction: Modulation by posture implicates biased competition in proprioceptively reconstructed space

Extinction is a common consequence of unilateral brain injury: contralesional events can be perceived in isolation, yet are missed when presented concurrently with competing events on the ipsilesional side. This can arise crossmodally, where a contralateral touch is extinguished by an ipsilateral visual event. Recent studies showed that repositioning the hands in visible space, or making visual events more distant, can modulate such crossmodal extinction. Here, in a detailed single-case study, we implemented a novel spatial manipulation when assessing crossmodal extinction. This was designed not only to hold somatosensory inputs and hand/arm-posture constant, but also to hold (retinotopic) visual inputs constant, yet while still changing the spatial relationship of tactile and visual events in the external world. Our right hemisphere patient extinguished left-hand touches due to visual stimulation of the right visual field (RVF) when tested in the usual default posture with eyes/head directed straight ahead. But when her eyes/head were turned to the far left (and any visual events shifted along with this), such that the identical RVF retinal stimulation now fell at the same external location as the left-hand touch, crossmodal extinction was eliminated. Since only proprioceptive postural cues could signal this changed spatial relationship for the critical condition, our results show for the first time that such postural cues alone are sufficient to modulate crossmodal extinction. Identical somatosensory and retinal inputs can lead to severe crossmodal extinction, or none, depending on current posture.     

Transcranial alternating brain stimulation at alpha frequency reduces hemispatial neglect symptoms in stroke patients

Background/ObjectiveNon-invasive brain stimulation techniques such as transcranial alternating current stimulation (tACS) may help alleviate attention deficits in stroke patients with hemispatial neglect by modulating oscillatory brain activity. We applied high-definition (HD)-tACS at alpha frequency over the contralesional hemisphere to support unilateral oscillatory alpha activity and correct for the pathologically altered attention bias in neglect patients.MethodsWe performed a within-subject, placebo-controlled study in which sixteen stroke patients with hemispatial neglect underwent 10 Hz (alpha) as well as sham (placebo) stimulation targeting the contralesional posterior parietal cortex. Attentional bias was measured with a computerized visual detection paradigm and two standard paper-and-pencil neglect tests.ResultsWe revealed a significant shift of attentional resources after alpha-HD-tACS, but not sham tACS, toward the ipsilateral and thus contralesional hemifield leading to a reduction in neglect symptoms, measured with a computerized visual detection paradigm and a widely used standard paper and pencil neglect tests.ConclusionsWe showed a significant alpha-HD-tACS-induced shift of attentional resources toward the contralesional hemifield, thus leading to a reduction in neglect symptoms. Importantly, HD-tACS effects persisted after the stimulation itself had ended. This tACS protocol, based on intrinsic oscillatory processes, may be an effective and well-tolerated treatment option for neglect.     

Visual extinction and awareness: The importance of binding dorsal and ventral pathways

Patients with visual extinction were tested on three tasks involving stimulus identification and localization. In the first experiment, in which patients were to identify and localize stimuli, they demonstrated high levels of contralesional omissions. This primarily occurred under conditions of double simultaneous stimulation (DSS), consistent with the character of extinction. In contrast, when patients had to simply localize or count stimuli in Experiment 2, their contralesional omissions were very low. Similarly, when patients were to identify stimuli without localizing them (Experiment 3) they again showed very low contralesional error rates. These results support the view (Baylis, Driver, & Rafal, 1993) that visual extinction may be greatest when information about location cannot be bound to information about identity.     

Mechanisms of aphasia recovery after stroke and the role of noninvasive brain stimulation

One of the most frequent symptoms of unilateral stroke is aphasia, the impairment or loss of language functions. Over the past few years, behavioral and neuroimaging studies have shown that rehabilitation interventions can promote neuroplastic changes in aphasic patients that may be associated with the improvement of language functions. Following left hemisphere strokes, the functional reorganization of language in aphasic patients has been proposed to involve both intrahemispheric interactions between damaged left hemisphere and perilesional sites and transcallosal interhemispheric interactions between the lesioned left hemisphere language areas and homotopic regions in the right hemisphere. A growing body of evidence for such reorganization comes from studies using transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), two safe and noninvasive procedures that can be applied clinically to modulate cortical excitability during post-stroke language recovery. We discuss a hierarchical model for the plastic changes in language representation that occur in the setting of dominant hemisphere stroke and aphasia. We further argue that TMS and tDCS are potentially promising tools for enhancing functional recovery of language and for further elucidating mechanisms of plasticity in patients with aphasia.     

Transcranial magnetic stimulation as a tool for cognitive studies

Transcranial Magnetic Stimulation (TMS) is a tool for the non-invasive stimulation of the human brain. It allows the activation of arbitrary sites of the superficial cortex and, combined with other brain-imaging techniques such as EEG, PET, and fMRI, it can be used to evaluate cortical excitability and connectivity. This is of major importance in, for example, the study of cognitive processes such as language, learning, memory and self-representation, which are thought to be represented in multiple brain areas. The mechanisms of action of TMS are known on a basic level, but its effect on the activation state of brain tissue is still poorly understood. Clinical applications of TMS have also been proposed and guidelines for its safe use drafted.     

Rapid modulation of distributed brain activity by Transcranial Magnetic Stimulation of human motor cortex

This paper reviews the effects of single and repetitive transcranial magnetic stimuli (rTMS) delivered to one cortical area and measured across distributed brain regions using electrophysiological measures (e.g. motor thresholds, motor evoked potentials, paired-pulse stimulation), functional neuroimaging (including EEG, PET and fMRI) and behavioural measures. Discussion is restricted to changes in excitability in the primary motor cortex and behaviour during motor tasks following transcranial magnetic stimulation delivered to primary motor and premotor areas. Trains of rTMS have lasting effects on the excitability of intrinsic and corticofugal neurones, altering the responsiveness of local and remote sites. These effects lead to distributed changes in synaptic activity at rest, and during a range of motor tasks. It is possible to impair or improve performance following rTMS, but for most simple motor tasks performance is unaltered. Changes in distributed activity observed with functional imaging during motor behaviour may represent compensatory activity, enabling maintenance of performance; stimulation of additional cortical areas appears to impair performance. A detailed understanding of the distributed changes in excitability following rTMS may facilitate future attempts to modulate motor behaviour in the healthy brain and for therapeutic purposes.     

背外侧前额叶对主动遗忘负性社会反馈的作用：针对抑郁症的TMS研究

抑郁症患者的负性心境可能源于其抑制功能障碍。患者在主动遗忘负性材料时无法有效调用背外侧前额叶(the dorsolateral prefrontal cortex, DLPFC)等负责抑制控制的额叶脑网络。同时, 患者对社会信息的加工比对非社会信息的加工存在更明显的认知神经障碍, 很难主动遗忘对自己不利的社会反馈信息。为了提高抑郁症患者对负性社会反馈的主动遗忘能力, 本研究采用经颅磁刺激技术(transcranial magnetic stimulation, TMS), 考察抑郁症患者在左侧(n = 32)或右侧DLPFC (n = 30)被激活后其记忆控制能力的改变。结果表明, 当患者的DLPFC被TMS激活时, 他们对社会拒绝的回忆正确率与健康对照组(n = 31)无差异, 且TMS激活右侧DLPFC还改善了患者对他人的社会态度。本研究是采用TMS提高抑郁症患者主动遗忘能力的首次尝试, 研究结果不但支持了DLPFC与记忆控制功能的因果关系, 还为临床治疗抑郁症、创伤后应激障碍、药物成瘾等患者的记忆控制缺陷提供了明确的神经靶点。     

Cortico-spinal inhibition reflects time but not event preparation: neural mechanisms of preparation dissociated by transcranial magnetic stimulation.

Changes in cortico-spinal excitability related to time and event preparation were investigated by transcranial magnetic stimulation (TMS) of the motor cortex during the foreperiod of a movement-precuing task. Subjects performed a four alternative choice reaction time (RT) task involving a button-press with the index or middle finger (FI) of the left or right hand. Advance information about the to-be-signaled response was provided by a precue, which preceded the response signal by a 1 s foreperiod. The precue either indicated the hand (right or left) or FI (index or middle) with which the response would be executed or was uninformative. TMS was delivered to the left or right cortical hand area at one of five possible times during the foreperiod: -1000, -500, -333, -166 or 0 ms prior to the response signal. Surface EMG activity from a prime mover involved in flexion of the response FIs (Flexor digitorum superficialis) was used to measure the magnitude of the motor evoked potential (MEP) elicited by TMS. Cortico-spinal excitability--as assessed by the magnitude of the MEP evoked in the target muscle contralateral to the stimulated hemisphere--progressively decreased during the foreperiod. The identity of the precued responses, however, had no effect on MEP magnitude. These results suggest that preparation to respond at a particular time inhibited excitability of the cortico-spinal tract, while advance preparation to perform specific responses affected more central structures only.     

Neuromodulation as a cognitive enhancement strategy in healthy older adults: promises and pitfalls

Increases in life expectancy have been followed by an upsurge of age-associated cognitive decline. Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have risen as promising approaches to prevent or delay such cognitive decline. However, consensus has not yet been reached about their efficacy in improving cognitive functioning in healthy older adults. Here we review the effects of TMS and tDCS on cognitive abilities in healthy older adults. Despite considerable variability in the targeted cognitive domains, design features and outcomes, the results generally show an enhancement or uniform benefit across studies. Most studies employed tDCS, suggesting that this technique is particularly well-suited for cognitive enhancement. Further work is required to determine the viability of these techniques as tools for long-term cognitive improvement. Importantly, the combination of TMS/tDCS with other cognitive enhancement strategies may be a promising strategy to alleviate the cognitive decline associated with the healthy aging process.     

Emotional stimuli modulate readiness for action: A transcranial magnetic stimulation study

Emotional stimuli may prime the motor system and facilitate action readiness. Direct evidence for this effect has been shown by recent studies using transcranial magnetic stimulation (TMS). When administered over the primary motor cortex involved in responding, TMS pulses elicit motor-evoked potentials (MEPs) in the represented muscles. The amplitudes of these MEPs reflect the state of corticospinal excitability. Here, we investigated the dynamic effects of induced emotions on action readiness, as reflected by corticospinal excitability. Subjects performed a choice task while viewing task-irrelevant emotional and neutral pictures. The pattern of MEP amplitudes showed a typical increase as the TMS pulse was presented closer in time to the imminent response. This dynamic pattern was amplified by both pleasant and unpleasant emotional stimuli, but more so when unpleasant pictures were viewed. These patterns present novel evidence in support of the notion that emotional stimuli modulate action readiness.     

Transcranial magnetic stimulation in child psychiatry: disturbed motor system excitability in hypermotoric syndromes

Normal development and dysfunctions of motor system excitability can be investigated in vivo by means of single‐ and paired‐pulse transcranial magnetic stimulation (TMS). While different TMS‐parameters show different developmental time courses between 8 and 16 years of age, distinct dysfunctional patterns of motor system excitability can be demonstrated in child psychiatric disorders with hypermotoric behavior: in tic disorder, a shortened cortical silent period can be stated providing evidence for deficient inhibitory mechanisms within the sensorimotor loop, probably primarily at the level of the basal ganglia. In attention deficit hyperactivity disorder (ADHD), a decreased intracortical inhibition indicates deficient inhibitory mechanisms within the motor cortex (but enhancement of intracortical inhibition after oral intake of 10 mg methylphenidate). In children with comorbid ADHD and tic disorder, the findings of a reduced intracortical inhibition as well as a shortened cortical silent period provide evidence for additive effects at the level of motor system excitability. Thus, TMS allows us to obtain substantial insight into both the normal development and the neurobiological basis of hypermotoric syndromes in child psychiatry.     

Motor excitability is reduced prior to voluntary movements in children and adolescents with Tourette syndrome

Tourette syndrome (TS) is a neuro‐developmental disorder characterized by the occurrence of motor and vocal tics: involuntary, repetitive, stereotyped behaviours that occur with a limited duration, often typically many times in a single day. Previous studies suggest that children and adolescents with TS may undergo compensatory, neuroplastic changes in brain structure and function that help them gain control over their tics. In the current study we used single‐pulse and dual‐site paired‐pulse transcranial magnetic stimulation (TMS), in conjunction with a manual choice reaction time task that induces high levels of inter‐manual conflict, to investigate this conjecture in a group of children and adolescents with TS, but without co‐morbid Attention Deficit Hyperactivity Disorder (ADHD). We found that performance on the behavioural response‐conflict task did not differ between the adolescents with TS and a group of age‐matched typically developing individuals. By contrast, our study demonstrated that cortical excitability, as measured by TMS‐induced motor‐evoked potentials (MEPs), was significantly reduced in the TS group in the period immediately preceding a finger movement. This effect is interpreted as consistent with previous suggestions that the cortical hyper‐excitability that may give rise to tics in TS is actively suppressed by cognitive control mechanisms. Finally, we found no reliable evidence for altered patterns of functional inter‐hemispheric connectivity in TS. These results provide evidence for compensatory brain reorganization that may underlie the increased self‐regulation mechanisms that have been hypothesized to bring about the control of tics during adolescence.     

Amygdala and hippocampal activity during acquisition and extinction of human fear conditioning

Previous functional magnetic resonance imaging (fMRI) studies have characterized brain systems involved in conditional response acquisition during Pavlovian fear conditioning. However, the functional neuroanatomy underlying the extinction of human conditional fear remains largely undetermined. The present study used fMRI to examine brain activity during acquisition and extinction of fear conditioning. During the acquisition phase, participants were either exposed to light (CS) presentations that signaled a brief electrical stimulation (paired group) or received light presentations that did not serve as a warning signal (control group). During the extinction phase, half of the paired group subjects continued to receive the same treatment, whereas the remainder received light alone. Control subjects also received light alone during the extinction phase. Changes in metabolic activity within the amygdala and hippocampus support the involvement of these regions in each of the procedural phases of fear conditioning. Hippocampal activity developed during acquisition of the fear response. Amygdala activity increased whenever experimental contingencies were altered, suggesting that this region is involved in processing changes in environmental relationships. The present data show learning-related amygdala and hippocampal activity during human Pavlovian fear conditioning and suggest that the amygdala is particularly important for forming new associations as relationships between stimuli change.     

Representational momentum and the brain: An investigation into the functional necessity of V5/MT

The mental representation of objects can imply motion and momentum. This can be explored by investigating a distortion in recognition memory for pictures that depict objects “frozen” in mid-air, implying motion. This distortion is called representational momentum (RM). Recent functional neuroimaging studies have suggested that the V5/MT system (the area of the brain thought to be responsible for perceptual processing of motion) is involved in the mediation of RM. The results of these studies are reviewed here. However the presence of functional activity revealed in brain imaging studies does not mean that this part of the brain is necessary for a particular cognitive task. A greater degree of functional necessity can be inferred by disrupting function in that part of the brain. One way in which this can be done is with Transcranial Magnetic Stimulation (TMS, a method of temporarily suspending cortical activity). We extended the findings of the previous fMRI experiments by using TMS in conjunction with an RM paradigm. Repetitive magnetic stimulation to V5/MT during the so-called freeze-frame RM task resulted in an absence of the stereotypical distortion in recognition memory (compared to stimulation at the vertex) for approximately 60% of     

Asynchronous stimulus presentation in visual extinction: A psychophysical study

Patients showing visual extinction as a consequence of a unilateral brain lesion can correctly detect a single stimulus in either hemifield but fail to detect the contralesional stimulus (or at least process the stimulus less efficiently) when it is presented simultaneously with an ipsilesional stimulus. In an attempt to uncover the nature of the underlying deficit, some studies have manipulated the temporal characteristics of stimulus presentation. Contra- and ipsilesional stimuli with different stimulus onset asynchronies are typically used. In the present study, visual extinction was investigated in a group of left neglect patients (N=10) using a psychophysical paradigm with different stimulus onset asynchronies of target and distractor stimuli presented in different hemifields. Contrast thresholds for a target grating were determined with the target either in isolation or in the presence of an irrelevant distractor grating. When target and distractor gratings were presented simultaneously, neglect patients showed a significant extinction effect, i.e., a significant interference from the right hemifield distractor with left hemifield contrast sensitivity. When the right hemifield distractor preceded the left hemifield target stimulus by 250 ms, two different patterns of results were observed in the neglect patients. Five patients showed a significant improvement compared to the simultaneous presentation condition, five other patients showed a significant increase of the extinction effect. The results suggest that different underlying mechanisms, maybe due to different lesion locations, can cause extinction in neglect patients.     

Transcranial magnetic stimulation: neurophysiological applications and safety

TMS is a non-invasive tool for measuring neural conduction and processing time, activation thresholds, facilitation and inhibition in brain cortex, and neural connections in humans. It is used to study motor, visual, somatosensory, and cognitive functions. TMS does not appear to cause long-term adverse neurological, cardiovascular, hormonal, motor, sensory, or cognitive effects in healthy subjects. Single-pulse (<1Hz) TMS is safe in normal subjects. High frequency, high-intensity repetitive TMS (rTMS) can elicit seizures even in normal subjects. Safety guidelines for using rTMS have been published.     

Magnetic stimulation studies of visual cognition

The panoply of non-invasive techniques for brain imaging is responsible for much of the current excitement in cognitive neuroscience; sensory, perceptual and cognitive behaviour can now be correlated with cerebral blood flow as assessed by functional imaging, the electrical fields generated by populations of neurons or changes in magnetic fields created by electrical activity. Correlations between localized brain activity and behaviour, however, do not of themselves establish that any brain area is necessary for a particular task; necessity is the domain of the lesion technique. Transcranial magnetic stimulation (TMS) is a technique that can be used non-invasively to produce reversible functional disruption and has already been used to investigate visual detection, discrimination, attention and plasticity. The power of TMS as a `lesion' technique lies in the opportunity to combine reversible disruption with high degrees of spatial and temporal resolution. In this review we trace some of the major developments in the use of TMS as a technique for the investigation of visual cognition.     

Mechanisms and the current state of transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is unique among the current brain stimulation techniques because it is relatively non-invasive. TMS markedly differs from vagus nerve stimulation, deep brain stimulation and magnetic seizure therapy, all of which require either an implanted prosthesis or general anesthesia, or both. Since its rebirth in its modern form in 1985, TMS has already shown potential usefulness in at least three important domains-as a basic neuroscience research instrument, as a potential clinical diagnostic tool, and as a therapy for several different neuropsychiatric conditions. The TMS scientific literature has now expanded beyond what a single summary article can adequately cover. This review highlights several new developments in combining TMS with functional brain imaging, using TMS as a psychiatric therapy, potentially using TMS to enhance performance, and finally recent advances in the core technology of TMS. TMS' ability to non-invasively and focally stimulate the brain of an awake human is proving to be a most important development for neuroscience in general, and neuropsychiatry in particular.