Modulation of I-wave generating pathways by TBS: a model of plasticity induction

KEY POINTS: • Mechanisms underlying plasticity induction by repetitive transcranial magnetic stimulation protocols such as intermittent theta-burst stimulation (iTBS) remain poorly understood. • Individual response to iTBS is associated with recruitment of late indirect wave (I-wave) generating pathways that can be probed by the onset latency of TMS applied to primary motor cortex (M1) at different coil orientations. • We found an association between late I-wave recruitment (reflected by AP-LM latency, i.e. the excess latency of motor evoked potentials (MEPs) generated by TMS with an anterior-posterior (AP) orientation over the latency of MEPs evoked by direct activation of corticospinal axons using latero-medial (LM) stimulation) and changes in cortical excitability following iTBS, confirming previous studies. •AP-LM latency significantly decreased following iTBS, and this decrease correlated with the iTBS-induced increase in cortical excitability across subjects. •Plasticity in the motor network may in part derive from a modulation of excitability and recruitment of late I-wave generating cortical pathways. ABSTRACT: Plasticity-induction following theta burst transcranial stimulation (TBS) varies considerably across subjects, and underlying neurophysiological mechanisms remain poorly understood, representing a challenge for scientific and clinical applications. In human motor cortex (M1), recruitment of indirect waves (I-waves) can be probed by the excess latency of motor evoked potentials (MEPs) elicited by TMS with an anterior-posterior (AP) orientation over the latency of MEPs evoked by direct activation of corticospinal axons using latero-medial (LM) stimulation, referred to as "AP-LM latency" difference. Importantly, AP-LM latency has been shown to predict individual responses to TBS across subjects. We, therefore, hypothesized that the plastic changes in corticospinal excitability induced by TBS are the result, at least in part, of changes in excitability of these same I-wave generating pathways. We investigated in 20 healthy subjects whether intermittent TBS (iTBS) modulates I-wave recruitment as reflected by changes in the AP-LM latency. As expected, we found that AP-LM latencies before iTBS were associated with iTBS-induced excitability changes. A novel finding was that iTBS reduced the AP-LM latency, and that this correlated significantly with changes in cortical excitability observed following iTBS: subjects with the largest reductions in AP-LM latencies had the largest increases in cortical excitability following iTBS. Our findings suggest that plasticity-induction by iTBS may derive from the modulation of I-wave generating pathways projecting onto M1, accounting for the predictive potential of I-wave recruitment. The excitability of I-wave generating may serve a critical role in modulating motor cortical excitability and hence represent a promising target for novel rTMS protocols

Augmentation of Leptin and Hypoxia-Inducible Factor 1 alpha mRNAs in Preeclamptic Placenta

Schizophrenia is characterized by marked deficits in executive and psychomotor functions, as demonstrated for goal-directed actions in the antisaccade task. Recent studies, however, suggest that this deficit represents only one manifestation of a general deficit in stimulus-response integration and volitional initiation of motor responses. We here used functional magnetic resonance imaging to investigate brain activation patterns during a manual stimulus-response compatibility task in 18 schizophrenic patients and 18 controls. We found that across groups incongruent vs. congruent responses recruited a bilateral network consisting of dorsal fronto-parietal circuits as well as bilateral anterior insula, dorsolateral prefrontal cortex (DLPFC) and the presupplementary motor area (preSMA). When testing for the main-effect across all conditions, patients showed significantly lower activation of the right DLPFC and, in turn, increased activation in a left hemispheric network including parietal and premotor areas as well as the preSMA. For incongruent responses patients showed significantly increased activation in a similar left hemispheric network, as well as additional activation in parietal and premotor regions in the right hemisphere. The present study reveals that hypoactivity in the right DLPFC in schizophrenic patients is accompanied by hyperactivity in several fronto-parietal regions associated with task execution. Impaired top-down control due to a dysfunctional DLPFC might thus be partly compensated by an up-regulation of task-relevant regions in schizophrenic patients

Reorganization of cerebral networks after stroke: new insights from neuroimaging with connectivity approaches

The motor system comprises a network of cortical and subcortical areas interacting via excitatory and inhibitory circuits, thereby governing motor behaviour. The balance within the motor network may be critically disturbed after stroke when the lesion either directly affects any of these areas or damages-related white matter tracts. A growing body of evidence suggests that abnormal interactions among cortical regions remote from the ischaemic lesion might also contribute to the motor impairment after stroke. Here, we review recent studies employing models of functional and effective connectivity on neuroimaging data to investigate how stroke influences the interaction between motor areas and how changes in connectivity relate to impaired motor behaviour and functional recovery. Based on such data, we suggest that pathological intra- and inter-hemispheric interactions among key motor regions constitute an important pathophysiological aspect of motor impairment after subcortical stroke. We also demonstrate that therapeutic interventions, such as repetitive transcranial magnetic stimulation, which aims to interfere with abnormal cortical activity, may correct pathological connectivity not only at the stimulation site but also among distant brain regions. In summary, analyses of connectivity further our understanding of the pathophysiology underlying motor symptoms after stroke, and may thus help to design hypothesis-driven treatment strategies to promote recovery of motor function in patients

Optimal use of visual information in adolescents and young adults with developmental coordination disorder

Recent reports offer contrasting views on whether or not the use of online visual control is impaired in individuals with developmental coordination disorder (DCD). This study explored the optimal temporal basis for processing and using visual information in adolescents and young adults with DCD. Participants were 22 adolescents and young adults (12 males and 10 females; M = 19 years, SD = 3). Half had been diagnosed with DCD as children and still performed poorly on the movement assessment battery for children (DCD group; n = 11), and half reported typical development (TD group; n = 11) and were age- and gender-matched with the DCD group. We used performance on a steering task as a measure of information processing and examined the use of advance visual information. The conditions varied the duration of advance visual information: 125, 250, 500, 750, and 1,000 ms. With increased duration of advance visual information, the TD group showed a pattern of linear improvement. For the DCD group, however, the pattern was best described by a U-curve where optimal performance occurred with about 750 ms of advance information. The results suggest that the DCD group has an underlying preference for immediate online processing of visual information. The exact timing for optimal online control may depend crucially on the task, but too much advance information is detrimental to performance

Recovery in Stroke Rehabilitation through the Rotation of Preferred Directions Induced by Bimanual Movements: A Computational Study

Stroke patients recover more effectively when they are rehabilitated with bimanual movement rather than with unimanual movement; however, it remains unclear why bimanual movement is more effective for stroke recovery. Using a computational model of stroke recovery, this study suggests that bimanual movement facilitates the reorganization of a damaged motor cortex because this movement induces rotations in the preferred directions (PDs) of motor cortex neurons. Although the tuning curves of these neurons differ during unimanual and bimanual movement, changes in PD, but not changes in modulation depth, facilitate such reorganization. In addition, this reorganization was facilitated only when encoding PDs are rotated, but decoding PDs are not rotated. Bimanual movement facilitates reorganization because this movement changes neural activities through inter-hemispheric inhibition without changing cortical-spinal-muscle connections. Furthermore, stronger inter-hemispheric inhibition between motor cortices results in more effective reorganization. Thus, this study suggests that bimanual movement is effective for stroke rehabilitation because this movement rotates the encoding PDs of motor cortex neurons

Saccadic Eye Movement Abnormalities in Children with Epilepsy

Childhood onset epilepsy is associated with disrupted developmental integration of sensorimotor and cognitive functions that contribute to persistent neurobehavioural comorbidities. The role of epilepsy and its treatment on the development of functional integration of motor and cognitive domains is unclear. Oculomotor tasks can probe neurophysiological and neurocognitive mechanisms vulnerable to developmental disruptions by epilepsy-related factors. The study involved 26 patients and 48 typically developing children aged 8–18 years old who performed a prosaccade and an antisaccade task. Analyses compared medicated chronic epilepsy patients and unmedicated controlled epilepsy patients to healthy control children on saccade latency, accuracy and dynamics, errors and correction rate, and express saccades. Patients with medicated chronic epilepsy had impaired and more variable processing speed, reduced accuracy, increased peak velocity and a greater number of inhibitory errors, younger unmedicated patients also showed deficits in error monitoring. Deficits were related to reported behavioural problems in patients. Epilepsy factors were significant predictors of oculomotor functions. An earlier age at onset predicted reduced latency of prosaccades and increased express saccades, and the typical relationship between express saccades and inhibitory errors was absent in chronic patients, indicating a persistent reduction in tonic cortical inhibition and aberrant cortical connectivity. In contrast, onset in later childhood predicted altered antisaccade dynamics indicating disrupted neurotransmission in frontoparietal and oculomotor networks with greater demand on inhibitory control. The observed saccadic abnormalities are consistent with a dysmaturation of subcortical-cortical functional connectivity and aberrant neurotransmission. Eye movements could be used to monitor the impact of epilepsy on neurocognitive development and help assess the risk for poor neurobehavioural outcomes

Dynamic Visuomotor Transformation Involved with Remote Flying of a Plane Utilizes the ‘Mirror Neuron’ System

Brain regions involved with processing dynamic visuomotor representational transformation are investigated using fMRI. The perceptual-motor task involved flying (or observing) a plane through a simulated Red Bull Air Race course in first person and third person chase perspective. The third person perspective is akin to remote operation of a vehicle. The ability for humans to remotely operate vehicles likely has its roots in neural processes related to imitation in which visuomotor transformation is necessary to interpret the action goals in an egocentric manner suitable for execution. In this experiment for 3rd person perspective the visuomotor transformation is dynamically changing in accordance to the orientation of the plane. It was predicted that 3rd person remote flying, over 1st, would utilize brain regions composing the ‘Mirror Neuron’ system that is thought to be intimately involved with imitation for both execution and observation tasks. Consistent with this prediction differential brain activity was present for 3rd person over 1st person perspectives for both execution and observation tasks in left ventral premotor cortex, right dorsal premotor cortex, and inferior parietal lobule bilaterally (Mirror Neuron System) (Behaviorally: 1st>3rd). These regions additionally showed greater activity for flying (execution) over watching (observation) conditions. Even though visual and motor aspects of the tasks were controlled for, differential activity was also found in brain regions involved with tool use, motion perception, and body perspective including left cerebellum, temporo-occipital regions, lateral occipital cortex, medial temporal region, and extrastriate body area. This experiment successfully demonstrates that a complex perceptual motor real-world task can be utilized to investigate visuomotor processing. This approach (Aviation Cerebral Experimental Sciences ACES) focusing on direct application to lab and field is in contrast to standard methodology in which tasks and conditions are reduced to their simplest forms that are remote from daily life experience

Motor Properties of Peripersonal Space in Humans

Background: A stimulus approaching the body requires fast processing and appropriate motor reactions. In monkeys, fronto-parietal networks are involved both in integrating multisensory information within a limited space surrounding the body (i.e. peripersonal space, PPS) and in action planning and execution, suggesting an overlap between sensory representations of space and motor representations of action. In the present study we investigate whether these overlapping representations also exist in the human brain. Methodology/Principal Findings: We recorded from hand muscles motor-evoked potentials (MEPs) induced by single-pulse of transcranial magnetic stimulation (TMS) after presenting an auditory stimulus either near the hand or in far space. MEPs recorded 50 ms after the near-sound onset were enhanced compared to MEPs evoked after far sounds. This near-far modulation faded at longer inter-stimulus intervals, and reversed completely for MEPs recorded 300 ms after the sound onset. At that time point, higher motor excitability was associated with far sounds. Such auditory modulation of hand motor representation was specific to a hand-centred, and not a body-centred reference frame. Conclusions/Significance: This pattern of corticospinal modulation highlights the relation between space and time in the PPS representation: an early facilitation for near stimuli may reflect immediate motor preparation, whereas, at later time intervals, motor preparation relates to distant stimuli potentially approaching the body

Long-latency modulation of motor cortex excitability by ipsilateral posterior inferior frontal gyrus and pre-supplementary motor area

The primary motor cortex (M1) is strongly influenced by several frontal regions. Dual-site transcranial magnetic stimulation (dsTMS) has highlighted the timing of early (<40 ms) prefrontal/premotor influences over M1. Here we used dsTMS to investigate, for the first time, longer-latency causal interactions of the posterior inferior frontal gyrus (pIFG) and pre-supplementary motor area (pre-SMA) with M1 at rest. A suprathreshold test stimulus (TS) was applied over M1 producing a motor-evoked potential (MEP) in the relaxed hand. Either a subthreshold or a suprathreshold conditioning stimulus (CS) was administered over ipsilateral pIFG/pre-SMA sites before the TS at different CS-TS inter-stimulus intervals (ISIs: 40-150 ms). Independently of intensity, CS over pIFG and pre-SMA (but not over a control site) inhibited MEPs at an ISI of 40 ms. The CS over pIFG produced a second peak of inhibition at an ISI of 150 ms. Additionally, facilitatory modulations were found at an ISI of 60 ms, with supra-but not subthreshold CS intensities. These findings suggest differential modulatory roles of pIFG and pre-SMA in M1 excitability. In particular, the pIFG-but not the pre-SMA-exerts intensity-dependent modulatory influences over M1 within the explored time window of 40-150 ms, evidencing fine-tuned control of M1 output

Restoring brain function after stroke - bridging the gap between animals and humans

Stroke is the leading cause of complex adult disability in the world. Recovery from stroke is often incomplete, which leaves many people dependent on others for their care. The improvement of long-term outcomes should, therefore, be a clinical and research priority. As a result of advances in our understanding of the biological mechanisms involved in recovery and repair after stroke, therapeutic opportunities to promote recovery through manipulation of poststroke plasticity have never been greater. This work has almost exclusively been carried out in preclinical animal models of stroke with little translation into human studies. The challenge ahead is to develop a mechanistic understanding of recovery from stroke in humans. Advances in neuroimaging techniques now enable us to reconcile behavioural accounts of recovery with molecular and cellular changes. Consequently, clinical trials can be designed in a stratified manner that takes into account when an intervention should be delivered and who is most likely to benefit. This approach is expected to lead to a substantial change in how restorative therapeutic strategies are delivered in patients after stroke