Gesa Hartwigsen

Combining non-invasive transcranial brain stimulation with neuroimaging and electrophysiology: Current approaches and future perspectives.

Non-invasive transcranial brain stimulation (NTBS) techniques such as transcranial magnetic stimulation (TMS) and transcranial current stimulation (TCS) are important tools in human systems and cognitive neuroscience because they are able to reveal the relevance of certain brain structures or neuronal activity patterns for a given brain function. It is nowadays feasible to combine NTBS, either consecutively or concurrently, with a variety of neuroimaging and electrophysiological techniques. Here we discuss what kind of information can be gained from combined approaches, which often are technically demanding. We argue that the benefit from this combination is twofold. Firstly, neuroimaging and electrophysiology can inform subsequent NTBS, providing the required information to optimize where, when, and how to stimulate the brain. Information can be achieved both before and during the NTBS experiment, requiring consecutive and concurrent applications, respectively. Secondly, neuroimaging and electrophysiology can provide the readout for neural changes induced by NTBS. Again, using either concurrent or consecutive applications, both online NTBS effects immediately following the stimulation and offline NTBS effects outlasting plasticity-inducing NTBS protocols can be assessed. Finally, both strategies can be combined to close the loop between measuring and modulating brain activity by means of closed-loop brain state-dependent NTBS. In this paper, we will provide a conceptual framework, emphasizing principal strategies and highlighting promising future directions to exploit the benefits of combining NTBS with neuroimaging or electrophysiology.

Low-Frequency Transcranial Magnetic Stimulation over Left Dorsal Premotor Cortex Improves the Dynamic Control of Visuospatially Cued Actions

Left rostral dorsal premotor cortex (rPMd) and supramarginal gyrus (SMG) have been implicated in the dynamic control of actions. In 12 right-handed healthy individuals, we applied 30 min of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over left rPMd to investigate the involvement of left rPMd and SMG in the rapid adjustment of actions guided by visuospatial cues. After rTMS, subjects underwent functional magnetic resonance imaging while making spatially congruent button presses with the right or left index finger in response to a left- or right-sided target. Subjects were asked to covertly prepare motor responses as indicated by a directional cue presented 1 s before the target. On 20% of trials, the cue was invalid, requiring subjects to readjust their motor plan according to the target location. Compared with sham rTMS, real rTMS increased the number of correct responses in invalidly cued trials. After real rTMS, task-related activity of the stimulated left rPMd showed increased task-related coupling with activity in ipsilateral SMG and the adjacent anterior intraparietal area (AIP). Individuals who showed a stronger increase in left-hemispheric premotor–parietal connectivity also made fewer errors on invalidly cued trials after rTMS. The results suggest that rTMS over left rPMd improved the ability to dynamically adjust visuospatial response mapping by strengthening left-hemispheric connectivity between rPMd and the SMG–AIP region. These results support the notion that left rPMd and SMG–AIP contribute toward dynamic control of actions and demonstrate that low-frequency rTMS can enhance functional coupling between task-relevant brain regions and improve some aspects of motor performance.

Incidental findings are frequent in young healthy individuals undergoing magnetic resonance imaging in brain research imaging studies: A prospective single-center study

Objective: There is an ongoing debate about how to handle incidental findings (IF) detected in healthy individuals who participate in research-driven magnetic resonance imaging (MRI) studies. There are currently no established guidelines regarding their management. Methods: We prospectively assessed the frequency of IF in 206 young healthy volunteers who additionally underwent structural MRIs of the whole brain as part of a scientific MRI protocol. Results: Assessment of the structural MRI by 2 board-certified neuroradiologists revealed IF in 19% of the subjects (n = 39). In approximately half of these subjects (n = 21), these findings were of potential clinical relevance (eg, arteriovenous malformations, cavernomas, pituitary abnormalities) and required further diagnostic investigations. None of these potentially relevant IF prompted immediate active medical treatment. Conclusions: Incidental findings are very frequent in young healthy volunteers. Because many of the IF require further diagnostic workup, standardized procedures for MRI and the handling of these images are mandatory to ensure competent clinical management.

Left inferior parietal lobe engagement in social cognition and language

Social cognition and language are two core features of the human species. Despite distributed recruitment of brain regions in each mental capacity, the left parietal lobe (LPL) represents a zone of topographical convergence. The present study quantitatively summarizes hundreds of neuroimaging studies on social cognition and language. Using connectivity-based parcellation on a meta-analytically defined volume of interest (VOI), regional coactivation patterns within this VOI allowed identifying distinct subregions. Across parcellation solutions, two clusters emerged consistently in rostro-ventral and caudo-ventral aspects of the parietal VOI. Both clusters were functionally significantly associated with social-cognitive and language processing. In particular, the rostro-ventral cluster was associated with lower-level processing facets, while the caudo-ventral cluster was associated with higher-level processing facets in both mental capacities. Contrarily, in the (less stable) dorsal parietal VOI, all clusters reflected computation of general-purpose processes, such as working memory and matching tasks, that are frequently co-recruited by social or language processes. Our results hence favour a rostro-caudal distinction of lower- versus higher-level processes underlying social cognition and language in the left inferior parietal lobe.

Dissociating Parieto-Frontal Networks for Phonological and Semantic Word Decisions: A Condition-and-Perturb TMS Study

Left posterior inferior frontal gyrus (pIFG) and supramarginal gyrus (SMG) are key regions for phonological decisions, whereas angular gyrus (ANG) and anterior IFG (aIFG) are associated with semantics. However, it is less clear whether the functional contribution of one area changes in the presence of a dysfunctional area within the network. Using repetitive transcranial magnetic stimulation (rTMS), we first tested whether perturbing one area would disrupt behavior. Second, we applied a condition-and-perturb approach, combining parietal offline rTMS with frontal online rTMS to investigate how the functional contribution of a frontal region changes in the presence of a dysfunctional parietal region. We found that rTMS over SMG or pIFG delayed phonological decisions, but this was not enhanced by combining supramarginal rTMS with pIFG rTMS. In contrast, semantic decisions were only impaired when angular rTMS was combined with aIFG rTMS. We infer that offline rTMS caused a dysfunction of ANG which increased the functional relevance of aIFG for semantic decisions and sensitized this network to the disruptive effects of aIFG rTMS. The results provide causal evidence that ANG and aIFG contribute to semantics and that the functional significance of one area within this network depends on the functional integrity of the other.

Modeling the effects of noninvasive transcranial brain stimulation at the biophysical, network, and cognitive level.

Noninvasive transcranial brain stimulation (NTBS) is widely used to elucidate the contribution of different brain regions to various cognitive functions. Here we present three modeling approaches that are informed by functional or structural brain mapping or behavior profiling and discuss how these approaches advance the scientific potential of NTBS as an interventional tool in cognitive neuroscience. (i) Leveraging the anatomical information provided by structural imaging, the electric field distribution in the brain can be modeled and simulated. Biophysical modeling approaches generate testable predictions regarding the impact of interindividual variations in cortical anatomy on the injected electric fields or the influence of the orientation of current flow on the physiological stimulation effects. (ii) Functional brain mapping of the spatiotemporal neural dynamics during cognitive tasks can be used to construct causal network models. These models can identify spatiotemporal changes in effective connectivity during distinct cognitive states and allow for examining how effective connectivity is shaped by NTBS. (iii) Modeling the NTBS effects based on neuroimaging can be complemented by behavior-based cognitive models that exploit variations in task performance. For instance, NTBS-induced changes in response speed and accuracy can be explicitly modeled in a cognitive framework accounting for the speed-accuracy trade-off. This enables to dissociate between behavioral NTBS effects that emerge in the context of rapid automatic responses or in the context of slow deliberate responses. We argue that these complementary modeling approaches facilitate the use of NTBS as a means of dissecting the causal architecture of cognitive systems of the human brain.

Intraoperative dynamic susceptibility contrast MRI (iDSC-MRI) is as reliable as preoperatively acquired perfusion mapping

DSC-MRI was applied intraoperatively during human brain tumor removal. Immediately after complete tumor resection was presumed, MRI including a dynamic susceptibility contrast T2-weighted EPI sequence was performed in 30 patients while the skull was still open using a flexible two-channel coil system at an intraoperative 1.5-Tesla MR scanner. Maps of relative regional blood flow (rCBF), blood volume (rCBV), and mean transit time (MTT) were calculated, and ratios of these maps were compared to preoperatively acquired DSC-MRI data. The extent of the resection was compared with the postoperative MRI performed 24 h after the operation. In 8 of these patients residual tumor tissue was depicted at the time of intraoperative MRI. In corresponding regions ratios for rCBV and rCBF did not differ significantly between pre- and intraoperatively acquired data (two-tailed t-test). Furthermore, we found a high correlation between ratios created from pre- and intraoperatively measured data for both rCBV and rCBF, respectively (Pearson correlation; r(2)(rCBV)=0.86, p<or=0.01; r(2)(rCBF)=0.86, p<or=0.01). DSC-MRI is a powerful tool for the differential diagnosis of brain lesions. Its use intraoperatively provides pathophysiologic information that is up-to-date, independently of an intraoperative brain shift and also independently of the known leakage phenomenon caused by surgical manipulation. It can assist in the decision to depict residual tumor burden beyond conventional imaging. Our data demonstrate that iDSC-MRI is as reliable as preoperatively acquired data.

Repetitive transcranial magnetic stimulation over left angular gyrus modulates the predictability gain in degraded speech comprehension

Increased neural activity in left angular gyrus (AG) accompanies successful comprehension of acoustically degraded but highly predictable sentences, as previous functional imaging studies have shown. However, it remains unclear whether the left AG is causally relevant for the comprehension of degraded speech. Here, we applied transient virtual lesions to either the left AG or superior parietal lobe (SPL, as a control area) with repetitive transcranial magnetic stimulation (rTMS) while healthy volunteers listened to and repeated sentences with high- versus low-predictable endings and different noise vocoding levels. We expected that rTMS of AG should selectively modulate the predictability gain (i.e., the comprehension benefit from sentences with high-predictable endings) at a medium degradation level. We found that rTMS of AG indeed reduced the predictability gain at a medium degradation level of 4-band noise vocoding (relative to control rTMS of SPL). In contrast, the behavioral perturbation induced by rTMS changed with increased signal quality. Hence, at 8-band noise vocoding, rTMS over AG versus SPL decreased the number of correctly repeated keywords for sentences with low-predictable endings. Together, these results show that the degree of the rTMS interference depended jointly on signal quality and predictability. Our results provide the first causal evidence that the left AG is a critical node for facilitating speech comprehension in challenging listening conditions.

Novel Methods to Study Aphasia Recovery after Stroke

The neural mechanisms that support aphasia recovery are not yet fully understood. It has been argued that the functional reorganization of language networks after left-hemisphere stroke may engage perilesional left brain areas as well as homologous right-hemisphere regions. In this chapter, we summarize how noninvasive brain stimulation can be used to elucidate mechanisms of plasticity in language networks and enhance language recovery after stroke. We first outline some basic principles of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). We then present evidence from studies in healthy volunteers for a causal role of the right hemisphere in different language functions. Finally, we review recent studies that used TMS or tDCS to promote language recovery after stroke. Most of these studies applied noninvasive brain stimulation over contralateral right-hemisphere areas to suppress maladaptive plasticity. However, some studies also suggest that right-hemisphere regions may beneficially contribute to recovery in some patients. More recently, some investigators have targeted perilesional brain regions to promote neurorehabilitation. In sum, these studies indicate that language recovery after stroke may integrate left- as well as right-hemisphere brain regions to a different degree over the time course of recovery. Although the results of these preliminary studies provide some evidence that noninvasive brain stimulation may promote aphasia recovery, the reported effect sizes are not striking. Future studies on larger patient collectives are needed to explore whether noninvasive brain stimulation can enhance language functions at a level that is clinically relevant.

Left posterior inferior frontal gyrus is causally involved in reordering during sentence processing

Abstract Storage and reordering of incoming information are two core processes required for successful sentence comprehension. Storage is necessary whenever the verb and its arguments (i.e., subject and object) are separated over a long distance, while reordering is necessary whenever the argument order is atypical (e.g., object‐first order in German, where subject‐first order is typical). Previous neuroimaging work has associated storage with the left planum temporale (PT), and reordering with the left posterior inferior frontal gyrus (pIFG). Here, we tested the causal role of the PT and pIFG in storage and reordering using repetitive transcranial magnetic stimulation (rTMS). We applied either effective rTMS over PT or pIFG, or sham rTMS, while subjects listened to sentences that independently varied storage demands (short vs. long argument–verb distance) and reordering demands (subject– vs. object‐first argument order). We found that rTMS over pIFG, but not PT, selectively affected reordering during the processing of sentences with a long argument–verb distance. Specifically, relative to sham rTMS, rTMS over pIFG significantly increased the performance difference between object– and subject‐first long‐distance sentences. These results demonstrate a causal involvement of left pIFG in reordering during sentence comprehension and thus contribute to a better understanding of the role of the pIFG in language processing. HighlightsTMS over left pIFG disrupts argument reordering during sentence processing.pIFG‐TMS increases performance decline for object‐ vs. subject‐first sentences.pIFG‐TMS selectively impairs sentences with a long argument–verb distance.Left pIFG is necessary for reordering during sentence comprehension.