Neural response during prefrontal theta burst stimulation: Interleaved TMS-fMRI of full iTBS protocols.

BACKGROUND: Left prefrontal intermittent theta-burst stimulation (iTBS) has emerged as a safe and effective transcranial magnetic stimulation (TMS) treatment protocol in depression. Though network effects after iTBS have been widely studied, the deeper mechanistic understanding of target engagement is still at its beginning. Here, we investigate the feasibility of a novel integrated TMS-fMRI setup and accelerated echo planar imaging protocol to directly observe the immediate effects of full iTBS treatment sessions. OBJECTIVE/HYPOTHESIS: In our effort to explore interleaved iTBS-fMRI feasibility, we hypothesize that TMS will induce acute BOLD signal changes in both the stimulated area and interconnected neural regions. METHODS: Concurrent TMS-fMRI with full sessions of neuronavigated iTBS (i.e. 600 pulses) of the left dorsolateral prefrontal cortex (DLPFC) was investigated in 18 healthy participants. In addition, we conducted four TMS-fMRI sessions in a single patient on long-term maintenance iTBS for bipolar depression to test the transfer to clinical cases. RESULTS: Concurrent TMS-fMRI was feasible for iTBS sequences with 600 pulses. During interleaved iTBS-fMRI, an increase of the BOLD signal was observed in a network including bilateral DLPFC regions. In the clinical case, a reduced BOLD response was found in the left DLPFC and the subgenual anterior cingulate cortex, with high variability across individual sessions. CONCLUSIONS: Full iTBS sessions as applied for the treatment of depressive disorders can be established in the interleaved iTBS-fMRI paradigm. In the future, this experimental approach could be valuable in clinical samples, for demonstrating target engagement by iTBS protocols and investigating their mechanisms of therapeutic action.

Chronometric TMS-fMRI of personalized left dorsolateral prefrontal target reveals state-dependency of subgenual anterior cingulate cortex effects.

Transcranial magnetic stimulation (TMS) applied to a left dorsolateral prefrontal cortex (DLPFC) area with a specific connectivity profile to the subgenual anterior cingulate cortex (sgACC) has emerged as a highly effective non-invasive treatment option for depression. However, antidepressant outcomes demonstrate significant variability among therapy plans and individuals. One overlooked contributing factor is the individual brain state at the time of treatment. In this study we used interleaved TMS-fMRI to investigate the influence of brain state on acute TMS effects, both locally and remotely. TMS was performed during rest and during different phases of cognitive task processing. Twenty healthy participants were included in this study. In the first session, imaging data for TMS targeting were acquired, allowing for identification of individualized targets in the left DLPFC based on highest anti-correlation with the sgACC. The second session involved chronometric interleaved TMS-fMRI measurements, with 10 Hz triplets of TMS administered during rest and at distinct timings during an N-back task. Consistent with prior findings, interleaved TMS-fMRI revealed significant BOLD activation changes in the targeted network. The precise timing of TMS relative to the cognitive states during the task demonstrated distinct BOLD response in clinically relevant brain regions, including the sgACC. Employing a standardized timing approach for TMS using a task revealed more consistent modulation of the sgACC at the group level compared to stimulation during rest. In conclusion, our findings strongly suggest that acute local and remote effects of TMS are influenced by brain state during stimulation. This study establishes a basis for considering brain state as a significant factor in designing treatment protocols, possibly improving TMS treatment outcomes.

Assessing cortical excitability with electroencephalography: A pilot study with EEG-iTBS.

BACKGROUND: Cortical excitability measures neural reactivity to stimuli, usually delivered via Transcranial Magnetic Stimulation (TMS). Excitation/inhibition balance (E/I) is the ongoing equilibrium between excitatory and inhibitory activity of neural circuits. According to some studies, E/I could be estimated in-vivo and non-invasively through the modeling of electroencephalography (EEG) signals and termed 'intrinsic excitability' measures. Several measures have been proposed (phase consistency in the gamma band, sample entropy, exponent of the power spectral density 1/f curve, E/I index extracted from detrend fluctuation analysis, and alpha power). Intermittent theta burst stimulation (iTBS) of the primary motor cortex (M1) is a non-invasive neuromodulation technique allowing controlled and focal enhancement of TMS cortical excitability and E/I of the stimulated hemisphere. OBJECTIVE: Investigating to what extent E/I estimates scale with TMS excitability and how they relate to each other. METHODS: M1 excitability (TMS) and several E/I estimates extracted from resting state EEG recordings were assessed before and after iTBS in a cohort of healthy subjects. RESULTS: Enhancement of TMS M1 excitability, as measured through motor-evoked potentials (MEPs), and phase consistency of the cortex in high gamma band correlated with each other. Other measures of E/I showed some expected results, but no correlation with TMS excitability measures or strong consistency with each other. CONCLUSIONS: EEG E/I estimates offer an intriguing opportunity to map cortical excitability non-invasively, with high spatio-temporal resolution and with a stimulus independent approach. While different EEG E/I estimates may reflect the activity of diverse excitatory-inhibitory circuits, spatial phase synchrony in the gamma band is the measure that best captures excitability changes in the primary motor cortex.

Concurrent TMS/fMRI reveals individual DLPFC dose-response pattern.

BACKGROUND: TMS is a valuable tool in both research and clinical settings, playing a crucial role in understanding brain-behavior relationships and providing treatment for various neurological and psychiatric conditions. Importantly, TMS over left DLPFC is an FDA approved treatment for MDD. Despite its potential, response variability to TMS remains a challenge, with stimulation parameters, particularly the stimulation intensity, being a primary contributor to these differences. OBJECTIVE: The objective of this study was to establish dose-response relationships of TMS stimulation in DLPFC by means of concurrent TMS/fMRI. METHODS: Here, we stimulated 15 subjects at different stimulation intensities of 80, 90, 100 and 110 % relative to the motor threshold during concurrent TMS/fMRI. The experiment comprised two sessions: one session to collect anatomical data in order to perform neuronavigation and one session dedicated to dose-response mapping. We calculated GLMs for each intensity level and each subject, as well as at a group-level per intensity. RESULTS: On a group level, we show that the strongest BOLD-response was at 100 % stimulation. However, investigating individual dose response-relationships showed differences in response patterns across the group: subjects that responded to subthreshold stimulation, subjects that required above threshold stimulation in order to show a significant BOLD-response and atypical responders. CONCLUSIONS: We observed qualitative inter-subject variability in terms of dose-response relationship to TMS over left DLPFC, which hints towards the motor threshold not being directly transferable to the excitability of the DLPFC. Concurrent TMS/fMRI might have the potential to improve response rates to rTMS applications. As such, it may be valuable in the future to consider implementing this approach prior to clinical TMS or validating more cost-effective methods to determine dose and target with respect to changes in clinical symptoms.

Comparison of procedural characteristics of percutaneous annuloplasty and edge-to-edge repair for the treatment of severe tricuspid regurgitation.

Background: In recent years, new interventional therapies for tricuspid regurgitation (TR) demonstrated their effectiveness in reducing TR severity and improving symptoms. Currently, tricuspid transcatheter edge-to-edge repair (T-TEER) and percutaneous annuloplasty are the most widely used techniques in Europe. In this retrospective study, we compared procedural characteristics and learning curves of both TR devices in a real-world cohort. Material and methods: Eligible patients with severe to torrential TR underwent either percutaneous annuloplasty or T-TEER as recommended by the local heart team. Patients with combined mitral and tricuspid interventions were excluded from the analysis. The study focused on procedural characteristics, TR reduction and learning curves. Results: A total of 122 patients underwent either percutaneous annuloplasty (n = 64) or T-TEER (n = 58) with a technical and device success rate of 98% and 97%, respectively. Reasons for technical failure included right coronary artery (RCA) dissection prior to percutaneous annuloplasty, and two single leaflet device attachments (SLDA) during T-TEER implantation. The mean improvement of TR severity was 2.4 ± 0.8 degrees after T-TEER and 2.5 ± 0.8 after percutaneous annuloplasty. T-TEER procedures were shorter in terms of both procedure time and radiation exposure, while percutaneous annuloplasty, although taking longer, showed a significant reduction in procedure time over the course of the analysed period. Conclusion: In summary, both interventional therapies reduce TR severity by approximately two degrees when used in the appropriate anatomy. The learning curve for annuloplasty group showed a significant decrease of procedure times.

Auditory white noise exposure results in intrinsic cortical excitability changes.

Cortical excitability is commonly measured by applying magnetic stimulation in combination with measuring behavioral response. This measure has, however, some shortcomings including spatial limitation to the primary motor cortex and not accounting for intrinsic excitability fluctuations. Here, we use a measure for intrinsic excitability based on phase synchronization previously validated for epilepsy. We apply this measure in 30 healthy participants' magnetoencephalography (MEG) recordings during the exposure of auditory white noise, a stimulus that has been suggested to modify cortical excitability. Using cortical parcellation of the MEG source data, we could find a specific pattern of increased and decreased excitability while participants are exposed to white noise vs. silence. Specifically, excitability during white noise exposure decreases in the frontal lobe and increases in the temporal lobe. This study thus adds to the understanding of cortical excitability changes due to specific environmental stimuli as well as the spatial extent of these effects.

Functional connectivity explains how neuronavigated TMS of posterior temporal subregions differentially affect language processing.

BACKGROUND: "Wernicke's area" is most often used to describe the posterior superior temporal gyrus (STG) and refers to a region traditionally thought to support language comprehension. However, the posterior STG additionally plays a critical role in language production. The purpose of the current study was to determine to what extent regions within the posterior STG are selectively recruited during language production. METHODS: 23 healthy right-handed participants completed an auditory fMRI localizer task, resting-state fMRI and underwent neuronavigated TMS language mapping. We applied repetitive TMS bursts during a picture naming paradigm to probe speech disruptions of different categories (anomia, speech arrest, semantic paraphasia and phonological paraphasia). We combined an in-house built high precision stimulation software suite with E-field modeling to map the naming errors to cortical regions and revealed a dissociation of language functions within the temporal gyrus. Resting state fMRI was used to explain how E-field peaks of different categories differentially affected language production. RESULTS: Peaks for phonological and semantic errors were found in the STG while those for anomia and speech arrest were located in the MTG. Seed-based connectivity analysis revealed a local connectivity pattern for phonological and semantic errors, while anomia and speech arrest seeds resulted in a larger network between IFG and posterior MTG. CONCLUSIONS: Our study provides important insights into the functional neuroanatomy of language production and might help to increase the current understanding of specific language production difficulties on a causal level.

Reduced connectivity of primary auditory and motor cortices during exposure to auditory white noise.

Auditory white noise (WN) is widely used in daily life for inducing sleep, and in neuroscience to mask unwanted environmental noise and cues. However, WN was recently reported to influence corticospinal excitability and behavioral performance. Here, we expand previous preliminary findings on the influence of WN exposure on cortical functioning, and we hypothesize that it may modulate cortical connectivity. We tested our hypothesis by performing magnetoencephalography in 20 healthy subjects. WN reduces cortical connectivity of the primary auditory and motor regions with very distant cortical areas, showing a right lateralized connectivity reduction for primary motor cortex. The present results, together with previous finding concerning WN impact on corticospinal excitability and behavioral performance, further support the role of WN as a modulator of cortical function. This suggest avoiding its unrestricted use as a masking tool, while purposely designed and controlled WN application could be exploited to harness brain function and to treat neuropsychiatric conditions.

Stimulation with acoustic white noise enhances motor excitability and sensorimotor integration.

Auditory white noise (WN) is widely used in neuroscience to mask unwanted environmental noise and cues, e.g. TMS clicks. However, to date there is no research on the influence of WN on corticospinal excitability and potentially associated sensorimotor integration itself. Here we tested the hypothesis, if WN induces M1 excitability changes and improves sensorimotor performance. M1 excitability (spTMS, SICI, ICF, I/O curve) and sensorimotor reaction-time performance were quantified before, during and after WN stimulation in a set of experiments performed in a cohort of 61 healthy subjects. WN enhanced M1 corticospinal excitability, not just during exposure, but also during silence periods intermingled with WN, and up to several minutes after the end of exposure. Two independent behavioural experiments highlighted that WN improved multimodal sensorimotor performance. The enduring excitability modulation combined with the effects on behaviour suggest that WN might induce neural plasticity. WN is thus a relevant modulator of corticospinal function; its neurobiological effects should not be neglected and could in fact be exploited in research applications.

Auditory driven gamma synchrony is associated with cortical thickness in widespread cortical areas.

OBJECTIVE: Gamma synchrony is a fundamental functional property of the cerebral cortex, impaired in multiple neuropsychiatric conditions (i.e. schizophrenia, Alzheimer's disease, stroke etc.). Auditory stimulation in the gamma range allows to drive gamma synchrony of the entire cortical mantle and to estimate the efficiency of the mechanisms sustaining it. As gamma synchrony depends strongly on the interplay between parvalbumin-positive interneurons and pyramidal neurons, we hypothesize an association between cortical thickness and gamma synchrony. To test this hypothesis, we employed a combined magnetoencephalography (MEG) - Magnetic Resonance Imaging (MRI) study. METHODS: Cortical thickness was estimated from anatomical MRI scans. MEG measurements related to exposure of 40 Hz amplitude modulated tones were projected onto the cortical surface. Two measures of cortical synchrony were considered: (a) inter-trial phase consistency at 40 Hz, providing a vertex-wise estimation of gamma synchronization, and (b) phase-locking values between primary auditory cortices and whole cortical mantle, providing a measure of long-range cortical synchrony. A correlation between cortical thickness and synchronization measures was then calculated for 72 MRI-MEG scans. RESULTS: Both inter-trial phase consistency and phase locking values showed a significant positive correlation with cortical thickness. For inter-trial phase consistency, clusters of strong associations were found in the temporal and frontal lobes, especially in the bilateral auditory and pre-motor cortices. Higher phase-locking values corresponded to higher cortical thickness in the frontal, temporal, occipital and parietal lobes. DISCUSSION AND CONCLUSIONS: In healthy subjects, a thicker cortex corresponds to higher gamma synchrony and connectivity in the primary auditory cortex and beyond, likely reflecting underlying cell density involved in gamma circuitries. This result hints towards an involvement of gamma synchrony together with underlying brain structure in brain areas for higher order cognitive functions. This study contributes to the understanding of inherent cortical functional and structural brain properties, which might in turn constitute the basis for the definition of useful biomarkers in patients showing aberrant gamma synchronization.

Resting state network connectivity is attenuated by fMRI acoustic noise.

INTRODUCTION: During the past decades there has been an increasing interest in tracking brain network fluctuations in health and disease by means of resting state functional magnetic resonance imaging (rs-fMRI). Rs-fMRI however does not provide the ideal environmental setting, as participants are continuously exposed to noise generated by MRI coils during acquisition of Echo Planar Imaging (EPI). We investigated the effect of EPI noise on resting state activity and connectivity using magnetoencephalography (MEG), by reproducing the acoustic characteristics of rs-fMRI environment during the recordings. As compared to fMRI, MEG has little sensitivity to brain activity generated in deep brain structures, but has the advantage to capture both the dynamic of cortical magnetic oscillations with high temporal resolution and the slow magnetic fluctuations highly correlated with BOLD signal. METHODS: Thirty healthy subjects were enrolled in a counterbalanced design study including three conditions: a) silent resting state (Silence), b) resting state upon EPI noise (fMRI), and c) resting state upon white noise (White). White noise was employed to test the specificity of fMRI noise effect. The amplitude envelope correlation (AEC) in alpha band measured the connectivity of seven Resting State Networks (RSN) of interest (default mode network, dorsal attention network, language, left and right auditory and left and right sensory-motor). Vigilance dynamic was estimated from power spectral activity. RESULTS: fMRI and White acoustic noise consistently reduced connectivity of cortical networks. The effects were widespread, but noise and network specificities were also present. For fMRI noise, decreased connectivity was found in the right auditory and sensory-motor networks. Progressive increase of slow theta-delta activity related to drowsiness was found in all conditions, but was significantly higher for fMRI . Theta-delta significantly and positively correlated with variations of cortical connectivity. DISCUSSION: rs-fMRI connectivity is biased by unavoidable environmental factors during scanning, which warrant more careful control and improved experimental designs. MEG is free from acoustic noise and allows a sensitive estimation of resting state connectivity in cortical areas. Although underutilized, MEG could overcome issues related to noise during fMRI, in particular when investigation of motor and auditory networks is needed.

fMRI Acoustic Noise Enhances Parasympathetic Activity in Humans.

BACKGROUND: Functional magnetic resonance imaging (fMRI) is one of the most important neuroimaging techniques; nevertheless, the acoustic noise of the MR scanner is unavoidably linked to the process of data acquisition. We hypothesized that the auditory noise of the scanner has an effect on autonomic activity. METHODS: We measured heart rate variability (HRV) while exposing 30 healthy subjects to fMRI noise. In doing so, we demonstrated an increase in parasympathetic nervous system (PNS) activity compared to silence and white noise and a decrease in sympathetic nervous system (SNS) activity compared to white noise. CONCLUSIONS: The influence of MR scanner noise on the autonomic nervous system should be taken into account when performing fMRI experiments.

Cortical Thickness of Brain Areas Beyond Stroke Lesions and Sensory-Motor Recovery: A Systematic Review.

Background: The clinical outcome of patients suffering from stroke is dependent on multiple factors. The features of the lesion itself play an important role but clinical recovery is remarkably influenced by the plasticity mechanisms triggered by the stroke and occurring at a distance from the lesion. The latter translate into functional and structural changes of which cortical thickness might be easy to quantify one of the main players. However, studies on the changes of cortical thickness in brain areas beyond stroke lesion and their relationship to sensory-motor recovery are sparse. Objectives: To evaluate the effects of cerebral stroke on cortical thickness (CT) beyond the stroke lesion and its association with sensory-motor recovery. Materials and Methods: Five electronic databases (PubMed, Embase, Web of Science, Scopus and the Cochrane Library) were searched. Methodological quality of the included studies was assessed with the Newcastle-Ottawa Scale for non-randomized controlled trials and the Risk of Bias Cochrane tool for randomized controlled trials. Results: The search strategy retrieved 821 records, 12 studies were included and risk of bias assessed. In most of the included studies, cortical thinning was seen at the ipsilesional motor area (M1). Cortical thinning can occur beyond the stroke lesion, typically in regions anatomically connected because of anterograde degeneration. Nonetheless, studies also reported cortical thickening of regions of the unaffected hemisphere, likely related to compensatory plasticity. Some studies revealed a significant correlation between changes in cortical thickness of M1 or somatosensory (S1) cortical areas and motor function recovery. Discussion and Conclusions: Following a stroke, changes in cortical thickness occur both in regions directly connected to the stroke lesion and in contralateral hemisphere areas as well as in the cerebellum. The underlying mechanisms leading to these changes in cortical thickness are still to be fully understood and further research in the field is needed. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020200539; PROSPERO 2020, identifier: CRD42020200539.

Reproducibility of amygdala activation in facial emotion processing at 7T.

Despite its importance as the prime method for non-invasive assessment of human brain function, functional MRI (fMRI) was repeatedly challenged with regards to the validity of the fMRI-derived brain activation maps. Amygdala fMRI was particularly targeted, as the amygdala's anatomical position in the ventral brain combined with strong magnetic field inhomogeneities and proximity to large vessels pose considerable obstacles for robust activation mapping. In this high-resolution study performed at ultra-high field (7T) fMRI, we aimed at (1) investigating systematic replicability of amygdala group-level activation in response to an established emotion processing task by varying task instruction and acquisition parameters and (2) testing for intra- and intersession reliability. At group-level, our results show statistically significant activation in bilateral amygdala and fusiform gyrus for each of the runs acquired. In addition, while fusiform gyrus activations are consistent across runs and sessions, amygdala activation levels show habituation effects across runs. This amygdala habituation effect is replicated in a session repeated two weeks later. Varying task instruction between matching emotions and matching persons does not change amygdala activation strength. Also, comparing two acquisition protocols with repetition times of either 700 â€‹ms or 1400 â€‹ms did not result in statistically significant differences of activation levels. Regarding within-subject reliability of amygdala activation, despite considerable variance in individual habituation patterns, we report fair to good inter-session reliability for the first run and excellent reliability for averages over runs. We conclude that high-resolution fMRI at 7T allows for robust mapping of amygdala activation in a broad range of variations. Our results of amygdala 7T fMRI are suitable to inform methodology and may encourage future studies to continue using emotion discrimination paradigms in clinical and non-clinical applications.

Modulations in resting state networks of subcortical structures linked to creativity.

Creativity is a sine qua non ability for almost all aspects of everyday life. Although very profound behavioural models were provided by 21st century psychologists, the neural correlates of these personality features associated with creativity are largely unknown. Recent models suggest strong relationships between dopamine release and various creative skills. Herein, we employed functional connectivity analyses of resting-state functional magnetic imaging data in order to shed light on these neural underpinnings of creative aspects. For improved sensitivity, we performed the study at ultra-high magnetic field (7 T). Seed regions were defined based on subcortical (ventral tegmental area/substantia nigra, nucleus caudatus) activation foci of a remote associates task (RAT). In addition, bilateral PCC was used as seed region to examine the default-mode network. Network strength across subjects was regressed against a battery of psychological variables related to creativity. Dopaminergic network variations turned out to be indicative for individual differences in creative traits. In this regard, the caudate network showed stronger connectivity in individuals with higher extraversion measures, while connectivity with the midbrain network was found increased with higher ideational behaviour and emotional stability.

Atypical language representation is unfavorable for language abilities following childhood stroke.

Brain plasticity has often been quoted as a reason for the more favorable outcome in childhood stroke compared to adult stroke. We investigated the relationship between language abilities and language localization in childhood stroke. Seventeen children and adolescents with left- or right-sided ischemic stroke and 18 healthy controls were tested with a comprehensive neurolinguistic test battery, and the individual neural representation of language was measured with an fMRI language paradigm. Overall, 12 of 17 stroke patients showed language abilities below average, and five patients exhibited impaired language performance. fMRI revealed increased activity in right hemisphere areas homotopic to left hemisphere language regions. In sum, seven stroke patients revealed atypical, i.e. bilateral or right lateralized language representation. Typical left hemispheric language lateralization was associated with better performance in naming and word fluency, whereas increased involvement of right homologues was accompanied by worse language outcome. In contrast, lesion lateralization or lesion volume did not correlate with language outcome or atypical language lateralization. Thus, atypical language lateralization is unfavorable for language outcome, and right homologues do not have the same cognitive capacity, even in young children.

Weaker semantic language lateralization associated with better semantic language performance in healthy right-handed children.

INTRODUCTION: The relationship between language abilities and language lateralization in the developing brain is important for our understanding of the neural architecture of language development. METHODS: We investigated 35 right-handed children and adolescents aged 7-16 years with a functional magnetic resonance imaging language paradigm and a comprehensive language and verbal memory examination. RESULTS: We found that less lateralized language was significantly correlated with better language performance across areas of the brain and across different language tasks. Less lateralized language in the overall brain was associated with better in-scanner task accuracy on a semantic language decision task and out-of-scanner vocabulary and verbal fluency. Specifically, less lateralized frontal lobe language dominance was associated with better in-scanner task accuracy and out-of-scanner verbal fluency. Furthermore, less lateralized parietal language was associated with better out-of-scanner verbal memory across learning, short- and long-delay trials. In contrast, we did not find any relationship between temporal lobe language laterality and verbal performance. CONCLUSIONS: This study suggests that semantic language performance is better with some involvement of the nondominant hemisphere.

Tracing the structural origins of atypical language representation: consequences of prenatal mirror-imaged brain asymmetries in a dizygotic twin couple.

We investigated the predictive value of prenatal superior temporal sulcus (STS) depth asymmetry in a special case of a female dizygotic twin that showed inverted prenatal asymmetry of this structure. For this purpose, we performed a follow-up investigation in this former fetus at the age of seven, where we assessed the functional language lateralization using task-based and resting-state functional magnetic resonance imaging (fMRI). As control group we employed her twin brother, who showed a typical folding pattern prenatally, as well as a complementary set of four age-matched children that had fetal MRI of their brains and typical STS depth asymmetry. We could show that the twin with the atypical fetal asymmetry of the STS also showed significantly differing rightward language lateralization in the frontal and temporal lobes. Additionally, resting-state data suggest a stronger connectivity between inferior frontal gyri in this case. The twin showed normal cognitive development. This result gives a first glimpse into the STS' atypical asymmetry being a very early morphological marker for later language lateralization.

When two are better than one: Bilateral mesial temporal lobe contributions associated with better vocabulary skills in children and adolescents.

This study considered the involvement of the mesial temporal lobe (MTL) in language and verbal memory functions in healthy children and adolescents. We investigated 30 healthy, right-handed children and adolescents, aged 7-16, with a fMRI language paradigm and a comprehensive cognitive test battery. We found significant MTL activations during language fMRI in all participants; 63% of them had left lateralized MTL activations, 20% exhibited right MTL lateralization, and 17% showed bilateral MTL involvement during the fMRI language paradigm. Group analyses demonstrated a strong negative correlation between the lateralization of MTL activations and language functions. Specifically, children with less lateralized MTL activation showed significantly better vocabulary skills. These findings suggest that the mesial temporal lobes of both hemispheres play an important role in language functioning, even in right-handers. Our results furthermore show that bilateral mesial temporal lobe involvement is advantageous for vocabulary skills in healthy, right-handed children and adolescents.