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Objective Navigated transcranial magnetic stimulation (nTMS) is targeted at different cortical sites for diagnostic, therapeutic, and neuroscientific purposes. Correct identification of the cortical target areas is important for achieving desired effects, but it is challenging when no direct responses arise upon target area stimulation. We aimed at utilizing atlas-based marking of cortical areas for nTMS targeting to present a convenient, rater-independent method for overlaying the individual target sites with brain anatomy. Methods We developed a pipeline, which fits a brain atlas to the individual brain and enables visualization of the target areas during the nTMS session. We applied the pipeline to our previous nTMS data, focusing on depression and schizophrenia patients. Furthermore, we included examples of Tourette syndrome and tinnitus therapies, as well as neurosurgical and motor mappings. Results In depression and schizophrenia patients, the visually selected dorsolateral prefrontal cortex (DLPFC) targets were close to the border between atlas areas A9/46 and A8. In the other areas, the atlas-based areas were in agreement with the treatment targets. Conclusions The atlas-based target areas agreed well with the cortical targets selected by experts during the treatments. Significance Overlaying atlas information over the navigation view is a convenient and useful add-on for improving nTMS targeting.

Excessive alcohol use results in cerebellar damage in adults, but there has been less research on how alcohol use during adolescence affects the cerebellum. In this study, we observed that heavy drinking from adolescence to young adulthood was associated with altered volumes of cerebellar lobules. The study included two groups consisting of 33 heavy-drinking and 25 light-drinking participants. The heavy-drinking participants were highly functional young adults without alcohol use disorder, but with a history of regular heavy alcohol consumption. The participants were 13–18 years old at baseline and were followed for 10 years. At the age of 21–28 years, the participants underwent magnetic resonance imaging (MRI). From the MR images, the cerebellum was segmented into 12 lobules using the CERES pipeline. Heavy drinking did not influence the absolute cerebellar volume, but changes were observed in posterior cerebellar lobules associated with motor and cognitive functions. The absolute volume (p = 0.038) and gray matter volume (p = 0.034) of Crus II (hemispheres combined) were smaller in the heavy-drinking group. Furthermore, the relative volume of the right VIIIB lobule was larger in the HD group (p = 0.036). However, there were no differences in the absolute right VIIIB volumes (p = 0.198) between the groups. Our results suggest changes in the cerebellum in healthy young adults with a history of heavy drinking from adolescence. The exact implications and significance of these findings require further research.

Objectives: The aim of this exploratory study was to evaluate whether three-dimensional texture analysis (3D-TA) features of non-contrast-enhanced T1 weighted MRI associate with traditional prognostic factors and disease-free survival (DFS) of breast cancer. Methods: 3D-T1 weighted images from 78 patients with 81 malignant histopathologically verified breast lesions were retrospectively analysed using standard-size volumes of interest. Grey-level co-occurrence matrix (GLCM)-based features were selected for statistical analysis. In statistics the Mann–Whitney U and the Kruskal–Wallis tests, the Cox proportional hazards model and the Kaplan–Meier method were used. Results: Tumours with higher histological grade were significantly associated with higher contrast (1 voxel: p = 0.033, 2 voxels: p = 0.036). All the entropy parameters showed significant correlation with tumour grade (p = 0.015–0.050) but there were no statistically significant associations between other TA parameters and tumour grade. The Nottingham Prognostic Index (NPI) was correlated with contrast and sum entropy parameters. A higher sum variance TA parameter was a significant predictor of shorter DFS. Conclusion: Texture parameters, assessed by 3D-TA from non-enhanced T1 weighted images, indicate tumour heterogeneity but have limited independent prognostic value. However, they are associated with tumour grade, NPI, and DFS. These parameters could be used as an adjunct to contrast-enhanced TA parameters. Advances in knowledge: 3D-TA of non-contrast enhanced T1 weighted breast MRI associates with tumour grade, NPI, and DFS. The use of non-contrast 3D-TA parameters in adjunct with contrast-enhanced 3D-TA parameters warrants further research.

Objectives To investigate the benefits of the image fusion technique for precise postoperative assessment of intracochlear placement with six different electrode arrays. Study design Consecutive retrospective case study. Settings Tertiary referral center. Patients Analyses of imaging data of 30 patients implanted with six different electrode arrays. Interventions Electrode reconstructions obtained from postoperative cone-beam computed tomography (CBCT) were overlaid onto preoperative magnetic resonance imaging (MRI) and/or high-resolution computed tomography (HRCT) registrations to create artefact-free images. Main outcome measures Each electrode's intracochlear position was analyzed with the image fusion reconstructions and compared with the results obtained by CBCT alone. The electrode location was classified according to its position in relation to the basal membrane at four different insertion angles. Results In 40 out of 151 measurements (26.5%), the location grading obtained by CBCT alone changed after the assessment with the image fusion reconstructions. A significant association was found between deep insertions (over 360 degrees) and the effectiveness of image fusion (p = 0.019). The difference between the impact of the fusion technique for the basal turn versus the apical part was highly significant (p = 0.001). There was no significant difference between the effectiveness of the image fusion and the different electrodes. Conclusions By utilizing an image fusion technique, a more accurate assessment of electrode placement could be achieved for all types of electrodes. Image fusion was especially beneficial for insertions beyond 360 degrees.

Repetition suppression (RS) is the adaptation of the neural activity in response to a repeated external stimulus. It has been proposed that RS occurs at the thalamo-cortical level, hence activating a feedback loop to the cortex in order to counteract with the repeated motor cortical activation. In this study, to elucidate the common modulators between the RS and the inhibitory/facilitatory cortical networks, two TMS paradigms were applied, i.e. the characteristic long-interval intracortical inhibition (LICI) and the I1-wave timed short-interval intracortical facilitation (SICF). Since LICI is a local intracortical inhibitory phenomenon affecting cortical excitation over a long interval like the RS, the interaction between RS and LICI was tested. As the I1-wave timed SICF is likely not affected by inhibitory modulation, the appearance of the RS with respect to SICF was investigated. Non-linear interaction between LICI and RS was observed, while I1-wave timed SICF facilitated all MEP responses of RS by a common offset still preserving the RS. These findings implicate that the underlying mechanism for the observed interaction is likely contributed to the activation of the negative thalamo-cortical feedback loop represented by the RS, most likely at the cortical level.

Study design: A controlled radiologic follow-up study. Objective: The aim of this study was to ascertain whether changes in cord excursion with straight leg raise test (SLR) at 1.5-year follow- up time accompany changes in clinical symptoms. Summary of background data: Lumbar intervertebral disc herniation (LIDH) is known to be a key cause of sciatica. Previously, we found that a significant limitation of neural displacement (66.6%) was evident with the SLR on the symptomatic side of patients with subacute single level posterolateral LIDH. Methods: Fourteen patients with significant sciatic symptoms due to a subacute single-level posterolateral LIDH were reassessed clinically and radiologically at 1.5 years follow-up with a 1.5T MRI scanner. Displacement of the conus medullaris during the unilateral and bilateral SLR was quantified reliably with a randomized procedure and compared between SLRs and to data from baseline. Multivariate regression models and backward variable selection method were employed to identify variables more strongly associated with a decrease in low back pain (LBP) and radicular symptoms. Results: Compared with previously presented baseline values, the data showed a significant increase in neural sliding in all the quantified maneuvers (P ≤ 0.01), and particularly of 2.52 mm (P ≤ 0.001) with the symptomatic SLR.Increase in neural sliding correlated significantly with decrease of both radicular symptoms (Pearson = -0.719, P ≤ 0.001) and LBP (Pearson = -0.693, P ≤ 0.001). Multivariate regression models and backward variable selection method confirmed the improvement of neural sliding effects (P ≤ 0.004) as the main variable being associated with improvement of self- reported clinical symptoms. Conclusion: To our knowledge, these are the first noninvasive data to objectively support the association between increase in magnitude of neural adaptive movement and resolution of both radicular and LBP symptoms in in vivo and structurally intact human subjects. Level of evidence: 2.

Background: The suggested association between severe obstructive sleep apnea (OSA) and risk of Alzheimer’s disease (AD) needs further study. Only few recent reports exist on associations between brain amyloid-β (Aβ) burden and severe OSA in middle-aged patients. Objective: Examine the possible presence of cortical Aβ accumulation in middle-aged patients with severe OSA. Methods: We performed detailed multimodal neuroimaging in 19 cognitive intact patients (mean 44.2 years) with severe OSA (Apnea-Hypopnea Index >30 h–1). Known etiological factors for possible Aβ accumulation were used as exclusion criteria. Aβ uptake was studied with [11C]-PiB-PET, glucose metabolism with [18F]-FDG-PET, and structural imaging with 3.0T MRI. Results: When analyzed individually, in [11C]-PiB-PET a substantial number (∼32%) of the patients exhibited statistically significant evidence of increased cortical Aβ uptake based on elevated regional Z-score values, mostly seen bilaterally in the precuneus and posterior cingulum regions. Cortical glucose hypometabolism in [18F]-FDG-PET was seen in two patients. MRI did not show structural changes suggestive of AD-related pathology. Conclusion: Increased [11C]-PiB uptake was seen in middle-aged cognitively intact patients with severe OSA. These findings are similar to those described in cognitive unimpaired older OSA patients. The changes in cortical Aβ uptake suggest that severe OSA itself may predispose to alterations related to AD already in middle-age. Aβ clearance may be compromised without simultaneous evidence of metabolic or structural alterations. The results emphasize the importance of early diagnostics and proper treatment of severe OSA in cognitively intact middle-aged subjects, possibly diminishing the individual risk for later cognitive dysfunction.

The development of the organization of the motor representation areas in children and adolescents is not well-known. This cross-sectional study aimed to provide an understanding for the development of the functional motor areas of the upper extremity muscles by studying healthy right-handed children (6–9 years, n = 10), preadolescents (10–12 years, n = 13), adolescents (15–17 years, n = 12), and adults (22–34 years, n = 12). The optimal representation site and resting motor threshold (rMT) for the abductor pollicis brevis (APB) were assessed in both hemispheres using navigated transcranial magnetic stimulation (nTMS). Motor mapping was performed at 110% of the rMT while recording the EMG of six upper limb muscles in the hand and forearm. The association between the motor map and manual dexterity (box and block test, BBT) was examined. The mapping was well-tolerated and feasible in all but the youngest participant whose rMT exceeded the maximum stimulator output. The centers-of-gravity (CoG) for individual muscles were scattered to the greatest extent in the group of preadolescents and centered and became more focused with age. In preadolescents, the CoGs in the left hemisphere were located more laterally, and they shifted medially with age. The proportion of hand compared to arm representation increased with age (p = 0.001); in the right hemisphere, this was associated with greater fine motor ability. Similarly, there was less overlap between hand and forearm muscles representations in children compared to adults (p

Our aim was to analyze metabolite profile changes in serum associated with moderate-to-heavy consumption of alcohol in young adults and to evaluate whether these changes are connected to reduced brain gray matter volumes. These study population consisted of young adults with a 10-year history of moderate-to-heavy alcohol consumption (n = 35) and light-drinking controls (n = 27). We used the targeted liquid chromatography mass spectrometry method to measure concentrations of metabolites in serum, and 3.0 T magnetic resonance imaging to assess brain gray matter volumes. Alterations in amino acid and energy metabolism were observed in the moderate-to-heavy drinking young adults when compared to the controls. After correction for multiple testing, the group of moderate-to-heavy drinking young adults had increased serum concentrations of 1-methylhistamine (p = 0.001, d = 0.82) when compared to the controls. Furthermore, concentrations of 1-methylhistamine (r = 0.48, p = 0.004) and creatine (r = 0.52, p = 0.001) were negatively correlated with the brain gray matter volumes in the females. Overall, our results show association between moderate-to-heavy use of alcohol and altered metabolite profile in young adults as well as suggesting that some of these changes could be associated with the reduced brain gray matter volume. (C) 2018 Elsevier Inc. All rights reserved.

The purpose of this investigation was to provide a full set of normal data describing neural biomechanics within the vertebral canal in all three planes with unilateral and bilateral SLR tests to allow for clinical comparison with clinical cases. This is done following the notion that, due to neural continuum, tensile forces are transmitted through the lumbosacral nerve roots and dura to the conus medullaris (linear dependency principle). In this controlled radiologic study 10 asymptomatic volunteers were scanned with 1.5T magnetic resonance scanner (Siemens Magnetom Aera, Erlangen, Germany) using different scanning sequences for planning and for measurement purposes. Conus displacement in both antero-posterior direction (sagittal slices) and lateral direction (axial slices) was quantified during unilateral passive left, right SLR, and bilateral SLR and compared with the position of the conus in the neutral (anatomic) position. It is shown that the conus medullaris displaced laterally and anteroposteriorly in response to unilateral and bilateral SLRs. Pearson's correlations were higher than 0.95 for both intra- and inter-observer reliability. The observed power was higher than 0.99 for all the variables tested. Following this, the authors conclude that lateral and antero-posterior displacement of conus medullaris into the vertebral canal occurs consistently with unilateral and bilateral SLRs following directions predicted by tension vectors. Summative information collected in this line of research in neuroradiology is here presented. We believe we have presented the first conclusive and complete full set of normal data on non-invasive, in vivo, normative measurement of spinal cord displacement with the SLR ever presented. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1335-1342, 2017.

Alcohol-related white matter (WM) microstructural changes have not been fully elucidated in adolescents. We aimed to investigate influences of subclinical alcohol use during adolescence on WM microstructure and to characterize those with serum metabolic alterations. 35 moderate-to-heavy drinkers (15 males, 20 females) and 27 controls (12 males, 15 females) were selected based on their ten-year Alcohol Use Disorders Identification Test scores measured at three time points. Magnetic resonance imaging was conducted at endpoint time. Whole brain analysis of fractional anisotropy (FA) was performed. Diffusivity indices in the significant regions were computed for between-group comparisons and correlation analyses with serum metabolite concentrations. Decreased FA was found in moderate-to-heavy drinking men in anterior corpus callosum, superior/anterior corona radiata and right inferior fronto-occipital fasciculus, accompanied by increased radial diffusivity and a smaller area of reduced axial diffusivity, which correlated with serum metabolites playing roles in energy metabolism, myelination and axonal degeneration. No significant difference in FA was detected between female or mixed-gender moderate-to-heavy drinking subjects and controls, supporting gender differences in the relationship between adolescent alcohol use and neurodevelopmental trajectories. Future researches with longitudinal imaging data are warranted for comprehensive evaluation on potentially reversible effects of alcohol use over adolescent brain.

Motor functions improve during childhood and adolescence, but little is still known about the development of cortical motor circuits during early life. To elucidate the neurophysiological hallmarks of motor cortex development, we investigated the differences in motor cortical excitability and connectivity between healthy children, adolescents, and adults by means of navigated suprathreshold motor cortex transcranial magnetic stimulation (TMS) combined with high-density electroencephalography (EEG). We demonstrated that with development, the excitability of the motor system increases, the TMS-evoked EEG waveform increases in complexity, the magnitude of induced activation decreases, and signal spreading increases. Furthermore, the phase of the oscillatory response to TMS becomes less consistent with age. These changes parallel an improvement in manual dexterity and may reflect developmental changes in functional connectivity. Hum Brain Mapp 38:2599-2615, 2017. © 2017 Wiley Periodicals, Inc.

Background and aims Cognitive impairment has been associated with excessive alcohol use, but its neural basis is poorly understood. Chronic excessive alcohol use in adolescence may lead to neuronal loss and volumetric changes in the brain. Our objective was to compare the grey matter volumes of heavy- and light-drinking adolescents. Design This was a longitudinal study: heavy-drinking adolescents without an alcohol use disorder and their light-drinking controls were followed-up for 10 years using questionnaires at three time-points. Magnetic resonance imaging was conducted at the last time-point. Setting The area near Kuopio University Hospital, Finland. Participants The 62 participants were aged 22–28 years and included 35 alcohol users and 27 controls who had been followed-up for approximately 10 years. Measurements Alcohol use was measured by the Alcohol Use Disorders Identification Test (AUDIT)-C at three time-points during 10 years. Participants were selected based on their AUDIT-C score. Magnetic resonance imaging was conducted at the last time-point. Grey matter volume was determined and compared between heavy- and light-drinking groups using voxel-based morphometry on three-dimensional T1-weighted magnetic resonance images using predefined regions of interest and a threshold of P

Long-term alcohol use affects cognitive and neurophysiological functioning as well as structural brain development. Combining simultaneous electroencephalogram (EEG) recording with transcranial magnetic stimulation (TMS) enables direct, in vivo exploration of cortical excitability and assessment of effective and functional connectivity. In the central nervous system, the effects of alcohol are particularly mediated by alterations in gamma-aminobutyric acid (GABA)ergic neurotransmission, and TMS-evoked potentials (TEPs) N45 and N100 in EEG are known to reflect GABAergic function. However, no previous studies have examined the effects of long-term alcohol use in adolescence on TEPs. In this study, a total of 27 young adults with heavy alcohol use in adolescence and 25 age-matched, gender-matched and education-matched controls with little or no alcohol use participated in TMS-EEG measurements. The motor cortex (M1) was stimulated with an intensity of 90 percent of the resting motor threshold of the abductor pollicis brevis muscle. No significant differences were found in the resting motor threshold, TEP latencies or neuropsychological functioning between the groups. We observed an increase in the global mean field power in the time window of 54- to 75-millisecond post-TMS, as well as significant topographical differences in the P60 and N100 in those with a history of heavy drinking. Furthermore, there was a marked increase in the GABAergic N45 amplitude in alcohol users. These findings suggest that long-term alcohol use in adolescence, even when not meeting the diagnostic criteria for a disorder, is associated with changes in connectivity and cortical excitability.

Objectives To investigate whether semi-quantitative and pharmacokinetic perfusion dynamic contrast-enhanced (DCE) parameters are associated with traditional prognostic factors and can predict clinical outcome in ovarian cancer (OC). Methods This prospective study, approved by local ethical committee, enrolled 38 patients with primary OC, 2011–2014. After preoperative DCE-MRI (3.0 T), two observers measured perfusion (Ktrans, Kep, Ve, Vp) and semi-quantitative parameters (area under the curve, peak, time-to-peak) by drawing regions of interest (ROIs) covering the large solid lesion (L-ROI) and the most enhancing small area (S-ROI) (NordicICE platform). Kruskal–Wallis was used to analyze associations between MRI parameters and classified prognostic factors. Results Mean Ktrans values were higher in high-grade serous OC than in other types (L-ROI, P = 0.041; S-ROI, P = 0.018), and lower mean Ktrans values predicted residual tumor (L-ROI P = 0.030; S-ROI, P = 0.012). Higher minimum Vp values were associated with higher International Federation of Gynecology and Obstetrics (FIGO) stage (S-ROI, P = 0.023).Shorter recurrence-free survival was predicted by higher Ve (minimum L-ROI, P = 0.035; maximum S-ROI, P = 0.046), Vp (maximum S-ROI, P = 0.033), and lower time-to-peak (maximum S-ROI, P = 0.047) in Kaplan–Meier analysis. Multiparametric MRI variables combining DCE and diffusion weighted data were also predictive for survival. Conclusion DCE-MRI parameters may represent imaging biomarkers for predicting tumor aggressiveness and prognosis in OC. Higher Ktrans levels were associated with better results in cytoreductive surgery but with earlier recurrence.

BackgroundHypoxia significantly influences treatment response and clinical outcome in solid tumors. A noninvasive marker for hypoxia will help physicians in treatment planning and encourage the efficient use of hypoxia targeted therapies. The purpose of this study was to investigate whether pharmacokinetic dynamic contrast-enhanced (DCE) perfusion parameters are associated with a specific marker of hypoxia, hypoxia-inducible factor 1 alpha (HIF-1α) in ovarian cancer (OC).Materials and methodsThirty-eight patients with primary OC were enrolled in this prospective study approved by the local ethical committee. Patients underwent dynamic gadolinium-enhanced 3.0 T MRI as part of their staging investigations. Pharmacokinetic perfusion parameters, including a rate constant for transfer of contrast agent from plasma to extravascular extracellular space (EES) (Ktrans) and a rate constant from EES to plasma (Kep), were measured by drawing two types of regions of interest (ROIs): a large solid lesion (L-ROI) and a solid, most enhancing small area (S-ROI) (NordicICE platform). Tissue samples for immunohistochemical analysis were collected during surgery. Kruskal-Wallis, Mann-Whitney U and Chi-square tests were used in statistical analyses. Receiver Operating Characteristic curve analyzes were done for DCE parameters to discriminate high HIF-1α expression.ResultsPharmacokinetic perfusion parameters Ktrans and Kep were inversely associated with HIF-1α expression (Ktrans L-ROI P = 0.021; Ktrans S-ROI P = 0.018 and Kep L-ROI P = 0.032; Kep S-ROI P = 0.033). Ktrans and Kep showed good accuracy in identifying high HIF-1α expression (AUC = 0.832 Ktrans L-ROI; 0.840 Ktrans S-ROI; 0.808 Kep L-ROI and 0.808 Kep L-ROI).ConclusionThis preliminary study demonstrated that pharmacokinetic DCE-MRI perfusion parameters are associated with the hypoxia specific marker, HIF-1α in OC. DCE-MRI may be a useful supplementary tool in the characterization of OC tumors in a staging investigation.

The combination of transcranial magnetic stimulation with simultaneous electroencephalography (TMS–EEG) offers direct neurophysiological insight into excitability and connectivity within neural circuits. However, there have been few developmental TMS–EEG studies to date, and they all have focused on primary motor cortex stimulation. In the present study, we used navigated high‐density TMS–EEG to investigate the maturation of the superior frontal cortex (dorsal premotor cortex [PMd]), which is involved in a broad range of motor and cognitive functions known to develop with age. We demonstrated that reactivity to frontal cortex TMS decreases with development. We also showed that although frontal cortex TMS elicits an equally complex TEP waveform in all age groups, the statistically significant between‐group differences in the topography of the TMS‐evoked peaks and differences in current density maps suggest changes in effective connectivity of the right PMd with maturation. More generally, our results indicate that direct study of the brain's excitability and effective connectivity via TMS–EEG co‐registration can also be applied to pediatric populations outside the primary motor cortex, and may provide useful information for developmental studies and studies on developmental neuropsychiatric disorders. peerReviewed

Motor functions are frequently impaired in Asperger syndrome (AS). In this study, we examined the motor cortex structure and function using navigated transcranial magnetic stimulation (nTMS) and voxel-based morphometry (VBM) and correlated the results with the box and block test (BBT) of manual dexterity and physical activity in eight boys with AS, aged 8–11 years, and their matched controls. With nTMS, we found less focused cortical representation areas of distinct hand muscles in AS. There was hemispheric asymmetry in the motor maps, silent period duration and active MEP latency in the AS group, but not in controls. Exploratory VBM analysis revealed less gray matter in the left postcentral gyrus, especially in the face area, and less white matter in the precentral area in AS as compared to controls. On the contrary, in the right leg area, subjects with AS displayed an increased density of gray matter. The structural findings of the left hemisphere correlated negatively with BBT score in controls, whereas the structure of the right hemisphere in the AS group correlated positively with motor function as assessed by BBT. These preliminary functional (neurophysiological and behavioral) findings are indicative of asymmetry, and co-existing structural alterations may reflect the motor impairments causing the deteriorations in manual dexterity and other motor functions commonly encountered in children with AS. Electronic supplementary material The online version of this article (10.1007/s10548-019-00704-0) contains supplementary material, which is available to authorized users.

Prevention of the recurrence of major depression and its residual symptoms requires effective treatment. Our aim was to study the effects of bifrontal active rTMS controlled by sham rTMS in treatment-resistant unipolar major depressive disorder (MDD).Thirty-seven patients with treatment-resistant MDD were randomized into two groups. One group received a total of 30 sessions of active bifrontal rTMS (10 Hz rTMS on left dorsolateral prefrontal cortex (DLPFC) and 1 Hz rTMS on right DLPFC) and the other group received bilateral sham rTMS on five days a week for six weeks.Depressive symptoms significantly improved in both the groups, but without a significant group difference. Furthermore, patients with psychotic depression improved similarly to those with moderate or severe depression.The results of present study indicate a large sham effect of stimulation treatment. The intensive structured treatment protocol may explain the positive outcome in both the groups. It is important to recognize, appreciate, and utilize placebo effects as a significant means of rehabilitation in psychiatric care.

Several studies have shown that, in spite of the fact that motor symptoms manifest late in the course of Alzheimer's disease (AD), neuropathological progression in the motor cortex parallels that in other brain areas generally considered more specific targets of the neurodegenerative process. It has been suggested that motor cortex excitability is enhanced in AD from the early stages, and that this is related to disease's severity and progression. To investigate the neurophysiological hallmarks of motor cortex functionality in early AD we combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). We demonstrated that in mild AD the sensorimotor system is hyperexcitable, despite the lack of clinically evident motor manifestations. This phenomenon causes a stronger response to stimulation in a specific time window, possibly due to locally acting reinforcing circuits, while network activity and connectivity is reduced. These changes could be interpreted as a compensatory mechanism allowing for the preservation of sensorimotor programming and execution over a long period of time, regardless of the disease's progression. Hum Brain Mapp 37:2083-2096, 2016. © 2016 Wiley Periodicals, Inc.

Background Although the relationship between neuronavigated transcranial magnetic stimulation (nTMS) and functional magnetic resonance imaging (fMRI) has been widely studied in motor mapping, it is unknown how the motor response type or the choice of motor task affect this relationship. New method Centers of gravity (CoGs) and response maxima were measured with blood-oxygen-level dependent (BOLD) and arterial spin labeling (ASL) fMRI during motor tasks against nTMS CoGs and response maxima, which were mapped with motor evoked potentials (MEPs) and silent periods (SPs). Results No differences in motor representations (CoGs and response maxima) were observed in lateral-medial direction ( p = 0.265). fMRI methods localized the motor representation more posterior than nTMS ( p p > 0.999) nor nTMS response type ( p > 0.999). ASL fMRI maxima did not differ from the nTMS nor BOLD fMRI CoGs ( p ≥ 0.070), but the ASL CoG was deeper in comparison to other methods ( p ≤ 0.042). The BOLD fMRI motor task did not influence the depth of the motor representation ( p ≥ 0.745). The median Euclidean distances between the nTMS and fMRI motor representations varied between 7.7 mm and 14.5 mm and did not differ between the methods ( F ≤ 1.23, p ≥ 0.318). Comparison with existing methods The relationship between fMRI and nTMS mapped excitatory (MEP) and inhibitory (SP) responses, and whether the choice of motor task affects this relationship, have not been studied before. Conclusions The congruence between fMRI and nTMS is good. The choice of nTMS motor response type nor BOLD fMRI motor task had no effect on this relationship.

Corticospinal excitability (CSE) is modulated by stroke-induced lesions affecting the brain. This modulation is known to be dependent on the timing of the evaluation, and strongest abnormalities are often found in the acute stage. Our study aimed to characterize changes in CSE asymmetry between the affected and the unaffected hemisphere (AH and UH) during the first month after stroke onset and at 6 month follow-up. Neuronavigated transcranial magnetic stimulation (nTMS) was used to assess the CSE of the abductor pollicis brevis (APB) muscle of the hand and tibialis anterior (TA) muscle of the leg in 16 patients over 5 time-points. AH excitability recovered significantly during 6 months, whereas interhemispheric asymmetry remained significant up to 1 month post-stroke in the APB muscle. Greater initial CSE was associated with good motor function at 6 months. The motor cortical excitatory recovery initiated within week of the stroke and was most prominent within 1 month after stroke onset. Lesion size correlated with CSE of the UH at 10 days, while overall severity of the symptoms correlated inversely with CSE of the AH. This study demonstrates the quick improvement in the CSE via estimation of interhemispheric asymmetry; however, the recovery in the asymmetry continues to normalize even after reaching the threshold for normal values in CSE. peerReviewed

Objective To assess the inter-hemispheric differences in neuronal function and structure of the motor cortex in a small group of chronic stroke patients having suffered a restricted ischemic lesion affecting hand motor representation. GABAergic intracortical inhibition, known to be affected by stroke lesion, was also investigated. Methods Eight patients exhibiting little or no motor impairment were studied using transcranial magnetic stimulation (TMS) and diffusion weighted imaging (DWI) >15months from diagnosis. Resting motor threshold (MT) for 50μV and 2mV motor evoked potentials, and short-interval intracortical inhibition (SICI) were measured from hand muscles. Apparent diffusion coefficients (ADCs) were analyzed from the DWI for the primary motor cortex (M1), the supplementary motor area (SMA) and thalamus for reflecting changes in neuronal organization. Results The MTs did not differ between the affected (AH) and unaffected hemisphere (UH) in 50μV responses, while the MTs for 2mV responses were higher ( p =0.018) in AH. SICI was weakened in AH ( p =0.008). ADCs were higher in the affected M1 compared to the unaffected M1 ( p =0.018) while there were no inter-hemispheric differences in SMA or thalamus. Conclusions Inter-hemispheric asymmetry and neuronal organization demonstrated abnormalities in the M1. However, no confident inference can be made whether the observed alterations in neurophysiological and imaging measures have causal role for motor rehabilitation in these patients. Significance Neurophysiological changes persist and are detectable using TMS years after stroke even though clinical symptoms have normalized.

Background Transcranial magnetic stimulation (TMS) can evaluate cortical excitability and integrity of motor pathways via TMS-induced responses. The responses are affected by the orientation of the stimulated neurons with respect to the direction of the TMS-induced electric field. Therefore, besides being a functional imaging tool, TMS may potentially assess the local structural properties. Yet, TMS has not been used for this purpose. New method A novel principle to evaluate the relation between function and structure of the motor cortex is presented. This functional anisotropy is evaluated by an anisotropy index (AI), based on motor evoked potential amplitudes induced with different TMS coil orientations, i.e. different electric field directions at a cortical target. To compare the AI with anatomical anisotropy in an explorative manner, diffusion tensor imaging-derived fractional anisotropy (FA) was estimated at different depths near the stimulation site. Results AI correlated inversely with cortical excitability through the TMS-induced electric field at motor threshold level. Further, there was a trend of negative correlation between AI and FA. Comparison with existing methods None of the existing methods alone can detect the relationship between direct motor cortex activation and local neuronal structure. Conclusions The AI appears to provide information on the functional neuronal anisotropy of the motor cortex by coupling neurophysiology and neuroanatomy within the stimulated cortical region. The AI could prove useful in the evaluation of neurological disorders and traumas involving concurrent structural and functional changes in the motor cortex. Further studies on patients are needed to confirm the usability of AI.

Transcranial magnetic stimulation (TMS) can be used for evaluating the function of motor pathways. According to the principles of electromagnetism and electrophysiology, TMS activates those neurons that are suitably oriented with respect to the TMS-induced electric field. We hypothesized that TMS could potentially be able to evaluate the neuronal structure, although until now, this putative application has not been exploited. We have developed a TMS-based method to evaluate the function and structure of the motor cortex concurrently in a quantitative manner. This method produced a measure, the anisotropy index (AI), which is based on the motor-evoked potentials induced at different coil orientations. The AI was demonstrated to exhibit an association with both motor cortex excitability and neuronal structure. In the present study, we evaluated the repeatability (intrasession and intersession) of AI in three consecutive measurements. In addition, we studied the repeatability of the optimal coil angle in inducing motor-evoked potentials. Two of the measurements were conducted on the same stimulation target and the third on a remapped target. The coefficient of repeatability of the AI was 0.022 for intrasession and 0.040 for intersession assessments. For the optimal stimulation angle, the coefficients of repeatability were 3.7° and 5.1°, respectively. Both the AI and the optimal stimulation angle demonstrated good repeatability (Cronbach's α>0.760). In conclusion, the results indicate that the AI can provide a reliable estimation of local functional anisotropy changes under conditions affecting the cortex, such as during stroke or focal dysplasia.

Long-term alcohol use affects cognitive and neurophysiological functioning as well as structural brain development. Combining simultaneous electroencephalogram (EEG) recording with transcranial magnetic stimulation (TMS) enables direct, in vivo exploration of cortical excitability and assessment of effective and functional connectivity. In the central nervous system, the effects of alcohol are particularly mediated by alterations in gamma-aminobutyric acid (GABA)ergic neurotransmission, and TMS-evoked potentials (TEPs) N45 and N100 in EEG are known to reflect GABAergic function. However, no previous studies have examined the effects of long-term alcohol use in adolescence on TEPs. In this study, a total of 27 young adults with heavy alcohol use in adolescence and 25 age-matched, gender-matched and education-matched controls with little or no alcohol use participated in TMS-EEG measurements. The motor cortex (M1) was stimulated with an intensity of 90 percent of the resting motor threshold of the abductor pollicis brevis muscle. No significant differences were found in the resting motor threshold, TEP latencies or neuropsychological functioning between the groups. We observed an increase in the global mean field power in the time window of 54- to 75-millisecond post-TMS, as well as significant topographical differences in the P60 and N100 in those with a history of heavy drinking. Furthermore, there was a marked increase in the GABAergic N45 amplitude in alcohol users. These findings suggest that long-term alcohol use in adolescence, even when not meeting the diagnostic criteria for a disorder, is associated with changes in connectivity and cortical excitability.

The most thoroughly studied transcranial magnetic stimulation (TMS)-evoked electroencephalogram (EEG) potential (TEP), N100, is often defined as a measure of cortical inhibition. We explored the association of the N100 amplitude with attention in 51 young healthy adults. Navigated TMS with simultaneous EEG registering was applied over the left primary motor cortex at the intensity of 110% of the resting motor threshold. Attention was assessed with the Paced Auditory Serial Addition Test (PASAT). We found a negative Pearson correlation (p = .023, r = −0.317) between the left centroparietal N100 amplitude and the PASAT score. Of the participants, the 17 with the highest PASAT scores and 17 with the lowes scores were selected for further analysis, in which a significant between-group difference in the left centroparietal N100 was found (p = .017). The topographic specificity of this finding was further confirmed with linear mixed model (LMM) analysis, in which significant differences were detected in the N100 amplitude; most prominently in the left centroparietal region (p = .001). A smaller N100 amplitude was associated with better performance in the attention task. Our findings suggest that the GABA-B-ergic TEP N100 is associated with attentional processes and thus represents cortical inhibition beyond motor inhibition.

We characterized the maturation of the excitability of the motor cortex and corticospinal tract from childhood to adulthood using electric field (EF) navigated TMS and correlated the results with manual dexterity.Both hemispheres of healthy right-handed children (6-9 years, n=10), preadolescents (10-12 years, n=13), adolescents (14-17 years, n=12) and young adults (22-34 years, n=12) of both genders were examined. The optimal cortical representation site and resting motor threshold (rMT) were determined for the abductor pollicis brevis muscle. Motor-evoked potential (MEP) latencies and amplitudes in relaxed and active states, input-output curves and silent period (SP) durations were determined. Manual dexterity was assessed with the Box and Block Test.rMT (in terms of maximal stimulator output or EF strength) decreased with age (P0.001) and stabilized when reaching adolescence. The MEP amplitude (P=0.037) and latency increased (P0.001) with age. Input-output curves showed age-dependent changes in several parameters. SP duration decreased with age (P0.001), and demonstrated hemispheric asymmetry in the children (P=0.030). Manual dexterity correlated negatively with rMT (P0.001).The excitation/inhibition balance develops with age and correlates with manual dexterity. Strong corticospinal inhibition was observed in the children and this was found to decrease with age. Interhemispheric asymmetry was only observed for SP duration in the children. Knowledge of normal development is crucial for the understanding of developmental disabilities and using estimates of effective EF may be advantageous in future pediatric studies.

Navigated transcranial magnetic stimulation (nTMS) is used for mapping muscle representations in the primary motor cortex. We used sulcus-aligned mapping and electric field (E-field) modeling to investigate the excitability of the motor hand area for further understanding the methodological limitations of nTMS.We studied 10 healthy volunteers to locate the cortical target eliciting the largest responses (the hotspot) in the first dorsal interosseous (FDI) muscle. Six additional targets were placed along the central sulcus at 5-mm distances. Resting motor thresholds (rMTs) and optimal coil orientations were determined at all targets, and a conventional motor mapping was conducted. The cortical E-fields, induced by stimulating the targets with rMT intensities and optimal coil orientations, were modeled in a realistic head geometry to estimate the activated cortical sites.The rMTs increased with increasing distance from the hotspot (p 0.001). The greatest motor-evoked potential (MEP) amplitudes occurred with the coil perpendicular to the sulcus and with the coil pointing towards the hotspot or the center of gravity of the motor map. The E-field strengths at the hotspot (99±26 V/m) remained above previously estimated thresholds for activation.Depending on the target location, optimal coil orientations may deviate significantly from the conventional perpendicular-to-sulcus angle, which is often assumed optimal. These orientations seem to maintain the E-field stable in the hand knob, regardless of the sulcal shape near the stimulated target.The coil orientation is crucial for the accuracy of motor mapping, and the apparent motor map may extend due to remote hotspot activation.