A novel method for integrating MEG and BOLD fMRI signals with the linear convolution model in human primary somatosensory cortex

Characterizing the neurovascular coupling between hemodynamic signals and their neural origins is crucial to functional neuroimaging research, even more so as new methods become available for integrating results from different functional neuroimaging modalities. We present a novel method to relate magnetoencephalography (MEG) and BOLD fMRI data from primary somatosensory cortex within the context of the linear convolution model. This model, which relates neural activity to BOLD signal change, has been widely used to predict BOLD signals but typically lacks experimentally derived measurements of neural activity. In this study, an fMRI experiment is performed using variable-duration (< or =1 s) vibrotactile stimuli applied at 22 Hz, analogous to a previously published MEG study (Nangini et al., [2006]: Neuroimage 33:252-262), testing whether MEG source waveforms from the previous study can inform the convolution model and improve BOLD signal estimates across all stimulus durations. The typical formulation of the convolution model in which the input is given by the stimulus profile is referred to as Model 1. Model 2 is based on an energy argument relating metabolic demand to the postsynaptic currents largely responsible for the MEG current dipoles, and uses the energy density of the estimated MEG source waveforms as input to the convolution model. It is shown that Model 2 improves the BOLD signal estimates compared to Model 1 under the experimental conditions implemented, suggesting that MEG energy density can be a useful index of hemodynamic activity.     

Comparison of primary motor cortex localization using functional magnetic resonance imaging and magnetoencephalography

The primary goal of the study was to compare estimates of motor cortex localization from functional magnetic resonance imaging (FMRI) and magnetoencephalography (MEG). Thirteen normal volunteers were studied using both methods. FMRI was performed on a clinical 1.5 T system using gradient-echo acquisitions and basic t-test processing. MEG primary motor field was characterized by a single dipole model. Comparisons between the location of the best-fitting MEG dipole and the FMRI activation results were made using both fixed regions-of-interest weighted averaging and clustering analysis to reduce the observed FMRI activations to a single representative location. Both FMRI and MEG identified expected anatomic regions of primary motor activity and there was overall agreement to within 10 mm between these two functional imaging modalities. Given the observed agreement between these two techniques, it does not appear that the proposed artifactual mechanisms of local bulk motions or large-vessel sensitivity will seriously preclude the clinical utility of FMRI for preoperative localization of sensorimotor cortex. © 1996 Wiley-Liss, Inc.     

Functional imaging of subthalamic nucleus deep brain stimulation in Parkinson's disease

Deep brain stimulation of the subthalamic nucleus is an accepted treatment for the motor complications of Parkinson's disease. The therapeutic mechanism of action remains incompletely understood. Although the results of deep brain stimulation are similar to the results that can be obtained by lesional surgery, accumulating evidence from functional imaging and clinical neurophysiology suggests that the effects of subthalamic nucleus‐deep brain stimulation are not simply the result of inhibition of subthalamic nucleus activity. Positron emission tomography/single‐photon emission computed tomography has consistently demonstrated changes in cortical activation in response to subthalamic nucleus‐deep brain stimulation. However, the technique has limited spatial and temporal resolution, and therefore the changes in activity of subcortical projection sites of the subthalamic nucleus (such as the globus pallidus, substantia nigra, and thalamus) are not as clear. Clarifying whether clinically relevant effects from subthalamic nucleus‐deep brain stimulation in humans are mediated through inhibition or excitation of orthodromic or antidromic pathways (or both) would contribute to our understanding of the precise mechanism of action of deep brain stimulation and may allow improvements in safety and efficacy of the technique. In this review we discuss the published evidence from functional imaging studies of patients with subthalamic nucleus‐deep brain stimulation to date, together with how these data inform the mechanism of action of deep brain stimulation. © 2011 Movement Disorder Society     

Effects of DBS on auditory and somatosensory processing in Parkinson's disease

Motor symptoms of Parkinson's disease (PD) can be relieved by deep brain stimulation (DBS). The mechanism of action of DBS is largely unclear. Magnetoencephalography (MEG) studies on DBS patients have been unfeasible because of strong magnetic artifacts. An artifact suppression method known as spatiotemporal signal space separation (tSSS) has mainly overcome these difficulties. We wanted to clarify whether tSSS enables noninvasive measurement of the modulation of cortical activity caused by DBS. We have studied auditory and somatosensory‐evoked fields (AEFs and SEFs) of advanced PD patients with bilateral subthalamic nucleus (STN) DBS using MEG. AEFs were elicited by 1‐kHz tones and SEFs by electrical pulses to the median nerve with DBS on and off. Data could be successfully acquired and analyzed from 12 out of 16 measured patients. The motor symptoms were significantly relieved by DBS, which clearly enhanced the ipsilateral auditory N100m responses in the right hemisphere. Contralateral N100m responses and somatosensory P60m responses also had a tendency to increase when bilateral DBS was on. MEG with tSSS offers a novel and powerful tool to investigate DBS modulation of the evoked cortical activity in PD with high temporal and spatial resolution. The results suggest that STN‐DBS modulates auditory processing in advanced PD. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

Neuromagnetic evidence for early semantic access in word recognition

Magnetic brain responses recorded in the human magnetoencephalogram (MEG) distinguished between words with different semantics but carefully matched for frequency and length. Multiple recordings from a single subject showed that 100 ms following stimulus onset, significantly stronger neuromagnetic responses were elicited by words with strong multimodal semantic associations than by other word material. At this early processing step, there was a highly significant correlation (0.80) between the magnitude of brain responses to individual words recorded over parieto-occipital areas and their semantic association strengths. Subsequent to this early difference related to word meaning, additional differences in MEG responses emerged for words from different grammatical categories. Together, these results suggest that word meaning can be reflected by early neuromagnetic brain responses and before the grammatical information about the word is encoded.     

Postmortem diffusion MRI of the human brainstem and thalamus for deep brain stimulator electrode localization

Deep brain stimulation (DBS) is an established surgical therapy for medically refractory tremor disorders including essential tremor (ET) and is currently under investigation for use in a variety of other neurologic and psychiatric disorders. There is growing evidence that the anti‐tremor effects of DBS for ET are directly related to modulation of the dentatorubrothalamic tract (DRT), a white matter pathway that connects the cerebellum, red nucleus, and ventral intermediate nucleus of the thalamus. Emerging white matter targets for DBS, like the DRT, will require improved three‐dimensional (3D) reference maps of deep brain anatomy and structural connectivity for accurate electrode targeting. High‐resolution diffusion MRI of postmortem brain specimens can provide detailed volumetric images of important deep brain nuclei and 3D reconstructions of white matter pathways with probabilistic tractography techniques. We present a high spatial and angular resolution diffusion MRI template of the postmortem human brainstem and thalamus with 3D reconstructions of the nuclei and white matter tracts involved in ET circuitry. We demonstrate registration of these data to in vivo, clinical images from patients receiving DBS therapy, and correlate electrode proximity to tractography of the DRT with improvement of ET symptoms. Hum Brain Mapp 36:3167–3178, 2015. © 2015 Wiley Periodicals, Inc.     

Time course of superior temporal sulcus activity in response to eye gaze: a combined fMRI and MEG study

The human superior temporal sulcus (STS) has been suggested to be involved in gaze processing, but temporal data regarding this issue are lacking. We investigated this topic by combining fMRI and MEG in four normal subjects. Photographs of faces with either averted or straight eye gazes were presented and subjects passively viewed the stimuli. First, we analyzed the brain areas involved using fMRI. A group analysis revealed activation of the STS for averted compared to straight gazes, which was confirmed in all subjects. We then measured brain activity using MEG, and conducted a 3D spatial filter analysis. The STS showed higher activity in response to averted versus straight gazes during the 150–200 ms period, peaking at around 170 ms, after stimulus onset. In contrast, the fusiform gyrus, which was detected by the main effect of stimulus presentations in fMRI analysis, exhibited comparable activity across straight and averted gazes at about 170 ms. These results indicate involvement of the human STS in rapid processing of the eye gaze of another individual.     

Mismatch responses to randomized gradient switching noise as reflected by fMRI and whole-head magnetoencephalography

The central auditory system of the human brain uses a variety of mechanisms to analyze auditory scenes, among others, preattentive detection of sudden changes in the sound environment. Electroencephalography (EEG) and magnetoencephalography (MEG) provide a measure to monitor neuronal cortical currents. The mismatch negativity (MMN) or field (MMNm) reflect preattentive activation in response to deviants within a sequence of homogenous auditory stimuli. Functional magnetic resonance imaging (fMRI) allows for a higher spatial resolution as compared to the extracranial electrophysiological techniques. The image encoding gradients of echo planar imaging (EPI) sequences, however, elicit an interfering background noise. To circumvent this shortcoming, the present study applied multi-echo EPI mimicking an auditory oddball design. The gradient trains (SOA = 800 msec, 94.5 dB SPL, stimulus duration = 152 msec) comprised amplitude (-9 dB) and duration (76 msec) deviants in a randomized sequence. Moreover, the scanner noise was recorded and applied in a whole-head MEG device to validate the properties of this specific material. Robust fMRI activation patterns emerged in response to the deviant gradient switching. Changes in amplitude activated the entire auditory cortex, whereas the duration deviants elicited right-lateralized signal increase in secondary areas. The recorded scanner noise evoked reliably right-lateralized mismatch MEG responses. Source localization was in accordance with activation of secondary auditory cortex. The presented paradigm provides a robust and feasible tool to study the functional anatomy of early cognitive auditory processing in clinical populations such as schizophrenia.     

Measuring alterations in oscillatory brain networks in schizophrenia with resting-state MEG: State-of-the-art and methodological challenges

Objective

Neuroimaging studies provide evidence of disturbed resting-state brain networks in Schizophrenia (SZ). However, untangling the neuronal mechanisms that subserve these baseline alterations requires measurement of their electrophysiological underpinnings. This systematic review specifically investigates the contributions of resting-state Magnetoencephalography (MEG) in elucidating abnormal neural organization in SZ patients.

Comparison of electric field modeling pipelines for transcranial direct current stimulation

ObjectivesElectric field modeling utilizes structural brain magnetic resonance images (MRI) to model the electric field induced by non-invasive transcranial direct current stimulation (tDCS) in a given individual. Electric field modeling is being integrated with clinical outcomes to improve understanding of inter-individual variability in tDCS effects and to optimize tDCS parameters, thereby enhancing the predictability of clinical effects. The successful integration of modeling in clinical use will primarily be driven by choice of tools and procedures implemented in computational modeling. Thus, the electric field predictions from different modeling pipelines need to be investigated to ensure the validity and reproducibility of tDCS modeling results across clinical or translational studies.MethodsWe used T1w structural MRI from 32 healthy volunteer subjects and modeled the electric field distribution for a fronto-temporal tDCS montage. For five different computational modeling pipelines, we quantitatively compared brain tissue segmentation and electric field predicted in whole-brain, brain tissues and target brain regions between the modeling pipelines.ResultsOur comparisons at various levels did not reveal any systematic trend with regards to similarity or dissimilarity of electric field predicted in brain tissues and target brain regions. The inconsistent trends in the predicted electric field indicate variation in the procedures, routines and algorithms used within and across the modeling pipelines.ConclusionOur results suggest that studies integrating electric field modeling and clinical outcomes of tDCS will highly depend upon the choice of the modeling pipelines and procedures. We propose that using these pipelines for further research and clinical applications should be subject to careful consideration, and indicate general recommendations.     

DBSproc: An open source process for DBS electrode localization and tractographic analysis

Deep brain stimulation (DBS) is an effective surgical treatment for movement disorders. Although stimulation sites for movement disorders such as Parkinson's disease are established, the therapeutic mechanisms of DBS remain controversial. Recent research suggests that specific white‐matter tract and circuit activation mediates symptom relief. To investigate these questions, we have developed a patient‐specific open‐source software pipeline called ‘DBSproc’ for (1) localizing DBS electrodes and contacts from postoperative CT images, (2) processing structural and diffusion MRI data, (3) registering all images to a common space, (4) estimating DBS activation volume from patient‐specific voltage and impedance, and (5) understanding the DBS contact‐brain connectivity through probabilistic tractography. In this paper, we explain our methodology and provide validation with anatomical and tractographic data. This method can be used to help investigate mechanisms of action of DBS, inform surgical and clinical assessments, and define new therapeutic targets. Hum Brain Mapp 37:422–433, 2016. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.     

Guidelines for TMS/tES clinical services and research through the COVID-19 pandemic

BackgroundThe COVID-19 pandemic has broadly disrupted biomedical treatment and research including non-invasive brain stimulation (NIBS). Moreover, the rapid onset of societal disruption and evolving regulatory restrictions may not have allowed for systematic planning of how clinical and research work may continue throughout the pandemic or be restarted as restrictions are abated. The urgency to provide and develop NIBS as an intervention for diverse neurological and mental health indications, and as a catalyst of fundamental brain research, is not dampened by the parallel efforts to address the most life-threatening aspects of COVID-19; rather in many cases the need for NIBS is heightened including the potential to mitigate mental health consequences related to COVID-19.ObjectiveTo facilitate the re-establishment of access to NIBS clinical services and research operations during the current COVID-19 pandemic and possible future outbreaks, we develop and discuss a framework for balancing the importance of NIBS operations with safety considerations, while addressing the needs of all stakeholders. We focus on Transcranial Magnetic Stimulation (TMS) and low intensity transcranial Electrical Stimulation (tES) - including transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS).MethodsThe present consensus paper provides guidelines and good practices for managing and reopening NIBS clinics and laboratories through the immediate and ongoing stages of COVID-19. The document reflects the analysis of experts with domain-relevant expertise spanning NIBS technology, clinical services, and basic and clinical research – with an international perspective. We outline regulatory aspects, human resources, NIBS optimization, as well as accommodations for specific demographics.ResultsA model based on three phases (early COVID-19 impact, current practices, and future preparation) with an 11-step checklist (spanning removing or streamlining in-person protocols, incorporating telemedicine, and addressing COVID-19-associated adverse events) is proposed. Recommendations on implementing social distancing and sterilization of NIBS related equipment, specific considerations of COVID-19 positive populations including mental health comorbidities, as well as considerations regarding regulatory and human resource in the era of COVID-19 are outlined. We discuss COVID-19 considerations specifically for clinical (sub-)populations including pediatric, stroke, addiction, and the elderly. Numerous case-examples across the world are described.ConclusionThere is an evident, and in cases urgent, need to maintain NIBS operations through the COVID-19 pandemic, including anticipating future pandemic waves and addressing effects of COVID-19 on brain and mind. The proposed robust and structured strategy aims to address the current and anticipated future challenges while maintaining scientific rigor and managing risk.     

Deep Brain Stimulation for Alzheimer’s Disease: Tackling Circuit Dysfunction

ObjectivesTreatments for Alzheimer’s disease are urgently needed given its enormous human and economic costs and disappointing results of clinical trials targeting the primary amyloid and tau pathology. On the other hand, deep brain stimulation (DBS) has demonstrated success in other neurological and psychiatric disorders leading to great interest in DBS as a treatment for Alzheimer’s disease.Materials and MethodsWe review the literature on 1) circuit dysfunction in Alzheimer’s disease and 2) DBS for Alzheimer’s disease. Human and animal studies are reviewed individually.ResultsThere is accumulating evidence of neural circuit dysfunction at the structural, functional, electrophysiological, and neurotransmitter level. Recent evidence from humans and animals indicate that DBS has the potential to restore circuit dysfunction in Alzheimer’s disease, similarly to other movement and psychiatric disorders, and may even slow or reverse the underlying disease pathophysiology.ConclusionsDBS is an intriguing potential treatment for Alzheimer’s disease, targeting circuit dysfunction as a novel therapeutic target. However, further exploration of the basic disease pathology and underlying mechanisms of DBS is necessary to better understand how circuit dysfunction can be restored. Additionally, robust clinical data in the form of ongoing phase III clinical trials are needed to validate the efficacy of DBS as a viable treatment.     

Transcranial direct current stimulation effects on neural processing in post‐stroke aphasia

Non‐invasive transcranial direct current stimulation (tDCS) can enhance recovery after stroke. However, fundamental knowledge about how tDCS impacts neural processing in the lesioned human brain is currently lacking. In the present study, it was investigated how tDCS modulates brain function in patients with post‐stroke language impairment (aphasia). In a cross‐over, randomized trial, patients named pictures of common objects during functional magnetic resonance imaging (fMRI). Concurrently, excitatory (anodal‐) or sham‐tDCS (1 mA, 20 min, or 30 s, respectively) was administered to the left primary motor cortex, a montage with demonstrated potential to improve aphasic language. By choosing stimuli that could reliable be named by the patients, the authors aimed to derive a pure measure of stimulation effects that was independent of treatment or performance effects and to assess how tDCS interacts with the patients' residual language network. Univariate fMRI data analysis revealed reduced activity in domain‐general regions mediating high‐level cognitive control during anodal‐tDCS. Independent component functional network analysis demonstrated selectively increased language network activity and an inter‐correlated shift from higher to lower frequency bands, indicative of increased within‐network communication. Compared with healthy controls, anodal‐tDCS resulted in overall “normalization” of brain function in the patients. These results demonstrate for the first time how tDCS modulates neural processing in stroke patients. Such information is crucial to assure that behavioral treatments targeting specific neural circuits overlap with regions that are modulated by tDCS, thereby maximizing stimulation effects during therapy. Hum Brain Mapp 38:1518–1531, 2017. © 2016 Wiley Periodicals, Inc.     

Gait-related frequency modulation of beta oscillatory activity in the subthalamic nucleus of parkinsonian patients

BackgroundAbnormal beta band activity in the subthalamic nucleus (STN) is known to be exaggerated in patients with Parkinson’s disease, and the amplitude of such activity has been associated with akinetic rigid symptoms. New devices for deep brain stimulation (DBS) that operate by adapting the stimulation parameters generally rely on the detection of beta activity amplitude modulations in these patients. Movement-related frequency modulation of beta oscillatory activity has been poorly investigated, despite being an attractive variable for extracting information about basal ganglia activity.ObjectiveWe studied the STN oscillatory activity associated with locomotion and proposed a new approach to extract movement related information from beta band activity.MethodsWe recorded bilateral local field potential of the STN in eight parkinsonian patients implanted with DBS electrodes during upright quiet standing and unperturbed walking. Neurophysiological recordings were combined with kinematic measurements and individual molecular brain imaging studies. We then determined the information carried by the STN oscillatory activity about locomotion and we identified task-specific biomarkers.ResultsWe found a gait-related peak frequency modulation of the beta band of STN recordings of parkinsonian patients. This novel biomarker and the associated power modulations were highly informative to detect the walking state (with respect to standing) in each single patient.ConclusionFrequency modulation in the human STN represents a fundamental aspect of information processing of locomotion. Our information-driven approach could significantly enrich the spectrum of Parkinson’s neural markers, with input signals encoding ongoing tasks execution for an appropriate online tuning of DBS delivery.     

Alzheimer’s disease: The state of the art in resting-state magnetoencephalography

Alzheimer’s disease (AD) is accompanied by functional brain changes that can be detected in imaging studies, including electromagnetic activity recorded with magnetoencephalography (MEG). Here, we systematically review the studies that have examined resting-state MEG changes in AD and identify areas that lack scientific or clinical progress. Three levels of MEG analysis will be covered: (i) single-channel signal analysis, (ii) pairwise analyses over time series, which includes the study of interdependencies between two time series and (iii) global network analyses. We discuss the findings in the light of other functional modalities, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Overall, single-channel MEG results show consistent changes in AD that are in line with EEG studies, but the full potential of the high spatial resolution of MEG and advanced functional connectivity and network analysis has yet to be fully exploited. Adding these features to the current knowledge will potentially aid in uncovering organizational patterns of brain function in AD and thereby aid the understanding of neuronal mechanisms leading to cognitive deficits.     

Reliability and reproducibility of brain tissue volumetry from segmented MR scans

Reliable measurement of different tissue volumes in the living brain is of great importance for human brain research. In this article, we report on the inter- and intraoperator reliability and scan-rescan reproducibility of segmented intracranial tissue volumes from MR images using the image analysis software suite BRAINS. The absolute data of tissue volume measurements are also presented. The reliability and consistency of the measurements of the segmented volumes were excellent. The segmentation is robust and rapid and the volume measurements are plausible and suitable for quantitative studies in clinical brain research. Received: 24 April 2001 / Accepted: 24 September 2001     

Tracking of iron-labeled human neural stem cells by magnetic resonance imaging in cell replacement therapy for Parkinson’s disease

Human neural stem cells (hNSCs) derived from the ventral mesencephalon are powerful research tools and candidates for cell therapies in Parkinson’s disease. However, their clinical translation has not been fully realized due, in part, to the limited ability to track stem cell regional localization and survival over long periods of time afterin vivo transplantation. Magnetic resonance imaging provides an excellent non-invasive method to study the fate of transplanted cellsin vivo. For magnetic resonance imaging cell tracking, cells need to be labeled with a contrast agent, such as magnetic nanoparticles, at a concentration high enough to be easily detected by magnetic resonance imaging. Grafting of human neural stem cells labeled with magnetic nanoparticles allows cell tracking by magnetic resonance imaging without impairment of cell survival, prolif-eration, self-renewal, and multipotency. However, the results reviewed here suggest that in long term grafting, activated microglia and macrophages could contribute to magnetic resonance imaging signal by engulifng dead labeled cells or iron nanoparticles dispersed freely in the brain parenchyma over time.     

Neurochemical correlates of caudate atrophy in Huntington's disease

The precise pathogenic mechanisms of Huntington's disease (HD) are unknown but can be tested in vivo using proton magnetic resonance spectroscopy (¹H MRS) to measure neurochemical changes. The objective of this study was to evaluate neurochemical differences in HD gene mutation carriers (HGMCs) versus controls and to investigate relationships among function, brain structure, and neurochemistry in HD. Because previous ¹H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two ¹H MRS data analysis approaches. HGMCs with premanifest to early HD and controls underwent evaluation of motor function, magnetic resonance imaging, and localized ¹H MRS in the caudate and the frontal lobe. Analytical approaches that were tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel). We identified a suite of neurochemicals that were reduced in concentration proportionally to loss of caudate volume in HGMCs. Caudate concentrations of N‐acetylaspartate (NAA), creatine, choline, and caudate and frontal lobe concentrations of glutamate plus glutamine (Glx) and glutamate were correlated with caudate volume in HGMCs. The relative, but not the absolute, quantitation approach revealed disease‐related differences; the Glx signal was decreased relative to other neurochemicals in the caudate of HGMCs versus controls. This is the first study to demonstrate a correlation among structure, function, and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable the magnification of subtle differences between groups. Observation of decreased Glx suggests that glutamate signaling may be disrupted relatively early in HD, which has important implications for therapeutic approaches. © 2014 International Parkinson and Movement Disorder Society     

Simultaneous EEG and MEG source reconstruction in sparse electromagnetic source imaging

Electroencephalography (EEG) and magnetoencephalography (MEG) have different sensitivities to differently configured brain activations, making them complimentary in providing independent information for better detection and inverse reconstruction of brain sources. In the present study, we developed an integrative approach, which integrates a novel sparse electromagnetic source imaging method, i.e., variation‐based cortical current density (VB‐SCCD), together with the combined use of EEG and MEG data in reconstructing complex brain activity. To perform simultaneous analysis of multimodal data, we proposed to normalize EEG and MEG signals according to their individual noise levels to create unit‐free measures. Our Monte Carlo simulations demonstrated that this integrative approach is capable of reconstructing complex cortical brain activations (up to 10 simultaneously activated and randomly located sources). Results from experimental data showed that complex brain activations evoked in a face recognition task were successfully reconstructed using the integrative approach, which were consistent with other research findings and validated by independent data from functional magnetic resonance imaging using the same stimulus protocol. Reconstructed cortical brain activations from both simulations and experimental data provided precise source localizations as well as accurate spatial extents of localized sources. In comparison with studies using EEG or MEG alone, the performance of cortical source reconstructions using combined EEG and MEG was significantly improved. We demonstrated that this new sparse ESI methodology with integrated analysis of EEG and MEG data could accurately probe spatiotemporal processes of complex human brain activations. This is promising for noninvasively studying large‐scale brain networks of high clinical and scientific significance. Hum Brain Mapp, 2013. © 2010 Wiley Periodicals, Inc.