Identifying the joint signature of brain atrophy and gene variant scores in Alzheimer's Disease.

The joint modeling of genetic data and brain imaging information allows for determining the pathophysiological pathways of neurodegenerative diseases such as Alzheimer's disease (AD). This task has typically been approached using mass-univariate methods that rely on a complete set of Single Nucleotide Polymorphisms (SNPs) to assess their association with selected image-derived phenotypes (IDPs). However, such methods are prone to multiple comparisons bias and, most importantly, fail to account for potential cross-feature interactions, resulting in insufficient detection of significant associations. Ways to overcome these limitations while reducing the number of traits aim at conveying genetic information at the gene level and capturing the integrated genetic effects of a set of genetic variants, rather than looking at each SNP individually. Their associations with brain IDPs are still largely unexplored in the current literature, though they can uncover new potential genetic determinants for brain modulations in the AD continuum. In this work, we explored an explainable multivariate model to analyze the genetic basis of the grey matter modulations, relying on the AD Neuroimaging Initiative (ADNI) phase 3 dataset. Cortical thicknesses and subcortical volumes derived from T1-weighted Magnetic Resonance were considered to describe the imaging phenotypes. At the same time the genetic counterpart was represented by gene variant scores extracted by the Sequence Kernel Association Test (SKAT) filtering model. Moreover, transcriptomic analysis was carried on to assess the expression of the resulting genes in the main brain structures as a form of validation. Results highlighted meaningful genotype-phenotype interactionsas defined by three latent components showing a significant difference in the projection scores between patients and controls. Among the significant associations, the model highlighted EPHX1 and BCAS1 gene variant scores involved in neurodegenerative and myelination processes, hence relevant for AD. In particular, the first was associated with decreased subcortical volumes and the second with decreasedtemporal lobe thickness. Noteworthy, BCAS1 is particularly expressed in the dentate gyrus. Overall, the proposed approach allowed capturing genotype-phenotype interactions in a restricted study cohort that was confirmed by transcriptomic analysis, offering insights into the underlying mechanisms of neurodegeneration in AD in line with previous findings and suggesting new potential disease biomarkers.

Dual-echo ASL contributes to decrypting the link between functional connectivity and cerebral blow flow.

Arterial spin labeling (ASL) MRI with a dual-echo readout module (DE-ASL) enables noninvasive simultaneous acquisition of cerebral blood flow (CBF)-weighted images and blood oxygenation level dependent (BOLD) contrast. Up to date, resting-state functional connectivity (FC) studies based on CBF fluctuations have been very limited, while the BOLD is still the method most frequently used. The purposes of this technical report were (i) to assess the potentiality of the DE-ASL sequence for the quantification of resting-state FC and brain organization, with respect to the conventional BOLD (cvBOLD) and (ii) to investigate the relationship between a series of complex network measures and the CBF information. Thirteen volunteers were scanned on a 3 T scanner acquiring a pseudocontinuous multislice DE-ASL sequence, from which the concomitant BOLD (ccBOLD) simultaneously to the ASL can be extracted. In the proposed comparison, the brain FC and graph-theoretical analysis were used for quantifying the connectivity strength between pairs of regions and for assessing the network model properties in all the sequences. The main finding was that the ccBOLD part of the DE-ASL sequence provided highly comparable connectivity results compared to cvBOLD. As expected, because of its different nature, ASL sequence showed different patterns of brain connectivity and graph indices compared to BOLD sequences. To conclude, the resting-state FC can be reliably detected using DE-ASL, simultaneously to CBF quantifications, whereas a single fMRI experiment precludes the quantitative measurement of BOLD signal changes. Hum Brain Mapp 38:5831-5844, 2017. © 2017 Wiley Periodicals, Inc.

Investigation of brain hemodynamic changes induced by active and passive movements: a combined arterial spin labeling-BOLD fMRI study.

PURPOSE: To assess the applicability of arterial spin labeling (ASL) in comparison to blood-oxygenation-level-dependent (BOLD) contrast fMRI in detecting brain activations elicited by active and passive hand movements. MATERIALS AND METHODS: A block design for ASL and BOLD fMRI was applied in 8 healthy subjects using active and passive hand tasks. Data analyses were performed at individual and group level, comparing both the different movements and the performance of the two techniques. RESULTS: Group analyses showed involvement of the same areas during both tasks, as the contralateral sensorimotor cortex, supplementary motor area, cerebellum, inferior parietal lobes, thalamus. ASL detected smaller activation volumes than BOLD, but the areas had a high degree of colocalization. Few significant differences (P < 0.05) were found when the two tasks were compared for the number of activated voxels, coordinates of center of mass, and CBF estimates. Considering together all the areas, the mean %BOLD change was 0.79 ± 0.27 and 0.73 ± 0.24 for the active and passive movements respectively, while the mean %CBF changes were 34.1 ± 8.9 and 27.1 ± 14.8. CONCLUSION: Our findings confirm passive and active tasks are strongly coupled, supporting the importance of passive tasks as a diagnostic tool in the clinical setting. ASL fMRI proved suitable for functional mapping and quantifying CBF changes, making it a promising technique for patient cohort applications.

The use of electrical source imaging in targeting lesional mesial temporal epilepsy for radiosurgical treatment.

Gamma knife radiosurgery (GK-RS) is a technique applied in selected cases of mesial-temporal epilepsy, although still limited to centres with adequate instrumentation and expertise. Here, we report a case of radio surgery targeted with the aid of electrical source imaging that localizes the cortical area generating the scalp epileptic discharges. The patient, a 39-year-old male, presented with a right mesio-temporal lesion; electrical source imaging localization partially overlapped with the lesional area but showed an important activation of the omolateral frontal area, concordant with the epileptic network. The patient underwent GK-RS, with good neurosurgical and clinical results. A radiosurgical ellipsoidal treatment volume area of 2 × 2 × 2 cm³, located over the right temporo-mesial region within a centre showing abnormal signal intensity, was considered. Seven months after treatment, the patient developed brain oedema that gradually resolved after one year. After three years of follow-up, the patient was seizure-free (Engel class I). Our very preliminary experience suggests that electrical source imaging appears to be a useful supporting tool for the definition of the radiosurgical treatment volume in selected patients with temporo-mesial lesional epilepsy.

A multimodal imaging approach to the evaluation of post-traumatic epilepsy.

OBJECT: Electroencephalography-functional magnetic resonance imaging (EEG-fMRI) coregistration and high-density EEG (hdEEG) can be combined to map noninvasively abnormal brain activation elicited by epileptic processes. By combining noninvasive imaging techniques in a multimodal approach, we sought to investigate pathophysiological mechanisms underlying epileptic activity in seven patients with severe traumatic brain injury. MATERIALS AND METHODS: Standard EEG and fMRI data were acquired during a single scanning session. The EEG-fMRI data were analyzed using the general linear model and independent component analysis. Source localization of interictal epileptiform discharges (IEDs) was performed using 256-channel hdEEG. Blood oxygenation level dependent (BOLD) localizations were then compared to EEG source reconstruction. RESULTS: On hdEEG, focal source localization was detected in all seven patients; in six out of seven it was concordant with the expected epileptic activity as defined by EEG data and clinical evaluation; and in four out of seven in whom IEDs were recorded, BOLD signal changes were observed. These activities were partially concordant with the source localization. CONCLUSION: Multimodal integration of EEG-fMRI and hdEEG combining two different methods to localize the same epileptic foci appears to be a promising tool to noninvasively map abnormal brain activation in patients with post-traumatic brain injury.

Connectivity modulations induced by reach&grasp movements: a multidimensional approach.

Reach&grasp requires highly coordinated activation of different brain areas. We investigated whether reach&grasp kinematics is associated to EEG-based networks changes. We enrolled 10 healthy subjects. We analyzed the reach&grasp kinematics of 15 reach&grasp movements performed with each upper limb. Simultaneously, we obtained a 64-channel EEG, synchronized with the reach&grasp movement time points. We elaborated EEG signals with EEGLAB 12 in order to obtain event related synchronization/desynchronization (ERS/ERD) and lagged linear coherence between Brodmann areas. Finally, we evaluated network topology via sLORETA software, measuring network local and global efficiency (clustering and path length) and the overall balance (small-worldness). We observed a widespread ERD in α and ß bands during reach&grasp, especially in the centro-parietal regions of the hemisphere contralateral to the movement. Regarding functional connectivity, we observed an α lagged linear coherence reduction among Brodmann areas contralateral to the arm involved in the reach&grasp movement. Interestingly, left arm movement determined widespread changes of α lagged linear coherence, specifically among right occipital regions, insular cortex and somatosensory cortex, while the right arm movement exerted a restricted contralateral sensory-motor cortex modulation. Finally, no change between rest and movement was found for clustering, path length and small-worldness. Through a synchronized acquisition, we explored the cortical correlates of the reach&grasp movement. Despite EEG perturbations, suggesting that the non-dominant reach&grasp network has a complex architecture probably linked to the necessity of a higher visual control, the pivotal topological measures of network local and global efficiency remained unaffected.

EEG to Identify Attempted Movement in Unresponsive Wakefulness Syndrome.

Assessment of consciousness following severe brain-injury is challenging. Our hypothesis is that electroencephalography (EEG) can provide information on awareness, in terms of oscillatory activity and network task-related modifications, in people with disorders of consciousness. Similar results were obtained with neuroimaging techniques; we aim at demonstrating the use of EEG, which is low cost and routinely implemented, to the same goal. Nineteen-channel EEG was recorded in 7 persons with unresponsive wakefulness syndrome (UWS) and in 10 healthy subjects during the execution of active (attempted movement) and passive motor tasks as well as 2 mental imagery tasks. Event-related synchronization/desynchronization (ERS/ERD), coherence and network parameters were calculated in delta (1-4 Hz), theta (4-8 Hz), alpha1 (8-10 Hz), alpha2 (10-12 Hz), and beta (13-30 Hz) ranges. In UWS subjects, passive movement induced a weak alpha2 ERD over contralateral sensorimotor area. During motor imagery, ERD was detected over the frontal and motor contralateral brain areas; during spatial imagery, ERS in lower alpha band over the right temporo-parietal regions was missing. In UWS, functional connectivity provided evidence of network disruption and isolation of the motor areas, which cannot dialog with adjacent network nodes, likely suggesting a diffuse structural alteration. Our findings suggest that people with a clinical diagnosis of UWS were able to modulate their brain activity when prompted to perform movement tasks and thus suggest EEG as a potential tool to support diagnosis of disorders of consciousness.

How Expertise Changes Cortical Sources of EEG Rhythms and Functional Connectivity in Divers Under Simulated Deep-Sea Conditions.

Although the recent years have witnessed a growing interest in functional connectivity (FC) through brain sources, the FC in extreme situations has not been completely elucidated. This paper is aimed at investigating whether the expertise acquired during the deep-sea diving is reflected in FC in a group of professional divers (PDs) compared to a group of new divers (NDs), and how it could affect the concentration and stress levels. The sources of brain frequency rhythms, derived by the electroencephalography acquisition in a hyperbaric chamber, were extracted in different frequency bands and the corresponding FC was estimated in order to compare the two groups. The results highlighted a significant decrease of the alpha source in PDs during air breathing and a significant increase of the upper beta source over central areas at the beginning of post-oxygen air, as well as an increase of beta FC between fronto-temporal regions in the last minutes of oxygen breathing and in the early minutes of post-oxygen air. This provides evidence in support of the hypothesis that experience and expertise differences would modulate brain networks. These experiments provided the unique opportunity of investigating the impact of the neurophysiological activity in simulated critical scenarios in view of the investigation in real sea-water experiments.

Behavioural and electrophysiological effects of tDCS to prefrontal cortex in patients with disorders of consciousness.

OBJECTIVES: Left dorsolateral prefrontal cortex anodal transcranial direct current stimulation (tDCS) was applied in a group of patients with disorders of consciousness to determine the effects of modulation of spontaneous oscillatory brain activity. METHODS: 12 patients in an unresponsive wakefulness syndrome (UWS) and 12 in a minimally conscious state (MCS) underwent 2-weeks active and 2-weeks sham tDCS. Neurophysiological assessment was performed with EEG power spectra and coherence analysis directly before and after each session. RESULTS: An increase of power and coherence of the frontal and parietal alpha and beta frequency bands and significant clinical improvements were seen after the active tDCS in MCS patients. In contrast, UWS patients showed some local frontal changes in the slow frequencies. No treatment effect was observed after sham. CONCLUSIONS: tDCS could induce changes in cortical EEG oscillations, modulating the travel of alpha and beta waves between anterior and posterior brain areas when some cognitive functions were preserved. This plays an important role in consciousness by integrating cognitive-emotional processing with the state of arousal. In unresponsive people, brain integration seems to be lost. SIGNIFICANCE: Our results further support the critical role of long-range fronto-parietal connections in consciousness and show the potential therapeutic utility of tDCS.

Neurophysiological and BOLD signal uncoupling of giant somatosensory evoked potentials in progressive myoclonic epilepsy: a case-series study.

In progressive myoclonic epilepsy (PME), a rare epileptic syndrome caused by a variety of genetic disorders, the combination of peripheral stimulation and functional magnetic resonance imaging (fMRI) can shed light on the mechanisms underlying cortical dysfunction. The aim of the study is to investigate sensorimotor network modifications in PME by assessing the relationship between neurophysiological findings and blood oxygen level dependent (BOLD) activation. Somatosensory-evoked potential (SSEP) obtained briefly before fMRI and BOLD activation during median-nerve electrical stimulation were recorded in four subjects with typical PME phenotype and compared with normative data. Giant scalp SSEPs with enlarger N20-P25 complex compared to normal data (mean amplitude of 26.2 ± 8.2 µV after right stimulation and 27.9 ± 3.7 µV after left stimulation) were detected. Statistical group analysis showed a reduced BOLD activation in response to median nerve stimulation in PMEs compared to controls over the sensorimotor (SM) areas and an increased response over subcortical regions (p < 0.01, Z > 2.3, corrected). PMEs show dissociation between neurophysiological and BOLD findings of SSEPs (giant SSEP with reduced BOLD activation over SM). A direct pathway connecting a highly restricted area of the somatosensory cortex with the thalamus can be hypothesized to support the higher excitability of these areas.

Bluetooth Communication Interface for EEG Signal Recording in Hyperbaric Chambers.

Recording biological signals inside a hyperbaric chamber poses technical challenges (the steel walls enclosing it greatly attenuate or completely block the signals as in a Faraday cage), practical (lengthy cables creating eddy currents), and safety (sparks hazard from power supply to the electronic apparatus inside the chamber) which can be overcome with new wireless technologies. In this technical report we present the design and implementation of a Bluetooth system for electroencephalographic (EEG) recording inside a hyperbaric chamber and describe the feasibility of EEG signal transmission outside the chamber. Differently from older systems, this technology allows the online recording of amplified signals, without interference from eddy currents. In an application of this technology, we measured EEG activity in professional divers under three experimental conditions in a hyperbaric chamber to determine how oxygen, assumed at a constant hyperbaric pressure of 2.8 ATA , affects the bioelectrical activity. The EEG spectral power estimated by fast Fourier transform and the cortical sources of the EEG rhythms estimated by low-resolution brain electromagnetic analysis were analyzed in three different EEG acquisitions: breathing air at sea level; breathing oxygen at a simulated depth of 18 msw, and breathing air at sea level after decompression.

Spatial and Temporal EEG-fMRI Changes During Preictal and Postictal Phases in a Patient With Posttraumatic Epilepsy.

The combined use of electroencephalography (EEG) and functional magnetic resonance imaging (EEG-fMRI) in epilepsy allows the noninvasive hemodynamic characterization of epileptic discharge-related neuronal activations. The aim of this study was to investigate pathophysiologic mechanisms underlying epileptic activity by exploring the spatial and temporal distribution of fMRI signal modifications during seizure in a single patient with posttraumatic epilepsy. EEG and fMRI data were acquired during two scanning sessions: a spontaneous critical episode was observed during the first, and interictal events were recorded during the second. The EEG-fMRI data were analyzed using the general linear model (GLM). Blood oxygenation level-dependent (BOLD) localization derived from the preictal and artifact-free postictal phase was concordant with the BOLD localization of the interictal epileptiform discharges identified in the second session, pointing to a left perilesional mesiofrontal area. Of note, BOLD signal modifications were already visible several seconds before seizure onset. In brief, BOLD activations from the preictal, postictal, and interictal epileptiform discharge analysis appear to be concordant with the clinically driven localization hypothesis, whereas a widespread network of activations is detected during the ictal phase in a partial seizure.

Frequency and time-frequency analysis of intraoperative ECoG during awake brain stimulation.

Electrocortical stimulation remains the standard for functional brain mapping of eloquent areas to prevent postoperative functional deficits. The aim of this study was to investigate whether the short-train technique (monopolar stimulation) and Penfield's technique (bipolar stimulation) would induce different effects on brain oscillatory activity in awake patients, as quantified by electrocorticography (ECoG). The study population was seven patients undergoing brain tumor surgery. Intraoperative bipolar and monopolar electrical stimulation for cortical mapping was performed during awake surgery. ECoG was recorded using 1 × 8 electrode strip. Spectral estimation was calculated using a parametric approach based on an autoregressive model. Wavelet-based time-frequency analysis was then applied to evaluate the temporal evolution of brain oscillatory activity. Both monopolar and bipolar stimulation produced an increment in delta and a decrease in beta powers for the motor and the sensory channels. These phenomena lasted about 4 s. Comparison between monopolar and bipolar stimulation showed no significant difference in brain activity. Given the importance of quantitative signal analysis for evaluating response accuracy, ECoG recording during electrical stimulation is necessary to characterize the dynamic processes underlying changes in cortical responses in vivo. This study is a preliminary approach to the quantitative analysis of post-stimulation ECoG signals.

Time-frequency analysis of short-lasting modulation of EEG induced by TMS during wake, sleep deprivation and sleep.

The occurrence of dynamic changes in spontaneous electroencephalogram (EEG) rhythms in the awake state or sleep is highly variable. These rhythms can be externally modulated during transcranial magnetic stimulation (TMS) with a perturbation method to trigger oscillatory brain activity. EEG-TMS co-registration was performed during standard wake, during wake after sleep deprivation and in sleep in six healthy subjects. Dynamic changes in the regional neural oscillatory activity of the cortical areas were characterized using time-frequency analysis based on the wavelet method, and the modulation of induced oscillations were related to different vigilance states. A reciprocal synchronizing/desynchronizing effect on slow and fast oscillatory activity was observed in response to focal TMS after sleep deprivation and sleep. We observed a sleep-related slight desynchronization of alpha mainly over the frontal areas, and a widespread increase in theta synchronization. These findings could be interpreted as proof of the interference external brain stimulation can exert on the cortex, and how this could be modulated by the vigilance state. Potential clinical applications may include evaluation of hyperexcitable states such as epilepsy or disturbed states of consciousness such as minimal consciousness.