Optimized microburst VNS elicits fMRI responses beyond thalamic-specific response from standard VNS.

OBJECTIVE: In parallel to standard vagus nerve stimulation (VNS), microburst stimulation delivery has been developed. We evaluated the fMRI-related signal changes associated with standard and optimized microburst stimulation in a proof-of-concept study (NCT03446664). METHODS: Twenty-nine drug-resistant epilepsy patients were prospectively implanted with VNS. Three 3T fMRI scans were collected 2 weeks postimplantation. The maximum tolerated VNS intensity was determined prior to each scan starting at 0.125 mA with 0.125 mA increments. FMRI scans were block-design with alternating 30 sec stimulation [ON] and 30 sec no stimulation [OFF]: Scan 1 utilized standard VNS and Scan 3 optimized microburst parameters to determine target settings. Semi-automated on-site fMRI data processing utilized ON-OFF block modeling to determine VNS-related fMRI activation per stimulation setting. Anatomical thalamic mask was used to derive highest mean thalamic t-value for determination of microburst stimulation parameters. Paired t-tests corrected at P < 0.05 examined differences in fMRI responses to each stimulation type. RESULTS: Standard and microburst stimulation intensities at Scans 1 and 3 were similar (P = 0.16). Thalamic fMRI responses were obtained in 28 participants (19 with focal; 9 with generalized seizures). Group activation maps showed standard VNS elicited thalamic activation while optimized microburst VNS showed widespread activation patterns including thalamus. Comparison of stimulation types revealed significantly greater cerebellar, midbrain, and parietal fMRI signal changes in microburst compared to standard VNS. These differences were not associated with seizure responses. INTERPRETATION: While standard and optimized microburst VNS elicited thalamic activation, microburst also engaged other brain regions. Relationship between these fMRI activation patterns and clinical response warrants further investigation. CLINICAL TRIAL REGISTRATION: The study was registered with clinicaltrials.gov (NCT03446664).

The Scanner as the Stimulus: Deficient Gamma-BOLD Coupling in Schizophrenia at Rest.

Functional magnetic resonance imaging (fMRI) scanners are unavoidably loud and uncomfortable experimental tools that are necessary for schizophrenia (SZ) neuroscience research. The validity of fMRI paradigms might be undermined by well-known sensory processing abnormalities in SZ that could exert distinct effects on neural activity in the presence of scanner background sound. Given the ubiquity of resting-state fMRI (rs-fMRI) paradigms in SZ research, elucidating the relationship between neural, hemodynamic, and sensory processing deficits during scanning is necessary to refine the construct validity of the MR neuroimaging environment. We recorded simultaneous electroencephalography (EEG)-fMRI at rest in people with SZ (n = 57) and healthy control participants without a psychiatric diagnosis (n = 46) and identified gamma EEG activity in the same frequency range as the background sounds emitted from our scanner during a resting-state sequence. In participants with SZ, gamma coupling to the hemodynamic signal was reduced in bilateral auditory regions of the superior temporal gyri. Impaired gamma-hemodynamic coupling was associated with sensory gating deficits and worse symptom severity. Fundamental sensory-neural processing deficits in SZ are present at rest when considering scanner background sound as a "stimulus." This finding may impact the interpretation of rs-fMRI activity in studies of people with SZ. Future neuroimaging research in SZ might consider background sound as a confounding variable, potentially related to fluctuations in neural excitability and arousal.

Functional Connectivity of the Anterior Nucleus of the Thalamus in Pediatric Focal Epilepsy.

Objective: Whilst stimulation of the anterior nucleus of the thalamus has shown efficacy for reducing seizure frequency in adults, alterations in thalamic connectivity have not been explored in children. We tested the hypotheses that (a) the anterior thalamus has increased functional connectivity in children with focal epilepsy, and (b) this alteration in the connectome is a persistent effect of the disease rather than due to transient epileptiform activity. Methods: Data from 35 children (7-18 years) with focal, drug-resistant epilepsy and 20 healthy children (7-17 years) were analyzed. All subjects underwent functional magnetic resonance imaging (fMRI) whilst resting and were simultaneously monitored with scalp electroencephalography (EEG). The fMRI timeseries were extracted for each Automated Anatomical Labeling brain region and thalamic subregion. Graph theory metrics [degree (DC) and eigenvector (EC) centrality] were used to summarize the connectivity profile of the ipsilateral thalamus, and its thalamic parcellations. The effect of interictal epileptiform discharges (IEDs) captured on EEG was used to determine their effect on DC and EC. Results: DC was significantly higher in the anterior nucleus (p = 0.04) of the thalamus ipsilateral to the epileptogenic zone in children with epilepsy compared to controls. On exploratory analyses, we similarly found a higher DC in the lateral dorsal nucleus (p = 0.02), but not any other thalamic subregion. No differences in EC measures were found between patients and controls. We did not find any significant difference in DC or EC in any thalamic subregion when comparing the results of children with epilepsy before, and after the removal of the effects of IEDs. Conclusions: Our data suggest that the anterior and lateral dorsal nuclei of the thalamus are more highly functionally connected in children with poorly controlled focal epilepsy. We did not detect a convincing change in thalamic connectivity caused by transient epileptiform activity, suggesting that it represents a persistent alteration to network dynamics.

The relationship between EEG and fMRI connectomes is reproducible across simultaneous EEG-fMRI studies from 1.5T to 7T.

Both electroencephalography (EEG) and functional Magnetic Resonance Imaging (fMRI) are non-invasive methods that show complementary aspects of human brain activity. Despite measuring different proxies of brain activity, both the measured blood-oxygenation (fMRI) and neurophysiological recordings (EEG) are indirectly coupled. The electrophysiological and BOLD signal can map the underlying functional connectivity structure at the whole brain scale at different timescales. Previous work demonstrated a moderate but significant correlation between resting-state functional connectivity of both modalities, however there is a wide range of technical setups to measure simultaneous EEG-fMRI and the reliability of those measures between different setups remains unknown. This is true notably with respect to different magnetic field strengths (low and high field) and different spatial sampling of EEG (medium to high-density electrode coverage). Here, we investigated the reproducibility of the bimodal EEG-fMRI functional connectome in the most comprehensive resting-state simultaneous EEG-fMRI dataset compiled to date including a total of 72 subjects from four different imaging centers. Data was acquired from 1.5T, 3T and 7T scanners with simultaneously recorded EEG using 64 or 256 electrodes. We demonstrate that the whole-brain monomodal connectivity reproducibly correlates across different datasets and that a moderate crossmodal correlation between EEG and fMRI connectivity of r ≈ 0.3 can be reproducibly extracted in low- and high-field scanners. The crossmodal correlation was strongest in the EEG-ß frequency band but exists across all frequency bands. Both homotopic and within intrinsic connectivity network (ICN) connections contributed the most to the crossmodal relationship. This study confirms, using a considerably diverse range of recording setups, that simultaneous EEG-fMRI offers a consistent estimate of multimodal functional connectomes in healthy subjects that are dominantly linked through a functional core of ICNs across spanning across the different timescales measured by EEG and fMRI. This opens new avenues for estimating the dynamics of brain function and provides a better understanding of interactions between EEG and fMRI measures. This observed level of reproducibility also defines a baseline for the study of alterations of this coupling in pathological conditions and their role as potential clinical markers.

The Role of EEG-fMRI in Studying Cognitive Network Alterations in Epilepsy.

Brain functions do not arise from isolated brain regions, but from interactions in widespread networks necessary for both normal and pathological conditions. These Intrinsic Connectivity Networks (ICNs) support cognitive processes such as language, memory, or executive functions, but can be disrupted by epileptic activity. Simultaneous EEG-fMRI can help explore the hemodynamic changes associated with focal or generalized epileptic discharges, thus providing information about both transient and non-transient impairment of cognitive networks related to spatio-temporal overlap with epileptic activity. In the following review, we discuss the importance of interictal discharges and their impact on cognition in different epilepsy syndromes. We explore the cognitive impact of interictal activity in both animal models and human connectivity networks in order to confirm that this effect could have a possible clinical impact for prescribing medication and characterizing post-surgical outcome. Future work is needed to further investigate electrophysiological changes, such as amplitude/latency of single evoked responses or spontaneous epileptic activity in either scalp or intracranial EEG and determine its relative change in hemodynamic response with subsequent network modifications.

Thalamic volume reduction in drug-naive patients with new-onset genetic generalized epilepsy.

OBJECTIVE: Patients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED-naive patients with GGE at disease onset. We hypothesize that drug-naive patients at disease onset have gray matter changes compared to age-matched healthy controls. METHODS: We performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED-naive patients with new-onset GGE and compared them to 32 age-matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups. RESULTS: The thalamus was the only structure to show reduced gray matter volume in AED-naive patients with new-onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions. SIGNIFICANCE: Structural abnormalities in the thalamus are present at the initial onset of GGE in AED-naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration.

Combined electroencephalography-functional magnetic resonance imaging and electrical source imaging improves localization of pediatric focal epilepsy.

OBJECTIVE: Surgical treatment in epilepsy is effective if the epileptogenic zone (EZ) can be correctly localized and characterized. Here we use simultaneous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) data to derive EEG-fMRI and electrical source imaging (ESI) maps. Their yield and their individual and combined ability to (1) localize the EZ and (2) predict seizure outcome were then evaluated. METHODS: Fifty-three children with drug-resistant epilepsy underwent EEG-fMRI. Interictal discharges were mapped using both EEG-fMRI hemodynamic responses and ESI. A single localization was derived from each individual test (EEG-fMRI global maxima [GM]/ESI maximum) and from the combination of both maps (EEG-fMRI/ESI spatial intersection). To determine the localization accuracy and its predictive performance, the individual and combined test localizations were compared to the presumed EZ and to the postsurgical outcome. RESULTS: Fifty-two of 53 patients had significant maps: 47 of 53 for EEG-fMRI, 44 of 53 for ESI, and 34 of 53 for both. The EZ was well characterized in 29 patients; 26 had an EEG-fMRI GM localization that was correct in 11, 22 patients had ESI localization that was correct in 17, and 12 patients had combined EEG-fMRI and ESI that was correct in 11. Seizure outcome following resection was correctly predicted by EEG-fMRI GM in 8 of 20 patients, and by the ESI maximum in 13 of 16. The combined EEG-fMRI/ESI region entirely predicted outcome in 9 of 9 patients, including 3 with no lesion visible on MRI. INTERPRETATION: EEG-fMRI combined with ESI provides a simple unbiased localization that may predict surgery better than each individual test, including in MRI-negative patients. Ann Neurol 2017;82:278-287.

Interictal activity is an important contributor to abnormal intrinsic network connectivity in paediatric focal epilepsy.

Patients with focal epilepsy have been shown to have reduced functional connectivity in intrinsic connectivity networks (ICNs), which has been related to neurocognitive development and outcome. However, the relationship between interictal epileptiform discharges (IEDs) and changes in ICNs remains unclear, with evidence both for and against their influence. EEG-fMRI data was obtained in 27 children with focal epilepsy (mixed localisation and aetiologies) and 17 controls. A natural stimulus task (cartoon blocks verses blocks where the subject was told "please wait") was used to enhance the connectivity within networks corresponding to ICNs while reducing potential confounds of vigilance and motion. Our primary hypothesis was that the functional connectivity within visual and attention networks would be reduced in patients with epilepsy. We further hypothesized that controlling for the effects of IEDs would increase the connectivity in the patient group. The key findings were: (1) Patients with mixed epileptic foci showed a common connectivity reduction in lateral visual and attentional networks compared with controls. (2) Having controlled for the effects of IEDs there were no connectivity differences between patients and controls. (3) A comparison within patients revealed reduced connectivity between the attentional network and basal ganglia associated with interictal epileptiform discharges. We also found that the task activations were reduced in epilepsy patients but that this was unrelated to IED occurrence. Unexpectedly, connectivity changes in ICNs were strongly associated with the transient effects of interictal epileptiform discharges. Interictal epileptiform discharges were shown to have a pervasive transient influence on the brain's functional organisation. Hum Brain Mapp 38:221-236, 2017. © 2016 Wiley Periodicals, Inc.

Optimising EEG-fMRI for Localisation of Focal Epilepsy in Children.

BACKGROUND: Early surgical intervention in children with drug resistant epilepsy has benefits but requires using tolerable and minimally invasive tests. EEG-fMRI studies have demonstrated good sensitivity for the localization of epileptic focus but a poor yield although the reasons for this have not been systematically addressed. While adults EEG-fMRI studies are performed in the "resting state"; children are commonly sedated however, this has associated risks and potential confounds. In this study, we assessed the impact of the following factors on the tolerability and results of EEG-fMRI in children: viewing a movie inside the scanner; movement; occurrence of interictal epileptiform discharges (IED); scan duration and design efficiency. This work's motivation is to optimize EEG-fMRI parameters to make this test widely available to paediatric population. METHODS: Forty-six children with focal epilepsy and 20 controls (6-18) underwent EEG-fMRI. For two 10 minutes sessions subjects were told to lie still with eyes closed, as it is classically performed in adult studies ("rest sessions"), for another two sessions, subjects watched a child friendly stimulation i.e. movie ("movie sessions"). IED were mapped with EEG-fMRI for each session and across sessions. The resulting maps were classified as concordant/discordant with the presumed epileptogenic focus for each subject. FINDINGS: Movement increased with scan duration, but the movie reduced movement by ~40% when played within the first 20 minutes. There was no effect of movie on the occurrence of IED, nor in the concordance of the test. Ability of EEG-fMRI to map the epileptogenic region was similar for the 20 and 40 minute scan durations. Design efficiency was predictive of concordance. CONCLUSIONS: A child friendly natural stimulus improves the tolerability of EEG-fMRI and reduces in-scanner movement without having an effect on IED occurrence and quality of EEG-fMRI maps. This allowed us to scan children as young as 6 and obtain localising information without sedation. Our data suggest that ~20 minutes is the optimal length of scanning for EEG-fMRI studies in children with frequent IED. The efficiency of the fMRI design derived from spontaneous IED generation is an important factor for producing concordant results.

FIACH: A biophysical model for automatic retrospective noise control in fMRI.

Different noise sources in fMRI acquisition can lead to spurious false positives and reduced sensitivity. We have developed a biophysically-based model (named FIACH: Functional Image Artefact Correction Heuristic) which extends current retrospective noise control methods in fMRI. FIACH can be applied to both General Linear Model (GLM) and resting state functional connectivity MRI (rs-fcMRI) studies. FIACH is a two-step procedure involving the identification and correction of non-physiological large amplitude temporal signal changes and spatial regions of high temporal instability. We have demonstrated its efficacy in a sample of 42 healthy children while performing language tasks that include overt speech with known activations. We demonstrate large improvements in sensitivity when FIACH is compared with current methods of retrospective correction. FIACH reduces the confounding effects of noise and increases the study's power by explaining significant variance that is not contained within the commonly used motion parameters. The method is particularly useful in detecting activations in inferior temporal regions which have proven problematic for fMRI. We have shown greater reproducibility and robustness of fMRI responses using FIACH in the context of task induced motion. In a clinical setting this will translate to increasing the reliability and sensitivity of fMRI used for the identification of language lateralisation and eloquent cortex. FIACH can benefit studies of cognitive development in young children, patient populations and older adults.