Evaluating the Safety of Simultaneous Intracranial Electroencephalography and Functional Magnetic Resonance Imaging Acquisition Using a 3 Tesla Magnetic Resonance Imaging Scanner

Background: The unsurpassed sensitivity of intracranial electroencephalography (icEEG) and the growing interest in understanding human brain networks and ongoing activities in health and disease have make the simultaneous icEEG and functional magnetic resonance imaging acquisition (icEEG-fMRI) an attractive investigation tool. However, safety remains a crucial consideration, particularly due to the impact of the specific characteristics of icEEG and MRI technologies that were safe when used separately but may risk health when combined. Using a clinical 3-T scanner with body transmit and head-receive coils, we assessed the safety and feasibility of our icEEG-fMRI protocol. Methods: Using platinum and platinum-iridium grid and depth electrodes implanted in a custom-made acrylic-gel phantom, we assessed safety by focusing on three factors. First, we measured radio frequency (RF)-induced heating of the electrodes during fast spin echo (FSE, as a control) and the three sequences in our icEEG-fMRI protocol. Heating was evaluated with electrodes placed orthogonal or parallel to the static magnetic field. Using the configuration with the greatest heating observed, we then measured the total heating induced in our protocol, which is a continuous 70-min icEEG-fMRI session comprising localizer, echo-planar imaging (EPI), and magnetization-prepared rapid gradient-echo sequences. Second, we measured the gradient switching-induced voltage using configurations mimicking electrode implantation in the frontal and temporal lobes. Third, we assessed the gradient switching-induced electrode movement by direct visual detection and image analyses. Results: On average, RF-induced local heating on the icEEG electrode contacts tested were greater in the orthogonal than parallel configuration, with a maximum increase of 0.2°C during EPI and 1.9°C during FSE. The total local heating was below the 1°C safety limit across all contacts tested during the 70-min icEEG-fMRI session. The induced voltage was within the 100-mV safety limit regardless of the configuration. No gradient switching-induced electrode displacement was observed. Conclusion: We provide evidence that the additional health risks associated with heating, neuronal stimulation, or device movement are low when acquiring fMRI at 3 T in the presence of clinical icEEG electrodes under the conditions reported in this study. High specific absorption ratio sequences such as FSE should be avoided to prevent potential inadvertent tissue heating

Neural Activity Elicited by a Cognitive Task can be Detected in Single-Trials with Simultaneous Intracerebral EEG-fMRI Recordings.

Recent studies have shown that it is feasible to record simultaneously intracerebral EEG (icEEG) and functional magnetic resonance imaging (fMRI) in patients with epilepsy. While it has mainly been used to explore the hemodynamic changes associated with epileptic spikes, this approach could also provide new insight into human cognition. However, the first step is to ensure that cognitive EEG components, that have lower amplitudes than epileptic spikes, can be appropriately detected under fMRI. We compared the high frequency activities (HFA, 50-150[Formula: see text]Hz) elicited by a reading task in icEEG-only and subsequent icEEG-fMRI in the same patients ([Formula: see text]), implanted with depth electrodes. Comparable responses were obtained, with 71% of the recording sites that responded during the icEEG-only session also responding during the icEEG-fMRI session. For all the remaining sites, nearby clusters (distant of 7[Formula: see text]mm or less) also demonstrated significant HFA increase during the icEEG-fMRI session. Significant HFA increases were also observable at the single-trial level in icEEG-fMRI recordings. Our results show that low-amplitude icEEG signal components such as cognitive-induced HFAs can be reliably recorded with simultaneous fMRI. This paves the way for the use of icEEG-fMRI to address various fundamental and clinical issues, notably the identification of the neural correlates of the BOLD signal

Investigating early functional alteration in a human iPSC-based model of Parkinson’s Disease

[eng] Dopaminergic neurons (DAn) were efficiently differentiated from 6 different iPSC lines derived from a 2 control, 3 PD lines, and an isogenic PD line. We characterize the culture at different time point in order to verify the composition of the culture. At day 35 almost 50% of the cells expressed the neuronal marker TUJ1, of which 20% were of DA lineage as judged by TH expression. No astrocytes were found in the culture. Interestingly at day 50 of differentiation the amount of DAn increased up to 25-35% of which 35% were expressing Girk2, a midbrain DA neuronal marker that was not expressed at day 35 and 45-60% of the DA neurons express FOXA2, another important transcription factor that confirm the midbrain fate. Even more importantly, at day 80 of the differentiation process, the amount of DAn that expressed Girk2 increased up to 50%, while the expression of FOXA2 in DA remain stable, confirming the ventral midbrain phenotype. We then test for each line the neuronal activity by calcium imaging assay. Comparing the two groups of controls and isogenic PD line versus PD lines, interestingly we identify two distinct patterns of activity: controls lines display a mixed mode, oscillatory activity normally associated with healthy networks while PD lines display a two-state dynamics, with strong bursting combined with intervals of almost no activity that suggest an impairment in the communication between the neurons. These dynamic differences suggest a more in depth analysis of the functional network that controls and PD create. Using a custom algorithm we demonstrate that just the PD lines were functionally impaired because their neurons, especially at day 80, were not able to form a homogeneous network like the controls one that can be described as a scale-free like systems. Analyzing separately TH and non TH neurons we were able to conclude that the functional connectivity of PD1 lines shows a higher departure from the controls lines along maturation, which indicates poor information flow efficiency. Particularly, PD TH+ neurons connectomes display abnormal network organization that occurs primarily before the general alteration of the network, suggesting that TH+ are leading to general neural connectome alteration. Due to the biophysical simulation analysis we were able to identify as a cause of the functional impairment the reduction in the neurite arborization TH specific just in the PD lines and confirm this phenotype in our biological samples. We then used our in vitro model to take a step backwards and examine the biological and molecular behavior before the functional alteration manifests. We analyzed the culture at D50, when the data suggests that the functional alteration has not yet developed fully, using gene expression profile analysis to identify possible deregulations in pathways that can be connected to the altered functionality. Bioinformatics analysis focused on differentially expressed genes, selected with a pAdjValue of 0.05 and a fold change ≤-2 and ≥ 2. Within these strict selection criteria, we were unable to highlight any gene related to LRRK2 PD and isogenic PD. This confirms the validity of the in vitro model and the robustness of the differentiation protocol and shows that the functional phenotype is not due to macroscopic neurodegenerative conditions.[spa] La enfermedad de Parkinson (EP) es una enfermedad incurable, crónica y progresiva que conduce a la invalidez prematura y la muerte. Se espera que el diagnóstico temprano de la EP mejore dramáticamente el resultado de las terapias actuales. Para ello, empleamos un modelo de EP basado en células neuronales humanas, para detectar alteraciones funcionales tempranas que nos den un diagnostico de la enfermedad antes de la aparición de síntomas motores. Utilizando neuronas derivadas de células madre pluripotentes inducidas (iPSC) de individuos sanos y pacientes con EP asociados con la mutación familiar en el gen LRRK2, hemos comprobado que los dos grupos forman redes complejas y muestran signos evidentes de maduración funcional a lo largo del tiempo. Sin embargo, las redes neuronales de la EP desarrollaron una híper-sincronía anormal, en comparación con las redes de los controles y de la línea isogénica de LRRK2. En esto estudio combinamos análisis de la actividad neuronal a lo largo de tiempo utilizando la técnica del “calcium imaging”, un modelo in silico de “network”, líneas reporteras de neuronas dopaminérgicas, y el análisis del perfil de expresión génica. Con estos experimentos, encontramos que una disminución en la longitud de la neurita de neuronas dopaminérgicas es, entre otras causas, una de las primeras alteraciones funcionales presentes en la red de neuronas derivada de EP. Por lo tanto, nuestros resultados identifican alteraciones tempranas en la función neuronal de la EP que son anteriores al inicio de la degeneración neuronal, resaltando la extraordinaria ventaja que ofrece este modelo de iPSC en la evaluación pre sintomática de las enfermedades degenerativas crónicas

Safety of Simultaneous Scalp and Intracranial Electroencephalography Functional Magnetic Resonance Imaging

Understanding the brain and its activity is one of the great challenges of modern science. Normal brain activity (cognitive processes, etc.) has been extensively studied using electroencephalography (EEG) since the 1930’s, in the form of spontaneous fluctuations in rhythms, and patterns, and in a more experimentally-driven approach in the form of event-related potentials allowing us to relate scalp voltage waveforms to brain states and behaviour. The use of EEG recorded during functional magnetic resonance imaging (EEG-fMRI) is a more recent development that has become an important tool in clinical neuroscience, for example, for the study of epileptic activity. The primary aim of this thesis is to devise a protocol in order to minimise the health risks that are associated with simultaneous scalp and intracranial EEG during fMRI (S- icEEG-fMRI). The advances in this technique will be helpful in presenting a new imaging method that will allow the measurement of brain activity with unprecedented sensitivity and coverage. However, this cannot be achieved without assessing the safety implications of such a technique. Therefore, five experiments were performed to fulfil the primary aim. First, the safety of icEEG- fMRI using body transmit RF coil was investigated to improve the results of previous attempts using a head transmit coil at 1.5T. The results of heating increases during a high-SAR sequence were in the range of 0.2-2.4 °C at the contacts with leads positioned along the central axis inside the MRI bore. These findings suggest the need for careful lead placement. Second, also for the body transmit coil we compared the heating in the vicinity of icEEG electrodes placed inside a realistically-shaped head phantom following the addition of scalp EEG electrodes. The peak temperature change was +2.7 °C at the most superior icEEG electrode contact without scalp electrodes, and +2.1 °C at the same contact and the peak increase in the vicinity of a scalp electrode contact was +0.6 °C (location FP2). These findings show that the S-icEEG-fMRI technique is feasible if our protocol is followed carefully. Third, the heating of a realistic 3D model of icEEG electrode during MRI using EM computational simulation was investigated. The resulting peak 10 g averaged SAR was 20% higher than without icEEG. Moreover, the superior icEEG placed perpendicular to B0 showed significant local SAR increase. These results were in line with previous studies. Fourth, the possibility of simplifying a complete 8-contact with 8 wires depth icEEG electrode model into an electrode with 1-contact and 1 wire using EM simulations was addressed. The results showed similar patterns of averaged SAR values around the electrode tip during phantom and electrode position along Z for the Complete and Simplified models, except an average maximum at Z = ~2.5 W/kg for the former. The SAR values during insertion depth for the Simplified model were double those for the Complete model. The effect of extension cable length is in agreement with previous experiments. Fifth, further simulations were implemented using two more simplified models: 8-contact with 1 wire shared with all contact and 8-contact 1 wire connected to each contact at a time as well as the previously modelled simplified 1-contact 1 wire. Two sets of simulations were performed: with a single electrode and with multiple electrodes. For the single electrode, three scenarios were tested: the first simplified model used only, the second simplified models used only and the third model positioned in different 13 locations. The results of these simulations showed about 11.4-20.5-fold lower SAR for the first model than the second and 0.29-5.82-fold lower SAR for the first model than the complete model. The results also showed increased SAR for the electrode close to the head coil than the ones away from it. For the multiple electrodes, three scenarios were tested: two 1-contact and wire electrodes in different separations, multiple electrodes with their wires separated and multiple electrodes with their wires shorted. The results showed interaction between the two tested electrodes. The results of the multiple electrodes presented 2 to ~10 times higher SAR for the separated setup than the shorted. The comparison between the 1-contact with 1 wire model and the complete model is still unknown and more tests are required to show it. From the findings of this PhD research, we conclude that a body RF coil can be utilized for icEEG-fMRI at 1.5 T; however, the safety protocol has to be implemented. In addition, scalp EEG can be used in conjunction with icEEG electrodes inside the body RF coil at 1.5 T and the safety protocol has to be followed. Finally, it is feasible to perform EM computational simulations using realistic icEEG electrodes on a human model. However, simplifying the realistic icEEG electrode model might result in overestimations of the heating, although it is possible that the simplification of the model can help to simulate more complex implantations such as the implantation of multiple electrodes with their leads open circuited or short circuited, which can provide more information about the safety of implanted patients inside the MRI