Ismael Gaxiola-Valdez

Reduced Intrinsic Connectivity of Amygdala in Adults with Major Depressive Disorder

Imaging studies of major depressive disorder (MDD) have demonstrated enhanced resting-state activity of the amygdala as well as exaggerated reactivity to negative emotional stimuli relative to healthy controls (HCs). However, the abnormalities in the intrinsic connectivity of the amygdala in MDD still remain unclear. As the resting-state activity and functional connectivity (RSFC) reflect fundamental brain processes, we compared the RSFC of the amygdala between unmedicated MDD patients and HCs. Seventy-four subjects, 55 adults meeting the DSM-IV criteria for MDD and 19 HCs, underwent a resting-state 3-T functional magnetic resonance imaging scan. An amygdala seed-based low frequency RSFC map for the whole brain was generated for each group. Compared with HCs, MDD patients showed a wide-spread reduction in the intrinsic connectivity of the amygdala with a variety of brain regions involved in emotional processing and regulation, including the ventrolateral prefrontal cortex, insula, caudate, middle and superior temporal regions, occipital cortex, and cerebellum, as well as increased connectivity with the bilateral temporal poles (p < 0.05 corrected). The increase in the intrinsic connectivity of amygdala with the temporal poles was inversely correlated with symptom severity and anxiety scores. Although the directionality of connections between regions cannot be inferred from temporal correlations, the reduced intrinsic connectivity of the amygdala predominantly with regions involved in emotional processing may reflect impaired bottom-up signaling for top-down cortical modulation of limbic regions leading to abnormal affect regulation in MDD.

Feasibility of an intracranial EEG–fMRI protocol at 3 T: Risk assessment and image quality

Integrating intracranial EEG (iEEG) with functional MRI (iEEG-fMRI) may help elucidate mechanisms underlying the generation of seizures. However, the introduction of iEEG electrodes in the MR environment has inherent risk and data quality implications that require consideration prior to clinical use. Previous studies of subdural and depth electrodes have confirmed low risk under specific circumstances at 1.5T and 3T. However, no studies have assessed risk and image quality related to the feasibility of a full iEEG-fMRI protocol. To this end, commercially available platinum subdural grid/strip electrodes (4×5 grid or 1×8 strip) and 4 or 6-contact depth electrodes were secured to the surface of a custom-made phantom mimicking the conductivity of the human brain. Electrode displacement, temperature increase of electrodes and surrounding phantom material, and voltage fluctuations in electrode contacts were measured in a GE Discovery MR750 3T MR scanner during a variety of imaging sequences, typical of an iEEG-fMRI protocol. An electrode grid was also used to quantify the spatial extent of susceptibility artifact. The spatial extent of susceptibility artifact in the presence of an electrode was also assessed for typical imaging parameters that maximize BOLD sensitivity at 3T (TR=1500 ms; TE=30 ms; slice thickness=4mm; matrix=64×64; field-of-view=24 cm). Under standard conditions, all electrodes exhibited no measurable displacement and no clinically significant temperature increase (<1°C) during scans employed in a typical iEEG-fMRI experiment, including 60 min of continuous fMRI. However, high SAR sequences, such as fast spin-echo (FSE), produced significant heating in almost all scenarios (>2.0°C) that in some cases exceeded 10°C. Induced voltages in the frequency range that could elicit neuronal stimulation (<10 kHz) were well below the threshold of 100 mV. fMRI signal intensity was significantly reduced within 20mm of the electrodes for the imaging parameters used in this study. Thus, for the conditions tested, a full iEEG-fMRI protocol poses a low risk at 3T; however, fMRI sensitivity may be reduced immediately adjacent to the electrodes. In addition, high SAR sequences must be avoided.

Frontal Lobe Epilepsy Alters Functional Connections Within the Brain's Motor Network: A Resting-State fMRI Study

Patients with frontal lobe epilepsy (FLE) often experience motor deficits, yet little is known of the impact of FLE on the activity of motor networks in the brain. Resting-state functional magnetic resonance imaging (rs-fMRI) has previously demonstrated an association between cognitive deficits in temporal lobe epilepsy patients and disruption of activity within pertinent brain networks. Hence, in the present study, rs-fMRI was used to determine whether FLE is associated with motor network disruption. Seven right-hemisphere FLE patients, six left-hemisphere FLE patients, and nine control subjects underwent rs-fMRI. Functional connectivity was computed between the sensorimotor cortex contralateral to the seizure focus and each voxel in the brain, and then compared voxel-by-voxel between patient groups and controls. A laterality index (LI) of connectivity between contralateral and ipsilateral sensorimotor cortices was calculated to investigate its association with epilepsy duration and seizure frequency. Positive laterality indices indicate reduced connectivity, and zero values indicate strong connectivity. Connectivity between the left and right sensorimotor cortices was significantly reduced in FLE patients compared with controls (p<0.05), and LI was positively correlated with the number of lifetime seizures (left FLE: rs=0.89, right FLE: rs=1.00). Patients with FLE exhibit decreased connectivity within the motor network, in correlation with the number of lifetime seizures, thus demonstrating a potential relationship between seizure activity and changes in motor network organization. These findings suggest that motor network disturbances may in part be responsible for the motor deficits observed in FLE patients.

Postictal behavioural impairments are due to a severe prolonged hypoperfusion/hypoxia event that is COX-2 dependent.

Seizures are often followed by sensory, cognitive or motor impairments during the postictal phase that show striking similarity to transient hypoxic/ischemic attacks. Here we show that seizures result in a severe hypoxic attack confined to the postictal period. We measured brain oxygenation in localized areas from freely-moving rodents and discovered a severe hypoxic event (pO2 < 10 mmHg) after the termination of seizures. This event lasted over an hour, is mediated by hypoperfusion, generalizes to people with epilepsy, and is attenuated by inhibiting cyclooxygenase-2 or L-type calcium channels. Using inhibitors of these targets we separated the seizure from the resulting severe hypoxia and show that structure specific postictal memory and behavioral impairments are the consequence of this severe hypoperfusion/hypoxic event. Thus, epilepsy is much more than a disease hallmarked by seizures, since the occurrence of postictal hypoperfusion/hypoxia results in a separate set of neurological consequences that are currently not being treated and are preventable. DOI: http://dx.doi.org/10.7554/eLife.19352.001

Co-localization between the BOLD response and epileptiform discharges recorded by simultaneous intracranial EEG-fMRI at 3 T

Objectives Simultaneous scalp EEG-fMRI can identify hemodynamic changes associated with the generation of interictal epileptiform discharges (IEDs), and it has the potential of becoming a standard, non-invasive technique for pre-surgical assessment of patients with medically intractable epilepsy. This study was designed to assess the BOLD response to focal IEDs recorded via simultaneous intracranial EEG-functional MRI (iEEG-fMRI). Methods Twelve consecutive patients undergoing intracranial video EEG monitoring were recruited for iEEG-fMRI studies at 3 T. Depth, subdural strip, or grid electrodes were implanted according to our standard clinical protocol. Subjects underwent 10–60 min of continuous iEEG-fMRI scanning. IEDs were marked, and the most statistically significant clusters of BOLD signal were identified (Z-score 2.3, p value < 0.05). We assessed the concordance between the locations of the BOLD response and the IED. Concordance was defined as a distance <1.0 cm between the IED and BOLD response location. Negative BOLD responses were not studied in this project. Results Nine patients (7 females) with a mean age of 31 years (range 22–56) had 11 different types of IEDs during fMR scanning. The IEDs were divided based on the location of the active electrode contact into mesial temporal, lateral temporal, and extra-temporal. Seven (5 left) mesial temporal IED types were recorded in 5 patients (110–2092 IEDs per spike location). Six of these IEDs had concordant BOLD response in the ipsilateral mesial temporal structures, <1 cm from the most active contact. One of the two subjects with left lateral temporal IEDs had BOLD responses concordant with the location of the most active contact, as well other ipsilateral and contralateral sites. Notably, the remaining two subjects with extratemporal discharges showed no BOLD signal near the active electrode contact. Conclusions iEEG-fMRI is a feasible and low-risk method for assessment of hemodynamic changes of very focal IEDs that may not be recorded by scalp EEG. A high concordance rate between the location of the BOLD response and IEDs was seen for mesial temporal (6/7) IEDs. Significant BOLD activation was also seen in areas distant from the active electrode and these sites exhibited maximal BOLD activation in the majority of cases. This implies that iEEG-fMRI may further describe the areas involved in the generation of IEDs beyond the vicinity of the electrode(s).

Patient specific hemodynamic response functions associated with interictal discharges recorded via simultaneous intracranial EEG-fMRI.

Simultaneous collection of scalp EEG and fMRI has become an important tool for studying the hemodynamic changes associated with interictal epileptiform discharges (IEDs) in persons with epilepsy, and has become a standard presurgical assessment tool in some centres. We previously demonstrated that performing EEG‐fMRI using intracranial electrodes (iEEG‐fMRI) is of low risk to patients in our research centre, and offers unique insight into BOLD signal changes associated with IEDs recorded from very discrete sources. However, it is unknown whether the BOLD response corresponding to IEDs recorded by iEEG‐fMRI follows the canonical hemodynamic response. We therefore scanned 11 presurgical epilepsy patients using iEEG‐fMRI, and assessed the hemodynamic response associated with individual IEDs using two methods: assessment of BOLD signal changes associated with isolated IEDs at the location of the active intracranial electrode, and by estimating subject‐specific impulse response functions to isolated IEDs. We found that the hemodynamic response associated with the intracranially recorded discharges varied by patient and by spike location. The observed shape and timing differences also deviated from the canonical hemodynamic response function traditionally used in many fMRI experiments. It is recommended that future iEEG‐fMRI studies of IEDs use a flexible hemodynamic response model when performing parametric tests to accurately characterize these data. Hum Brain Mapp 36:5252–5264, 2015.

Amygdala responses to quetiapine XR and citalopram treatment in major depression: The role of 5-HTTLPR-S/Lg polymorphisms

Genotype and drug pharmacology may contribute to variations in brain response to antidepressants. We examined the impact of two antidepressants with differential actions on serotonin transporter and the 5‐HHTLPR‐S/Lg polymorphisms on amygdala responses in major depressive disorder (MDD).

Recent seizure activity alters motor organization in frontal lobe epilepsy as revealed by task-based fMRI

PURPOSE Patients with frontal lobe epilepsy (FLE) commonly demonstrate motor impairments, suggesting that frontal lobe seizures affect motor function. However, the underlying mechanisms of these deficits are not known, nor has any study systematically examined motor organization in these patients. We therefore examined cortical motor organization in a group of adult patients with FLE, using task-based fMRI. METHODS Eleven right FLE patients, six left FLE patients, and ten control subjects underwent task-based fMRI. Two tasks were performed using the right and left hands separately, and both hands together. The first task was a finger-tapping task and the second task was a more complex coordination task. Functional MR data were compared between patient groups and controls. A laterality index of brain activation was also calculated between the epileptic and healthy hemisphere to determine hemispheric dominance during task performance to explore its relationship with a variety of patient-specific epilepsy factors. RESULTS Overall, right FLE patients demonstrated decreased BOLD activity in the epileptic hemisphere and increased BOLD activity in the healthy hemisphere compared to controls (p<0.05). The comparison of left FLE patients to controls provided less conclusive differences, possibly due to the low number of left FLE patients studied. Laterality indices of the coordination task were positively correlated to the number of months since the last seizure in both patient groups (right FLE: rs=0.779, left FLE: rs=0.943). Patients that had experienced a recent seizure relied more on the sensorimotor cortex of the healthy hemisphere during task performance, compared to those that were relatively seizure free (p<0.05). SIGNIFICANCE Patients with FLE exhibited changes in motor BOLD activity that was dependent on the duration of seizure freedom. These results demonstrate the presence of seizure-related alteration of cortical motor organization in FLE, which may underlie the motor deficits seen in these patients.

Origins of intersubject variability of blood oxygenation level dependent and arterial spin labeling fMRI: implications for quantification of brain activity

Accurate localization of brain activity using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been challenged because of the large BOLD signal within distal veins. Arterial spin labeling (ASL) techniques offer greater sensitivity to the microvasculature but possess low temporal resolution and limited brain coverage. In this study, we show that the physiological origins of BOLD and ASL depend on whether percent change or statistical significance is being considered. For BOLD and ASL fMRI data collected during a simple unilateral hand movement task, we found that in the area of the contralateral motor cortex the centre of gravity (CoG) of the intersubject coefficient of variation (CV) of BOLD fMRI was near the brain surface for percent change in signal, whereas the CoG of the intersubject CV for Z-score was in close proximity of sites of brain activity for both BOLD and ASL. These findings suggest that intersubject variability of BOLD percent change is vascular in origin, whereas the origin of inter-subject variability of Z-score is neuronal for both BOLD and ASL. For longer duration tasks (12 s or greater), however, there was a significant correlation between BOLD and ASL percent change, which was not evident for short duration tasks (6 s). These findings suggest that analyses directly comparing percent change in BOLD signal between pre-defined regions of interest using short duration stimuli, as for example in event-related designs, may be heavily weighted by large-vessel responses rather than neuronal responses.

Seizure onset zone localization using postictal hypoperfusion detected by arterial spin labelling MRI

Neurological dysfunction following epileptic seizures is a well-recognized phenomenon. Several potential mechanisms have been suggested to explain postictal dysfunction, with alteration in cerebral blood flow being one possibility. These vascular disturbances may be long lasting and localized to brain areas involved in seizure generation and propagation, as supported by both animal and human studies. Therefore, measuring perfusion changes in the postictal period may help localize the seizure onset zone. Arterial spin labelling is a non-invasive, rapid and reproducible magnetic resonance imaging technique that measures cerebral perfusion. To this end, we measured postictal perfusion in patients with drug resistant focal epilepsy who were admitted to our seizure-monitoring unit for presurgical evaluation. Twenty-one patients were prospectively recruited and underwent arterial spin labelling scanning within 90 min of a habitual seizure. Patients also underwent a similar scan in the interictal period, after they were seizure-free for at least 24 h. The acquired scans were subtracted to identify the areas of significant postictal hypoperfusion. The location of the maximal hypoperfusion was compared to the presumed seizure onset zone to assess for concordance. Also, the localizing value of this technique was compared to other structural and functional imaging modalities. Postictal perfusion reductions of >15 units (ml/100 g/l) were seen in 15/21 patients (71.4%). In 12/15 (80%) of these patients, the location of the hypoperfusion was partially or fully concordant with the location of the presumed seizure onset zone. This technique compared favourably to other neuroimaging modalities, being similar or superior to structural magnetic resonance imaging in 52% of cases, ictal single-photon emission computed tomography in 60% of cases and interictal positron emission tomography in 71% of cases. Better arterial spin labelling results were obtained in patients in whom the seizure onset zone was discernible based on non-invasive data. Thus, this technique is a safe, non-invasive and relatively inexpensive tool to detect postictal hypoperfusion that may provide useful data to localize the seizure onset zone. This technique may be incorporated into the battery of conventional investigations for presurgical evaluation of patients with drug resistant focal epilepsy.