1. Clinical application of EEG-fMRI in epilepsy
Carolina Cuello Oderiz, MD
Postdoctoral Research Fellow
Jean Gotman, PhD Laboratory

2. Learning objectives Review basic knowledge about functional MRI
Review some evidence of the contribution of the EEG/fMRI to the definition of the epilepticus focus
Compare the differences in the response of focal versus generalized epilepsy

3. An increase in neural activity in a region of cortex stimulates an increase in the local blood flow
fMRI: detects the blood oxygen level-dependent (BOLD) changes in the MRI signal that arise when changes in neuronal activity occur following a change in brain state, such as may be produced, for example, by a stimulus or task.

5. There is a time delay before the necessary vasodilation can occur to increase flow, and for the wash-out of deoxyhemoglobin from the region to occur  BOLD response is delayed several seconds following the stimulating event

8. Corrections should be performed for:
Within a single image there may be over 10,000 voxels (volume elements)
Voxels provide a sequence of data points in which the signal alternates in intensity in synchrony with the stimulation because of the BOLD effect
Statistical parametric map of brain slice. Using some statistical decision criterion such as p ,0.05
Corrections should be performed for:
Patient motion
Respiration
Cardiac pulsations (Ballistocardiogram artifacts are removed using independent component analysis)
Physiologically related variations

9. Limitations:
Spatial resolution: few millimeters.
Temporal resolution is limited by hemodynamic response time; typically the BOLD response has a width of ~3s and a peak occurring ~5–6s after the onset of a brief neural stimulus. This is much slower than the underlying neural processes.
BOLD effect is small, and thus the sensitivity is limited, so that fMRI experiments require multiple samplings of brain responses.
BOLD response is an indirect measure of neural activity
fMRI provides an accurate and painless method for mapping of critical functions and likely has a much larger role to play in the management of clinical patients for diverse disorders in the future

10. EEG/fMRI remains mostly an experimental procedure
It is performed in patients with frequent IEDs (>10 IEDs/h) during routine EEG or telemetry monitoring
Sometimes in patients whose focus localization was not clear even without a very active EEG.

11. Recording fMRI and EEG simultaneously is a noninvasive method detecting cerebral hemodynamic changes related to interictal epileptic discharges (IEDs) on scalp EEG.
EEG changes would occur approximately 6s before the BOLD response peaks (Jacobs J et al 2009)
Simultaneous intracranial EEG/fMRI recordings have shown IED-related BOLD changes in the immediate vicinity of the intracranial EEG focus, confirming spatial concordance between neuronal and BOLD changes.
Distant BOLD changes related to specific IED patterns were also observed.
In a postsurgical population, it was shown that when the resection included the BOLD activation region, patients showed good outcome.

12. Validation: depth electrodes

13. BOLD responses occurred in all patients having IEDs during scanning (33 of 43 patients). This rate is higher than that in previous studies in which the rate was approximately 50%. We explain these results by the fact that this is the first large patient group scanned at 3 T.
Considering the 33 patients with active EEG during EEG/fMRI, the BOLD response was concordant with the spike field in 88%.
We considered BOLD responses concordant if the maximum t value corresponded to the localization of the EEG spike field.
As reported, the BOLD changes we measured were often more extensive than expected from electroclinical findings.
Distant or diffuse activations could be part of an epileptic network remote from the focus.

15. BOLD changes as a result of epileptic activity can be positive or negative deviations from the baseline.
Earlier positive BOLD response peaking before the spike
Disrupted neurovascular coupling
BOLD signal can be seen areas remote from the epileptogenic regions

16. frontal areas, dorsolateral and mesial parieto-occipital regions,
Focal concordant deactivation to T5-P3-O1 spikes in a patient with temporoparietal epilepsy and
a left frontal subcortical cyst.
The “default” pattern of deactivation, involving bilaterally the anterior
frontal areas, dorsolateral and mesial parieto-occipital regions,
and posterior cingulate gyri. Related to bursts of generalized sharp-slow waves in a patient with idiopathic generalized epilepsy.

17. Methods:
All consecutive patients with focal epilepsy from our database of EEG/fMRI who underwent surgery after EEG/
fMRI from April 2006 to December 2010 and with at least 12-month follow-up were included in this study.

18. Comparison of BOLD response with resection
included
Excluded: “inconclusive”

19. Results
Forty-seven patients had surgery after EEG/fMRI study, and 12 were excluded: 11 had no IEDs inside the scanner and one showed only deactivation in the default mode network.
Thus, 35 patients were included (17 male; mean age at evaluation, years, range, 15–65).
These patients were studied over 57 months
Presurgical anatomic MRI was normal in 9 patients, showed mesial temporal sclerosis (MTS) in 11, a malformation of cortical development in 9 (FCD in 4, multilobar polymicrogyria in 2, nodular heterotopia in 2, and hemimegalencephaly in 1), brain tumor in 3, cerebral atrophy in one, an occipital cyst and cortical atrophy in one, and a temporal horn cyst and bilateral mesial temporal shape changes in one.

20. Each patient had one type of event with BOLD response for further comparison.
The number of IEDs recorded during the fMRI ranged from 2 to 1,451
Two of the 35 patients showed activations only, three presented deactivations only, and 30 had activations and deactivations.
The size of resection was not a factor in the distribution of patients in the different groups.
Mean time of postsurgical follow-up was months (range, 12– 60)
Ten (28.6%) of 35 patients were classified in group 1, nine (25.7%) in group 2, five (14.3%) in group 3, and 11 (31.4%) in group 4.
Fifteen patients (43%) had a good outcome (Engel I-II).

21. Group 1 (fully concordant): Seven (70%) of 10 patients achieved seizure freedom (class I)
Group 2 (partially concordant): The t-max corresponded to activation in six patients and to deactivation in three. Four (44%) of nine patients achieved seizure freedom (Engel’s class I)
Group 3 (partially discordant): Three (60%) of five patients had a good outcome (class I)
Group 4 (fully discordant): Only patient 22 (1/11, 9%) achieved seizure freedom (class I) at 12-month follow-up

22. Sensitivity and specificity evaluation
Sensitivity= patients with good outcome + concordant/ patients with good outcome x 100%
Specificity= patients with poor outcome+ discordant/patients with poor outcome x 100%
PPV= patients concordant+ good outcome/ patients concordant x 100%
NPV= patients discordant+ poor outcome/ patients discordant x 100%

24. In patient 2, the IED resulted in two clusters within the spike field having almost the same t value. Both clusters could be epileptogenic, and the removal of only one might explain the unsatisfactory outcome.
The maximum BOLD activation of patient 25 was in the small part of neocortex, which was removed as part of a transcortical selective amygdalo-hippocampectomy. A larger neocortical removal may have been more effective.
In the group with partial concordance, the four patients with a favorable outcome showed a focal confined BOLD cluster, suggesting that removal of a critical or sufficiently large portion of a focal BOLD response could lead to good outcome

25. Six patients had deactivation fully or partially concordant with the resection, three with a good outcome
It is difficult to formally validate the EEG/fMRI results, given that EEG/fMRI, like most imaging methods, does not always give a clear- cut conclusive result for each subject, and sometimes shows BOLD responses in the EZ and in remote areas.
BOLD clusters also have different statistical t values and sizes, which are difficult to combine systematically and quantitatively as one criterion
Patients were recruited from a tertiary epilepsy center with usually complex cases

26. Fourteen had a lesion completely or mostly removed and nine did well
Fourteen had a lesion completely or mostly removed and nine did well. Twelve had their lesion partly removed and three did well
The impact of this correlation on our study is not obvious, as the peak BOLD response is not always in the lesion.

27. Activations in thalamus and midfrontal regions confirm known involvement of these regions in the generation or spread of generalized epileptic discharges.
Involvement of the insulae in generalized discharges had not previously been described.
Cerebellar activation is not believed to reflect the generation of discharges.
Deactivations in frontal and parietal regions remarkably followed the pattern of the default state of brain function.

29. References
John C. Gore Principles and practice of functional MRI of the human brain, J Clin Invest v.112(1); 2003 Jul 1
Francesca Pittau, MD, François Dubeau, MD, and Jean Gotman, PhD , Contribution of EEG/fMRI to the definition of the epileptic focus, Neurology May 8; 78(19): 1479– 1487
Dongmei An, Firas Fahoum, JefferyHall, Andr eOlivier, Jean Gotman, and Fran ois Dubeau, Electroencephalography/functional magnetic resonance imaging responses help predict surgical outcome in focal epilepsy, Epilepsia, 54(12):2184–2194, 2013
Eliane Kobayashi, Andrew P. Bagshaw, Christophe Grova, Francois Dubeau, and Jean Gotman, Negative BOLD Responses to Epileptic Spikes, Human Brain Mapping 27:488 – 497(2006)
J. Gotman, C. Grova, A. Bagshaw, E. Kobayashi, Y. Aghakhani, and F. Dubeau, Generalized epileptic discharges show thalamocortical activation and suspension of the default state of the brain, PNAS, October 18, 2005, vol. 102, 42, –15240