c o r t e x 6 4 ( 2 0 1 5 ) 1 e7
Available online at www.sciencedirect.com
ScienceDirect Journal homepage: www.elsevier.com/locate/cortex
Research report
Neuro-anatomical differences among epileptic and ja -vu non-epileptic de Angelo Labate a,b,*, Antonio Cerasa b, Laura Mumoli a, Edoardo Ferlazzo a, Umberto Aguglia a, Aldo Quattrone a,b and Antonio Gambardella a,b,** a
Institute of Neurology, University Magna Græcia, Catanzaro, Italy Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR), Germaneto, CZ, Italy
b
article info
abstract
Article history:
ja -vu` (DV) can occur as a seizure of mesial temporal lobe epilepsy (MTLE) and Objective: De
Received 20 March 2014
in almost 80% of healthy individuals. The remarkable similarity between epileptic DV and
Reviewed 11 June 2014
DV in healthy individuals raises the possibility that DV might sometimes be an ictal phe-
Revised 19 June 2014
nomenon in apparently normal individuals. Thus, we studied a group of healthy subjects
Accepted 23 September 2014
versus individuals with benign MTLE (bMTLE) both experiencing DV.
Action editor Gus Buchtel
Methods: 63 individuals with epilepsy patients with bMTLE and 39 healthy controls at ja Vu (DV) Catanzaro University were recruited. Participants completed the Inventory for De
Published online 7 October 2014
Experiences Assessment (IDEA) test, underwent awake and asleep electroencephalogram, Keywords: ja -vu` De
MRI of the brain using a 3T scanner and whole brain voxel-based morphometry (VBM).
Imaging
campal sclerosis.
VBM
Results: Our controls had no history of neurological or psychiatric illness, epilepsy or his-
bMTLE patients with DV and without DV were also matched for the presence of hippo-
tory of febrile convulsions. Neurological and cognitive examinations were normal. Electroencephalographic procedures were unremarkable in all controls. In bMTLE group, the direct comparison of VBM between individuals with epilepsy with DV versus those without DV revealed abnormal anatomical changes in the left hippocampus, parahippocampal gyrus and visual cortex. The VBM of healthy controls with DV showed abnormal anatomical changes only in the left insular cortex. Conclusions: Our VBM results demonstrated different morphologic patterns in individuals with epilepsy and control subjects experiencing DV, involving the memory circuit in bMTLE patients and cerebral regions in the emotional network in healthy controls. © 2014 Elsevier Ltd. All rights reserved.
degli Studi “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy. * Corresponding author. Clinica Neurologica, Universita degli Studi “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy. ** Corresponding author. Clinica Neurologica, Universita E-mail addresses: [email protected] (A. Labate), [email protected] (A. Gambardella). http://dx.doi.org/10.1016/j.cortex.2014.09.020 0010-9452/© 2014 Elsevier Ltd. All rights reserved.
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c o r t e x 6 4 ( 2 0 1 5 ) 1 e7
1.
Introduction
ja vu (DV) is a transitory mental state of incongruous De impression of familiarity of present experience with an undefined past. Although almost 80% of healthy individuals have zdil et al., 2012), this experienced DV at once in their lives (Bra fascinating phenomenon is also very often present in patients with mesial temporal lobe epilepsy (MTLE) mainly with familial trend (Gambardella et al., 2000). To date, it is already very well known that epileptic illusions of DV are ictal manifestations arising from discharge within either mesial or lateral temporal cortex (Bancaud, Brunet-Bourgin, Chauvel, & Halgren, 1994) whereas anatomical basis for DV in healthy subjects is less delineated and interpreted. zdil et al., 2012) Very recently, Brazdil and coworkers (Bra described for the first time the anatomical correlates associated with DV in healthy population, illustrating volumetric differences in several brain regions involving predominantly mesio-temporal regions where the loss of gray matter was significant. Very interestingly, the present author found the same well-known epileptic network (Hippocampus-Thamalus-Basal Ganglia) involved in the genesis of refractory MTLE together with critical brain areas involved in the limbic system (Amygdala, Orbitofrontal cortex and insular cortex) (Bonilha et al., 2004; Catani et al., 2012; Labate et al., 2010). These epileptic networks have also been extensively described in patients with milder form of sporadic MTLE called benign MTLE (bMTLE), which is characterized by seizure onset in adulthood, frequent familial history and simple partial epileptic DV that often represents the only predominant ictal symptom (Labate et al., 2010; Labate, Cerasa, Gambardella, Aguglia, & Quattrone, 2008; Labate et al., 2011). Fascinatingly, the remarkable similarity between DV as an epileptic phenomenon and DV observed in healthy individuals, and the observation in patients with bMTLE that the DV experience often represents the only type of seizure, raises the possibility that DV itself might sometimes be an ictal phenomenon in apparently normal individuals, and could represent the mildest manifestation on the TLE phenotype as zdil et al., 2012). Thus, we proposed by Brazdil et al. (Bra thought and proposed (Labate & Gambardella, 2013) an
attempt to clarify whether there are some structural/ morphologic differences between healthy subjects and individuals with bMTLE both suffering from DV.
2.
Materials and methods
2.1.
Demographic features
Demographic features of our population are summarized in Table 1. The research ethic committee approved this study and written informed consent was obtained from all participants. From May 2012 to May 2013, we prospectively recruited four groups of participants from the University of Catanzaro, Italy: 32 bMTLE patients with DV (21 women, mean age 37.0 ± 11, range 20e57 years); 31 bMTLE patients without DV (20 women, mean age 38.6 ± 10, range 23e60 years); 22 healthy controls with DV (14 women, mean age 33.7 ± 8.6, range 20e49 years) and 17 healthy controls without DV (eight women, mean age 34.7 ± 8.4, range 27e49 years). The healthy controls were all volunteers who were enrolled from the staff of our University in Catanzaro among university students, paramedics and doctors. Ninety healthy volunteers were interviewed, and 39 (22 with DV and 17 without DV) agreed to participate at the study and undergo brain MRI evaluation. Healthy controls were selected based on lack of history of febrile seizures, epilepsy or abnormal neurological examination. Importantly, much attention was paid to check for the presence of hippocampal sclerosis among the patients with epilepsy since there is a large amount of evidence that this specific neuroradiological sign is associated with hippocampal atrophy in bMTLE patients. The diagnosis of bMTLE was made according to current accepted features (Labate et al., 2011). Any suggestion of seizure onset outside the mesial temporal structures, by semiology or EEG findings, or patients with refractory TLE, led to exclusion from the study. The only accepted MRI sign was hippocampal sclerosis, which was based on the characteristic MRI pattern of abnormalities because it is a finding often observed in bMTLE (Labate et al. 2006). None of the patients had mental retardation.
Table 1 e Features of bMTLE DV and non-DV compared to healthy control. Features Number Sex (%) Age (y) Age at onset of epilepsy (y) Duration of epilepsy (y) Family history of FC/epilepsy Antecedent FCs Hippocampal sclerosis on MRI (%) Ictal EEG n (%) Interictal Pathological EEG (%)
bMTLE DV
bMTLE non-DV
Healthy controls DV
Healthy controls non-DV
32 62% Female 37.0 ± 10.9 yr (20e57) 21 ± 13.7 yr (2e49) 15 ± 12.4 yr (1e42) 14 (43.7%) 6 (18.7%) 10 (33%) 4 (12.5%) 22 (68.7%)
31 62% Female 38.6 ± 10.3 yr (23e60) 22.8 ± 13.8 yr (1e55) 15.2 ± 11.6 yr (1e42) 11 (35.4%) 6 (19.3%) 10 (32%) 4 (12.9%) 21 (67.7%)
22 63% Female 33.5 ± 7.9 yr (20e49) / / 0 0 0 0 0
17 47% Female 34.8 ± 7.94 yr (27e49) / / 0 0 0 0 0
ja vu; FC: febrile convulsions. bMTLE: benign mesial-temporal lobe epilepsy; DV: de a c2 test. b one-way ANOVA. c unpaired t test.
p Value
.674a .34b .59c .92c .6a .79a .85a .74a .85a
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All patients underwent a formal neuropsychological investigation. We administered the Italian version of the Inventory for DV Experiences Assessment (translated from Czech version and approved by Sno) (Sno, Schalken, de Jonghe, & Koeter, 1994), which is a 23-item self-administered questionnaire containing a general section of nine questions and a qualitative section of fourteen questions. Results of the second IDEA section focusing on qualitative characteristics of DV experiences were not included in this study because we wanted to be very homogeneous with Brazdil's study. Patients and controls underwent MRI of the brain using a 3T scanner and routine and asleep electroencephalogram with supplementary T1 and T2 electrodes.
2.2.
MRI data acquisition
Brain MRI was performed according to our routine protocol (Labate et al., 2010, 2008) by a 3 T scanner with an 8-channel head coil (Discovery MR-750, GE, Milwaukee, WI, USA). Structural MRI data were acquired using a 3D T1-weighted spoiled gradient echo (SPGR) sequence with the following parameters: TR: 3.7 msec, TE: 9.2 msec, flip angle 12 , voxelsize 1 1 1 mm3. Subjects were positioned to lie comfortably in the scanner with a forehead-restraining strap and various foam pads to ensure head fixation.
2.3.
Voxel-based morphometry (VBM)
Data were processed using the SPM8 software (http://www.fil. ion.ucl.ac.uk/spm), where we applied VBM implemented in the VBM8 toolbox, incorporating the DARTEL toolbox that was used to obtain a high-dimensional normalization protocol (Ashburner, 2007). Images were bias-corrected, tissue classified, and registered using linear (12-parameter affine) and non-linear transformations, within a unified model. Subsequently, the warped gray matter segments were affine transformed into MNI space and were scaled by the Jacobian determinants of the deformations (modulation). Finally, the modulated volumes were smoothed with a Gaussian kernel of 8 mm. The gray matter volume maps were statistically analyzed using the general linear model based on Gaussian random field theory. To assess the main/interaction effects of diagnosis (bMTLE vs Controls) and DV (yes vs no) on gray matter volume, the smoothed and modulated gray matter images were entered into a second-level ANCOVA model, with age and total intracranial volume (ICV) as covariates of nointerest. Based on previous findings, we decided to use the following regions of interest: thalamus, hippocampus, basal ganglia, parahippocampal gyrus, visual cortex, temporal cortex, the sensorimotor cortex, the orbitofrontal cortex, the insular cortex as a priori ROIs given their consolidated role in pathophysiological mechanisms of MTLE and in neural basis zdil et al., 2012; Labate et al., 2010). All ROIs were of DV (Bra created with the “aal.02” atlas included in the Wake Forest University Pickatlas software version 1.04 (Functional MRI Laboratory at the Wake Forest University School of Medicine, WinstoneSalem, North Carolina; http://www.fmri.wfubmc. edu/download.htm). All analyses were thresholded by using correction for multiple comparisons (Family-Wise Error (FWE)
3
p < .05) within ROIs. VBM analysis was only focused on these 9 ROIs, given their critical role in pathophysiological mechanisms of DV. No significant anatomical changes were detected in other brain regions when we performed statistical comparisons among groups.
2.4.
Automated hippocampal volumetry
To corroborate voxel-based findings we further performed automated labeling and quantification of hippocampal volume using FreeSurfer 5.0. The automated procedures for volumetric measures of several deep gray matter structures have been previously described (Labate et al., 2013). This procedure automatically provides segments and labels for up to 40 unique structures and assigns a neuroanatomical label to each voxel in an MRI volume based on probabilistic information estimated automatically from a manually labeled training set. Normalized hippocampal values were calculated as follows: [raw hippocampal volume/ICV]*1000.
3.
Results
3.1.
Clinical findings
Standard and asleep electroencephalogram did not display abnormalities in the entire control group. The structural brain MRI was normal in all subjects and an expert neuroradiologist with 10 years of expertise in epilepsy confirmed the absence of hippocampal sclerosis. There was no difference in sex, age, age at onset (21 vs 22.8; p ¼ .59), duration of epilepsy (15 vs 15.2; p ¼ .92), family history of febrile convulsions or epilepsy (14 vs 11; p ¼ .6), personal antecedent of febrile convulsions (6 vs 6; p ¼ .79) between bMTLE subjects with and without DV. Interictal EEG was normal in ten out of 32 bMTLE with DV (31.2%) and in ten out of 31 bMTLE without DV (32.2%). None of the neuropsychological assessment results displayed any deficits. The radiological presence of hippocampal sclerosis was equally distributed in both groups (33%, ten bMTLE with DV; 32%, ten bMTLE without DV). All patients had been seizure-free for at least 6 months before the scanning.
3.2.
VBM results
Table 2 displays the results of ANCOVA analysis investigating the main effects of: a) Group (bMTLE vs healthy controls, independently by the presence of DV); b) DV (yes vs no, independently by diagnosis) and c) the interaction among them. The main effect of group displayed significant differences in the right primary motor/premotor cortex, the right insular cortex and the right thalamus; the bMTLE patients, who exhibited the lower gray matter volumes with respect to healthy controls, primarily drove the effect. Otherwise, the main effect of DV, as well as the interaction effect did not reveal any significant findings. For exploratory purpose and given previous evidence zdil et al., 2012), we further performed separate t-test (Bra analyses within each group to better characterize neuroanatomical changes related to DV. In bMTLE groups, the direct
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Table 2 e VBM findings. Cerebral region
Brodmann areas (BA)
pFwe-value
Main Effect of Diagnosis (F-test) Right Motor Cortex BA 4 .048 Right Premotor Cortex BA 6 .001 Right Insular Cortex BA 13 .003 Right Thalamus .04 Main effect of DV (F-test) N.S. Interactive effect diagnosis X DV (F-test) N.S. The effect of DV in bMTLE group (DV vs non-DV) (t-test) N.S. The effect of DejaVu` in healthy controls group (DejaVu` þ Vs DejaVu`-) (t-test) N.S. Left Hippocampus .01 Left ParaHyppocampal Gyrus .04 Left Visual Cortex (Calcarine) BA 17 .02 The effect of DV in healthy controls group (DV vs non-DV) (t-test) Left Insular Cortex BA 13 .04
F/t values
MNI coordinates (x; y; z)
16.96 28.06 23.31 11.23
10 46 48 18
9 8 9 25
58 12 6 0
4.08 3.33 3.91
20 18 10
19 21 78
14 18 16
3.82
30
9
18
VBM analysis of significant changes in gray matter volume. Significant volumetric differences met the criteria of p < .05, Family Wise Error (FWE) at a whole brain level. bMTLE: benign mesial-temporal lobe epilepsy; N.S. Not Significant.
comparison between bMTLE DV versus bMTLE without DV revealed an abnormal increase of gray matter volume in the left hippocampus, parahippocampal gyrus and left visual cortex (calcarine regions). The effect was primarily driven by the bMTLE patients having DV, who exhibited the higher gray matter volumes (Fig. 1). On the other hand, in the healthy controls group, we detected only one significant cluster within the left insular cortex, where healthy controls having DV showed lower gray matter volume with respect to their respective counterparts (Fig. 2). Finally, the direct comparison between bMTLE patients and healthy controls individuals with DV, revealed the same pattern of findings detected in the main effect of group (thalamic-cortex), thus confirming the relevant role of disease with respect to the presence of DV symptoms.
3.3.
Automated hippocampal measurement findings
Automated labeling of the hippocampus, as provided by Freesurfer, confirmed the involvement of the left hippocampus. Indeed, significant findings emerged only in the comparison between bMTLE patients with and without DV (t ¼ 9.44; p-level < .005) (see Supplementary Materials).
4.
Conclusion
This is the first study that addressed potential neuroanatomical differences related to the experience of DV in bMTLE and healthy individuals. We decided to study individuals with sporadic bMTLE because of its peculiarity being patients with a very benign clinical course that may suffer from simple partial DV sometimes in life as unique epileptic symptom (Labate et al., 2011). Indeed, bMTLE syndrome represents a mild type of temporal lobe epilepsy that shares very close similitude with healthy subjects experiencing DV as zdil et al., 2012). recently described by some authors (Bra
Specifically, we found that bMTLE patients with DV were characterized by increased gray matter volume of the left mesio-temporal region, involving the parahippocampal gyrus and the hippocampus, together with the left visual cortex (calcarine regions), when compared with bMTLE patients without DV. When we compared healthy controls experiencing or not DV, we found that control individuals with DV were characterized by reduced gray matter volume in the left insular cortex. In this study we have given further evidence that the hippocampal, parahippocampal and visual cortex regions are the brain regions mainly involved in the genesis of epileptic DV (Guedj, Aubert, McGonigal, Mundler, & Bartolomei, 2010). On the other hand, we did not find evidence of the involvement of lateral temporal neocortex as reported by some authors with electrodes stereotaxically implanted (Bancaud et al., 1994; Bartolomei et al., 2004). However, even in these studies the involvement of lateral temporal cortex was always subsequent to anterior hippocampal activation (Bancaud et al., 1994). Hence, as previously demonstrated in experimental models using 18FDG-PET, DV experiences in epilepsy could represent restricted activation of memory systems used for memory retrieval or disruption of the recognition memory network (Gloor, 1990; Guedj et al., 2010). Furthermore, in our study the involvement of the hippocampal region may contribute to the typical reduced ability to recall the phenomenon (Ffytche & Zeki, 2011; Warren-Gash & Zeman, 2014). The connection between the visual cortex and temporal lobe through the inferior longitudinal fasciculus could additionally explain false memory or false account of visual perceptual experience (Craig, 2003). The morphological regions that, unlike the case for healthy individuals, epileptic DV were identified by our VBM study are also consistent with clinical observations that compared to healthy individuals epileptic DV is usually accompanied with feelings of depersonalization and bizarreness, and patients are less likely to remember the original occasion of what they felt (Warren-Gash & Zeman,
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5
Fig. 1 e VBM results. 3D/2D surface renders show the significant cluster deriving from the comparison between bMTLE groups with and without DV. Significant differences (**surviving correction for multiple comparisons, FWE < .05) are found only within the left hippocampus and calcarine cortex, where bMTLE patients with DV display an abnormal increase of the gray matter volume in comparison with their respective bMTLE counterparts. Mean differences (±SEM) between groups within regions of statistical significance have been plotted below. Data analyses have been further corrected for age and intracranial volume. The colour bar represents T-statistics. bMTLE: patients with benign mesial temporal lobe epilepsy; HC: healthy controls.
2014). Moreover, we were unable to make any conclusion about DV and laterality of hippocampal sclerosis because of the small numbers in each group of individuals with epilepsy. In healthy DV individuals we found morphological abnormality in the anterior insular cortex, which is part of the limbic system and plays an important role in emotional experience related to both the perception of bodily reactions to emotion-provoking objects and the cognitive appraisal of contexts (Craig, 2003). There is also evidence that the left anterior insular cortices play a role in social-emotional functions (Duerden, Arsalidou, Lee, & Taylor, 2013). Curiously, a study using VBM found increased gray matter concentrations in the insula and other limbic areas of the brain in experienced € lzel et al., 2008). We can speculate that these meditators (Ho volume changes could lead to altered emotional revocation of memories and most likely represent secondary consequences of altered anatomical connectivity within the hippocampal (Crofts et al., 2011). Indeed, the anterior regions of the insula
have agranular and dysgranular subfields and have reciprocal connections with frontal cognitive, motor association, and limbic cortices (lateral and ventromedial prefrontal cortex, supplementary motor area, cingulate cortex, entorhinal cortex and the periamygdaloid complex) (Duerden et al., 2013). It could be argued that the healthy group recruited might develop epilepsy later on in life, however the extensive panel of electro-clinical and imaging exams performed make this very unlikely. Secondly, it could be noticed that when we reported the main effect of group, individuals with epilepsy did not show hippocampal atrophy. It could be noted that, unlike other studies (Bartolomei et al., 2004; Voets, Bernhardt, Kim, Yoon, & Bernasconi, 2011), we included patients with a very mild form of MTLE and with a reduced presence of hippocampal sclerosis (Labate et al., 2010, 2008). So, it is possible that VBM failed to detect gray matter volume-related abnormalities in the hippocampal regions as the severity and extent of damage seen on brain VBM typically parallel the damage
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Fig. 2 e VBM results in healthy controls with and without DV. Significant difference is found only within the left insular cortex, where healthy controls with DV display an abnormal decrease of the gray matter volume in comparison with their respective counterparts.
detected on routine MRI study (Labate et al., 2008). Finally, the reported patterns of neural abnormalities emerged only when post-hoc comparisons within each single group were performed. Nonetheless, our findings are strengthened by the magnitude of the detected volumetric changes (surviving correction for multiple comparisons), the employment of two complementary morphologic MR measurements and the fact that all reported anatomical changes are part of well-known neural networks involved either in the DV mechanisms or in the TLE phenomenology. In conclusion, our study revealed different anatomical correlates between epileptic and non-epileptic DV. Further studies in larger population using functional tests (electrophysiology or functional imaging with specific tasks for DV) are warranted to provide a direct measure of the neurophysiology of DV and to better understand if there are shared neural mechanisms between TLE patients and healthy controls experiencing this fascinating psychological phenomenon.
Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.cortex.2014.09.020.
references
Ashburner, J. (2007). A fast diffeomorphic image registration algorithm. NeuroImage, 38, 95e113. Bancaud, J., Brunet-Bourgin, F., Chauvel, P., & Halgren, E. (1994). ja vu and vivid ‘memories’ in human Anatomical origin of de temporal lobe epilepsy. Brain, 117, 71e90.
Bartolomei, F., Barbeau, E., Gavaret, M., Guye, M., McGonigal, A., gis, J., et al. (2004). Cortical stimulation study of the role of Re ja vu and reminiscence of memories. rhinal cortex in de Neurology, 63, 858e864. Bonilha, L., Rorden, C., Castellano, G., Pereira, F., Rio, P. A., Cendes, F., et al. (2004). Voxel-based morphometry reveals GM network atrophy in refractory medial temporal lobe epilepsy. Archives Neurology, 61, 1379e1384. zdil, M., Marec ek, R., Urba nek, T., Ka rek, T., Mikl, M., Bra spa ja vu: the Rektor, I., et al. (2012). Unveiling the mystery of de ja vu. Cortex, 48, 1240e1243. structural anatomy of de Catani, M., Dell'acqua, F., Bizzi, A., Forkel, S. J., Williams, S. C., Simmons, A., et al. (2012). Beyond cortical localization in clinico-anatomical correlation. Cortex, 48, 1262e1287. Craig, A. D. (2003). A new view of pain as a homeostatic emotion. Trends in Neurosciences, 26, 303e307. Crofts, J. J., Higham, D. J., Bosnell, R., Jbabdi, S., Matthews, P. M., Behrens, T. E., et al. (2011). Network analysis detects changes in the contralesional hemisphere following stroke. NeuroImage, 54, 161e169. Duerden, E. G., Arsalidou, M., Lee, M., & Taylor, M. J. (2013). Lateralization of affective processing in the insula. NeuroImage, 78, 159e175. Ffytche, D. H., & Zeki, S. (2011). The primary visual cortex, and feedback to it, are not necessary for conscious vision. Brain, 134, 247e257. Gambardella, A., Messina, D., Le Piane, E., Oliveri, R. L., Annesi, G., Zappia, M., et al. (2000). Familial temporal lobe epilepsy autosomal dominant inheritance in a large pedigree from southern Italy. Epilepsy Research, 38, 127e132. Gloor, P. (1990). Experiential phenomena of temporal lobe epilepsy. Facts and hypotheses. Brain, 113, 1673e1694. Guedj, E., Aubert, S., McGonigal, A., Mundler, O., & Bartolomei, F. ja -vu in temporal lobe epilepsy: metabolic pattern of (2010). De cortical involvement in patients with normal brain MRI. Neuropsychologia, 48, 2174e2181. € lzel, B. K., Ott, U., Gard, T., Hempel, H., Weygandt, M., Ho Morgen, K., et al. (2008). Investigation of mindfulness
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meditation practitioners with voxel-based morphometry. Cognitive and Affective Neuroscience, 3, 55e61. Labate, A., Cerasa, A., Aguglia, U., Mumoli, L., Quattrone, A., & Gambardella, A. (2010). Voxel-based-morphometry of sporadic epileptic patients with mesio-temporal sclerosis. Epilepsia, 51, 506e510. Labate, A., Cerasa, A., Cherubini, A., Aguglia, U., Quattrone, A., & Gambardella, A. (2013). Advanced MRI morphologic study shows no atrophy in healthy individuals with hippocampal hyperintensity. American Journal of Neuroradiology, 34, 1585e1588. Labate, A., Cerasa, A., Gambardella, A., Aguglia, U., & Quattrone, A. (2008). Hippocampal and thalamic atrophy in mild temporal lobe epilepsy: a VBM study. Neurology, 71, 1094e1101. zdil (2012) Labate, A., & Gambardella, A. (2013). Comment on Bra ja -vu`: the structural anatomy of “unveiling the mystery of de ja -vu`”. Cortex, 49, 1162. de
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Labate, A., Gambardella, A., Andermann, E., Aguglia, U., Cendes, F., Berkovic, S. F., et al. (2011). Benign mesial temporal lobe epilepsy. Nature Reviews Neurology, 7, 237e240. Labate, A., Ventura, P., Gambardella, A., Le Piane, E., Colosimo, E., Leggio, U., et al. (2006). MRI evidence of mesial temporal sclerosis in sporadic “benign” temporal lobe epilepsy. Neurology, 66, 562e565. Sno, H. N., Schalken, H. F., de Jonghe, F., & Koeter, M. W. (1994). ja vu experiences assessment. The inventory for de Development, utility, reliability, and validity. Journal of Nervous And Mental Disease, 182, 27e33. Voets, N. L., Bernhardt, B. C., Kim, H., Yoon, U., & Bernasconi, N. (2011). Increased temporolimbic cortical folding complexity in temporal lobe epilepsy. Neurology, 76, 138e144. Warren-Gash, C., & Zeman, A. (2014). Short report: is there anything distinctive about epileptic deja vu? Journal of Neurology, Neurosurgery and Psychiatry, 85, 143e147.
Available online at www.sciencedirect.com
ScienceDirect Journal homepage: www.elsevier.com/locate/cortex
Research report
Neuro-anatomical differences among epileptic and ja -vu non-epileptic de Angelo Labate a,b,*, Antonio Cerasa b, Laura Mumoli a, Edoardo Ferlazzo a, Umberto Aguglia a, Aldo Quattrone a,b and Antonio Gambardella a,b,** a
Institute of Neurology, University Magna Græcia, Catanzaro, Italy Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR), Germaneto, CZ, Italy
b
article info
abstract
Article history:
ja -vu` (DV) can occur as a seizure of mesial temporal lobe epilepsy (MTLE) and Objective: De
Received 20 March 2014
in almost 80% of healthy individuals. The remarkable similarity between epileptic DV and
Reviewed 11 June 2014
DV in healthy individuals raises the possibility that DV might sometimes be an ictal phe-
Revised 19 June 2014
nomenon in apparently normal individuals. Thus, we studied a group of healthy subjects
Accepted 23 September 2014
versus individuals with benign MTLE (bMTLE) both experiencing DV.
Action editor Gus Buchtel
Methods: 63 individuals with epilepsy patients with bMTLE and 39 healthy controls at ja Vu (DV) Catanzaro University were recruited. Participants completed the Inventory for De
Published online 7 October 2014
Experiences Assessment (IDEA) test, underwent awake and asleep electroencephalogram, Keywords: ja -vu` De
MRI of the brain using a 3T scanner and whole brain voxel-based morphometry (VBM).
Imaging
campal sclerosis.
VBM
Results: Our controls had no history of neurological or psychiatric illness, epilepsy or his-
bMTLE patients with DV and without DV were also matched for the presence of hippo-
tory of febrile convulsions. Neurological and cognitive examinations were normal. Electroencephalographic procedures were unremarkable in all controls. In bMTLE group, the direct comparison of VBM between individuals with epilepsy with DV versus those without DV revealed abnormal anatomical changes in the left hippocampus, parahippocampal gyrus and visual cortex. The VBM of healthy controls with DV showed abnormal anatomical changes only in the left insular cortex. Conclusions: Our VBM results demonstrated different morphologic patterns in individuals with epilepsy and control subjects experiencing DV, involving the memory circuit in bMTLE patients and cerebral regions in the emotional network in healthy controls. © 2014 Elsevier Ltd. All rights reserved.
degli Studi “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy. * Corresponding author. Clinica Neurologica, Universita degli Studi “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy. ** Corresponding author. Clinica Neurologica, Universita E-mail addresses: [email protected] (A. Labate), [email protected] (A. Gambardella). http://dx.doi.org/10.1016/j.cortex.2014.09.020 0010-9452/© 2014 Elsevier Ltd. All rights reserved.
2
c o r t e x 6 4 ( 2 0 1 5 ) 1 e7
1.
Introduction
ja vu (DV) is a transitory mental state of incongruous De impression of familiarity of present experience with an undefined past. Although almost 80% of healthy individuals have zdil et al., 2012), this experienced DV at once in their lives (Bra fascinating phenomenon is also very often present in patients with mesial temporal lobe epilepsy (MTLE) mainly with familial trend (Gambardella et al., 2000). To date, it is already very well known that epileptic illusions of DV are ictal manifestations arising from discharge within either mesial or lateral temporal cortex (Bancaud, Brunet-Bourgin, Chauvel, & Halgren, 1994) whereas anatomical basis for DV in healthy subjects is less delineated and interpreted. zdil et al., 2012) Very recently, Brazdil and coworkers (Bra described for the first time the anatomical correlates associated with DV in healthy population, illustrating volumetric differences in several brain regions involving predominantly mesio-temporal regions where the loss of gray matter was significant. Very interestingly, the present author found the same well-known epileptic network (Hippocampus-Thamalus-Basal Ganglia) involved in the genesis of refractory MTLE together with critical brain areas involved in the limbic system (Amygdala, Orbitofrontal cortex and insular cortex) (Bonilha et al., 2004; Catani et al., 2012; Labate et al., 2010). These epileptic networks have also been extensively described in patients with milder form of sporadic MTLE called benign MTLE (bMTLE), which is characterized by seizure onset in adulthood, frequent familial history and simple partial epileptic DV that often represents the only predominant ictal symptom (Labate et al., 2010; Labate, Cerasa, Gambardella, Aguglia, & Quattrone, 2008; Labate et al., 2011). Fascinatingly, the remarkable similarity between DV as an epileptic phenomenon and DV observed in healthy individuals, and the observation in patients with bMTLE that the DV experience often represents the only type of seizure, raises the possibility that DV itself might sometimes be an ictal phenomenon in apparently normal individuals, and could represent the mildest manifestation on the TLE phenotype as zdil et al., 2012). Thus, we proposed by Brazdil et al. (Bra thought and proposed (Labate & Gambardella, 2013) an
attempt to clarify whether there are some structural/ morphologic differences between healthy subjects and individuals with bMTLE both suffering from DV.
2.
Materials and methods
2.1.
Demographic features
Demographic features of our population are summarized in Table 1. The research ethic committee approved this study and written informed consent was obtained from all participants. From May 2012 to May 2013, we prospectively recruited four groups of participants from the University of Catanzaro, Italy: 32 bMTLE patients with DV (21 women, mean age 37.0 ± 11, range 20e57 years); 31 bMTLE patients without DV (20 women, mean age 38.6 ± 10, range 23e60 years); 22 healthy controls with DV (14 women, mean age 33.7 ± 8.6, range 20e49 years) and 17 healthy controls without DV (eight women, mean age 34.7 ± 8.4, range 27e49 years). The healthy controls were all volunteers who were enrolled from the staff of our University in Catanzaro among university students, paramedics and doctors. Ninety healthy volunteers were interviewed, and 39 (22 with DV and 17 without DV) agreed to participate at the study and undergo brain MRI evaluation. Healthy controls were selected based on lack of history of febrile seizures, epilepsy or abnormal neurological examination. Importantly, much attention was paid to check for the presence of hippocampal sclerosis among the patients with epilepsy since there is a large amount of evidence that this specific neuroradiological sign is associated with hippocampal atrophy in bMTLE patients. The diagnosis of bMTLE was made according to current accepted features (Labate et al., 2011). Any suggestion of seizure onset outside the mesial temporal structures, by semiology or EEG findings, or patients with refractory TLE, led to exclusion from the study. The only accepted MRI sign was hippocampal sclerosis, which was based on the characteristic MRI pattern of abnormalities because it is a finding often observed in bMTLE (Labate et al. 2006). None of the patients had mental retardation.
Table 1 e Features of bMTLE DV and non-DV compared to healthy control. Features Number Sex (%) Age (y) Age at onset of epilepsy (y) Duration of epilepsy (y) Family history of FC/epilepsy Antecedent FCs Hippocampal sclerosis on MRI (%) Ictal EEG n (%) Interictal Pathological EEG (%)
bMTLE DV
bMTLE non-DV
Healthy controls DV
Healthy controls non-DV
32 62% Female 37.0 ± 10.9 yr (20e57) 21 ± 13.7 yr (2e49) 15 ± 12.4 yr (1e42) 14 (43.7%) 6 (18.7%) 10 (33%) 4 (12.5%) 22 (68.7%)
31 62% Female 38.6 ± 10.3 yr (23e60) 22.8 ± 13.8 yr (1e55) 15.2 ± 11.6 yr (1e42) 11 (35.4%) 6 (19.3%) 10 (32%) 4 (12.9%) 21 (67.7%)
22 63% Female 33.5 ± 7.9 yr (20e49) / / 0 0 0 0 0
17 47% Female 34.8 ± 7.94 yr (27e49) / / 0 0 0 0 0
ja vu; FC: febrile convulsions. bMTLE: benign mesial-temporal lobe epilepsy; DV: de a c2 test. b one-way ANOVA. c unpaired t test.
p Value
.674a .34b .59c .92c .6a .79a .85a .74a .85a
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All patients underwent a formal neuropsychological investigation. We administered the Italian version of the Inventory for DV Experiences Assessment (translated from Czech version and approved by Sno) (Sno, Schalken, de Jonghe, & Koeter, 1994), which is a 23-item self-administered questionnaire containing a general section of nine questions and a qualitative section of fourteen questions. Results of the second IDEA section focusing on qualitative characteristics of DV experiences were not included in this study because we wanted to be very homogeneous with Brazdil's study. Patients and controls underwent MRI of the brain using a 3T scanner and routine and asleep electroencephalogram with supplementary T1 and T2 electrodes.
2.2.
MRI data acquisition
Brain MRI was performed according to our routine protocol (Labate et al., 2010, 2008) by a 3 T scanner with an 8-channel head coil (Discovery MR-750, GE, Milwaukee, WI, USA). Structural MRI data were acquired using a 3D T1-weighted spoiled gradient echo (SPGR) sequence with the following parameters: TR: 3.7 msec, TE: 9.2 msec, flip angle 12 , voxelsize 1 1 1 mm3. Subjects were positioned to lie comfortably in the scanner with a forehead-restraining strap and various foam pads to ensure head fixation.
2.3.
Voxel-based morphometry (VBM)
Data were processed using the SPM8 software (http://www.fil. ion.ucl.ac.uk/spm), where we applied VBM implemented in the VBM8 toolbox, incorporating the DARTEL toolbox that was used to obtain a high-dimensional normalization protocol (Ashburner, 2007). Images were bias-corrected, tissue classified, and registered using linear (12-parameter affine) and non-linear transformations, within a unified model. Subsequently, the warped gray matter segments were affine transformed into MNI space and were scaled by the Jacobian determinants of the deformations (modulation). Finally, the modulated volumes were smoothed with a Gaussian kernel of 8 mm. The gray matter volume maps were statistically analyzed using the general linear model based on Gaussian random field theory. To assess the main/interaction effects of diagnosis (bMTLE vs Controls) and DV (yes vs no) on gray matter volume, the smoothed and modulated gray matter images were entered into a second-level ANCOVA model, with age and total intracranial volume (ICV) as covariates of nointerest. Based on previous findings, we decided to use the following regions of interest: thalamus, hippocampus, basal ganglia, parahippocampal gyrus, visual cortex, temporal cortex, the sensorimotor cortex, the orbitofrontal cortex, the insular cortex as a priori ROIs given their consolidated role in pathophysiological mechanisms of MTLE and in neural basis zdil et al., 2012; Labate et al., 2010). All ROIs were of DV (Bra created with the “aal.02” atlas included in the Wake Forest University Pickatlas software version 1.04 (Functional MRI Laboratory at the Wake Forest University School of Medicine, WinstoneSalem, North Carolina; http://www.fmri.wfubmc. edu/download.htm). All analyses were thresholded by using correction for multiple comparisons (Family-Wise Error (FWE)
3
p < .05) within ROIs. VBM analysis was only focused on these 9 ROIs, given their critical role in pathophysiological mechanisms of DV. No significant anatomical changes were detected in other brain regions when we performed statistical comparisons among groups.
2.4.
Automated hippocampal volumetry
To corroborate voxel-based findings we further performed automated labeling and quantification of hippocampal volume using FreeSurfer 5.0. The automated procedures for volumetric measures of several deep gray matter structures have been previously described (Labate et al., 2013). This procedure automatically provides segments and labels for up to 40 unique structures and assigns a neuroanatomical label to each voxel in an MRI volume based on probabilistic information estimated automatically from a manually labeled training set. Normalized hippocampal values were calculated as follows: [raw hippocampal volume/ICV]*1000.
3.
Results
3.1.
Clinical findings
Standard and asleep electroencephalogram did not display abnormalities in the entire control group. The structural brain MRI was normal in all subjects and an expert neuroradiologist with 10 years of expertise in epilepsy confirmed the absence of hippocampal sclerosis. There was no difference in sex, age, age at onset (21 vs 22.8; p ¼ .59), duration of epilepsy (15 vs 15.2; p ¼ .92), family history of febrile convulsions or epilepsy (14 vs 11; p ¼ .6), personal antecedent of febrile convulsions (6 vs 6; p ¼ .79) between bMTLE subjects with and without DV. Interictal EEG was normal in ten out of 32 bMTLE with DV (31.2%) and in ten out of 31 bMTLE without DV (32.2%). None of the neuropsychological assessment results displayed any deficits. The radiological presence of hippocampal sclerosis was equally distributed in both groups (33%, ten bMTLE with DV; 32%, ten bMTLE without DV). All patients had been seizure-free for at least 6 months before the scanning.
3.2.
VBM results
Table 2 displays the results of ANCOVA analysis investigating the main effects of: a) Group (bMTLE vs healthy controls, independently by the presence of DV); b) DV (yes vs no, independently by diagnosis) and c) the interaction among them. The main effect of group displayed significant differences in the right primary motor/premotor cortex, the right insular cortex and the right thalamus; the bMTLE patients, who exhibited the lower gray matter volumes with respect to healthy controls, primarily drove the effect. Otherwise, the main effect of DV, as well as the interaction effect did not reveal any significant findings. For exploratory purpose and given previous evidence zdil et al., 2012), we further performed separate t-test (Bra analyses within each group to better characterize neuroanatomical changes related to DV. In bMTLE groups, the direct
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Table 2 e VBM findings. Cerebral region
Brodmann areas (BA)
pFwe-value
Main Effect of Diagnosis (F-test) Right Motor Cortex BA 4 .048 Right Premotor Cortex BA 6 .001 Right Insular Cortex BA 13 .003 Right Thalamus .04 Main effect of DV (F-test) N.S. Interactive effect diagnosis X DV (F-test) N.S. The effect of DV in bMTLE group (DV vs non-DV) (t-test) N.S. The effect of DejaVu` in healthy controls group (DejaVu` þ Vs DejaVu`-) (t-test) N.S. Left Hippocampus .01 Left ParaHyppocampal Gyrus .04 Left Visual Cortex (Calcarine) BA 17 .02 The effect of DV in healthy controls group (DV vs non-DV) (t-test) Left Insular Cortex BA 13 .04
F/t values
MNI coordinates (x; y; z)
16.96 28.06 23.31 11.23
10 46 48 18
9 8 9 25
58 12 6 0
4.08 3.33 3.91
20 18 10
19 21 78
14 18 16
3.82
30
9
18
VBM analysis of significant changes in gray matter volume. Significant volumetric differences met the criteria of p < .05, Family Wise Error (FWE) at a whole brain level. bMTLE: benign mesial-temporal lobe epilepsy; N.S. Not Significant.
comparison between bMTLE DV versus bMTLE without DV revealed an abnormal increase of gray matter volume in the left hippocampus, parahippocampal gyrus and left visual cortex (calcarine regions). The effect was primarily driven by the bMTLE patients having DV, who exhibited the higher gray matter volumes (Fig. 1). On the other hand, in the healthy controls group, we detected only one significant cluster within the left insular cortex, where healthy controls having DV showed lower gray matter volume with respect to their respective counterparts (Fig. 2). Finally, the direct comparison between bMTLE patients and healthy controls individuals with DV, revealed the same pattern of findings detected in the main effect of group (thalamic-cortex), thus confirming the relevant role of disease with respect to the presence of DV symptoms.
3.3.
Automated hippocampal measurement findings
Automated labeling of the hippocampus, as provided by Freesurfer, confirmed the involvement of the left hippocampus. Indeed, significant findings emerged only in the comparison between bMTLE patients with and without DV (t ¼ 9.44; p-level < .005) (see Supplementary Materials).
4.
Conclusion
This is the first study that addressed potential neuroanatomical differences related to the experience of DV in bMTLE and healthy individuals. We decided to study individuals with sporadic bMTLE because of its peculiarity being patients with a very benign clinical course that may suffer from simple partial DV sometimes in life as unique epileptic symptom (Labate et al., 2011). Indeed, bMTLE syndrome represents a mild type of temporal lobe epilepsy that shares very close similitude with healthy subjects experiencing DV as zdil et al., 2012). recently described by some authors (Bra
Specifically, we found that bMTLE patients with DV were characterized by increased gray matter volume of the left mesio-temporal region, involving the parahippocampal gyrus and the hippocampus, together with the left visual cortex (calcarine regions), when compared with bMTLE patients without DV. When we compared healthy controls experiencing or not DV, we found that control individuals with DV were characterized by reduced gray matter volume in the left insular cortex. In this study we have given further evidence that the hippocampal, parahippocampal and visual cortex regions are the brain regions mainly involved in the genesis of epileptic DV (Guedj, Aubert, McGonigal, Mundler, & Bartolomei, 2010). On the other hand, we did not find evidence of the involvement of lateral temporal neocortex as reported by some authors with electrodes stereotaxically implanted (Bancaud et al., 1994; Bartolomei et al., 2004). However, even in these studies the involvement of lateral temporal cortex was always subsequent to anterior hippocampal activation (Bancaud et al., 1994). Hence, as previously demonstrated in experimental models using 18FDG-PET, DV experiences in epilepsy could represent restricted activation of memory systems used for memory retrieval or disruption of the recognition memory network (Gloor, 1990; Guedj et al., 2010). Furthermore, in our study the involvement of the hippocampal region may contribute to the typical reduced ability to recall the phenomenon (Ffytche & Zeki, 2011; Warren-Gash & Zeman, 2014). The connection between the visual cortex and temporal lobe through the inferior longitudinal fasciculus could additionally explain false memory or false account of visual perceptual experience (Craig, 2003). The morphological regions that, unlike the case for healthy individuals, epileptic DV were identified by our VBM study are also consistent with clinical observations that compared to healthy individuals epileptic DV is usually accompanied with feelings of depersonalization and bizarreness, and patients are less likely to remember the original occasion of what they felt (Warren-Gash & Zeman,
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Fig. 1 e VBM results. 3D/2D surface renders show the significant cluster deriving from the comparison between bMTLE groups with and without DV. Significant differences (**surviving correction for multiple comparisons, FWE < .05) are found only within the left hippocampus and calcarine cortex, where bMTLE patients with DV display an abnormal increase of the gray matter volume in comparison with their respective bMTLE counterparts. Mean differences (±SEM) between groups within regions of statistical significance have been plotted below. Data analyses have been further corrected for age and intracranial volume. The colour bar represents T-statistics. bMTLE: patients with benign mesial temporal lobe epilepsy; HC: healthy controls.
2014). Moreover, we were unable to make any conclusion about DV and laterality of hippocampal sclerosis because of the small numbers in each group of individuals with epilepsy. In healthy DV individuals we found morphological abnormality in the anterior insular cortex, which is part of the limbic system and plays an important role in emotional experience related to both the perception of bodily reactions to emotion-provoking objects and the cognitive appraisal of contexts (Craig, 2003). There is also evidence that the left anterior insular cortices play a role in social-emotional functions (Duerden, Arsalidou, Lee, & Taylor, 2013). Curiously, a study using VBM found increased gray matter concentrations in the insula and other limbic areas of the brain in experienced € lzel et al., 2008). We can speculate that these meditators (Ho volume changes could lead to altered emotional revocation of memories and most likely represent secondary consequences of altered anatomical connectivity within the hippocampal (Crofts et al., 2011). Indeed, the anterior regions of the insula
have agranular and dysgranular subfields and have reciprocal connections with frontal cognitive, motor association, and limbic cortices (lateral and ventromedial prefrontal cortex, supplementary motor area, cingulate cortex, entorhinal cortex and the periamygdaloid complex) (Duerden et al., 2013). It could be argued that the healthy group recruited might develop epilepsy later on in life, however the extensive panel of electro-clinical and imaging exams performed make this very unlikely. Secondly, it could be noticed that when we reported the main effect of group, individuals with epilepsy did not show hippocampal atrophy. It could be noted that, unlike other studies (Bartolomei et al., 2004; Voets, Bernhardt, Kim, Yoon, & Bernasconi, 2011), we included patients with a very mild form of MTLE and with a reduced presence of hippocampal sclerosis (Labate et al., 2010, 2008). So, it is possible that VBM failed to detect gray matter volume-related abnormalities in the hippocampal regions as the severity and extent of damage seen on brain VBM typically parallel the damage
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Fig. 2 e VBM results in healthy controls with and without DV. Significant difference is found only within the left insular cortex, where healthy controls with DV display an abnormal decrease of the gray matter volume in comparison with their respective counterparts.
detected on routine MRI study (Labate et al., 2008). Finally, the reported patterns of neural abnormalities emerged only when post-hoc comparisons within each single group were performed. Nonetheless, our findings are strengthened by the magnitude of the detected volumetric changes (surviving correction for multiple comparisons), the employment of two complementary morphologic MR measurements and the fact that all reported anatomical changes are part of well-known neural networks involved either in the DV mechanisms or in the TLE phenomenology. In conclusion, our study revealed different anatomical correlates between epileptic and non-epileptic DV. Further studies in larger population using functional tests (electrophysiology or functional imaging with specific tasks for DV) are warranted to provide a direct measure of the neurophysiology of DV and to better understand if there are shared neural mechanisms between TLE patients and healthy controls experiencing this fascinating psychological phenomenon.
Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.cortex.2014.09.020.
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