Brain Advance Access originally published online on July 13, 2005
Brain 2005 128(10):2442-2452; doi:10.1093/brain/awh599
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Analysis of shape and positioning of the hippocampal formation: an MRI study in patients with partial epilepsy and healthy controls
Department of Neurology and Brain Imaging Center, McGill University, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada
Correspondence to: Andrea Bernasconi, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada H3A 2B4 E-mail: andrea{at}bic.mni.mcgill.ca
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Summary |
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The purpose of this study was to evaluate systematically shape and positioning of the hippocampal formation (HF) in patients with partial epilepsy related to malformations of cortical development (MCD) and those with temporal lobe epilepsy (TLE). We studied 76 patients with MCD, including focal cortical dysplasia (n = 29; lesions located outside the temporal lobe in all), heterotopia (lesions outside of the temporal lobe, n = 14; lesions extending into the temporal lobe, n = 16), polymicrogyria (bilateral perisylvian, n = 14; unilateral perisylvian, n = 3) and 30 patients with TLE (hippocampal atrophy, n = 15; normal hippocampal volumes, n = 15). Shape and positioning of the HF were evaluated using a set of eight predefined morphological characteristics. In addition, the degree of hippocampal vertical orientation and medial positioning were assessed quantitatively. Patients were compared with 50 healthy controls. At least three criteria describing abnormal HF shape and positioning were found in 5/50 (10%) healthy controls, 37/76 (49%) MCD and 13/30 (43%) TLE patients. An association with all criteria was found in MCD and TLE, but not in healthy controls. In MCD there was no association between the side of HF shape abnormalities and the side of the cortical malformation or the EEG focus. Likewise, in TLE, HF abnormalities were not related to the side of the EEG focus. In both MCD and TLE patients who had hippocampal atrophy, no association was found between the side of HF shape abnormalities and the side of atrophy. Abnormal HF shape and positioning are found in a similar proportion in MCD and TLE. In TLE, they may be a marker of a more extensive disorder of brain development and may participate in the development of this condition.
Key Words: hippocampal developmental changes; epilepsy; hippocampal shape; heterotopia; polymicrogyria; temporal lobe epilepsy
Abbreviations: HF = hippocampal formation; MCD = malformations of cortical development; TLE = temporal lobe epilepsy
Received January 20, 2005. Revised June 22, 2005. Accepted June 23, 2005.
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Introduction |
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Malformations of cortical development (MCD) are caused by abnormalities in specific stages of cortical development (Rakic, 1995
). The pathogenesis of MCD is multifactorial and includes genetic mutations, in utero injuries, and perinatal or postnatal insults (Ross and Walsh, 2001). MCD are usually classified into three main categories: those resulting from abnormal cell proliferation (cortical dysplasia with balloon cells, hemimegalencephaly), abnormal neuronal migration (heterotopia, lissencephaly/subcortical band heterotopias spectrum), and cortical organization (polymicrogyria, cortical dysplasia without balloon cells) (Barkovich et al., 2001). Many MCD are epileptogenic and may cause pharmacologically intractable epilepsy (Raymond et al., 1995; D'Antuono et al., 2004).
High-resolution MRI has made it possible to detect in vivo MCD in an increasing number of patients with epilepsy. The MRI features of many MCD are now well known and have been extensively described (Kuzniecky, 1994). Pathological and imaging studies suggest that structural abnormalities in MCD may extend beyond the more obvious lesion. Volumetric MRI data have shown hippocampal atrophy, mostly in patients with nodular heterotopia (Raymond et al., 1995). MCD may also be associated with atypical shape and positioning of the hippocampus. This has been reported in lissencephaly, and agenesis of corpus callosum (Atlas et al., 1986; Barkovich et al., 1991) and in few patients with nodular heterotopia (Lehericy et al., 1995; Baulac et al., 1998). There is also considerable speculation and growing evidence that developmental hippocampal abnormalities increase susceptibility to seizures and neuronal loss, and may facilitate subsequent hippocampal sclerosis in patients with temporal lobe epilepsy (TLE) (Baulac et al., 1998; Fernandez et al., 1998; Thom et al., 2002).
The occurrence of unusual hippocampal shape in patients with partial epilepsy has not been systematically studied. It is also unclear whether abnormal shape and positioning of the hippocampal formation (HF) represent a pathological entity, since they have not been examined in healthy individuals.
Our purpose was to investigate shape and positioning characteristics of the HF in healthy subjects and patients with various types of MCD. In addition, we compared our results with a group of patients with medically intractable TLE.
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Subjects
From our MCD database collected between 1996 and 2002, we selected 76 adult patients who had a high-resolution T1-weighted 3D MRI and in whom the cortical malformations did not invade the HF. Our population included patients with focal cortical dysplasia (n = 29, 13 males, mean age ± SD = 26 ± 8 years, range = 16–43), heterotopia (n = 30, 15 males, mean age = 30 ± 11 years, range = 16–58) and polymicrogyria (n = 17, 7 males, mean age = 31 ± 8 years, range = 18–45). Focal cortical dysplasia was located outside the temporal lobe in all patients. Lesions of polymicrogyria were bilateral perisylvian in 14/17 patients and unilateral perisylvian in 3 patients. The heterotopia group included patients with double cortex (n = 8), bilateral periventricular nodular heterotopia (n = 12), unilateral periventricular nodular heterotopia (n = 7) and unilateral subcortical heterotopia (n = 3). Patients were compared with 50 age-matched and sex-matched healthy control subjects (27 males, mean age = 31 ± 8 years, range = 20–54) and with 30 patients with medically intractable TLE chosen randomly from our database to match healthy controls and MCD subjects for age and sex (15 males, mean age = 31 ± 9 years, range = 18–46). The TLE population comprised 15 patients with unilateral hippocampal atrophy and 15 with normal hippocampal volumes on volumetric MRI based on a 2 SD cut-off from the mean of healthy controls (see Table 1 for the results of volumetric analysis).
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Demographic and clinical data were obtained through interviews with the patients and their relatives, and by reviewing hospital charts. Seizure type and the site of seizure onset were determined by a comprehensive evaluation including seizure history and semiology, video-EEG telemetry with scalp electrodes, and neuropsychological evaluation in all patients. In MCD patients, the seizure focus was frontal in 14 patients, parietal in 6, temporal in 20 and multilobar or generalized in 23. Eight patients presented only with interictal slow activity and five patients had a normal EEG. In TLE, the seizure focus was left-sided in 16 patients and right-sided in 14. The Ethics Committee of the Montreal Neurological Institute and Hospital approved the study and written informed consent was obtained from all participants.
MRI acquisition and volumetric analysis
In all subjects, MRIs were acquired on a 1.5 T Gyroscan (Philips Medical System, Eindhoven, The Netherlands) using a 3D T1-fast field echo sequence (TR = 18, TE = 10, 1 acquisition average pulse sequence, flip angle = 30°, matrix size = 256 x 256, FOV = 256, slice thickness = 1 x 1 x 1 mm3). Images were acquired in the sagittal plane.
Volumetric analysis of the hippocampus was performed in all subjects according to our previously published protocol (Bernasconi et al., 2003). Based on a 2 SD cut-off from the mean of healthy controls, 18/76 (24%) MCD patients had hippocampal atrophy, which was unilateral in 16 (see Table 1 for results of volumetric analysis).
Qualitative assessment of the HF
High-resolution T1-weighted 3D MRI of healthy subjects and patients were reformatted in coronal orientation perpendicular to the midsagittal plane (slice thickness 1 mm). MRI were numerically coded and presented in random order on a console to two trained observers unaware of the clinical information, and a consensus report was obtained. Images were cropped so that only the temporal lobes were available for the visual inspection. Shape and positioning of the HF were evaluated on coronal sections. However, the observers could simultaneously view MRI in all three orientations using the interactive software DISPLAY developed at the Brain Imaging Center of the Montreal Neurological Institute. The assessment was based on the presence or absence of eight recognized criteria previously published by Baulac et al. (1998) with minor modifications.
Our visual evaluation of the HF included the following anatomical structures: the hippocampus, the parahippocampal gyrus, the collateral sulcus and the subiculum (Fig. 1). The following criteria were used to evaluate the hippocampal head, body and tail: (i) medial positioning with respect to temporal horn. In this case, the hippocampus comes in close contact with the crus cerebri in its anterior portion (level hippocampal head and anterior part of the body) and the collicular plate more posteriorly (posterior part of the body and tail); (ii) round, globular shape and vertical orientation; (iii) empty choroid fissure; (iv) the fimbria was assessed on the basis of it being misplaced on the dorsolateral edge of Ammon's horn. Since the fimbria is present only at the level of the hippocampal body, this criterion was assessed at that level. The collateral sulcus was evaluated on the basis of it being (v) deep and verticalized; or (vi) protruding into an empty choroid fissure; (vii) the evaluation of the parahippocampal gyrus was based on the reduction in its upper horizontal portion adjacent to the hippocampal fissure. This criterion was assessed at the level of hippocampal body, where the hippocampal fissure is best recognizable; and (viii) the subiculum was considered abnormal if it was bulging upward, therefore looking thickened. This criterion was assessed at the level of the hippocampal body, where the subiculum is best recognizable.
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Examples of abnormal shape and positioning of HF in healthy controls, patients with MCD and TLE are shown in Fig. 2.
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Quantitative assessment of the HF
Since vertical orientation and medial positioning are two of the main features of hippocampal malrotation (Baulac et al., 1998
), we further evaluated these characteristics on hardcopies of MRI in MCD patients using quantitative means. For consistency, measurements were performed in all subjects at the level of the first coronal slice in which the hippocampal body was visible (Fig. 3).
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Medial positioning
We measured the distance between the midline and the fimbria, which forms the medialmost border of the hippocampal body. To account for differences in temporal lobe size among subjects, this distance, that we named ‘medial distance’, was normalized by dividing it into the distance from the midline to the temporal lobe neocortex passing through the temporal horn of the lateral ventricle (Fig. 3A). In cases of medial positioning of the hippocampus, we expected the medial distance to be shortened. For each subject, we used either the left or right medial distance, depending on which exhibited the shortest distance. Examples of medial positioning are shown in Fig. 3B, C and D.
Vertical orientation
The hippocampus lies on the parahippocampal gyrus; therefore, any change in folding of one has an effect on the other. We assessed differences in vertical orientation by calculating the angle between the descending and ascending portion of the parahippocampal gyrus, which we named the ‘parahippocampal angle’ (Fig. 3E). In case of hippocampal verticalization, we anticipated that this angle would be more acute than in a normally oriented hippocampus. For each subject, we used either the left or right parahippocampal angle, depending on which exhibited the most acute angle. Examples of vertical orientation are shown in Fig. 3F, G and H.
Statistical analysis
The following conditions were assessed using 
2-test: (i) association between each criterion and groups (healthy controls, MCD and TLE); (ii) association between the side of shape abnormalities and the side of MCD lesion or hippocampal atrophy; (iii) association between the side of shape abnormality and side of EEG focus; and (iv) relationship between the side of MCD lesion and the EEG focus.
We tested parahippocampal angle and medial distance for normality using the Kolmogorov–Smirnov and Shapiro–Wilk test in each MCD group. Group differences for these two features were assessed using ANOVA, followed by Bonferroni planned comparisons.
For individual analysis, we considered the shape and positioning of the HF as abnormal if at least three of the eight above-mentioned criteria were present in the same subject.
To determine inter-observer reliability, two raters analysed independently 35 randomly selected subjects, including patients of all categories and healthy controls. Inter-observer agreement between the two raters was assessed using Cohen's kappa coefficient. Values of kappa between 0.81 and 1.0 indicate almost perfect agreement and values between 0.61 and 0.8 indicate substantial agreement (Landis and Koch, 1977). In many instances, frequency across cells was not evenly distributed. In this situation, kappa can be severely understated (Landis and Koch, 1977). Therefore, we also calculated the percentage of agreement (Perrault and Leigh, 1989). For both, kappa and percentage of agreement, the two raters had to agree if each of the eight criteria was present (positive) or absent (negative).
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As shown in Table 2, kappa values ranged from 0.64 to 1.0. For all features a high percentage of agreement was observed ranging from 89 to 100%.
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Group analysis
We found no association between any criteria and healthy control subjects. Comparing MCD patients with healthy controls, we found a significant association between all eight criteria and MCD (Table 3). Abnormalities were observed at all levels along the anteroposterior axis of the mesial temporal lobe, namely at the level of the hippocampal head, body and tail.
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Comparing TLE patients with healthy controls, we found a significant association between seven criteria and TLE (Table 4). There was no difference in the proportion of any criteria between MCD and TLE.
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Table 5 shows the frequencies of side-by-side distribution of the eight criteria in MCD patients, healthy controls and TLE patients.
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Individual analysis
Five healthy control subjects (5/50 = 10%) and 37/76 (49%) MCD patients had abnormal features (
2 = 20, df = 1, P < 0.001). Compared with healthy controls, there was a strong association between the presence of abnormal features and heterotopia (19/30 = 63%; 2 = 25, df = 1; P < 0.001), polymicrogyria (7/17 = 41%; 2 = 8, df = 1, P = 0.004) and focal cortical dysplasia (11/29 = 38%; 2 = 9, df = 1, P = 0.003). There was no difference in the relative frequency of abnormal features among the three MCD groups.
Compared with healthy controls, there was a higher proportion of TLE patients with abnormal features (13/30 = 43%; 2 = 10, df = 1, P = 0.001). This was true for TLE patients with hippocampal atrophy (8/15 = 53%; 2 = 11, df = 1; P = 0.001) and those with normal hippocampal volumes (5/15 = 33%; 2 = 5, df = 1; P = 0.04).
When comparing MCD and TLE, there was no difference in the proportion of patients with HF shape and positioning abnormalities (49% versus 43%).
Relationship of HF shape and positioning to EEG focus and hippocampal atrophy
There was a weak association between the side of MCD and EEG focus (2 = 5, df = 1, P = 0.03). However, no association was found between side of HF shape and positioning abnormalities and the side of the MCD lesion or the EEG focus. Among the 18 MCD patients with hippocampal atrophy, 10 had HF shape and positioning abnormalities. We found no association between the side of HF abnormalities and the side of atrophy.
Within the 13 patients with TLE who had abnormalities of shape and positioning of HF, these abnormalities were more often bilateral or contralateral than ipsilateral to the seizure focus (85% versus 15%; 2 = 6, df = 1, P = 0.01). There was no difference in the relative frequency of abnormal features between TLE patients with hippocampal atrophy and those with normal hippocampal volume.
Quantitative analysis
Details on the mean parahippocampal angle and medial distance in each MCD group are shown in Table 6. The parahippocampal angle was more acute and the medial distance was shorter in patients with heterotopia and focal cortical dysplasia who had HF shape and positioning abnormalities compared with those who did not. In patients with polymicrogyria, although there was a trend towards a more acute parahippocampal angle and shorter distance in those with evidence of HF shape and positioning abnormalities, values did not reach significance.
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Discussion |
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TopSummaryIntroductionMethodsResultsDiscussionReferences |
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Our purpose was to investigate shape and positioning characteristics of the HF in healthy subjects and patients with various types of MCD. In addition, we compared our findings with a group of patients with medically intractable TLE.
Our results showed abnormal shape and positioning of the HF in about half of the patients with MCD. Moreover, in these patients, our quantitative measures of vertical orientation and medial positioning of the hippocampus corroborated the results of the visual assessment by showing an acute parahippocampal angle and a short medial distance. Abnormal shape and positioning of the HF were present in a similar proportion among focal cortical dysplasia, polymicrogyria and heterotopia, and were observed at all levels along the anteroposterior axis of the medial temporal lobe.
To our knowledge, this is the first study of shape and position of the HF that provides an unbiased and objective comparison between healthy controls, MCD and TLE patients using a set of predefined criteria. The examiners were unaware of the clinical diagnosis and subjects were presented in a random fashion to them. Furthermore, we used a high-resolution MRI protocol with thin contiguous 1 mm thick slices and isotropic voxels in all subjects, allowing for a detailed and comparable examination of the HF across all individuals.
Most of the neurogenesis and positioning of the HF occurs early during prenatal development, the HF being the first cortical area to differentiate. With expansion of the dentate gyrus and the cornu Ammonis, infolding of the hippocampus occurs over the parahippocampal gyrus and the rotation of the HF to the adult position is complete at 
18 weeks of gestation, resulting in a nearly horizontal orientation as seen on coronal sections (Duvernoy, 1988; Kier et al., 1997; Baulac et al., 1998). Neuroanatomical post-mortem and MRI studies of the normal brain have been focused on the analysis of cortical sulcal and gyral variability (Ono et al., 1990; Armstrong et al., 1995; Thompson et al., 1996). Only rarely normal variants of hippocampal morphology have been described, such as the ‘gyri of Andreas Retzius’, characterized microscopically by folds in the CA1 region in the tail of the adult hippocampus (Duvernoy, 1988). In a recent histopathological study, morphological hippocampal abnormalities described as the bulbous expansion of the CA1 pyramidal cell-subicular layers accompanied by invaginations of the adjacent dentate gyrus have been reported in a series of patients who underwent temporal lobe resection for epileptic seizures. Similar, but less severe microscopic abnormalities were seen in hippocampi obtained at autopsy from controls without history of neurological illnesses (Sloviter et al., 2004). To the best of our knowledge, variability of shape and position of the HF on MRI have not been previously described in healthy human subjects. In 10% of our healthy controls, we found shape and positioning characteristics of the HF similar to those observed in MCD and TLE. The precise mechanisms of normal cortical folding processes are not well known and possibly involve a combination of mechanical forces with increased brain size and specific factors influencing gyrogenesis (Armstrong et al., 1995; Van Essen, 1997). Therefore, it is likely that the unusual hippocampal shape and position seen in a small proportion of our healthy controls may represent the end of the phenotypic spectrum of a normal HF.
Some theories suggest that structural features of the mammalian central nervous system could be explained by a morphogenetic mechanism involving mechanical tension along axons, dendrites and glial processes, and that the degree of folding might be correlated with the strength of connections. In the cerebral cortex, tension along axons in the white matter could explain sulcal and gyral patterns (Van Essen, 1997). It is unclear if the same concept would apply to the HF. The hippocampus is reciprocally connected to the cortex through the entorhinal cortex. Hippocampal-entorhinal connections are among the first connections established in the human brain (Hevner and Kinney, 1996). It is therefore conceivable that abnormalities of corticogenesis such as those leading to MCD could induce abnormal cortico-hippocampal connections, which could ultimately result in a modified, abnormal shape. Our findings were not confined to the hippocampus proper, but included also the parahippocampal gyrus and the subiculum. Since the development of the mesial temporal lobe is characterized by progressive infolding involving several adjacent structures, such as the fetal dentate gyrus, the cornu Ammonis (hippocampus), the subiculum and the parahippocampal gyrus, a disruption in the genesis of any of these structures is likely to have consequences on the development of the others (Hines, 1922; Macchi, 1951; Humphrey, 1967).
The occurrence of hippocampal shape abnormalities in MCD has not been previously established, since earlier studies did not evaluate systematically various MCD subtypes. Baulac et al. (1998) characterized in detail hippocampal shape abnormalities in three patients with heterotopia. Subsequently, there have been only few reports of such abnormalities in isolated patients with polymicrogyria (Barsi et al., 2000), schizencephaly (Barsi et al., 2000) and lissencephaly (Baker and Barkovich, 1992). In the present study, we analysed a large group of patients with the most common types of MCD. Abnormal shape and positioning of the HF was present in 63% of patients with heterotopias, 41% of those with polymicrogyrias and in 38% of those with focal cortical dysplasia. The co-occurrence of various types of malformations of neocortical structures and the HF suggest a common pathogenic mechanism, which would explain the involvement of structures that arise from different germinal matrices. MCD are a heterogeneous group of focal or diffuse developmental abnormalities that can occur at different stages of corticogenesis, as early as in the proliferation period or as late as in the organization period (Rakic, 1988). The fact that MCDs occurring at different stages of cortical development share similar HF shape abnormalities suggests that the hippocampus is susceptible to damage occurring at any time during corticogenesis.
In our study, HF abnormalities were found in a similar proportion in MCD and TLE. Our findings raise the question as to whether HF abnormalities in TLE are a marker of a more extensive subtle brain malformation (Baulac et al., 1998; Fernandez et al., 1998; Thom et al., 2002). However, to be definitive, analysis of post-mortem whole-brain specimens would be necessary. To date, only limited data examining the neuropathological correlates of MRI visible HF malformations in TLE have been published. In a patient with TLE and bilateral hippocampal malformation, Thom et al. (2002) reported an excessively long and abnormally folded CA1 and a verticalized dentate gyrus. There was no evidence of hippocampal dysplasia, neuronal loss or gliosis. In another TLE patient with isolated HF malrotation, Baulac et al. (1998) described the usual features of hippocampal sclerosis in combination with an abnormally folded subiculum. The medial upper and lower banks of the hippocampal fissure were open and the medial edge of the dentate gyrus was protruding instead of being buried. In a recent study, developmental changes of the HF were observed in patients with TLE at a microscopic level with no apparent structural changes on conventional MRI (Sloviter et al., 2004). Therefore, developmental changes of the HF in TLE may be more frequent than has been observed so far and encompass a spectrum of abnormalities ranging from microscopic to more obvious pathology visible on MRI.
In agreement with previous observations by Baulac et al. (1998), we did not find any relationship between HF shape abnormalities and either the lesion side or the epileptic focus in our MCD and TLE patients, indicating that the epileptogenic focus and structural changes may not always overlap. The significance of these abnormalities in relation to cognitive and clinical parameters, such as memory and outcome after surgery, remains to be established.
Although HF shape and positioning abnormalities are more prevalent in epilepsy patients than in healthy individuals, their impact in epilepsy, and indeed hippocampal sclerosis, is not yet determined. In the context of TLE, it is tempting to speculate that a developmentally abnormal hippocampus may become more vulnerable to injury in ways that a normal hippocampus is not. The presence of HF abnormalities have been noted previously in epileptic syndromes unrelated to MCD or TLE, such as idiopathic generalized epilepsy (Barsi et al., 2000), in other epilepsy-associated brain disorders (Fitoz et al., 2003; Grosso et al., 2003) and in brain pathologies unrelated to epilepsy (Sumi, 1970; Atlas et al., 1986; Riedl et al., 2002; Fitoz et al., 2003). Moreover, the fact that these abnormalities were present in 10% of our controls, indicates that in TLE additional factors (i.e. genetic or environmental) are necessary for the development of mesial temporal lobe sclerosis. Future studies are clearly needed to determine the relationship between MRI and histological findings in order to clarify the spectrum of HF developmental abnormalities and their significance in the genesis of seizures in various epileptic syndromes.
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Acknowledgements |
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The authors would like to thank Prof Gary Van Hoesen for his insightful comments on the manuscript.
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