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Mesial temporal lobe measurements on magnetic resonance imaging scans
Psychiatry Research: Neuroimaging Section 83 Ž1998. 85]94
Mesial temporal lobe measurements on magnetic resonance imaging scans Nancy A. HoneycuttU , Paige D. Smith, Elizabeth Aylward, Qiang Li, Michael Chan, Patrick E. Barta, Godfrey D. Pearlson Di¨ ision of Psychiatric Neuroimaging, Department of Psychiatry and Beha¨ ioral Sciences, The Johns Hopkins Uni¨ ersity School of Medicine, Meyer 3-166, 600 North Wolfe Street, Baltimore, MD 21287-7362, USA Received 18 February 1998; received in revised form 23 June 1998; accepted 28 June 1998
Abstract Changes in the mesial temporal lobe, particularly in the hippocampus, amygdala, and entorhinal cortex, are reported to occur in several neuropsychiatric conditions. Neuroimaging provides a non-invasive means of studying these changes. We present a method for reliably measuring the hippocampus, amygdala, and entorhinal cortex on MRI. The advantages of our method include high reliability, the use of orthogonal views in delineating boundaries and circumscription of measurement such that no tissue of any one anatomic structure is included in the measurement of another structure. Q 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hippocampus; Amygdala; Entorhinal cortex
1. Introduction There has been recent interest in the mesial temporal area of the brain, particularly the hippocampus, amygdala, and entorhinal cortex. Because these structures are affected in several different neuropsychiatric disorders, it is important to study their structure in a non-invasive quanti-
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Corresponding author. Tel.: q1 410 9554725; fax: q1 410 6143676; e-mail: [email protected]
tative manner. Magnetic resonance imaging ŽMRI. lends itself readily to this objective. The hippocampus has received considerable attention in the past decade. It is crucial in memory consolidation and has been shown to be susceptible to pathology in Alzheimer’s disease ŽJack et al., 1992; Pearlson et al., 1992; Casanova et al., 1993; Killiany et al., 1993; Lehtovirta et al., 1995., schizophrenia ŽMarsh et al., 1994; Becker et al., 1996., and complex partial seizures ŽCendes et al., 1993; Kuzniecky et al., 1996., as well as normal aging ŽWest, 1993; Filipek et al., 1994.. Various
0925-4927r98r$19.00 Q 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0925-4927Ž98. 00035-3
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methodologies have been published detailing techniques for measuring hippocampal volume on MRI. Most previous studies have measured the hippocampus in the coronal aspect ŽKesslak et al., 1991; Jack et al., 1992; Watson et al., 1992; Killiany et al., 1993; Filipek et al., 1994; Soininen et al., 1994; Honeycutt and Smith, 1995; Lehtovirta et al., 1995.. Indeed, the coronal view is adequate for viewing the majority of the hippocampus; however, it is often difficult to distinguish between the hippocampus and amygdala in this plane. Some MRI studies have avoided this problem by conjointly measuring the hippocampus and amygdala ŽBogerts, 1993; Buchanan et al., 1993; Rossi et al., 1994; DeLisi et al., 1995.. The disadvantage of doing so is that the hippocampus and amygdala subserve different functions and are not necessarily affected concurrently or to the same degree. Thus, it is important to have the capability to assess each separately. Specific landmarks have also differed between various studies. For example, Jack et al. Ž1989. chose the posterior commissure as the posterior hippocampal boundary while Reiss et al. Ž1994. set the posterior boundary at the level where the internal auditory canal becomes visible. Watson et al. Ž1992., as well as Honeycutt and Smith Ž1995., selected the crux of the fornix as the most posterior slice in which to measure the hippocampus. A problem with arbitrarily choosing a landmark is that, in doing so, several millimeters of hippocampal tissue may be excluded, a difference that may arguably differentiate between normal subjects and patient populations in which the hippocampus is affected. The amygdala, once thought to be essential only in olfaction, is now considered to be important in the emotional component of memory and recognition as well as the modulation of emotional expression ŽAmaral and Insausti, 1990; Carpenter, 1997.. Both neuropathologic and MRI studies have confirmed that the amygdala is affected in Alzheimer’s disease ŽPearlson et al., 1992; Lehtovirta et al., 1995., schizophrenia ŽBogerts et al., 1985; Marsh et al., 1994; Pearlson et al., 1997., and bipolar disorder ŽPearlson et al., 1997.. MRI volumetric measurement of the amygdala has been less often reported than that of the hippocampus, likely due to the difficulty in dif-
ferentiating amygdaloid tissue from surrounding gray matter. As with the hippocampus, the amygdala has traditionally been measured in the coronal aspect on MRI. In addition to the difficulty in distinguishing between the hippocampus and amygdala in the coronal view on MRI, it is often difficult to avoid the inclusion of adjacent nonamygdaloid gray matter Že.g. lateral geniculate, tail of the caudate. in amygdala measurements made solely on the coronal view. As is the case with the hippocampus, published guidelines for measuring the amygdala differ in boundary selection between researchers. For example, Kates et al. Ž1997. set the anterior boundary at the level of the anterior commissure, whereas Watson et al. Ž1992., as well as Cendes et al. Ž1993., set the anterior boundary at the level where the lateral sulcus closes to form the endorhinal sulcus. There has also been an upsurge of interest in the entorhinal cortex ŽERC., one of the main efferent and afferent connections with the hippocampus. In fact, the efferent path of ERC, known as the perforant pathway, is the largest cortical association tract in the temporal lobe ŽVan Hoesen, 1995.. In Alzheimer’s disease, ERC is one of the first brain structures altered by the disease and evidences more neurofibrillary tangles than any other part of the cortex ŽHyman et al., 1984; Arriagada et al., 1992; Braak et al., 1993.. ERC is affected pathologically to such an extent in Alzheimer’s disease that the hippocampus is essentially functionally dissociated from the cortex ŽHyman et al., 1986.. On MRI, ERC volume has been shown to be significantly smaller in patients with Alzheimer’s disease when compared with control subjects ŽPearlson et al., 1992; Desmond et al., 1994.. In schizophrenia, Pearlson et al. Ž1997. found a significant reduction in ERC volumes in comparison with both normal control subjects and bipolar patients. Their results concur with previous neuropathologic studies that have found ERC and parahippocampal abnormalities in schizophrenia ŽFalkai et al., 1988; Bogerts et al., 1990.. ERC has been difficult to measure on MRI due to its imprecise anterior and posterior boundaries. Pearlson et al. Ž1992, 1997. and Desmond et al. Ž1994. reported ERC volumes based on two representative slices of ERC. The
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drawback of this methodology is that small differences between patient and control groups may be obscured simply because of the fact that so little of the tissue was measured. Mesial temporal lobe structures can be easily viewed on magnetic resonance imaging scans, making quantitative volumetric assessments feasible to monitor degree and rate of change. Because the hippocampus, amygdala and entorhinal cortex are close in proximity to one another, it is important to utilize a methodology in MRI ratings that does not define the same tissue as belonging to more than one of the structures. Furthermore, because these structures are not necessarily altered to the same degree or at the same rate, it is important to be able to differentiate between them reliably. Most studies have relied on the coronal plane for mesial temporal lobe measurements, making structure differentiation more difficult than would be the case in examining all three planes where more anatomic information is available. We have developed a methodology that involves separate volumetric measurement of all three structures, taking into account data from all three orthogonal planes. 2. Methods 2.1. MRI acquisition and ¨ olumetric measurement MRI scans were obtained on a GE Signa 1.5-T unit. Contiguous slices were acquired through the entire brain in the coronal plane using a spoiled gradient recall acquisition in the steady state ŽGRASS. sequence ŽTRs 35, TEs 5. with a flip angle of 458. Slices were 1.5 mm thick with a field of view of 24 and a matrix size of 256 = 256. Scans were transferred using FTP from the MRI archive and stored on CD-ROMs. All scans were corrected for head tilt in all three planes, then resliced using a multiplanar reconstruction technique. Head tilt in the sagittal plane was corrected by aligning the anterior and posterior commissure, in the axial plane by aligning the cerebral aqueduct and the interhemispheric fissure and in the coronal plane using symmetry of the optic nerves. The resulting axial and sagittal slices were 0.9735 mm thick.
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Volumetric measurements were made using a locally developed custom graphics software Ž‘MEASURE’; Barta et al., 1997. running on a Gateway 2000 graphics workstation. ‘MEASURE’ allows images to be viewed simultaneously in all three orthogonal planes, a feature that enhances the ability to discern whether tissue is part of a particular structure. Tracings can be made in any plane and are able to be viewed simultaneously in all planes ŽFig. 1.. 2.2. Hippocampal boundaries In an effort to include the fullest extent of the hippocampus, the following methodology was employed. The rater started in the most posterior coronal images containing hippocampal gray matter ŽFig. 2.. Working in a posterior to anterior direction, the rater manually traced around hippocampal gray matter in each slice. To differentiate hippocampus from thalamic gray matter posteriorly and from amygdaloid gray matter anteriorly, sagittal and axial views were examined. In spoiled-GRASS images, the sagittal plane provides an excellent view of the seahorse shape for which the hippocampus is named ŽFig. 3.. The choroid fissure and the superior portion of the inferior horn of the lateral ventricle served as the superior boundary in slices posterior to the amyg-
Fig. 1. Display of all three orthogonal views ŽA, coronal; B, sagittal; C, axial..
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Fig. 3. Sagittal view of the hippocampus showing its seahorse shape ŽA, anterior; P, posterior..
Fig. 2. Tracing on the right hippocampus in its most posterior aspect. Left hippocampus is not yet in view.
dala while the amygdala was the superior boundary in anterior slices. The inferior temporal horn of the lateral ventricle or the white matter of the temporal stem served as the lateral boundary Ždepending on which was apparent in the particular slice.. The white matter of the parahippocampal gyrus served as the inferior boundary ŽFig. 4.. A linear boundary was determined mesially at the angle where the hippocampus curves down into the parahippocampal gyrus ŽFig. 5.. Any gray matter lateral and superior to this linear boundary was measured as hippocampus and any gray matter medial and inferior to this linear boundary was not measured as hippocampus. Because we were interested in measuring ERC as well as hippocampus and amygdala, we chose a diagonal boundary to avoid underestimating the volume of ERC, particularly since ERC is a small structure. Both the alveus and the subiculum were included in hippocampal measurements as well as the ambient gyrus posterior to the uncal notch. Any tissue measured medial to the uncal notch was erased ŽFig. 6..
nerves could be clearly viewed ŽFig. 7.. This level was set as the superior boundary in order to avoid inclusion of non-amygdaloid gray matter Že.g. lateral geniculate .. Although previous studies have measured the amygdala in the coronal view Že.g. Watson et al., 1992; Soininen et al., 1994., the spatial relationship between the amygdala, uncus and hippocampus can be readily seen in axial slices. We found that the axial view provided a reliable and consistent orientation for determining lateral and posterior boundaries. The lateral boundary was set at the most medial white matter
2.3. Amygdala boundaries The amygdala was first measured in axial slices with the superior boundary set at the level of the tubera where the mamillary bodies and optic
Fig. 4. Coronal view showing the superior portion of the inferior horn of the lateral ventricle ŽA., the choroid fissure ŽB., and the white matter of the parahippocampal gyrus ŽC..
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Fig. 5. Mesial boundary of the hippocampus. Note: the diagonal line is for illustrative purposes only and is not drawn on actual measurements.
protruding into amygdaloid gray matter, i.e. a straight line was drawn anteriorly and posteriorly from the most medial white matter protruding into the lateral side of the amygdaloid gray matter ŽFig. 8.. This method was employed in order to avoid lateral non-amygdaloid gray matter Že.g. the tail of the caudate, Fig. 9.. It also allowed a reliable boundary in the superolateral aspect of the amygdala. The medial boundary was set at the uncus, and the posterior boundary was set at the temporal horn of the lateral ventricle in superior slices and at the hippocampus in inferior slices. No gray matter was measured inferior to the level of the hippocampus. After measuring in axial
Fig. 6. Anterior hippocampal tracings showing exclusion of the uncus at the uncal notch ŽA, uncal notch..
Fig. 7. Most superior level of amygdala measurements ŽA, tuber on right side of brain; B, mamillary bodies; C, optic nerve on left side of brain..
slices, sagittal and coronal views were consulted; any gray matter anterior to the anterior commissure was erased as well as any gray matter medial to the uncal notch ŽFig. 10.. 2.4. Entorhinal cortex boundaries The entorhinal cortices were measured in the coronal view, in a posterior to anterior direction; the sagittal as well as the axial views were examined frequently to aid in measurement and to ensure structural continuity ŽFig. 11.. The posterior boundary was set at the level of the most anterior portion of the pons ŽFig. 12.. This level coincides with the level of the rostral pole of the lateral geniculate, an accepted posterior boundary ŽAmaral and Insausti, 1990; Insausti et al., 1995.. According to Amaral and Insausti Ž1990., the anterior boundary of ERC falls approx. 2]3 mm posterior to the frontotemporal junction; because our MRI slices were 1.5 mm each, our anterior boundary for ERC was set two slices Ži.e. 3 mm.
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Fig. 10. Coronal view of amygdalae showing exclusion of tissue medial to the uncal notches ŽA, uncal notches.. Fig. 8. Tracing of right amygdala in axial view. Note: the lateral boundary is set at the most medial white matter protruding into the lateral side of amygdaloid gray matter ŽA, anterior; P, posterior..
posterior to the frontotemporal junction. To measure ERCs, the rater started at the cusp of the mesial edge of the white matter of the parahippocampal gyrus and traced around the gray matter to the inferior edge of the gryus and then superolaterally with the collateral sulcus as the superolateral boundary. The apex of the collateral sulcus served as the superolateral boundary. Tracings continued along the superior gray matter back to the cusp of the mesial edge.
2.5. Independent circumscription The current measurement technique was designed such that the hippocampus, amygdala, and entorhinal cortex could be measured separately without overlap between the three structures Ži.e. no tissue was counted as belonging to more than one structure .. To accomplish this, first the hippocampi were measured and the rater’s boundaries saved. Next, with the hippocampal boundaries still in view, the amygdalae were measured. After completion of the amygdalae measurements, the hippocampal tracings were deleted; therefore, any tissue that had been included in both hippocampal and amygdaloid boundaries was excluded from the amygdala measure and included only in the hippocampus measure. The remaining measurement was saved as amygdalae. Measurement of the ERCs followed in the same manner, i.e. the hippocampal and amygdaloid boundaries were in view as ERCs were being measured, and then were summarily deleted, leaving only tissue belonging to the intended structure. 3. Results
Fig. 9. Cross hairs indicate the tail of the caudate.
Inter-rater reliability was assessed separately for each of the three structures. Two raters inde-
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Fig. 12. The posterior boundary of ERC shown in all three planes ŽA, coronal view; B, sagittal view; C, axial view.. The cross hairs intersect the most anterior slice of the pons.
Fig. 11. Orthogonal views of ERC measurements ŽA, coronal view; B, sagittal view; C, axial view..
pendently measured scans from 10 healthy, cognitively normal individuals and obtained total volumes for each structure. The intraclass correlations were 0.97 for hippocampus, 0.88 for amygdala, and 0.94 for entorhinal cortex. Intra-rater reliabilities were calculated in a similar manner, giving values of 0.95 for hippocampus, 0.84 for amygdala, and 0.92 for entorhinal cortex. 4. Discussion Because one or more regions of the mesial temporal lobe are structurally abnormal in several neuropsychiatric disorders, it is important to determine their volumes independently. In order to do this, one must have a reliable method for
determining volume separately for each of these structures. We present a method for reliable and independent measurement of the hippocampus, amygdala, and entorhinal cortex. To our knowledge, this is the first published method for measuring the entorhinal cortex in more than a few representative slices on MRI scans. Although we realize that the boundaries of the entorhinal cortex in brain tissue are difficult to delineate, after reviewing standard atlases ŽDuvernoy, 1988; DeArmond et al., 1989; Duvernoy, 1991. and neuropathologic and neuroimaging reports ŽBraak and Braak, 1991; Kesslak et al., 1991; Pearlson et al., 1992; Desmond et al., 1994; Deweer et al., 1995; Gomez-Isla et al., 1996., we believe that we have delimited the majority of this structure. Because pathology studies point to this area as affected early in the course of Alzheimer’s disease ŽErkinjuntti et al., 1993., it is an important region to assess in the incipient stages of the disease. Furthermore, it would also be useful to determine if the entorhinal cortex is affected in other types of dementia Že.g. vascular. or whether this is specific to Alzheimer’s disease. One advantage of our method is that no tissue is included as belonging to more than one structure. This decreases the likelihood that the degree of volume change will be underestimated for any one structure. Additionally, this method may help alleviate the problem of error due to partial
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volume effects. Soininen et al. Ž1994. stated that ‘even with slices as thin as 3 mm, the partial volume effect may cause a 30% error in the volume of the hippocampus if coronal slices are used’. Because our method relies on all three orthogonal views rather than only the coronal view, there is a greater likelihood of correctly assessing the boundaries of the structures. Furthermore, it is possible that the discrepancy in reported amygdala volumes is due to the indistinct boundary between the hippocampus and amygdala when viewed on coronal images. When all three orthogonal views are used, particularly the sagittal view, these boundaries are much clearer. A recent study ŽKates et al., 1997. employed both the coronal and sagittal views to define hippocampal and amygdaloid boundaries; however, in our experience, the axial view also has been shown to offer a valuable perspective in delineating the boundaries of these structures. Another advantage of our method is that it relies less on arbitrary structural boundaries so that the three structures can be measured in their fullest extent. For example, several previous studies ŽPearlson et al., 1992; Desmond et al., 1994. measured hippocampi and amygdalae in a predetermined number of slices. Using this method, individuals with larger structures are sometimes not given ‘credit’ for the entire volume if the structure extends beyond the predetermined number of slices. Furthermore, in cases in which the structure is much smaller, raters may be tempted to measure tissue in slices where the structure does not exist, thereby overestimating the size of the structure. Measuring as much of the structures as reliably possible also allows for investigation into differential degrees and rates of atrophy of different anatomical components of the structure Že.g. the hippocampal head vs. the tail.. The main disadvantage of this method is that it may be more time-consuming than other Že.g. automated. methods. Experienced raters report that measurements of hippocampi, amygdalae, and entorhinal cortices take approx. 40, 20 and 10 min, respectively. However, the extra time expended may be justified since it may mean that fewer subjects will be necessary to obtain signifi-
cant results, i.e. less exact methods may obscure small differences between groups. Acknowledgements
We gratefully acknowledge the assistance of Harvey Morris in the preparation of this manuscript. References
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Mesial temporal lobe measurements on magnetic resonance imaging scans Nancy A. HoneycuttU , Paige D. Smith, Elizabeth Aylward, Qiang Li, Michael Chan, Patrick E. Barta, Godfrey D. Pearlson Di¨ ision of Psychiatric Neuroimaging, Department of Psychiatry and Beha¨ ioral Sciences, The Johns Hopkins Uni¨ ersity School of Medicine, Meyer 3-166, 600 North Wolfe Street, Baltimore, MD 21287-7362, USA Received 18 February 1998; received in revised form 23 June 1998; accepted 28 June 1998
Abstract Changes in the mesial temporal lobe, particularly in the hippocampus, amygdala, and entorhinal cortex, are reported to occur in several neuropsychiatric conditions. Neuroimaging provides a non-invasive means of studying these changes. We present a method for reliably measuring the hippocampus, amygdala, and entorhinal cortex on MRI. The advantages of our method include high reliability, the use of orthogonal views in delineating boundaries and circumscription of measurement such that no tissue of any one anatomic structure is included in the measurement of another structure. Q 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hippocampus; Amygdala; Entorhinal cortex
1. Introduction There has been recent interest in the mesial temporal area of the brain, particularly the hippocampus, amygdala, and entorhinal cortex. Because these structures are affected in several different neuropsychiatric disorders, it is important to study their structure in a non-invasive quanti-
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Corresponding author. Tel.: q1 410 9554725; fax: q1 410 6143676; e-mail: [email protected]
tative manner. Magnetic resonance imaging ŽMRI. lends itself readily to this objective. The hippocampus has received considerable attention in the past decade. It is crucial in memory consolidation and has been shown to be susceptible to pathology in Alzheimer’s disease ŽJack et al., 1992; Pearlson et al., 1992; Casanova et al., 1993; Killiany et al., 1993; Lehtovirta et al., 1995., schizophrenia ŽMarsh et al., 1994; Becker et al., 1996., and complex partial seizures ŽCendes et al., 1993; Kuzniecky et al., 1996., as well as normal aging ŽWest, 1993; Filipek et al., 1994.. Various
0925-4927r98r$19.00 Q 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0925-4927Ž98. 00035-3
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methodologies have been published detailing techniques for measuring hippocampal volume on MRI. Most previous studies have measured the hippocampus in the coronal aspect ŽKesslak et al., 1991; Jack et al., 1992; Watson et al., 1992; Killiany et al., 1993; Filipek et al., 1994; Soininen et al., 1994; Honeycutt and Smith, 1995; Lehtovirta et al., 1995.. Indeed, the coronal view is adequate for viewing the majority of the hippocampus; however, it is often difficult to distinguish between the hippocampus and amygdala in this plane. Some MRI studies have avoided this problem by conjointly measuring the hippocampus and amygdala ŽBogerts, 1993; Buchanan et al., 1993; Rossi et al., 1994; DeLisi et al., 1995.. The disadvantage of doing so is that the hippocampus and amygdala subserve different functions and are not necessarily affected concurrently or to the same degree. Thus, it is important to have the capability to assess each separately. Specific landmarks have also differed between various studies. For example, Jack et al. Ž1989. chose the posterior commissure as the posterior hippocampal boundary while Reiss et al. Ž1994. set the posterior boundary at the level where the internal auditory canal becomes visible. Watson et al. Ž1992., as well as Honeycutt and Smith Ž1995., selected the crux of the fornix as the most posterior slice in which to measure the hippocampus. A problem with arbitrarily choosing a landmark is that, in doing so, several millimeters of hippocampal tissue may be excluded, a difference that may arguably differentiate between normal subjects and patient populations in which the hippocampus is affected. The amygdala, once thought to be essential only in olfaction, is now considered to be important in the emotional component of memory and recognition as well as the modulation of emotional expression ŽAmaral and Insausti, 1990; Carpenter, 1997.. Both neuropathologic and MRI studies have confirmed that the amygdala is affected in Alzheimer’s disease ŽPearlson et al., 1992; Lehtovirta et al., 1995., schizophrenia ŽBogerts et al., 1985; Marsh et al., 1994; Pearlson et al., 1997., and bipolar disorder ŽPearlson et al., 1997.. MRI volumetric measurement of the amygdala has been less often reported than that of the hippocampus, likely due to the difficulty in dif-
ferentiating amygdaloid tissue from surrounding gray matter. As with the hippocampus, the amygdala has traditionally been measured in the coronal aspect on MRI. In addition to the difficulty in distinguishing between the hippocampus and amygdala in the coronal view on MRI, it is often difficult to avoid the inclusion of adjacent nonamygdaloid gray matter Že.g. lateral geniculate, tail of the caudate. in amygdala measurements made solely on the coronal view. As is the case with the hippocampus, published guidelines for measuring the amygdala differ in boundary selection between researchers. For example, Kates et al. Ž1997. set the anterior boundary at the level of the anterior commissure, whereas Watson et al. Ž1992., as well as Cendes et al. Ž1993., set the anterior boundary at the level where the lateral sulcus closes to form the endorhinal sulcus. There has also been an upsurge of interest in the entorhinal cortex ŽERC., one of the main efferent and afferent connections with the hippocampus. In fact, the efferent path of ERC, known as the perforant pathway, is the largest cortical association tract in the temporal lobe ŽVan Hoesen, 1995.. In Alzheimer’s disease, ERC is one of the first brain structures altered by the disease and evidences more neurofibrillary tangles than any other part of the cortex ŽHyman et al., 1984; Arriagada et al., 1992; Braak et al., 1993.. ERC is affected pathologically to such an extent in Alzheimer’s disease that the hippocampus is essentially functionally dissociated from the cortex ŽHyman et al., 1986.. On MRI, ERC volume has been shown to be significantly smaller in patients with Alzheimer’s disease when compared with control subjects ŽPearlson et al., 1992; Desmond et al., 1994.. In schizophrenia, Pearlson et al. Ž1997. found a significant reduction in ERC volumes in comparison with both normal control subjects and bipolar patients. Their results concur with previous neuropathologic studies that have found ERC and parahippocampal abnormalities in schizophrenia ŽFalkai et al., 1988; Bogerts et al., 1990.. ERC has been difficult to measure on MRI due to its imprecise anterior and posterior boundaries. Pearlson et al. Ž1992, 1997. and Desmond et al. Ž1994. reported ERC volumes based on two representative slices of ERC. The
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drawback of this methodology is that small differences between patient and control groups may be obscured simply because of the fact that so little of the tissue was measured. Mesial temporal lobe structures can be easily viewed on magnetic resonance imaging scans, making quantitative volumetric assessments feasible to monitor degree and rate of change. Because the hippocampus, amygdala and entorhinal cortex are close in proximity to one another, it is important to utilize a methodology in MRI ratings that does not define the same tissue as belonging to more than one of the structures. Furthermore, because these structures are not necessarily altered to the same degree or at the same rate, it is important to be able to differentiate between them reliably. Most studies have relied on the coronal plane for mesial temporal lobe measurements, making structure differentiation more difficult than would be the case in examining all three planes where more anatomic information is available. We have developed a methodology that involves separate volumetric measurement of all three structures, taking into account data from all three orthogonal planes. 2. Methods 2.1. MRI acquisition and ¨ olumetric measurement MRI scans were obtained on a GE Signa 1.5-T unit. Contiguous slices were acquired through the entire brain in the coronal plane using a spoiled gradient recall acquisition in the steady state ŽGRASS. sequence ŽTRs 35, TEs 5. with a flip angle of 458. Slices were 1.5 mm thick with a field of view of 24 and a matrix size of 256 = 256. Scans were transferred using FTP from the MRI archive and stored on CD-ROMs. All scans were corrected for head tilt in all three planes, then resliced using a multiplanar reconstruction technique. Head tilt in the sagittal plane was corrected by aligning the anterior and posterior commissure, in the axial plane by aligning the cerebral aqueduct and the interhemispheric fissure and in the coronal plane using symmetry of the optic nerves. The resulting axial and sagittal slices were 0.9735 mm thick.
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Volumetric measurements were made using a locally developed custom graphics software Ž‘MEASURE’; Barta et al., 1997. running on a Gateway 2000 graphics workstation. ‘MEASURE’ allows images to be viewed simultaneously in all three orthogonal planes, a feature that enhances the ability to discern whether tissue is part of a particular structure. Tracings can be made in any plane and are able to be viewed simultaneously in all planes ŽFig. 1.. 2.2. Hippocampal boundaries In an effort to include the fullest extent of the hippocampus, the following methodology was employed. The rater started in the most posterior coronal images containing hippocampal gray matter ŽFig. 2.. Working in a posterior to anterior direction, the rater manually traced around hippocampal gray matter in each slice. To differentiate hippocampus from thalamic gray matter posteriorly and from amygdaloid gray matter anteriorly, sagittal and axial views were examined. In spoiled-GRASS images, the sagittal plane provides an excellent view of the seahorse shape for which the hippocampus is named ŽFig. 3.. The choroid fissure and the superior portion of the inferior horn of the lateral ventricle served as the superior boundary in slices posterior to the amyg-
Fig. 1. Display of all three orthogonal views ŽA, coronal; B, sagittal; C, axial..
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Fig. 3. Sagittal view of the hippocampus showing its seahorse shape ŽA, anterior; P, posterior..
Fig. 2. Tracing on the right hippocampus in its most posterior aspect. Left hippocampus is not yet in view.
dala while the amygdala was the superior boundary in anterior slices. The inferior temporal horn of the lateral ventricle or the white matter of the temporal stem served as the lateral boundary Ždepending on which was apparent in the particular slice.. The white matter of the parahippocampal gyrus served as the inferior boundary ŽFig. 4.. A linear boundary was determined mesially at the angle where the hippocampus curves down into the parahippocampal gyrus ŽFig. 5.. Any gray matter lateral and superior to this linear boundary was measured as hippocampus and any gray matter medial and inferior to this linear boundary was not measured as hippocampus. Because we were interested in measuring ERC as well as hippocampus and amygdala, we chose a diagonal boundary to avoid underestimating the volume of ERC, particularly since ERC is a small structure. Both the alveus and the subiculum were included in hippocampal measurements as well as the ambient gyrus posterior to the uncal notch. Any tissue measured medial to the uncal notch was erased ŽFig. 6..
nerves could be clearly viewed ŽFig. 7.. This level was set as the superior boundary in order to avoid inclusion of non-amygdaloid gray matter Že.g. lateral geniculate .. Although previous studies have measured the amygdala in the coronal view Že.g. Watson et al., 1992; Soininen et al., 1994., the spatial relationship between the amygdala, uncus and hippocampus can be readily seen in axial slices. We found that the axial view provided a reliable and consistent orientation for determining lateral and posterior boundaries. The lateral boundary was set at the most medial white matter
2.3. Amygdala boundaries The amygdala was first measured in axial slices with the superior boundary set at the level of the tubera where the mamillary bodies and optic
Fig. 4. Coronal view showing the superior portion of the inferior horn of the lateral ventricle ŽA., the choroid fissure ŽB., and the white matter of the parahippocampal gyrus ŽC..
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Fig. 5. Mesial boundary of the hippocampus. Note: the diagonal line is for illustrative purposes only and is not drawn on actual measurements.
protruding into amygdaloid gray matter, i.e. a straight line was drawn anteriorly and posteriorly from the most medial white matter protruding into the lateral side of the amygdaloid gray matter ŽFig. 8.. This method was employed in order to avoid lateral non-amygdaloid gray matter Že.g. the tail of the caudate, Fig. 9.. It also allowed a reliable boundary in the superolateral aspect of the amygdala. The medial boundary was set at the uncus, and the posterior boundary was set at the temporal horn of the lateral ventricle in superior slices and at the hippocampus in inferior slices. No gray matter was measured inferior to the level of the hippocampus. After measuring in axial
Fig. 6. Anterior hippocampal tracings showing exclusion of the uncus at the uncal notch ŽA, uncal notch..
Fig. 7. Most superior level of amygdala measurements ŽA, tuber on right side of brain; B, mamillary bodies; C, optic nerve on left side of brain..
slices, sagittal and coronal views were consulted; any gray matter anterior to the anterior commissure was erased as well as any gray matter medial to the uncal notch ŽFig. 10.. 2.4. Entorhinal cortex boundaries The entorhinal cortices were measured in the coronal view, in a posterior to anterior direction; the sagittal as well as the axial views were examined frequently to aid in measurement and to ensure structural continuity ŽFig. 11.. The posterior boundary was set at the level of the most anterior portion of the pons ŽFig. 12.. This level coincides with the level of the rostral pole of the lateral geniculate, an accepted posterior boundary ŽAmaral and Insausti, 1990; Insausti et al., 1995.. According to Amaral and Insausti Ž1990., the anterior boundary of ERC falls approx. 2]3 mm posterior to the frontotemporal junction; because our MRI slices were 1.5 mm each, our anterior boundary for ERC was set two slices Ži.e. 3 mm.
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Fig. 10. Coronal view of amygdalae showing exclusion of tissue medial to the uncal notches ŽA, uncal notches.. Fig. 8. Tracing of right amygdala in axial view. Note: the lateral boundary is set at the most medial white matter protruding into the lateral side of amygdaloid gray matter ŽA, anterior; P, posterior..
posterior to the frontotemporal junction. To measure ERCs, the rater started at the cusp of the mesial edge of the white matter of the parahippocampal gyrus and traced around the gray matter to the inferior edge of the gryus and then superolaterally with the collateral sulcus as the superolateral boundary. The apex of the collateral sulcus served as the superolateral boundary. Tracings continued along the superior gray matter back to the cusp of the mesial edge.
2.5. Independent circumscription The current measurement technique was designed such that the hippocampus, amygdala, and entorhinal cortex could be measured separately without overlap between the three structures Ži.e. no tissue was counted as belonging to more than one structure .. To accomplish this, first the hippocampi were measured and the rater’s boundaries saved. Next, with the hippocampal boundaries still in view, the amygdalae were measured. After completion of the amygdalae measurements, the hippocampal tracings were deleted; therefore, any tissue that had been included in both hippocampal and amygdaloid boundaries was excluded from the amygdala measure and included only in the hippocampus measure. The remaining measurement was saved as amygdalae. Measurement of the ERCs followed in the same manner, i.e. the hippocampal and amygdaloid boundaries were in view as ERCs were being measured, and then were summarily deleted, leaving only tissue belonging to the intended structure. 3. Results
Fig. 9. Cross hairs indicate the tail of the caudate.
Inter-rater reliability was assessed separately for each of the three structures. Two raters inde-
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Fig. 12. The posterior boundary of ERC shown in all three planes ŽA, coronal view; B, sagittal view; C, axial view.. The cross hairs intersect the most anterior slice of the pons.
Fig. 11. Orthogonal views of ERC measurements ŽA, coronal view; B, sagittal view; C, axial view..
pendently measured scans from 10 healthy, cognitively normal individuals and obtained total volumes for each structure. The intraclass correlations were 0.97 for hippocampus, 0.88 for amygdala, and 0.94 for entorhinal cortex. Intra-rater reliabilities were calculated in a similar manner, giving values of 0.95 for hippocampus, 0.84 for amygdala, and 0.92 for entorhinal cortex. 4. Discussion Because one or more regions of the mesial temporal lobe are structurally abnormal in several neuropsychiatric disorders, it is important to determine their volumes independently. In order to do this, one must have a reliable method for
determining volume separately for each of these structures. We present a method for reliable and independent measurement of the hippocampus, amygdala, and entorhinal cortex. To our knowledge, this is the first published method for measuring the entorhinal cortex in more than a few representative slices on MRI scans. Although we realize that the boundaries of the entorhinal cortex in brain tissue are difficult to delineate, after reviewing standard atlases ŽDuvernoy, 1988; DeArmond et al., 1989; Duvernoy, 1991. and neuropathologic and neuroimaging reports ŽBraak and Braak, 1991; Kesslak et al., 1991; Pearlson et al., 1992; Desmond et al., 1994; Deweer et al., 1995; Gomez-Isla et al., 1996., we believe that we have delimited the majority of this structure. Because pathology studies point to this area as affected early in the course of Alzheimer’s disease ŽErkinjuntti et al., 1993., it is an important region to assess in the incipient stages of the disease. Furthermore, it would also be useful to determine if the entorhinal cortex is affected in other types of dementia Že.g. vascular. or whether this is specific to Alzheimer’s disease. One advantage of our method is that no tissue is included as belonging to more than one structure. This decreases the likelihood that the degree of volume change will be underestimated for any one structure. Additionally, this method may help alleviate the problem of error due to partial
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volume effects. Soininen et al. Ž1994. stated that ‘even with slices as thin as 3 mm, the partial volume effect may cause a 30% error in the volume of the hippocampus if coronal slices are used’. Because our method relies on all three orthogonal views rather than only the coronal view, there is a greater likelihood of correctly assessing the boundaries of the structures. Furthermore, it is possible that the discrepancy in reported amygdala volumes is due to the indistinct boundary between the hippocampus and amygdala when viewed on coronal images. When all three orthogonal views are used, particularly the sagittal view, these boundaries are much clearer. A recent study ŽKates et al., 1997. employed both the coronal and sagittal views to define hippocampal and amygdaloid boundaries; however, in our experience, the axial view also has been shown to offer a valuable perspective in delineating the boundaries of these structures. Another advantage of our method is that it relies less on arbitrary structural boundaries so that the three structures can be measured in their fullest extent. For example, several previous studies ŽPearlson et al., 1992; Desmond et al., 1994. measured hippocampi and amygdalae in a predetermined number of slices. Using this method, individuals with larger structures are sometimes not given ‘credit’ for the entire volume if the structure extends beyond the predetermined number of slices. Furthermore, in cases in which the structure is much smaller, raters may be tempted to measure tissue in slices where the structure does not exist, thereby overestimating the size of the structure. Measuring as much of the structures as reliably possible also allows for investigation into differential degrees and rates of atrophy of different anatomical components of the structure Že.g. the hippocampal head vs. the tail.. The main disadvantage of this method is that it may be more time-consuming than other Že.g. automated. methods. Experienced raters report that measurements of hippocampi, amygdalae, and entorhinal cortices take approx. 40, 20 and 10 min, respectively. However, the extra time expended may be justified since it may mean that fewer subjects will be necessary to obtain signifi-
cant results, i.e. less exact methods may obscure small differences between groups. Acknowledgements
We gratefully acknowledge the assistance of Harvey Morris in the preparation of this manuscript. References
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