Brain Struct Funct DOI 10.1007/s00429-013-0665-9

ORIGINAL ARTICLE

Deficits in memory and visuospatial learning correlate with regional hippocampal atrophy in MS Giulia Longoni • Maria A. Rocca • Elisabetta Pagani • Gianna C. Riccitelli • Bruno Colombo • Mariaemma Rodegher Andrea Falini • Giancarlo Comi • Massimo Filippi



Received: 24 June 2013 / Accepted: 19 October 2013 Ó Springer-Verlag Berlin Heidelberg 2013

Abstract The hippocampus has a critical role in episodic memory and visuospatial learning and consolidation. We assessed the patterns of whole and regional hippocampal atrophy in a large group of multiple sclerosis (MS) patients, and their correlations with neuropsychological impairment. From 103 MS patients and 28 healthy controls (HC), brain dual-echo and high-resolution 3D T1-weighted images were acquired using a 3.0-Tesla scanner. All patients underwent a neuropsychological assessment of hippocampal-related cognitive functions, including Paired Associate Word Learning, Short Story, delayed recall of Rey-Osterrieth Complex Figure and Paced Auditory Serial Attention tests. The hippocampi were manually segmented and volumes derived. Regional atrophy distribution was assessed using a radial mapping analysis. Correlations between hippocampal atrophy and clinical,

neuropsychological and MRI metrics were also evaluated. Hippocampal volume was reduced in MS patients vs HC (p \ 0.001 for both right and hippocampus). In MS patients, radial atrophy affected CA1 subfield and subiculum of posterior hippocampus, bilaterally. The dentate hilus (DG:H) of the right hippocampal head was also affected. Regional hippocampal atrophy correlated with brain T2 and T1 lesion volumes, while no correlation was found with disability. Damage to the CA1 and subiculum was significantly correlated to the performances at hippocampal-targeted neuropsychological tests. These results show that hippocampal subregions have a different vulnerability to MS-related damage, with a relative sparing of the head of the left hippocampus. The assessment of regional hippocampal atrophy may help explain deficits of specific cognitive functions in MS patients, including memory and visuospatial abilities.

G. Longoni  M. A. Rocca  E. Pagani  G. C. Riccitelli  M. Filippi (&) Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy e-mail: [email protected]

Keywords Hippocampus  Radial mapping  Multiple sclerosis  Magnetic resonance imaging  Cognitive impairment

G. Longoni  M. A. Rocca  B. Colombo  M. Rodegher  G. Comi  M. Filippi Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy A. Falini Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy A. Falini CERMAC, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy

Introduction Multiple sclerosis (MS) is recognized as a central nervous system (CNS) disease involving both the white matter (WM) and gray matter (GM). Pathological studies have shown widespread GM demyelination which involves the neocortex, thalamus, basal ganglia, hypothalamus, hippocampus, cerebellum, and spinal cord (Geurts and Barkhof 2008). Several MRI studies have shown a marked involvement of the GM in MS in terms of focal lesions, diffuse tissue abnormalities, and irreversible tissue loss (i.e., atrophy).

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Defining in vivo the extent and topographic distribution of GM damage is likely to improve our understanding of some of the clinical manifestations of MS, particularly cognitive impairment. Episodic memory, information processing speed and working memory are typically affected in MS patients, with episodic memory impairment being described in 43–70 % of them (Amato et al. 2006). Due to its crucial role in declarative memory, the hippocampus represents an important target of investigation. Anatomically, the hippocampus is one of the most complex structures of the CNS, consisting of two archeocortical laminae rolled up one inside the other: the cornu Ammonis (CA) and the dentate gyrus (DG). The hippocampal formation includes also the subiculum, which prolongs the CA. The CA has a heterogeneous structure and has been divided into four histological subfields (CA1–CA4) (Duvernoy 2005). Function of hippocampus has been linked to long-term declarative memory, visuospatial integration and navigation, although recent pieces of evidence suggest its contribution also to working memory processes (Poch and Campo 2012). Despite this, only a few studies have investigated the role of hippocampal damage on cognitive deficits in MS. The number of hippocampal lesions has been related to visuospatial memory performance (Roosendaal et al. 2010), whereas global hippocampal atrophy has been correlated with memory impairment (Sicotte et al. 2008). Only one study (Sicotte et al. 2008) has evaluated the regional involvement of the hippocampus in MS and found that patients with the relapsing remitting (RR) form of the disease had a selective atrophy of the CA1 region, whereas in those with secondary progressive (SP) MS there was an involvement of other CA regions, which was associated with worst performance in a verbal memory task. Histopathological studies have shown that the CA1 subregion and the molecular layer of the DG (DG:SM) are prone to the formation of intracortical demyelinating lesions, while at least some portions of the hilus of the DG (DG:H, also known as CA4) and the CA2–CA3 regions are consistently spared (Geurts et al. 2007; Papadopoulos et al. 2009), suggesting that susceptibility to MS damage might differ in the different portions of the hippocampus. The aims of this work were to provide a detailed characterization of regional hippocampal atrophy in MS patients and to assess its relationship with deficits of hippocampal function in terms of verbal and spatial memory. To this end, we used a radial mapping method, which has been applied to study several neurodegenerative conditions and which allows an assessment of group differences by averaging hippocampal shapes using 3D parametric surface mesh models (Thompson et al. 2004).

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Methods Subjects One-hundred and three right-handed (Oldfield 1971) consecutive patients with MS (Polman et al. 2011) [22 RRMS (Lublin and Reingold 1996), 33 SPMS (Lublin and Reingold 1996), 23 primary progressive [PP] MS (Polman et al. 2011), and 25 benign MS (Pittock et al. 2004)] were studied. Twenty-eight age- and sex-matched right-handed (Oldfield 1971) healthy controls (HC) with no previous history of neurological, psychiatric, or cardiovascular disorders, and a normal neurological examination were also enrolled. To be included, patients had to be relapse- and steroid-free for at least 1 month before MRI acquisition. Sixty-nine patients were receiving disease-modifying treatments (interferon beta: 37 subjects; glatiramer acetate: 12 subjects; immunosuppressive treatment, including mitoxantrone and azathioprine: 20 patients) for at least 6 months prior to scan date. On the day of MRI scanning, all patients underwent a standard neurologic examination with rating using the Expanded Disability Status Scale (EDSS) score (Kurtzke 1983). Ethics committee approval Approval was received from the local ethical standards committee on human experimentation, and written informed consent was obtained from all subjects prior to study enrolment. Neuropsychological assessment Within 48 h of clinical and MRI assessment, all MS patients underwent a neuropsychological assessment performed by an experienced neuropsychologist unaware of clinical and MRI results. This assessment was specifically designed to assess hippocampal functions and included: (a) verbal and visuospatial memory (Paired Associate Word Learning [WL] Test (Novelli 1986), Short Story (SS) Test (Novelli 1986), and Rey-Osterrieth Complex Figure [ROCF]-delayed recall task) (Caffarra et al. 2002) and (b) working memory and information processing speed (Paced Auditory Serial Attention Test-300 Version [PASAT]) (Gronwall 1977). Briefly, in WL Test, 10 variably related word pairs are presented to the subject for three consecutive learning trials, each one followed by a retrieval trial. During each retrieval phase, the first word of each pair is presented, in a different fashion, as a cue word to fetch the corresponding response word. The number of word pairs correctly recalled is then scored. For the SS Test, the patients listen to a short story; after the listening phase they are asked to repeat the story, once immediately

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(‘‘immediate recall’’) and once after a 10-min interval during which they are involved in other non-verbal tasks (‘‘delayed recall’’). The number of correct details correctly remembered in each trial is then scored. All tests were adapted to and validated in the Italian language. Referring to normative data (Amato et al. 2006; Caffarra et al. 2002; Novelli 1986), individual raw scores were adjusted for age, sex and education. For each patient, the results from all neuropsychological tests were also scored using a standardized method based on a comparison with the percentile distribution of values from normal controls. The ‘‘equivalent scores’’ ranged from 0 to 4, and a score equal to 0 (original score lower then the 5th percentile of values from normal population) was considered pathological. Brain MRI acquisition and analysis Using a 3.0-Tesla scanner (Philips Medical Systems, Eindhoven, the Netherlands), the following sequences were obtained: (a) 3D T1-weighted fast field echo (FFE) (TR/TE = 25/4.6 ms, flip angle = 30°, matrix size = 256 9 256, FOV = 230 9 230 mm2; 220 contiguous, axial slices with voxel size = 0.89 9 0.89 9 0.8 mm), and (b) dual-echo turbo spin echo (TSE) (TR = 2,599 ms, TE = 16/80 ms, echo train length = 6.44 contiguous 3-mm-thick axial slices with a matrix size = 256 9 256, FOV = 240 mm2). All image pre-processing was performed by a single observer blinded to subjects’ identity and neuropsychological test results. T2 lesion volumes (LV) were quantified using a local thresholding segmentation technique (Jim 5, Xinapse Systems Ltd., Northants, UK). T1-hypointense lesions were identified and segmented on the 3D FFE images, which were previously coregistered to the dual-echo scans. On 3D T1-weighted images, normalized brain (NBV), WM (NWMV) and GM (NGMV) volumes were measured using SIENAx software (Smith et al. 2002), after T1hypointense lesion refilling (Chard et al. 2010). Hippocampal segmentation Hippocampal segmentation was obtained for each subject from the 3D T1-weighted images: first, image intensity non-uniformity was corrected using the Uniformity Correction Tool (Jim software). Images were then aligned to the Montreal Neurological Institute (MNI) space using the vtk-CISG tool and an affine transformation (Studholme et al. 1997). Finally, they were reformatted into the coronal plane (pixel size = 1 91 9 1 mm) using the Jim software. Based on the anatomical and MRI description provided by the Duvernoy atlas (Duvernoy 2005), hippocampal boundaries were manually traced according to a

standardized protocol (Pruessner et al. 2000). We traced the CA, the DG (including the dentate hilus [DG:H], also known as CA4, and the stratum moleculare of the DG [DG:SM]), and the subiculum (including prosubiculum, subiculum proper and presubiculum). Sporadic fluid-filled spaces in the hippocampal complex and choroid plexus were excluded. Manual tracing was performed on contiguous coronal slices using the MultiTracer software (http:// www.loni.ucla.edu/Software/MultiTracer) (Fig. 1). The same tool was used to compute the volumes of the traced structures, which were retained for subsequent analysis. To test intra- and inter-observer reproducibility of hippocampal segmentation, two observers evaluated the scans of 20 randomly selected subjects twice, 2 weeks apart. Intra-class correlation coefficient (ICC) was 0.93 for intrarater and 0.91 for inter-rater assessment. Radial atrophy mapping To identify regional differences in hippocampal morphology, we used surface-based mesh modeling (Thompson et al. 2004). This analysis was performed using functions available within the library LONI Shape Tools (http:// www.loni.ucla.edu/Software/ShapeTools version 1.3.11). Briefly, contour points were first corrected to have counterclockwise orientation, with the starting point at the maximum (right most) x value. Then, each hippocampus contour was resampled to have the same number of vertices across subjects, a 3D curve traced out the centroid of the hippocampal boundary in each section and the distance of each surface vertex from the center line calculated, resulting in a vertex-based measure of the radial size. Statistical analysis Statistical analysis of clinical, neuropsychological and conventional volumetric MRI variables was performed using the SPSS software (SPSS Inc, Chicago, III, release 20.0). Between-group comparisons were performed using an independent sample t test. Correlations between clinical, neuropsychological and MRI metrics were performed using Spearman’s rank correlation coefficient, and adjusted for multiple comparisons (Bonferroni correction). The statistical analysis of radial mapping data was performed using the LONI Rshape library (http://www. loni.ucla.edu/twiki/bin/view/MAST/RShape). An analysis of variance, adjusted for age, was used to evaluate local differences in radial size between HC and MS patients at equivalent locations. The correlation between hippocampal radial measures and clinical and brain MRI findings was assessed using the Pearson correlation, controlling for age. For visualization, the associated p values and Pearson correlation coefficients were plotted on the surface

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Brain Struct Funct Fig. 1 a Coronal magnetic resonance imaging (MRI) slices from a healthy control in rostrooccipital direction. a, b: Hippocampal head; c: hippocampal body; d: hippocampal tail (subsplenial gyrus). Subfields color labels: green Cornu Ammonis (CA1) subfield; yellow CA2 subfield; gray CA3 subfield; light blue stratum moleculare of the dentate gyrus (DG:SM); dark blue hilus of the DG (DG:H, i.e., CA4 subfield); red subiculum. Subfield mapping is based on Duvernoy (2005) and Yushkevich et al. (2009) b Schematic estimation of the location of hippocampal subfields superimposed on the average hippocampus obtained from healthy subjects

obtained by averaging radial sizes across subjects of the same group. A color map was created to display and differentiate ranges of p values. A p value \0.05 was considered statistically significant. False discovery rate (FDR) was used to confirm the results. To standardize the anatomical location of significant changes in radial size, we built a surface map of the hippocampal formation divided into its histological subfields (CA1–CA4, DG and subiculum), which was based on anatomical and MRI atlases (Duvernoy 2005; Yushkevich et al. 2009), and overlaid on the average hippocampus obtained from the HC group (Fig. 1).

Compared to HC, MS patients had lower NBV, NGMV and volume of the left and right hippocampus (p \ 0.001 for all the comparisons). No correlation was found between hippocampal volumes and age, neither in MS patients, nor in HC. Table 3 summarizes the correlation between hippocampal atrophy and clinical and MRI variables. In MS patients, hippocampal atrophy was correlated with disease duration, NBV, NGMV, T2 LV and T1 LV (r value ranged from -0.6 to -0.3 and from 0.51 to 0.56; p from 0.008 to 0.02, Bonferroni corrected). No correlation was found with performance in neuropsychological tests (data not shown). Radial mapping analysis

Results Clinical, neuropsychological and conventional MRI data Table 1 summarizes the main demographic, clinical and conventional MRI characteristics of MS patients and HC, while Table 2 shows the results of neuropsychological assessment of MS patients.

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Figure 2 shows the regional distribution of hippocampal radial atrophy in MS patients vs HC. Compared to HC, MS patients had volume loss (p \ 0.001) in regions corresponding to the right hippocampal head (DG:H and inferior subiculum), right hippocampal body (lateral aspect of the CA1 subfield and medial aspect of subiculum), and right tail. On the left side, significant shape changes were found in the lateral aspect of the CA1 subfield, and in the medial aspect of the subicular region. At p values between 0.001

Brain Struct Funct Table 1 Main demographic, clinical and conventional MRI characteristics of healthy subjects and patients with MS Healthy subjects (n = 28)

MS patients (n = 103)

p values

Women/men

18/10

67/36

n.s.

Mean age (range) (years)

44.8 (24.9–69)

45.4 (20.4–73.4)

n.s.

Mean disease duration (range) (years)



14.3 (1–34.3)



Mean EDSS (range)



4.1 (1.0–8.0)



Mean NBV (SD) (ml)

1,617 (87)

1,507 (98)

\0.001

Mean NGMV (SD) (ml)

761 (75)

644 (97)

\0.001

Mean NWMV (SD) (ml)

856 (105)

864 (99)

n.s.

Mean T2 LV (SD) (ml)



12.7 (12.1)



Mean T1 LV (SD) (ml)



8.3 (8.6)



Mean R NHV (SD) (ml)

3.9 (0.5)

3.4 (0.5)

\0.001

Mean L NHV (SD) (ml)

3.8 (0.5)

Table 3 Correlations between hippocampal volumes and demographic, clinical and conventional MRI findings Healthy subjects

MS patients

Right NHV r (p)

Left NHV r (p)

Right NHV r (p)

Left NHV r (p)

Age

n.s.

n.s.

n.s.

n.s.

Disease duration





-0.30 (0.02)

-0.36 (0.008)

EDSS





n.s.

n.s.

NBV

n.s.

0.54 (0.02)

0.56 (0.008)

0.52 (0.008)

NWMV

n.s.

n.s.

n.s.

n.s.

NGMV

n.s.

n.s.

0.56 (0.008)

0.51 (0.008)

T2 LV





-0.56 (0.008)

-0.51 (0.008)

T1 LV





-0.53 (0.008)

-0.46 (0.008)

r Spearman’s rank correlation coefficient (Bonferroni corrected) 3.4 (0.5)

\0.001

SD standard deviation, n.s. not significant, EDSS Expanded Disability Status Scale, NBV normalized brain volume, NGMV normalized gray matter volume, NWMV normalized white matter volume, LV lesion volume, NHV normalized hippocampal volume, R right, L left

Table 2 Neuropsychological performance of MS patients Mean scores (range)

Number of patients with abnormal performance (%)

WL Test

12.0 (4.5–20)

2 (2)

SS Test

11.3 (3.5–21)

22 (21)

ROCF recall task

11.6 (0–27.8)

37 (36)

PASAT Test

31.7 (0–60)

35 (34)

WL Word Pair Learning, SS Short Story, ROCF Rey-Osterrieth Complex Figure, PASAT Paced Auditory Serial Attention. See text for further details

and 0.05, shape changes were also found in the CA1 region and inferior subiculum of the hippocampal head. After FDR correction, the estimated FDR was 3 % on the right and 5 % on the left hippocampus. Correlation between regional hippocampal atrophy, brain lesion volumes, disease duration and performance in neuropsychological tests T2 LV and T1 LV were correlated with radial atrophy of the whole lateral CA1 subfield and part of the subiculum of both hippocampal body as well as the CA1 region of the hippocampal head, bilaterally (r values between -0.2 and -0.5; p \ 0.001; FDR rate at p \ 0.05 between 4 and 7 %). Disease duration correlated with some small clusters

NHV normalized hippocampal volume, n.s. not significant, R right, L left, NBV normalized brain volume, NWMV normalized white matter volume, NGMV normalized gray matter volume, LV lesion volume

of radial atrophy involving the CA1 and the subiculum, without showing a clear lateralization (r values ranged between -0.2 and -0.4; p values between \0.001 and 0.05; FDR rate were 33 % for the right and 22 % for left hippocampus) (Fig. 3). Correlations between regional hippocampal atrophy and performance in neuropsychological tests are displayed in Fig. 3 and summarized in Table 4. None of the structure– function correlations survived the FDR correction (FDR rate at p \ 0.05: PASAT test, 36 and 19 %; WL Test, 46 and 87 %; ROCF recall task, 56 and 80 % for right and left hippocampus, respectively; SS Test: 51 % bilaterally).

Discussion In this study, we first assessed global hippocampal atrophy in MS patients and its relation with clinico-radiological variables and performance in memory tests. Next, we investigated the regional anatomical distribution of hippocampal shape changes and their correlation with performance in hippocampal-dependent memory tasks. In line with previous reports (Anderson et al. 2010; Papadopoulos et al. 2009; Roosendaal et al. 2010; Sicotte et al. 2008), MS patients experienced a significant hippocampal atrophy, which was related to disease duration and global measures of brain damage. No relationship was found with performance in neuropsychological tests.

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Brain Struct Funct Fig. 2 Distribution of regions with significant hippocampal atrophy (color coded on the basis of the p values) in MS patients compared to healthy subjects. R right, L left

Regional hippocampal analysis showed a different vulnerability of hippocampal subregions, pointing to CA1 and subiculum as the most severely damaged regions in MS patients. Significant correlations were found between atrophy of these regions and poor performance in visuospatial memory-related tasks (ROCF-delayed recall test), and poor verbal memory performance (WL Test). Conversely, deficits of more integrated functions, such as working memory (PASAT Test), were correlated with a more anterior and distributed pattern of hippocampal atrophy. CA1 was the most affected hippocampal region in MS patients and this involvement was significantly correlated with the extent of brain WM lesions. Among hippocampal histological subfields, CA1 is known to have the highest susceptibility to damaging events (Blumcke et al. 2007; Mueller et al. 2007; West et al. 2004). Several factors are likely to contribute to an explanation of the preferential involvement of CA1, including a high concentration of glutamatergic N-methyl-D-aspartate receptors, an elevated intrinsic formation of reactive oxygen species (Wang et al. 2005) and a reduced expression of neuroprotective factors (Tohgi et al. 1995). Pathological studies of the hippocampus of MS patients have described a profound damage to CA1, with a reduction in neuronal count and size (Papadopoulos et al. 2009), as well as the presence of demyelinating lesions (Geurts et al. 2007; Papadopoulos et al. 2009). In line with a previous MRI study (Sicotte et al. 2008), we found that the subiculum is also involved and that this is influenced by T2 and T1 lesion burdens. This is not unexpected considering that, after receiving collaterals from intrahippocampal pathways, the subiculum provides the principal neocortical output of the hippocampus through fibers that are part of the alveus and the fimbria (Duvernoy 2005). Therefore, subicular atrophy could be interpreted as the consequence of neurodegeneration and metabolic derangement of the CA1 subfield or as a structural modification occurring in response to an altered network connectivity (Hulst et al. 2012). Moreover, intracortical and leukocortical demyelinating lesions are

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frequent in this region (Geurts et al. 2007; Papadopoulos et al. 2009), and may contribute to its morphologic alterations. It is noteworthy that volumetric abnormalities did not involve the CA2 subfield, in line with the notion of its relative resistance to hypoxic/ischemic damage and excitotoxic insults (Woodhams et al. 1993). Intriguingly, we found that in MS patients the right hippocampal head (and specifically the DG:H) was more affected than the left. Prior experimental data suggested a differential susceptibility to damage of the right and left hippocampi. Among these, Roosendaal et al. (2010) found a predominant atrophy of the right hippocampus in MS patients, accompanied by a more severe decrease of functional connectivity, when compared to the left side. Previous autoptic studies (Geurts et al. 2007; Papadopoulos et al. 2009) demonstrated that the different hippocampal subfields do not seem to be randomly affected by demyelination, and that there is a predilection for intrahippocampal lesion formation in the CA1 subfield and in the DG, with a relative sparing of the DG:H (when involved, the DG:H appears to be mainly affected by lesions extending inwards from the pial lining of the DG) (Papadopoulos et al. 2009). Conversely, leukocortical lesions appear to be far less anatomically specific, and the occurrence of such lesion pattern in the DG:H (Papadopoulos et al. 2009) might, at least partially, explain the presence of tissue loss in this region. It should also be noted that a reduction of myelin (Geurts et al. 2007) and synaptic density (Papadopoulos et al. 2009) has been reported in the DG:H of MS patients, and this could also account for the volume loss we detected. Nonetheless, it is of note that none of the two above-mentioned studies (Geurts et al. 2007; Papadopoulos et al. 2009) addressed the specific regions of the hippocampal head in which we detected volume loss. The DG:H appears on the surface of the hippocampus as the uncal apex, separated from the pia madre only by the alveus (Duvernoy 2005), and might be exposed to the same meningeal inflammatory milieu that leads to diffuse demyelination, cortical lesion formation and neurodegenerative processes in the neocortex and in the DG:SM

Brain Struct Funct Fig. 3 Radial mapping analysis: correlations between regional hippocampal atrophy and T2 and T1 lesion volumes, disease duration and neuropsychological test performances in patients with multiple sclerosis, expressed as maps of p and r values. r is the Pearson’s correlation coefficient. p represents the p values (uncorrected for FDR and multiple comparisons). R right, L left

(which in the hippocampal body is lined with pia mater). When considering the clinico-demographical characteristics of our sample and those of the two above-mentioned studies (Geurts et al. 2007; Papadopoulos et al. 2009), the lower age, shorter disease duration and higher prevalence of RRMS patients in our sample might contribute to explain the pattern of GM damage that we detected. Pathological studies have demonstrated that meningeal inflammation is prominent in early MS (Lucchinetti et al. 2011), and that it is topographically associated with

cortical demyelination (Popescu and Lucchinetti 2012). Given its particular connection with the meningeal lining, this region of the hippocampal head might represent a spyhole through which one may watch the early phases of cortical pathology in MS. Despite that a longer disease duration was associated with a global reduction of both right and left hippocampal volume, the shape analysis did not detect any significant pattern of atrophy associated with a longer disease duration, other than a sparse and fairly bilateral volume loss

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Brain Struct Funct Table 4 Correlations between performance in neuropsychological tests and atrophic changes of histological subfields (with their localization along the antero-posterior axis of the hippocampus) Right hippocampus

Left hippocampus

Head subfield

Body subfield

Tail subfield

Head subfield

Body subfield

r (p)

r (p)

r (p)

r (p)

r (p)

WL Test

n.s.

CA1 0.2–0.4 (0.001–0.05)

CA1 0.2–0.4 (\0.001)

n.s.

CA1 0.2–0.4 (\0.001)

n.s.

SS Test

Subiculum 0.2–0.4 (\0.001) n.s.

n.s.

n.s.

n.s.

n.s.

CA1, subiculum 0.2–0.4 (\0.001)

n.s.

Subiculum 0.2–0.4 (\0.001) n.s.

n.s.

n.s.

Subiculum 0.2–0.4 (\0.001)

CA1 0.2–0.4 (\0.001)

n.s.

Subiculum 0.2–0.4 (\0.001)

CA1 0.2–0.4 (\0.001)

n.s.

ROCF recall task PASAT Test

Tail subfield r (p)

For each hippocampal part (head, body and tail), the range of the correlation coefficients r and p values (uncorrected for multiple comparisons) of all the hippocampal surface points showing a significant correlation with a given neuropsychological task has been reported r Pearson’s correlation coefficient, p p values (uncorrected for FDR and multiple comparisons) WL Word Pair Learning, SS Short Story, ROCF Rey-Osterrieth Complex Figure, PASAT Paced Auditory Serial Attention

spanning across the CA1 subfield and the subiculum. This finding was not unexpected and likely relates to a diffuse volume loss throughout the hippocampal formation rather than a differential involvement of a specific substructure. Although the precise subdivision of functions between the left and right hippocampi is still largely unclear, there is evidence for lateralization of some of the hippocampaldependent memory functions (Bird and Burgess 2008; Burgess et al. 2002). In detail, the right hippocampus is thought to be involved in processing and encoding of spatial relationships, thus playing a crucial role in visuospatial memory. Consistent with this, we found that damage to the right subicular region was related to a poor performance in the ROCF-delayed recall test. Conversely, the left hippocampus is involved in episodic memory, contributing to storage of verbal material (Baxendale et al. 1998), and encoding of ‘‘relationships between linguistic entities in the form of narratives’’ (Burgess et al. 2002), which may help explain the relationship between atrophy of the body of the left hippocampus and the deficit in WL Test performance found in our patients. It should also be noted that an abnormal performance in the SS Test, the other verbal memory test included in our battery, was associated to a more anterior and bilateral pattern of hippocampal atrophy. This finding might reflect the occurrence of injury to a more distributed circuit involved in the spatio-temporal contextualization or episodic memory, which encompasses the exchange of temporal information between the hippocampi and the frontal lobes (Burgess et al. 2002). It is also noteworthy that the verbal and visuospatial cognitive performance of our patients correlated with a lateralized alteration of the CA1 subfield of the posterior part of the right hippocampus. This could partly

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be accounted for by the preponderance of damage affecting the right hippocampus in our patients. However, it is also consistent with recent observations suggesting an intrinsic structural and functional differentiation along the anteroposterior axis of the hippocampus, as well as with data indicating a structural segregation of the extrinsic connectivity of this structure. While the anterior medial temporal lobe participates in the representation and recognition of complex objects (Barense et al. 2010), recognition memory (Bird and Burgess 2008) and access to abstract semantic knowledge (Hodges and Patterson 2007), the posterior part of the hippocampus and parahippocampal gyrus are involved in visuospatial memory, mental imaging of spatial scenes (Bird and Burgess 2008), spatial navigation (Ekstrom and Bookheimer 2007), and in some aspects of the formation of declarative memory (Burgess et al. 2002). In contrast to a previous study (Sicotte et al. 2008) which found no relationship between working memory performance and global or regional hippocampal volumes, we found that performance in PASAT was correlated with atrophy of the infero-medial aspect of the subicular region of the hippocampal head, bilaterally. The traditional explanation for the impairment of executive functions in MS is injury to WM tracts connecting fronto-parietal associative areas (Dineen et al. 2009). However, recent studies have suggested a relationship between working memory performance and hippocampal functions. A functional MRI study with PASAT (Rachbauer et al. 2006) detected an increased recruitment of the left hippocampus in MS patients with normal task performance, compared to controls and clinically isolated syndrome patients. This finding was interpreted as an adaptive mechanism of

Brain Struct Funct

functional reorganization through which the hippocampus could support working memory processes in advanced phases of the disease. From an anatomical point of view, there is evidence that efferents from the subicular region of the anterior hippocampus project directly or indirectly to the prefrontal cortex (PFC) (Henny and Jones 2008). As a consequence, the integrity of the anterior hippocampus has been upheld as a critical factor in the regulation of PFCmediated cognitive processes and working memory functions (Riegert et al. 2004). Taken together, all of these suggest that damage of the subicular region of the anterior hippocampus could be implicated in the expression of overt working memory deficits in patients with MS. Our study is not without limitations. Firstly, radial mapping methods track surface expansions or contractions compared to a reference shape; therefore, it does not permit the determination of whether the observed change anatomically pertains to the superficial tissue or to internal structures. Moreover, since the radial size is calculated taking the midline as a reference, a distortion of the mapped structure that modified the path of the midline would lead to apparent changes in regional atrophy which would be impossible to discriminate from a real volumetric change. Nonetheless, our regional findings agree with previous pathological and imaging data in MS. Secondly, we did not acquire a double inversion recovery pulse sequence, which would have allowed us to detect at least some hippocampal focal lesions. As a consequence, the contribution of focal hippocampal demyelination to regional atrophy distribution and memory decline cannot be fully elucidated by this study. Thirdly, the cognitive performances of our patients have been tested using a standard neuropsychological battery, and we lack more specific tasks to test verbal and visuospatial memory. In addition, we did not perform a neuropsychological evaluation in our healthy subjects. Lastly, the data regarding the endogenous cortisol levels and the cumulative exogenous steroids exposition, as well as those regarding other anti non-steroid anti-inflammatory drugs and the number of relapses were not collected in our patients; thus, we were unable to investigate the effect of stress-related hormones and repeated cycles of neuroinflammation on hippocampal shape. Acknowledgments This study has been partially supported by a grant from Fondazione Italiana Sclerosi Multipla (FISM 2012/R/8).

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Deficits in memory and visuospatial learning correlate with regional hippocampal atrophy in MS.

The hippocampus has a critical role in episodic memory and visuospatial learning and consolidation. We assessed the patterns of whole and regional hip...
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