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Hippocampal damage in multiple sclerosis : the contribution of neuroimaging

PART OF MS Alumni FEATURE
Hippocampal damage in multiple sclerosis : the contribution of neuroimaging
  • Neurology

Maria A. Rocca MD.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Multiple sclerosis (MS) is now recognized as a central nervous system (CNS) disease involving both the white matter (WM) and gray matter (GM). Moreover, pathological studies have shown widespread GM demyelination which is not limited to the neocortex, but also involves the thalamus, basal ganglia, hypothalamus, hippocampus, cerebellum and spinal cord.1 Defining in vivo the extent and topographic distribution of GM damage is likely to improve our understanding of some clinical manifestations of MS, particularly cognitive impairment. Episodic memory, visuospatial memory, working memory and information processing speed are cognitive skills that are typically affected in MS patients, with episodic memory impairment being described in 43-70% of them.2

Due to its crucial role in declarative memory, the hippocampus represents an important target of investigation in understanding the pathological substrates of cognitive impairment in MS.

 

The structure of the hippocampus

Anatomically, the hippocampus is one of the most complex structures of the CNS. It is part of the limbic lobe, that is situated on the inferior medial aspect of the hemisphere, and separated from adjoining cortex by the limbic fissure. This fissure is a discontinuous sulcus composed successively of the cingulate, subparietal, anterior calcarine, collateral, and rhinal sulci. According to its structure, the limbic lobe is usually divided into the archeocortex, the simplest part of the cerebral cortex including the hippocampus, the proximal part of the subiculum and the amygdala, the mesocortex, made up of the transitional cortex between the archeocortex and the following neocortex, which includes the cingulate and parahippocampal gyri.

The hippocampus bulges into the temporal horn of the lateral ventricle, and its general appearance resembles a sea horse in shape. It is arched around the mesencephalon, and the arch can be divided into three segments, following an antero-posterior direction: 1) a head, or anterior segment, which is transversely oriented and dilated, and which shows elevations, the digitationes hippocampi; 2) a body, or middle segment, which is sagittally oriented; and 3) a tail, or posterior segment, which is also oriented transversely and which narrows, disappearing beneath the splenium. The human hippocampus has a total length of between 4 and 4.5 cm; the body is on average 1 cm wide, and the head is 1.5-2 cm wide.

The hippocampus is bilaminar, consisting of the cornu Ammonis (CA) and the gyrus dentatus (DG), with one lamina rolled up inside the other. During cerebral development a final position is arrived at, in which the CA and the DG resemble two interlocking, U-shaped laminae, one fitting into the other and separated from each other by the hippocampal sulcus. The deep part of the hippocampal sulcus can disappear or remain visible as the vestigial hippocampal sulcus, while its superficial part is clearly seen on the temporal lobe surface as the superficial hippocampal sulcus. In coronal sections, the CA has a heterogeneous structure due to different aspects of its pyramidal neurons, and has been divided into four histological subfields: CA1, CA2, CA3, CA4. In coronal sections of the hippocampal body, the DG is a narrow, dorsally concave lamina, and its concavity envelopes the CA4 segment. The CA and DG are fused together, separated only by the vestigial hippocampal sulcus.3

The “hippocampal formation” also includes the subiculum, which prolongs the CA. The subiculum itself is divided into several segments: 1) the prosubiculum, which continues CA1, 2) the subiculum proper, partly hidden by the DG, 3) the presubiculum, and 4) the parasubiculum, which passes around the margin of the parahippocampal gyrus to the entorhinal area.3

Functions and connections of the hippocampus

The hippocampus is involved in several functions, including learning and memory, regulation of emotional behavior, certain aspects of motor control, and regulation of hypothalamic function.

It is generally admitted that the hippocampus has a critical role in learning and memory. Information arising from large neocortical zones converges to the entorhinal area, and then to the hippocampus. Thus, newly acquired items cross the hippocampal filter before being fixed in the neocortex. While memory of new or recent items (short-term memory) depends on the hippocampus, memory of old ones (long-term memory) depends on the neocortex. The hippocampus is implicated in all aspects of the declarative memory: 1) semantic memory, which involves memory of facts and concepts, 2) episodic memory, which permits conscious recollection of events and of the relations between them, and 3) spatial memory, which involves spatial location recognition.

After passing through the hippocampus, the information is stored in the association cortex. The hippocampal projections involve large neocortical areas, in particular including the prefrontal and retrosplenial cortices. The intrahippocampal circuitry can be divided into two pathways: 1) the polysynaptic pathway, which links all parts of the hippocampus by a long neuronal chain, 2) the direct pathway, which directly reaches the output neurons of the hippocampus. The intrahippocampal polysynaptic circuitry is composed of a long neuronal chain made up of the entorhinal area, the DG, CA3, CA1, and the subiculum. The principal input to the polysynaptic pathway from the cortex is made up of fibers that originate in a large cortical area that includes the posterior parietal association cortex (area 7) and the neighboring temporal and occipital cortices (areas 40, 39, and 22). The posterior parietal association cortex sends fibers to the entorhinal area through the parahippocampal gyrus. The main function attributed to the posterior parietal association cortex, related to the superior visual system, is perception of the position of an object in space. This spatial perception is thought to then be encoded through the polysynaptic pathway. Apparently, also the episodic memory and the memory of facts in relation to each other depend on this system. The principal outputs following the polysynaptic pathway to the cortex follow the fimbria, the crus and body of the fornix, and the columns of the fornix, also known as the postcommissural fornix (behind the anterior commissure).The nervous impulses then reach the anterior thalamic nucleus, either directly or via the mammillary bodies, extending from there into the mammillo-thalamic tract. From the thalamus, impulses then reach the posterior cingulate cortex (area 23) and the retrosplenial cortex (areas 29 and 30). Some projections also reach the anterior cingulate cortex (area 24). In the direct hippocampal pathway the fibers directly reach CA1 and the hippocampal outputs without following the usual polysynaptic chain. The main input from the cortex is the inferior temporal association cortex (area 37, 20), which reaches the entorhinal area. The functions of this cortex, which is connected to the inferior visual system, are the recognition and description of objects; therefore the semantic memory is believed to involve this system.

Clinical observations in neurological diseases show that hippocampal damage mainly produces disorders of memory, particularly of short-term memory. Marked defects in remembering events that occur after appearance of the lesion (producing anterograde amnesia) can be observed, but the most frequent defects are in spatial memory. Taking into account the different sensitivity to hypoxia in the different subfields of the CA, CA1 and the adjacent subiculum are considered to be the “vulnerable sector”, whereas CA3 is called the “resistant sector”, and CA4 being a sector of medium vulnerability.

 

Identification on MRI of the hippocampus

In vivo measurement of human hippocampal volume and shape with MRI has become an important element of neuroimaging research. Nevertheless, volumetric findings are often controversial, since a large number of different anatomical protocols for delineating the hippocampus represents an important source of variance between studies.4, 5 While manual segmentation of the hippocampus is still considered to be the gold standard, semi-automated and automated methods for its delineation have been developed. Several studies have performed direct comparison of manual and automated hippocampal volume measurements and have shown that automated hippocampal techniques generate large volumes compared to manual techniques.6-8 In addition, it has been shown there was a lower agreement of measurements from automated and manual methods when the hippocampus was atrophied, suggesting that automated measurements of the hippocampus may not reliably detect volume loss.6

The dilemma of defining hippocampal borders in MRI is related to the anatomical complexity of this archeocortical structure. Therefore, any definition of the hippocampus based on macroanatomical landmarks in MRI is limited by the fact that the underlying cytoarchitecture is not obvious in MR images. Considering gray and WM structures involved in the hippocampal segmentation protocols, the majority of them include alveus and fimbria (the main efferent pathways from the hippocampus), and the subiculum. Since this latter structure is often indistinguishable from the CA on MRI, it is almost always included in the term hippocampus (referring to the hippocampal formation).

Delineating the anterior border of the hippocampus is one of the most difficult tasks in manual segmentation, as the amygdala and hippocampus are hard to discern on many MRI scans. One prevalent landmark used for differentiation of the amygdala and hippocampus on coronal planes is the alveus, which is internal to the hippocampus. The alveus has an anatomically fixed rapport with the hippocampus, it exhibits a high contrast to GM tissue and it is commonly visible in images with 1×1×1 mm3 or higher resolution. Alternatively, the CSF of the inferior horn of the lateral ventricle can be assumed as a landmark for the anterior border of the hippocampus, because of the high contrast between CSF and brain tissue. However, CSF clefts might be extremely small or even invisible in a minority of individuals, particularly in young and healthy subjects with small ventricular volume. Also the posterior end of the hippocampus seems to be a major source of variance between segmentation protocols. It seems that assessing the GM of the hippocampal tail, until it reaches its posterior ovoid form, corresponds best to the anatomical boundaries of this structure.9-11 The term inferior medial border of the hippocampus usually refers to the hippocampal field along the inferior part of the CA and the subiculum.

 

Hippocampal damage in MS: pathologic and neuroimaging features

Hippocampal lesions

The first histopathological study that systematically assessed hippocampal demyelination in MS was a postmortem study of hippocampal tissue samples of 19 chronic MS cases, compared with 7 controls.12 A high number of lesions (37) were found in 15/19 (79%) of MS cases. 27% of all lesions were mixed intrahippocampal-perihippocampal lesions, and had a larger size compared with isolated intrahippocampal lesions. Moderate microglial activation was frequently observed at the edges of mixed lesions, while it was rare in isolated intrahippocampal lesions. Moreover, isolated intrahippocampal lesions had a specific anatomical predilection: whereas the molecular layer of the DG and the CA1 subfield were relatively often affected, the CA2 subregion and the hilus of the DG were consistently spared. Regional variations in excitotoxic sensitivity to glutamate within the hippocampus could contribute to the different sensitivities to demyelination observed in this study, as it has been shown that oligodendrocytes are especially vulnerable to increased glutamate concentration.13, 14 Thus, this study indicated that hippocampal demyelination is frequent and extensive in MS, and that anatomical localization, size, and inflammatory activity vary for different lesion type. In another histopathological postmortem study from 45 progressive MS cases (mean disease duration 27.8 years) and 7 controls, the hippocampal archeocortex was found to share common pathological features with the MS neocortex concerning demyelinating pattern, inflammatory activity and de-afferentation.15 Demyelinating lesions were detected in 53.3% of all MS hippocampal samples, with demyelination averaging 30.4%, indicating that the hippocampus is a common site for lesion formation. As reported for neocortical lesions, the majority of archeocortical lesions were chronic and subpially or subependymally located. The most commonly affected hippocampal areas were the CA1 and DG subfields, that form most of the free hippocampal surface that is encompassed by CSF, corroborating the CSF humoral factor hypothesis of subpial cortical demyelination. Moreover, in keeping with previously reported observations from the MS neocortex, archeocortical lesions are characterized by a relative paucity of inflammatory cells, with activated microglia being the main inflammatory cell type.

Hippocampal lesions can be also visualized in vivo with 3D-DIR MRI. Using such a technique,16 14/16 MS patients had at least one hippocampal lesion, with a mean number of hippocampal lesions detected of 2.6, confirming the previous histopathological finding of extensive hippocampal demyelination in MS.12 A higher number of hippocampal lesions was found in patients with higher number of CL and WM lesions, although only the correlation between the number of hippocampal lesions and CLs number was significant. Roosendaal et al. investigated also the longitudinal behavior of WM, cortical and hippocampal lesions examining DIR images, from 13 MS patients and 7 healthy controls, at two time points with a median interval of 3 years.17 In patients the median number of CL and WM lesion was significantly increased at follow-up, whereas median hippocampal lesion number remained stable.

Hippocampal atrophy

Hippocampal atrophy has been reported in independent series of MS patients. Papadopoulos et al. provided the first systematic histopathological evidence of substantial hippocampal atrophy and neuronal pathology.15 Gross hippocampal atrophy was detected, with a 22.3% reduction in the average cross-sectional area, which strongly correlated with neuronal loss. Compared to controls, neuronal numbers were decreased by 27% in CA1 and 29.7% in CA3-2. Furthermore, the size of neurons was decreased by 17.4% in CA1. Hippocampal cross-sectional area did not exhibit significant association with the extent of demyelination, suggesting that atrophy in the MS archeocortex may be largely determined by neuronal loss. The finding of significant atrophy and neuronal loss not only in the hippocampal fields affected by lesions but also in the ones without evidence of demyelination, supports the concept of diffuse neuronal injury in the GM. Neuronal injury may be driven by inflammatory and autoimmune mediators. Moreover, since glutamate is the major excitatory transmitter in the hippocampal formation, excitotoxicity is likely to play an important role in hippocampal neuronal loss.18, 19 In addition, retrograde neuronal degeneration secondary to axotomy taking place in WM lesions20 is a plausible explanation for diffuse neuronal loss leading to generalized cortical atrophy. This hypothesis is also supported by the study from Papadopoulos et al.15 who found demyelinated lesions in the fimbria in 18/45 examined MS blocks, and in several cases they displayed evidence of axonal damage and loss.

One of the first pieces of MRI evidence for hippocampal atrophy in MS has been provided by Sicotte et al.21 By measuring hippocampal volumes in 23 RRMS, 11 SPMS patients and 18 controls, the authors found that both groups of MS patients had hippocampal atrophy, and that this volume loss was disproportionately in excess of global brain atrophy, with equally affected right and left hippocampi. Subregional analysis revealed early and selective volume loss of the CA1 region of the hippocampus in RRMS, with further worsening of CA1 loss and extension of atrophy into other CA regions in SPMS. The pattern of regional hippocampal atrophy detected in this study, which could reflect a variety of neuropathological processes (demyelination, decreased dendritic density and/or neuronal loss), confirms the higher vulnerability of the CA1 subregion to a variety of insults which has been implicated in MS-related damage (inflammation, ipoxia/ischaemia, glutamate-mediated excitotoxicity, etc.).22 Hippocampal atrophy was not correlated with brain T2 lesion volumes in RRMS patients.

Significant hippocampal atrophy has been found to occur within the first decade of disease in MS patients with both relapsing and progressive onset of the disease.23 In this study, using manual segmentation of volumetric MRI, hippocampal volume was investigated in a group of 23 PPMS patients and compared to that of 34 RRMS patients and 18 healthy controls. Hippocampal volumes were significantly and bilaterally reduced in MS patients compared with controls. The mean decrease in hippocampal volume was 317 mm3 on the right and 284 mm3 on the left side. The extent of hippocampal volume loss was similar in patients with RRMS and PPMS, approximately 10% in both groups compared to controls.

Considering hippocampal volume loss in the context of a more generalized subcortical deep GM (SDGM) atrophy, recent studies have shown that selective regional, but not global, GM atrophy occurs from clinical onset to conversion to clinically definite MS.24-27 From this background, Bergsland et al.28 have found that significant SDGM, but not cortical, atrophy developed during the first 4 years of the RRMS course, strengthening the hypothesis that neurodegeneration and inflammation are both relevant in the conversion to clinically definite MS and disease progression. Specifically, the authors investigated the difference in the extent of SDGM and cortical atrophy in 212 CIS patients and 117 early RRMS, and found that early RRMS showed significant volume decreases in multiple SDGM regions but not in cortical volumes compared with patients with CIS. Patients with CIS with a median T2 lesion volume > 4.49 mL showed lower total SDGM, caudate, thalamus, globus pallidus, hippocampus and putamen volumes and higher lateral ventricle volume, but not lower cortical volumes, compared with those with a median T2 lesion volume < 4.49 mL. These findings support the concept that atrophy in the SDGM is relevant from the clinical onset of the disease. Another MRI study29 showed that, six years post-diagnosis, in a cohort of patients with RRMS, relatively mild disability and low lesion volumes, almost all subcortical structures had extensive atrophy, with a male sex predominance. In this study, only the bilateral hippocampus, amygdala, and right nucleus accumbens in men, and right hippocampus and nucleus accumbens, bilateral amygdala and putamen in woman, showed no atrophy compared to controls. These results underline the possible relevance of gender-specific atrophy in MS.

Hippocampal ultrastructural damage

Hippocampal demyelination, presenting in the form of lesions visible on histopathological samples or MRI, is also a cause, at a substructural level, of synaptic alterations in MS patients. Dendritic transection30 and loss of synaptic input31 are well documented in neocortical MS lesions. In one of the first histopathological study of hippocampal lesions,15 the CA4 hippocampal subregion (which is rarely affected by demyelinating plaques) showed significant reduction in synaptic density. CA4 receives its synaptic input from the granule cell layer of the DG,3 which is a common site for lesion formation. This indicates that the reduction in synaptic density found in CA4 may, at least partly, reflect neuronal injury and loss in the granule cell layer of the DG. Although de-afferentation may indicate severe failure of neuronal circuits,32 evidence suggests it may be largely reversible through compensatory synaptic remodeling.

Metabolic hippocampal abnormalities have also been documented in MS. In a positron emission tomography (PET) study, a significant reduction of the regional cerebral glucose metabolism was found in the hippocampi of MS patients with memory deficits, indicating impaired hippocampal function.33 Moreover, a 1H-MRS study showed an increased concentration of myo-inositol, suggestive of gliosis, in the MS hippocampus, whereas NAA was found to be in normal ranges. This finding could indicate that although subtle gliosis may already be present, the integrity of the axons may not yet be impaired in the hippocampus of MS patients.34

 

Correlation between hippocampal damage and cognitive impairment

Approximately 40-65% of MS patients are cognitively impaired.35 Although information-processing speed, working memory, attention and executive functions are the most frequently detected cognitive deficits in MS,36, 37 episodic, spatial and verbal memory are also affected.38 Memory is one of the most commonly affected cognitive domains in MS, even in the earlier stages of the disease.39, 40 The hippocampus plays a crucial role in both episodic, verbal and visuospatial memory.37, 41-43

The neuropathological studies mentioned above and investigating hippocampal damage in MS, have also tried to find correlation between histological findings of hippocampal demyelination and the features of cognitive decline. Geurts et al., in their postmortem study of hippocampal tissue samples of 19 chronic MS cases compared with 7 controls, observed hippocampal lesions in both cognitively affected and cognitively unaffected cases.12 However, in cases with cognitive decline, a higher number of large and mixed hippocampal-perihippocampal lesions were found. Whether this finding indicated that the mixed lesion type was more likely to cause cognitive problems in MS or whether cognitive decline was simply proportional to the area of hippocampal demyelination was unclear. Moreover, because of the retrospective nature of the study, it was not possible to accurately extract more detailed information regarding the exact type of cognitive deficits. In order to investigate possible molecular mechanisms of memory impairment in MS patients, Dutta et al. compared morphological and molecular changes in myelinated and demyelinated hippocampi from 22 MS and 9 control brains.44 Most of the MS patients were cognitively impaired; however they were not specifically tested for memory deficits. Demyelinated hippocampi had minimal neuronal loss but significant decreases in synaptic density, particularly in the CA1 and DG sub regions, supporting hippocampal demyelination as a cause of synaptic alterations in MS patients. The retention of 80 to 90% of neuronal perikarya in these demyelinated hippocampi is therefore encouraging, as it identifies the demyelinated hippocampal neuron as a viable and abundant therapeutic target that could enhance memory function in MS patients. Neuronal proteins essential for axonal transport, synaptic plasticity, glutamate neurotransmission and homeostasis, neuronal survival and memory/learning were significantly decreased in demyelinated hippocampi. Very few of the neuronal gene products altered in demyelinated MS hippocampus were altered in demyelinated MS motor cortex, suggesting that myelination modulates neuronal gene expression in a manner that reflects the specialized functions of different neuronal populations.

Many MRI studies have tried to find correlations between structural and functional hippocampal changes and cognitive deficits in MS patients. Roosendal et al.17 investigating the longitudinal behavior of hippocampal lesions through DIR images from 13 MS patients and 7 healthy controls at two time points with a median interval of 3 years, and analyzing cognitive tests at follow-up, found that hippocampal lesion number was related to the Location Learning Test (LLT) delay score,45 which measures visuospatial memory, one of the hippocampal functions.43, 46 In the study by Sicotte et al.21 regional and total hippocampal volume loss were correlated with worsening performance at word-list learning, a screening test for verbal memory encoding and retrieval, but not with performance at the Paced Auditory Serial Addition Task (PASAT), a test of information-processing speed. Word-list learning was most closely associated with left total and sub regional hippocampal volumes, consistent with the verbal learning of the task. Interestingly, the volume of subiculum, which is the major target of CA1 projections, was also correlated with word-list-learning performance. In the study from Anderson et al.,23 a borderline association between hippocampal volume and memory performance was observed only in patients with PPMS. There was no evidence that the relation between hippocampal volume and memory performance differed significantly between patients with RRMS and PPMS. Thus, the authors suggested that, in patients with PPMS, who have a slightly longer disease duration than those with RRMS, compensatory mechanisms may be depleted as the disease progresses, contributing to a more discernible role in memory impairment.

Previous researches suggest that memory impairment in MS may be related to two separate pathology – dysfunction of DGM and subcortical axis, which may contribute to deficient encoding, and mesial temporal lobe (MTL) dysfunction, that probably leads to deficient consolidation. To determine the relative importance of MTL and DGM structures in predicting MS performance on memory the test presented in the auditory/verbal and visuospatial domains, by Benedict et al. examined structural brain MRI and neuropsychological tests of 50 MS patients.47 The volumes of the MTL (hippocampus, amygdala) and DGM (thalamus, caudate) structures were automatically segmented and calculated, then compared with control values; neuropsychological testing contributed measures of new learning, delayed recall and recognition memory, in the auditory/verbal and visuo/spatial modalities. The authors found that MTL and DGM atrophy play significant but different roles in the memory impairment of MS patients. Whereas the DGM atrophy is the primary predictor of new learning and acquisition impairment (i.e., memory encoding), MLT atrophy plays a more critical role in the recognition of recently learned information (i.e., memory retrieval). Significant correlations between lower regional volume and poorer test performance were observed across all memory tests.

In MS patients, substantial functional abnormalities of the hippocampus are already present before spatial memory function is impaired.48 In a study by Roosendaal et al., 25 MS patients with intact spatial memory function were compared with 30 age- and sex-matched controls, to investigate changes in hippocampal functional connectivity and structural measures of hippocampal damage. Right hippocampal volume was significantly lower in MS patients as compared with controls. RS functional connectivity between the hippocampus and its anatomic target areas, including the anterior cingulate gyrus, thalamus, and prefrontal cortex, was significantly decreased in MS patients vs controls. Decreased connectivity was associated with hippocampal damage, as the largest connectivity decreases were found in the group of patients with hippocampal atrophy, compared with the group of patients without hippocampal atrophy and healthy controls. Although not reaching significance, subtle decreases of functional connectivity were also found in patients with normal hippocampal sizes compared with controls, possibly indicating that functional connectivity abnormalities may precede hippocampal atrophy.

Another fMRI study has suggested the presence of functional adaptation in the memory network before cognitive decline becomes evident in MS.49 Hulst et al. used an episodic memory fMRI task of encoding and retrieval to investigate changes in hippocampal function in 34 cognitively preserved (CP) and 16 cognitively impaired (CI) MS patients, with cognitive impairment predominantly referred to as memory impairment. During the encoding of correctly remembered items in CP MS patients, increased brain activation was found in the left anterior cingulate gyrus, left hippocampus, and bilateral parahippocampal gyri compared to healthy controls, while no brain areas showed less activation. In CI MS patients less activation was found in the right hippocampal areas and the prefrontal cortex compared to controls, while the posterior cingulate gyrus and the left precuneus showed increased activation compared to controls. Thus, while the activity of the hippocampal memory system of CP MS patients is increased compared to healthy controls during the episodic memory task, in CI MS patients relatively few extra-limbic brain areas showed increased activation, while most limbic areas displayed less activation. The increased brain activation seen in the CP MS patients may reflect a functional adaptive process to prevent cognitive deficits. When this adaptive mechanism becomes exhausted, the functionality of the hippocampal memory system will deteriorate, which may relate to the decreased brain activation measured by fMRI as well as to the appearance of memory deficits. The finding of increased activation of the left hippocampal memory network in an episodic memory task gives evidence for the lateralization of hippocampus-dependent memory functions, that has also been described by literature. The right hippocampus is thought to be preferentially involved in visuospatial memory and the right parahippocampal gyrus in the processing of spatial scenes, while the left hippocampus is thought to be preferentially involved in episodic memory or verbal memory.50

WM damage to hippocampal efferents and afferents may also contribute to memory impairment in MS. The fornix is the major output of the hippocampus,3 therefore fornix damage can cause severe memory deficits.51 To assess the role that functional compensation and WM integrity of MTL structures may play in mediating verbal memory performance in RRMS patients, Kern et al.52 used a high-resolution cortical unfolding of structural MRI in conjunction with fMRI to localize sub regional hippocampal and MTL activity in 18 early RRMS patients (i.e., disease duration less than 5 years) and 16 healthy controls during an unrelated word-pairs memory task. RRMS patients showed greater activity in hippocampal and extrahippocampal areas during a task of word-pair learning and recall. Increased hippocampal activity, particularly in the right anterior hippocampus and left anterior CA1, was associated with higher verbal memory scores, suggesting that, at least in the earliest phases of RRMS, increased recruitment of right hippocampal areas, predominantly devoted to visuospatial memory tasks, may compensate for ongoing pathological damage, thereby limiting detectable memory impairment. However, this compensatory activity appears to relay on the integrity of hippocampal connectivity to other brain regions, since damage to the fornix, as assessed by DT MRI, was associated with reduction in right anterior hippocampal fMRI activity and poorer performance on the verbal memory task. Conversely, increased FA in the fornix was correlated with both greater fMRI activity in this region and better memory performance in the patient group, consistent with a compensatory process. During the functional task in this study, unlike the hippocampal changes, increased entorhinal-perirhinal cortex activity was associated with poorer performance on the memory task. Such activity may reflect non-adaptive physiological processes related to disease, such as disinhibition of reciprocal hippocampal-entorhinal cortex pathways or even interference from competing, aberrant sensory input signals.

 

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Preceptorship
Milan, Italy
Oct 30 - 31, 2014
Target audience
Clinicians and scientists currently involved in MS and/or NMO management., Radiologists
EACCME®
by Excemed
Neurology

MS Alumni

The MS Alumni programme is an educational initiative of EXCEMED that is intended to provide ongoing support for young physicians and specialists in neurology.