Thalamic amnesia after infarct

Objective: To improve current understanding of the mechanisms behind thalamic amnesia, as it is unclear whether it is directly related to damage to specific nuclei, in particular to the anterior or mediodorsal nuclei, or indirectly related to lesions of the mammillothalamic tract (MTT). Methods: We recruited 12 patients with a left thalamic infarction and 25 healthy matched controls. All underwent a comprehensive neuropsychological assessment of verbal and visual memory, executive functions, language, and affect, and a high-resolution structural volumetric MRI scan. Thalamic lesions were manually segmented and automatically localized with a computerized thalamic atlas. As well as comparing patients with controls, we divided patients into subgroups with intact or damaged MTT. Results: Only one patient had a small lesion of the anterior nucleus. Most of the lesions included the mediodorsal (n5 11) and intralaminar nuclei (n5 12). Patients performed worse than controls on the verbal memory tasks, but the 5 patients with intactMTTwho showed isolated lesions of the mediodorsal nucleus (MD) only displayed moderate memory impairment. The 7 patients with a damaged MTT performed worse on the verbal memory tasks than those whose MTT was intact. Conclusions: Lesions in the MTT and in the MD result in memory impairment, severely in the case of MTT and to a lesser extent in the case of MD, thus highlighting the roles played by these 2 structures in memory circuits. Neurology® 2015;85:2107–2115 GLOSSARY AN 5 anterior nucleus; dMTT 5 damaged mammillothalamic tract subgroup; FCSRT 5 Free and Cued Selective Reminding Test; FSL 5 FMRIB Software Library; iMTT 5 intact mammillothalamic tract subgroup; MD 5 mediodorsal nucleus; MDpc 5 parvocellular part of the mediodorsal nucleus; MNI 5 Montreal Neurological Institute; MTT 5 mammillothalamic tract. Amnesia following thalamic lesions was first described several decades ago, in particular following strokes, but the mechanisms underlying the memory impairment remain unclear. It is crucial to establish whether the impairment is directly related to damage to specific nuclei, and if so which ones, or whether it is indirectly related to lesion of the mammillothalamic tract (MTT), first described by Vicq d’Azyr in 1786, linking the hippocampus to the thalamus via a synapse in the mammillary body. As the anterior nucleus (AN) is connected with the hippocampus and the MTT, it was assumed to explain the memory impairment. The mediodorsal nucleus (MD) is another candidate owing to its dense connections with subhippocampal structures. The MTT runs through the medial thalamus. Therefore, anterior-medial thalamic strokes may also damage the MTT and cause memory impairment. An important caveat in previous studies is that many have relied on single or a few cases. Neuroimaging has been absent or of poor quality, and few studies have used a thalamic atlas fused with MRI scans to identify the damaged structures. From Inserm (L.D., P.E., M.P., F.B., P.P., J.P.) and Université de Toulouse III, UPS (L.D., P.E., M.P., F.B., P.P., J.P.), Imagerie Cérébrale et Handicaps Neurologiques, UMR 825, and Service de Neurologie, Pôle Neurosciences, CHU Purpan (L.D., M.P., N.R., J.-F.A., F.B., J.P.), Centre Hospitalier Universitaire de Toulouse; Centre de Recherche Cerveau et Cognition (CNRS, CerCO, UMR 5549) (L.D., E.J.B.), Université de Toulouse; and CHU de Bordeaux, Unité Neurovasculaire (I.S.), University of Bordeaux, France. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by UMR 825 Inserm. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially. © 2015 American Academy of Neurology 2107 Furthermore, because of the close vicinity of the AN, MD, and MTT, it is usually hard to say which structure is responsible for the memory impairment observed in thalamic stroke patients. The aim of this study was to assess the role of the AN, MD, and MTT in thalamic amnesia following a stroke. METHODS Standard protocol approvals, registrations, and patient consents. All participants provided written informed signed consent to take part in this study, which was approved by the local institutional review board (Comité de Protection des Personnes Sud-Ouest et Outre-Mer no. 2-11-04). Patients with single unilateral left ischemic thalamic stroke were recruited in the stroke units of Toulouse and Bordeaux university hospitals (France). All had brain infarcts observed on a diffusion-weighted MRI scan during the acute phase. They had no previously known neurovascular, inflammatory, or neurodegenerative diseases. We performed this study prospectively, with one recruitment criterion: the presence of a first symptomatic left thalamic infarct, regardless of complaint or neurobehavioral report at onset. We focused on left thalamic strokes to build a homogenous group. Following inclusion, all patients and healthy controls (matched for age and education level) underwent a clinical examination, a neuropsychological assessment, and an MRI scan (at least 3 months after stroke for patients). All the investigations took place in a single day and order. Neuropsychological assessment. We tested verbal memory (Free and Cued Selective Reminding Test [FCSRT], Logical Memory), visual memory (Rey-Osterrieth Complex Figure, DMS48), executive functions (Digit span and Spatial span, d2 test, Trail Making Test, Stroop, Symbol Search, literal and semantic lexical fluency, Similarities), language (ExaDé naming test), and affect (State-Trait Anxiety Inventory, Starkstein Apathy Scale, Beck Depression Inventory). Handedness was assessed with the Edinburgh Handedness Inventory. MRI acquisition. MRIs for the study were acquired on a 3T scanner (Philips Achieva; Best, the Netherlands). Thalamic lesions were documented using a 3D T2-weighted sequence (1 3 1 3 1-mm voxel size, echo time 337 ms, repetition time 8,000 ms, inversion time 2,400 ms, field of view 2403 2403 170, slice thickness 1 mm, slice number 170) and a 3D T1-weighted sequence (1 3 1 3 1-mm voxel size, echo time 8.1 ms, repetition time 3.7 ms, flip angle 8°, field of view 240 3 240 3 170, slice thickness 1 mm, slice number 170). White matter lesions were quantified with the Fazekas and Schmidt score by 2 independent raters (L.D. and M.P.). Nuclei volumes and lesion location. Lesions were manually segmented on the native T1 images by 2 independent investigators (L.D. and P.E.) using MRIcron software. Native images and segmented lesions were normalized on the Montreal Neurological Institute (MNI) template using first linear (FMRIB Linear Image Registration Tool [FLIRT]; FMRIB Software Library [FSL]) then nonlinear transformation (FMRIB Nonlinear Image Registration Tool [FNIRT]; FSL). The volumes of the normalized lesions were automatically calculated for each participant using the Fsl.anat toolbox, and expressed in mm. The Krauth et al. digital version of the Morel atlas of the thalamus, based on the MNI template, was implemented in FSL to automatically localize the lesions. The script allowed us to access the atlas via the FSL atlasquery function. We then calculated the volume (mm) and the proportion of the normalized lesions in each nucleus per patient using the labeled volumes of the Morel atlas. We then grouped the nuclei together according to Morel’s nomenclature: anterior group (anteroventral, anteromedial, anterodorsal, and lateral dorsal nuclei); medial group (mediodorsal parvocellular and magnocellular, intralaminar nuclei such as center median, central lateral, parafascicular, midline nuclei such as central medial, paraventricular, and habenula nuclei); lateral group (ventroposterior complex, ventral lateral posterior/anterior, and ventral anterior and ventral medial nuclei); posterior group (medial and lateral geniculate nuclei, posterior, suprageniculate/limitans, and lateral posterior and pulvinar nuclei); and reticular nucleus. The proportion of lesion outside the thalamus (expressed as %) was assessed. We used FIRST (FSL) for the automatic segmentation of the thalamus in native space. All lesions were overlapped and summed using the iCalc function in SPM8. The relevant Morel atlas sections and the thalamus mask were then superimposed on the summed lesions in order to illustrate the lesions’ distribution. MTT assessment. As the MTT is a relatively small structure, we used 2 methods to assess its integrity. These were applied to both patients and controls, and both left and right MTTs. First, using the MTT label in the Morel atlas, we assessed the number of voxels that were damaged in the MTT. Second, we carried out a volumetric analysis after patients’ and controls’ MTTs had been manually segmented on T1 axial slices by 2 independent examiners (L.D. and P.E.) using MRIcron software. Segmentations with an interrater agreement below 70% were reviewed by the 2 raters together. We calculated the z scores of the patients’MTT volumes using data from the control group. MTTs with a z score 2.5 SD below the mean were deemed to be damaged. Patients were grouped in the damaged MTT subgroup (dMTT) if at least one of the 2 methods indicated damage, and in the intact MTT subgroup (iMTT) if neither method indicated damage. Statistical analysis. Group comparisons were carried out using x, the nonparametric Mann-Whitney U test, and permutation tests. Correlations were realized using the nonparametric Spearman rho test. The significance threshold was set at p 5 0.05. Modified kappa scores were calculated to assess interobserver reproducibility for Fazekas and Schmidt scores, volumes of the segmented lesions, and volumes of the MTTs. RESULTS Participants’ characteristics. Between March 2012 and November 2013, we recruited 14 patients who had had a single left thalamic stroke. Two patients were excluded because of comorbidity: depressive syndrome that impaired cognitive performance (n 5 1) and a lacuna visible in the T1 sequence in the acute phase but not in the study MRI (n 5 1). The final sample therefore comprised 12 patients (P1–P12). All, except for 1 ambidextrous participant, were right-handed. Initial symptoms were visual (n 5 4), motor (n 5 5), sensory (n 5 1), and, for all the patients, cognitive, with tip-of-thetongue and paraphasia (n 5 8), jargon aphasia (n 5 1), verbal anterograde amnesia (n 5 7), spatial memory impairment (n 5 1), short-term memory loss (n 5 1), and anosognosia (n 5 3). Behavioral 2108 Neurology 85 December 15, 2015 disturbances were also reported: emotional incontinence (n5 2), aggressiveness (n 5 2), apathy (n 5 1), and hyperactivity (n 5 1). Details are provided in table e-1 on the Neurology® Web site at Neurology.org. The majority of the acute symptomatology significantly decreased in a few days or weeks, with the exception of amnesia. Patients were matched with 25 healthy participants for age and education level. The demographic details of both groups are provided in table 1. Patients’ lesions on native T1 and overlap of lesions are shown in figure 1A (k 5 0.82). Neuropsychological assessment. Patients performed worse than controls on the verbal memory tests, including free recall, cued recall, and recognition (table 2). We found no difference regarding visual memory. Patients also exhibited a moderate dysexecutive syndrome. Spontaneous language was clinically normal, but moderate naming difficulties were observed at the group level on a confrontation naming test. There was no correlation between naming and memory performances in patients. Patients’ and controls’ affect did not differ. No behavioral disturbance was observed during assessment. Neuroimaging analyses of the thalamic nuclei. The Fazekas and Schmidt score was #2 for all patients and controls (k 5 0.8). Following manual segmentation of the lesions and identification of the nuclei using the Krauth et al. digital version of the Morel atlas, all patients were found to have a lesion in the medial group, especially in the parvocellular part of the mediodorsal nucleus (MDpc) (n 5 11) and the intralaminar nuclei (n5 11) (figure 1B). Ten patients also had lesions in the lateral group. One patient had minor damage in the anterior group (1 mm in the anteromedial nucleus), and 1 had a small lesion in the posterior group (1 mm in the limitans nucleus) (table 3). The most severe damage (.10% of the nucleus damaged) was located in some areas of the medial group, such as the central medial (mean damage across patients: 28.2%, minimum 0.6%, maximum 76%) and paraventricular (13.1%, minimum 14.3%, maximum 85.7%) part of midline nuclei; parafascicular part of intralaminar nuclei (16.9%, minimum 1.1%, maximum 61.2%); and MDpc (13.7%, minimum 0.2%, maximum 31.6%); but also in nuclei of the lateral group, such as the ventral medial (19.3%, minimum 6.3%, maximum 100%), magnocellular ventral anterior (17.3%, minimum 4.1%, maximum 83.8%), and ventral lateral posterior (13%, minimum 2.3%, maximum 44.5%) (figure 1B). More than 20% of the lesions of P1, P3, and P10 were located outside the thalamus (in order of importance: brainstem, red nucleus, and white matter). Neuroimaging analyses of the MTT. The analysis based on the Morel atlas indicated that 6 of the 12 patients had left MTT damage. The volumetric analysis (see example in figure 2A) showed a group-level difference between patients and controls for the left but not the right MTT (respectively p , 0.001 vs p . 0.1), with 7 of the 12 patients exhibiting severe atrophy of the left MTT (z scores , 22.5, figure 2B). These 7 patients included all 6 patients who had been identified as having a damaged MTT in the Morel atlas analysis. The Morel atlas analysis did not detect a MTT lesion in one patient (P1) exhibiting MTT atrophy. In subsequent analyses, these 7 patients were included in the dMTT and the remaining 5 in the iMTT. Details of the 2 subgroups are provided in tables 1 and 3. Performance of dMTT and iMTT patients. dMTT patients were severely impaired on all the verbal memory tasks, and moderately impaired on the ExaDé naming task, compared with both controls and iMTT patients (demographic data in table 1; see figure 2C and details in table e-2). By contrast, the iMTT patients were impaired on the verbal memory tasks, performing worse than controls only on the FCSRT word free recall task. The dMTT and iMTT Table 1 Demographic details of patients, controls, and dMTT and iMTT subgroups Left thalamic infarct patients (n 5 12) Healthy control participants (n 5 25) p Value dMTT group (n 5 7) iMTT group (n 5 5) p Value Age, y 53.2 (14.6) [25, 75] 52.6 (11.6) [25, 69] 0.86 58.9 (16.6) [25, 75] 45.2 (6.3) [38, 52] 0.37 F/M 3/9 15/10 0.05 1/6 2/3 0.31 Education level, y 12.8 (4.1) [5, 17] 13.6 (4.1) [5, 21] 0.25 12.3 (4.2) [5, 17] 11 (4.2) [5, 17] 0.69 Handedness, R/L/ambidextrous 11/0/1 22/3/0 0.74 6/0/1 5/0/0 0.38 Time since onset 589 (588.9) d [3 mo, 4 y 11 mo] — — 527 (647.2) d [3 mo, 4 y 11 mo] 675 (556.1) d [3 mo, 3 y 8 mo] 0.81 Normalized volume of overall lesions, mm3 516.8 (265.2) [30, 982] — — 679.6 (160.7) [538, 982] 289 (208.5) [30, 605] 0.64 Abbreviations: dMTT 5 damaged mammillothalamic tract subgroup; iMTT 5 intact mammillothalamic tract subgroup. Values are mean (SD) [min, max]. Neurology 85 December 15, 2015 2109 subgroups did not differ significantly from controls on the rest of the assessment. Whole-group correlations. A significant correlation was observed between MTT volumes and verbal memory performances on the Logical Memory and FCRST tasks (figure 2D) but the distribution of MTT lesions was bimodal. By contrast, no correlation was found between total MD volume loss and memory performance (rho 5 20.24, p . 0.05). We found that overall lesion volume correlated significantly with FCRST scores (rho520.74*), but not with delayed recall performances on the Logical Memory test (rho 5 20.52). DISCUSSION In this study, we found that patients with left thalamic infarcts experienced severe verbal memory impairment compared with a group of healthy matched controls. Unexpectedly, none of the patients had a significant lesion in the AN. A subgroup of patients showed isolated lesions of the MD (n 5 5) and a memory deficit mainly impairing recall, suggesting that MD lesions alone can result in amnesia. Patients with MTT damage exhibited more severe memory impairment than those whose MTT was intact. Only one patient had a lesion in the AN (P4 lesion: 1 mm). This was an unexpected finding. Current neuroanatomical models of memory suggest that thalamic memory impairment may be due to damage located in the AN because of its links with the hippocampus via the mammillary bodies and the fornix. Moreover, studies have reported verbal memory impairment after left AN infarction. One possible explanation for the scarcity of AN lesions in our study is that we used a neuroimaging thalamic atlas, allowing more precision than in previous studies, where AN lesions may have been overestimated. Besides, tuberothalamic strokes occur less often than paramedian ones and one third of the population has no tuberothalamic artery. This may decrease the overall risk for AN stroke. Still, all our patients exhibited a pattern of memory impairment similar to that usually observed in the unilateral hippocampal lesion, including impaired verbal recall and recognition memory without confabulations or false alarms. Figure 1 Lesions (A) T1 axial sections of the patients’ native MRI. The red circles show infarcts. P5’s lesion is scarcely visible on the image (lesion volume 5 5 mm3). We therefore provide a zoom on the lesion on the fluid-attenuated inversion recovery sequence. (B) Overlap of the lesions across patients (% of patients, n5 12) in an axial view (top; A 5 anterior, P 5 posterior), sagittal view (bottom left; A 5 anterior, P 5 posterior), and coronal view (bottom right). A mask of the right thalamus (in green) obtained using the FIRST tool in FSL is provided for information. A slice of the Morel atlas featuring structures of interest is overlaid on the axial view. CeM5 central medial; CL5 central lateral; CM5 centromedian; GPe5 external globus pallidus; Hb5 habenula; ic5 internal capsule; MDpc5 parvocellular part of the mediodorsal nucleus; mtt 5 mammillothalamic tract; PuT 5 putamen; R 5 reticular nucleus; VA 5 ventral-anterior. 2110 Neurology 85 December 15, 2015 A recent study of 7 patients with lesions in the left MD (with no MTT damage) found that they had memory impairment. However, this study’s outcome is questionable because 3 of the patients also had lesions in the AN, and 3 had bilateral lesions. In the present study, 5 patients presented a MD lesion but no MTT damage, constituting the largest pure group of patients with isolated and quantitatively measured MD lesions that has ever been reported. Neuropsychological results showed that these patients exhibited memory impairment. Nevertheless, we did not observe any correlation between MD volume loss and memory performance. Several studies have highlighted the MD’s probable role in memory, showing that MD lesions affect recall, although the role of this nucleus in recognition memory remains unproven. This subgroup exhibited impaired recall of single items (words that had to be learned), but preserved recall of complex relational material (stories). No recognition memory impairment was observed. This may appear intriguing at first sight, considering that the Aggleton and Brown model predicts a recognition memory impairment related to impaired familiarity when the MD is damaged. This nucleus does indeed have links with subhippocampal structures, especially the perirhinal cortex. Table 2 Results of the neuropsychological assessment Tasks Subtests Patients Controls p Value