Cortical pathology in multiple sclerosis detected by the T1/T2-weighted ratio from routine magnetic resonance imaging.

OBJECTIVE: In multiple sclerosis, neuropathological studies have shown widespread changes in the cerebral cortex. In vivo imaging is critical, because the histopathological substrate of most measurements is unknown. METHODS: Using a novel magnetic resonance imaging analysis technique, based on the ratio of T1- and T2-weighted signal intensities, we studied the cerebral cortex of a large cohort of patients in early stages of multiple sclerosis. A total of 168 patients with clinically isolated syndrome or relapsing-remitting multiple sclerosis (Expanded Disability Status Scale: median = 1, range = 0-3.5) and 80 age- and sex-matched healthy controls were investigated. We also searched for the histopathological substrate of the T1/T2-weighted ratio by combining postmortem imaging and histopathology in 9 multiple sclerosis brain donors. RESULTS: Patients showed lower T1/T2-weighted ratio values in parietal and occipital areas. The 4 most significant clusters appeared in the medial occipital and posterior cingulate cortex (each left and right). The decrease of the T1/T2-weighted ratio in the posterior cingulate was related to performance in attention. Analysis of the T1/T2-weighted ratio values of postmortem imaging yielded a strong correlation with dendrite density but none of the other parameters including myelin. INTERPRETATION: The T1/T2-weighted ratio decreases in early stages of multiple sclerosis in a widespread manner, with a preponderance of posterior areas and with a contribution to attentional performance; it seems to reflect dendrite pathology. As the method is broadly available and applicable to available clinical scans, we believe that it is a promising candidate for studying and monitoring cortical pathology or therapeutic effects in multiple sclerosis. Ann Neurol 2017;82:519-529.

Intra- and interscanner variability of magnetic resonance imaging based volumetry in multiple sclerosis.

Brain volumetric measurements in multiple sclerosis (MS) reflect not only disease-specific processes but also other sources of variability. The latter has to be considered especially in multicenter and longitudinal studies. Here, we compare data generated by three different 3-Tesla magnetic resonance scanners (Philips Achieva; Siemens Verio; GE Signa MR750). We scanned two patients diagnosed with relapsing remitting MS six times per scanner within three weeks (T1w and FLAIR, 3D). We assessed T2-hyperintense lesions by an automated lesion segmentation tool and determined volumes of grey matter (GM), white matter (WM) and whole brain (GM+WM) from the lesion-filled T1-weighted images using voxel-based morphometry (SPM8/VBM8) and SIENAX (FSL). We measured cortical thickness using FreeSurfer from both, lesion-filled and original T1-weighted images. We quantified brain volume changes with SIENA. In both patients, we found significant differences in total lesion volume, global brain tissue volumes and cortical thickness measures between the scanners. Morphometric measures varied remarkably between repeated scans at each scanner, independent of the brain imaging software tool used. We conclude that for cross-sectional multicenter studies, the effect of different scanners has to be taken into account. For longitudinal monocentric studies, the expected effect size should exceed the size of false positive findings observed in this study. Assuming a physiological loss of brain volume of about 0.3% per year in healthy adult subjects (Good et al., 2001), which may double in MS (De Stefano et al., 2010; De Stefano et al., 2015), with current tools reliable estimation of brain atrophy in individual patients is only possible over periods of several years.

Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts.

OBJECTIVE: To study remote effects distant from acute ischemic infarcts by measuring longitudinal changes of cortical thickness in connected brain regions as well as changes in microstructural integrity in connecting fiber tracts. METHODS: Thirty-two patients (mean age 71 years) underwent a standardized protocol including multimodal MRI and clinical assessment both at stroke onset and 6 months after the event. Cortex connected to acute infarcts was identified by probabilistic diffusion tensor tractography starting from the acute lesion. Changes of cortical thickness were measured using the longitudinal stream of FreeSurfer. Microstructural damage in white matter tracts was assessed by changes of mean diffusivity. RESULTS: We found focal cortical thinning specifically in areas connected to acute infarcts (p < 0.001). Thinning was more pronounced in regions showing a high probability of connectivity to infarcts. Microstructural damage in white matter tracts connecting acute infarcts with distant cortex significantly correlated with thickness changes in that region (ρ = -0.39, p = 0.028). There was no indication of an influence of cavitation status or infarct etiology on the observed changes in cortex and white matter. CONCLUSIONS: These findings identify secondary degeneration of connected white matter tracts and remote cortex as key features of acute ischemic infarcts. Our observations may have implications for the understanding of structural and functional reorganization after stroke.

Impact of regional cortical and subcortical changes on processing speed in cerebral small vessel disease.

Slowed processing speed is common in elderly subjects and frequently related to cerebral small vessel disease. Previous studies have demonstrated associations between processing speed and subcortical ischemic lesions as well as cortical alterations but the precise functional-anatomical relationships remain poorly understood. Here we assessed the impact of both cortical and subcortical changes on processing speed by measuring regional cortical thickness and regional lesion volumes within distinct white-matter tracts. To limit confounding effects from age-related pathologies we studied patients with CADASIL, a genetic small vessel disease. General linear model analysis revealed significant associations between cortical thickness in the medial frontal and occipito-temporal cortex and processing speed. Bayesian network analysis showed a robust conditional dependency between the volume of lacunar lesions in the left anterior thalamic radiation and cortical thickness of the left medial frontal cortex, and between thickness of the left medial frontal cortex and processing speed, whereas there was no direct dependency between lesion volumes in the left anterior thalamic radiation and processing speed. Our results suggest that the medial frontal cortex has an intermediate position between lacunar lesions in the anterior thalamic radiation and deficits in processing speed. In contrast, we did not observe such a relationship for the occipito-temporal region. These findings reinforce the key role of frontal-subcortical circuits in cognitive impairment resulting from cerebral small vessel disease.

Incident subcortical infarcts induce focal thinning in connected cortical regions.

OBJECTIVE: Brain atrophy is common in subcortical ischemic vascular disease, but the underlying mechanisms are poorly understood. We set out to examine the effects of incident subcortical infarcts on cortical morphology. METHODS: A total of 276 subjects with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, an inherited small vessel disease, were enrolled in a prospective study. Incident subcortical infarcts were identified on follow-up magnetic resonance scans after 18, 36, and 54 months using difference images. Probabilistic fiber tracking and cortical thickness measurements were applied to study the longitudinal relationship between incident infarcts and connected cortical areas. Cortical thickness was assessed before and after infarction using FreeSurfer software. Focal cortical thinning was defined as change of cortical thickness in the connected region of interest exceeding the global change of cortical thickness. RESULTS: Nine subjects had a single incident infarct during the follow-up and were suitable for analysis. There was a strong correlation between the probability of connectivity and mean focal cortical thinning (p = 0.0039). In all subjects, there was focal cortical thinning in cortical regions with high probability of connectivity with the incident infarct. This pattern was not observed when using control tractography seeds. CONCLUSIONS: Our findings provide in vivo evidence for secondary cortical neurodegeneration after subcortical ischemia as a mechanism for brain atrophy in cerebrovascular disease.

Face perception in the mind's eye.

Perceptual filling-in occurs when visual stimuli are recognized in impoverished viewing conditions. Whether missing information is filled-in during face perception and which stages might be involved in this process are still unresolved questions. Because an identity can be brought to mind by seeing eyes only, we hypothesized that missing information might be filled-in from a memory trace for the whole face identity. We presented participants with faces in phase 1 and later we presented eyes-only in phase 2. For some of these eyes in phase 2, the whole face had been presented in the previous phase, for others identical eyes had been presented. Event-related potentials (ERPs) revealed an N170 component that was more negative when eyes were preceded by a whole face in the previous phase compared to eyes preceded by identical eyes-only. A more positive-going late positive complex (LPC) was also found, suggesting enhanced retrieval of face memory representations when eyes were preceded by whole faces. Our results show that pre-existing representations of face identity can influence early stages of visual encoding, 170 ms after stimulus onset. These effects may reflect top-down modulation by memory on visual recognition processes by filling-in the missing facial information.

Top-down activation of fusiform cortex without seeing faces in prosopagnosia.

Face processing can be modified by bottom-up and top-down influences, but it is unknown how these processes interact in patients with face-recognition impairments (prosopagnosia). We investigated a prosopagnosic with lesions in right occipital and left fusiform cortex but whose right fusiform gyrus is intact and still activated during face-processing tasks. P.S., a patient with a well-established and selective agnosia for faces, was instructed to detect the presence of either faces or houses in pictures with different amounts of noise. The right fusiform face area (FFA) showed reduced responses to face information when visual images were degraded with noise. However, her right FFA still activated to noise-only images when she was instructed to detect faces. These results reveal that fusiform activation is still selectively modulated by task demands related to the anticipation of a face, despite severe face-recognition deficits and the fact that no reliable stimulus-driven response is evoked by actual facial information. Healthy controls showed stimulus-driven responses to faces in fusiform, and in right but not left occipital cortex, suggesting that the latter area alone might provide insufficient facial information in P.S. These results provide a novel account for residual activation of the FFA and underscore the importance of controlling task demands during functional magnetic resonance imaging.

Rapid influence of emotional scenes on encoding of facial expressions: an ERP study.

In daily life, we perceive a person's facial reaction as part of the natural environment surrounding it. Because most studies have investigated how facial expressions are recognized by using isolated faces, it is unclear what role the context plays. Although it has been observed that the N170 for facial expressions is modulated by the emotional context, it was not clear whether individuals use context information on this stage of processing to discriminate between facial expressions. The aim of the present study was to investigate how the early stages of face processing are affected by emotional scenes when explicit categorizations of fearful and happy facial expressions are made. Emotion effects were found for the N170, with larger amplitudes for faces in fearful scenes as compared to faces in happy and neutral scenes. Critically, N170 amplitudes were significantly increased for fearful faces in fearful scenes as compared to fearful faces in happy scenes and expressed in left-occipito-temporal scalp topography differences. Our results show that the information provided by the facial expression is combined with the scene context during the early stages of face processing.

Neural correlates of perceiving emotional faces and bodies in developmental prosopagnosia: an event-related fMRI-study.

Many people experience transient difficulties in recognizing faces but only a small number of them cannot recognize their family members when meeting them unexpectedly. Such face blindness is associated with serious problems in everyday life. A better understanding of the neuro-functional basis of impaired face recognition may be achieved by a careful comparison with an equally unique object category and by a adding a more realistic setting involving neutral faces as well facial expressions. We used event-related functional magnetic resonance imaging (fMRI) to investigate the neuro-functional basis of perceiving faces and bodies in three developmental prosopagnosics (DP) and matched healthy controls. Our approach involved materials consisting of neutral faces and bodies as well as faces and bodies expressing fear or happiness. The first main result is that the presence of emotional information has a different effect in the patient vs. the control group in the fusiform face area (FFA). Neutral faces trigger lower activation in the DP group, compared to the control group, while activation for facial expressions is the same in both groups. The second main result is that compared to controls, DPs have increased activation for bodies in the inferior occipital gyrus (IOG) and for neutral faces in the extrastriate body area (EBA), indicating that body and face sensitive processes are less categorically segregated in DP. Taken together our study shows the importance of using naturalistic emotional stimuli for a better understanding of developmental face deficits.

Recognition of facial expressions is influenced by emotional scene gist.

Recognition of facial expressions has traditionally been investigated by presenting facial expressions without any context information. However, we rarely encounter an isolated facial expression; usually, we perceive a person's facial reaction as part of the surrounding context. In the present study, we addressed the question of whether emotional scenes influence the explicit recognition of facial expressions. In three experiments, participants were required to categorize facial expressions (disgust, fear, happiness) that were shown against backgrounds of natural scenes with either a congruent or an incongruent emotional significance. A significant interaction was found between facial expressions and the emotional content of the scenes, showing a response advantage for facial expressions accompanied by congruent scenes. This advantage was robust against increasing task load. Taken together, the results show that the surrounding scene is an important factor in recognizing facial expressions.

Impaired face and body perception in developmental prosopagnosia.

Prosopagnosia is a deficit in face recognition in the presence of relatively normal object recognition. Together with older lesion studies, recent brain-imaging results provide evidence for the closely related representations of faces and objects and, more recently, for brain areas sensitive to faces and bodies. This evidence raises the issue of whether developmental prosopagnosics may also have an impairment in encoding bodies. We investigated the first stages of face, body, and object perception in four developmental prosopagnosics by comparing event-related potentials to canonically and upside-down presented stimuli. Normal configural encoding was absent in three of four developmental prosopagnosics for faces at the P1 and for both faces and bodies at the N170 component. Our results demonstrate that prosopagnosics do not have this normal processing routine readily available for faces or bodies. A profound face recognition deficit characteristic of developmental prosopagnosia may not necessarily originate in a category-specific face recognition deficit in the initial stages of development. It may also have its roots in anomalous processing of the configuration, a visual routine that is important for other stimuli besides faces. Faces and bodies trigger configuration-based visual strategies that are crucial in initial stages of stimulus encoding but also serve to bootstrap the acquisition of more feature-based visual skills that progressively build up in the course of development.

Body expressions influence recognition of emotions in the face and voice.

The most familiar emotional signals consist of faces, voices, and whole-body expressions, but so far research on emotions expressed by the whole body is sparse. The authors investigated recognition of whole-body expressions of emotion in three experiments. In the first experiment, participants performed a body expression-matching task. Results indicate good recognition of all emotions, with fear being the hardest to recognize. In the second experiment, two alternative forced choice categorizations of the facial expression of a compound face-body stimulus were strongly influenced by the bodily expression. This effect was a function of the ambiguity of the facial expression. In the third experiment, recognition of emotional tone of voice was similarly influenced by task irrelevant emotional body expressions. Taken together, the findings illustrate the importance of emotional whole-body expressions in communication either when viewed on their own or, as is often the case in realistic circumstances, in combination with facial expressions and emotional voices.

Beyond the face: exploring rapid influences of context on face processing.

Humans optimize behavior by deriving context-based expectations. Contextual data that are important for survival are extracted rapidly, using coarse information, adaptive decision strategies, and dedicated neural infrastructure. In the field of object perception, the influence of a surrounding context has been a major research theme, and it has generated a large literature. That visual context, as typically provided by natural scenes, facilitates object recognition as has been convincingly demonstrated (Bar, M. (2004) Nat. Rev. Neurosci., 5: 617-629). Just like objects, faces are generally encountered as part of a natural scene. Thus far, the facial expression literature has neglected such context and treats facial expressions as if they stand on their own. This constitutes a major gap in our knowledge. Facial expressions tend to appear in a context of head and body orientations, body movements, posture changes, and other object-related actions with a similar or at least a closely related meaning. For instance, one would expect a frightened face when confronted to an external danger to be at least accompanied by withdrawal movements of head and shoulders. Furthermore, some cues provided by the environment or the context in which a facial expression appears may have a direct relation with the emotion displayed by the face. The brain may even fill in the natural scene context typically associated with the facial expression. Recognition of the facial expression may also profit from processing the vocal emotion as well as the emotional body language that normally accompany it. Here we review the emerging evidence on how the immediate visual and auditory contexts influence the recognition of facial expressions.

Context influences early perceptual analysis of faces--an electrophysiological study.

Electrophysiological and hemodynamic correlates of processing isolated faces have been investigated extensively over the last decade. A question not addressed thus far is whether the visual scene, which normally surrounds a face or a facial expression, has an influence on how the face is processed. Here we investigated this issue by presenting faces in natural contexts and measuring whether the emotional content of the scene influences processing of a facial expression. Event-related potentials were recorded to faces (fearful/neutral) embedded in scene contexts (fearful/neutral) while participants performed an orientation-decision task (face upright or inverted). Two additional experiments were run, one to examine the effects of context that occur without a face and the other to evaluate the effects of faces isolated from contexts. Faces without any context showed the largest N170 amplitudes. The presence of a face in a fearful context enhances the N170 amplitude over a face in neutral contexts, an effect that is strongest for fearful faces on left occipito-temporal sites. This N170 effect, and the corresponding topographic distribution, was not found for contexts-only, indicating that the increased N170 amplitude results from the combination of face and fearful context. These findings suggest that the context in which a face appears may influence how it is encoded.