Using augmented reality to assess spatial neglect: The Free Exploration Test (FET).

BACKGROUND: To capture the distortion of exploratory activity typical of patients with spatial neglect, traditional diagnostic methods and new virtual reality applications use confined workspaces that limit patients' exploration behavior to a predefined area. Our aim was to overcome these limitations and enable the recording of patients' biased activity in real, unconfined space. METHODS: We developed the Free Exploration Test (FET) based on augmented reality technology. Using a live stream via the back camera on a tablet, patients search for a (non-existent) virtual target in their environment, while their exploration movements are recorded for 30 s. We tested 20 neglect patients and 20 healthy participants and compared the performance of the FET with traditional neglect tests. RESULTS: In contrast to controls, neglect patients exhibited a significant rightward bias in exploratory movements. The FET had a high discriminative power (area under the curve = 0.89) and correlated positively with traditional tests of spatial neglect (Letter Cancellation, Bells Test, Copying Task, Line Bisection). An optimal cut-off point of the averaged bias of exploratory activity was at 9.0° on the right; it distinguished neglect patients from controls with 85% sensitivity. DISCUSSION: FET offers time-efficient (execution time: ∼3 min), easy-to-apply, and gamified assessment of free exploratory activity. It supplements traditional neglect tests, providing unrestricted recording of exploration in the real, unconfined space surrounding the patient.

Sustained bias of spatial attention in a 3 T MRI scanner.

When lying inside a MRI scanner and even in the absence of any motion, the static magnetic field of MRI scanners induces a magneto-hydrodynamic stimulation of subjects' vestibular organ (MVS). MVS thereby not only causes a horizontal vestibular nystagmus but also induces a horizontal bias in spatial attention. In this study, we aimed to determine the time course of MVS-induced biases in both VOR and spatial attention inside a 3 T MRI-scanner as well as their respective aftereffects after participants left the scanner. Eye movements and overt spatial attention in a visual search task were assessed in healthy volunteers before, during, and after a one-hour MVS period. All participants exhibited a VOR inside the scanner, which declined over time but never vanished completely. Importantly, there was also an MVS-induced horizontal bias in spatial attention and exploration, which persisted throughout the entire hour within the scanner. Upon exiting the scanner, we observed aftereffects in the opposite direction manifested in both the VOR and in spatial attention, which were statistically no longer detectable after 7 min. Sustained MVS effects on spatial attention have important implications for the design and interpretation of fMRI-studies and for the development of therapeutic interventions counteracting spatial neglect.

Beyond visual integration: sensitivity of the temporal-parietal junction for objects, places, and faces.

One important role of the TPJ is the contribution to perception of the global gist in hierarchically organized stimuli where individual elements create a global visual percept. However, the link between clinical findings in simultanagnosia and neuroimaging in healthy subjects is missing for real-world global stimuli, like visual scenes. It is well-known that hierarchical, global stimuli activate TPJ regions and that simultanagnosia patients show deficits during the recognition of hierarchical stimuli and real-world visual scenes. However, the role of the TPJ in real-world scene processing is entirely unexplored. In the present study, we first localized TPJ regions significantly responding to the global gist of hierarchical stimuli and then investigated the responses to visual scenes, as well as single objects and faces as control stimuli. All three stimulus classes evoked significantly positive univariate responses in the previously localized TPJ regions. In a multivariate analysis, we were able to demonstrate that voxel patterns of the TPJ were classified significantly above chance level for all three stimulus classes. These results demonstrate a significant involvement of the TPJ in processing of complex visual stimuli that is not restricted to visual scenes and that the TPJ is sensitive to different classes of visual stimuli with a specific signature of neuronal activations.

The neuroanatomy of visual extinction following right hemisphere brain damage: Insights from multivariate and Bayesian lesion analyses in acute stroke.

Multi-target attention, that is, the ability to attend and respond to multiple visual targets presented simultaneously on the horizontal meridian across both visual fields, is essential for everyday real-world behaviour. Given the close link between the neuropsychological deficit of extinction and attentional limits in healthy subjects, investigating the anatomy that underlies extinction is uniquely capable of providing important insights concerning the anatomy critical for normal multi-target attention. Previous studies into the brain areas critical for multi-target attention and its failure in extinction patients have, however, produced heterogeneous results. In the current study, we used multivariate and Bayesian lesion analysis approaches to investigate the anatomical substrate of visual extinction in a large sample of 108 acute right hemisphere stroke patients. The use of acute stroke patient data and multivariate/Bayesian lesion analysis approaches allowed us to address limitations associated with previous studies and so obtain a more complete picture of the functional network associated with visual extinction. Our results demonstrate that the right temporo-parietal junction (TPJ) is critically associated with visual extinction. The Bayesian lesion analysis additionally implicated the right intraparietal sulcus (IPS), in line with the results of studies in neurologically healthy participants that highlighted the IPS as the area critical for multi-target attention. Our findings resolve the seemingly conflicting previous findings, and emphasise the urgent need for further research to clarify the precise cognitive role of the right TPJ in multi-target attention and its failure in extinction patients.

Application of immersive virtual reality for assessing chronic neglect in individuals with stroke: the immersive virtual road-crossing task.

BACKGROUND: Neglect can be a long-term consequence of chronic stroke that can impede an individual's ability to perform daily activities, but chronic and discrete forms can be difficult to detect. We developed and evaluated the "immersive virtual road-crossing task" (iVRoad) to identify and quantify discrete neglect symptoms in chronic stroke patients. METHOD: The iVRoad task requires crossing virtual intersections and placing a letter in a mailbox placed either on the left or right. We tested three groups using the HTC Vive Pro Eye: (1) chronic right hemisphere stroke patients with (N = 20) and (2) without (N = 20) chronic left-sided neglect, and (3) age and gender-matched healthy controls (N = 20). We analyzed temporal parameters, errors, and head rotation to identify group-specific patterns, and applied questionnaires to measure self-assessed pedestrian behavior and usability. RESULTS: Overall, the task was well-tolerated by all participants with fewer cybersickness-induced symptoms after the VR exposure than before. Reaction time, left-sided errors, and lateral head movements for traffic from left most clearly distinguished between groups. Neglect patients committed more dangerous crossings, but their self-rated pedestrian behavior did not differ from that of stroke patients without neglect. This demonstrates their reduced awareness of the risks in everyday life and highlights the clinical relevance of the task. CONCLUSIONS: Our findings suggest that a virtual road crossing task, such as iVRoad, has the potential to identify subtle symptoms of neglect by providing virtual scenarios that more closely resemble the demands and challenges of everyday life. iVRoad is an immersive, naturalistic virtual reality task that can measure clinically relevant behavioral variance and identify discrete neglect symptoms.

Reducing alertness does not affect line bisection bias in neurotypical participants.

Alertness, or one's general readiness to respond to stimulation, has previously been shown to affect spatial attention. However, most of this previous research focused on speeded, laboratory-based reaction tasks, as opposed to the classical line bisection task typically used to diagnose deficits of spatial attention in clinical settings. McIntosh et al. (Cogn Brain Res 25:833-850, 2005) provide a form of line bisection task which they argue can more sensitively assess spatial attention. Ninety-eight participants were presented with this line bisection task, once with and once without spatial cues, and both before and after a 50-min vigilance task that aimed to decrease alertness. A single participant was excluded due to potentially inconsistent behaviour in the task, leaving 97 participants for the full analyses. While participants were, on a group level, less alert after the 50-min vigilance task, they showed none of the hypothesised effects of reduced alertness on spatial attention in the line bisection task, regardless of with or without spatial cues. Yet, they did show the proposed effect of decreased alertness leading to a lower level of general attention. This suggests that alertness has no effect on spatial attention, as measured by a line bisection task, in neurotypical participants. We thus conclude that, in neurotypical participants, the effect of alertness on spatial attention can be examined more sensitively with tasks requiring a speeded response compared to unspeeded tasks.

Spatial Neglect Therapy With the Augmented Reality App "Negami" for Active Exploration Training: A Randomized Controlled Trial on 20 Stroke Patients With Spatial Neglect.

OBJECTIVE: To investigate the efficacy of the augmented reality (AR) app "Negami" as an active exploration training for the treatment of spatial neglect. Improvements of the ipsilesional attention and orientation bias (and resulting contralesional neglect) will be examined in stroke patients with spatial neglect and compared with a control group. DESIGN: Randomized controlled trial with an experimental Negami group, consisting of patients with spatial neglect, and a group of neglect patients receiving standard neglect therapy. SETTING: Three rehabilitation hospitals. PARTICIPANTS: Twenty right hemispheric stroke patients with spatial neglect (N=20). INTERVENTION: Over a period of 2 weeks, both groups received 5 training sessions per week (à 25 minutes). Neglect behavior was assessed weekly over a 5-week period, with the Negami therapy group receiving a second follow-up assessment at 1-to-2-month intervals after completion of training. MAIN OUTCOME MEASURES: Letter Cancellation, Bells Test, Copying Task, Line Bisection Task, and a self-developed "Exploration Test". RESULTS: Both groups improved significantly. While the Negami therapy group improved in 4 of 5 neglect tests used, the standard therapy group improved in only 1 of these tests. We observed significantly better improvement in the Negami group already after the first week of training. This difference was also significant after the end of the training as well as 1 week after the end of training and remained stable 1-2 months after the end of treatment. CONCLUSION: Negami can be used as an effective alternative or addition to current standard neglect therapy, and may even be superior to it.

The need for hemispheric separation in pairwise structural disconnection studies.

The development of new approaches indirectly measuring the structural disconnectome has recently led to an increase in studies investigating pairwise structural disconnections following brain damage. Previous studies jointly analyzed patients with left hemispheric and patients with right hemispheric lesions when investigating a behavior of interest. An alternative approach would be to perform analyses separated by hemisphere, which has been applied in only a minority of studies to date. The present simulation study investigated whether joint or separate analyses (or both equally) are appropriate to reveal the ground truth disconnections. In fact, both approaches resulted in very different patterns of disconnection. In contrast to analyses separated by hemisphere, joint analyses introduced a bias to the disadvantage of intra-hemispheric disconnections. Intra-hemispheric disconnections were statistically underpowered in the joint analysis and thus surpassed the significance threshold with more difficulty compared to inter-hemispheric disconnections. This statistical imbalance was also shown by a greater number of significant inter-hemispheric than significant intra-hemispheric disconnections. This bias from joint analyses is based on mechanisms similar to those underlying the "partial injury problem." We therefore conclude that pairwise structural disconnections in patients with unilateral left hemispheric and with unilateral right hemispheric lesions exhibiting a specific behavior (or disorder) of interest should be studied separately by hemisphere rather than in a joint analysis.

[Clinical examination of spatial neglect and other disorders of spatial cognition]. / Klinische Untersuchung des unilateralen Neglects und weiterer Störungen der Raumkognition.

Neglect occurring after stroke, neoplasms or degenerative processes can lead to considerable disability in everyday life as can other disorders of spatial orientation. Therefore, a dedicated examination and early diagnostic classification are obligatory. Behavioral tests are helpful in this respect, enabling the clinician to obtain an initial overview of the existing deficits even at the patient's bedside. The clinical (bedside) examination of spatial neglect as well as the corresponding differential diagnostic procedure for the clarification of (possibly additionally or exclusively existing) hemianopia and extinction, as well as the examination of disorders of visuospatial perception, visuoconstructive disorders, topographic disorders, Bálint's syndrome, simultanagnosia, and optic ataxia are presented. The presentation is based on the newly revised (year 2023) guidelines of the Association of the Scientific Medical Societies in Germany (AWMF) on this subject area.

"Look straight ahead"-A new test to diagnose spatial neglect by computed tomography.

Spatial neglect is the dominant behavioral disorder after right hemisphere brain lesions. Reliabel diagnosis by formal neuropsychological testing is often achieved only later during hospitalization, leading to delays in targeted therapies. We propose a way to diagnose spatial neglect right at admission. We measured the conjugated eye deviation (CED) on the initial computed tomography (CT) scans, in combination with the verbal instruction "Please look straight ahead" during the scan. The command was implemented in the scanner program and automatically played before a cranial CT started. This prospective study included a total 46 consecutive subjects (16 patients with first ever right brain damage and no spatial neglect, 12 patients with first ever right brain damage and spatial neglect, and 18 healthy controls). The right brain damaged groups were submitted to paper pencil tests to access the diagnosis of a spatial neglect after radiological confirmation of the brain damage during the initial phase of their hospitalisation. This procedure allowed us to define a cut-off value of 14.1 degrees of CED to the ipsilesional side to differentiate right hemispheric stroke patients with versus without spatial neglect with a confidence interval of 99%. This simple addition to a radiological routine procedure provides a new tool to help diagnose spatial neglect at the earliest stage possible and thus offers the possibility of providing patients with optimized rehabilitative therapy from a very early stage on.

Thalamocortical disconnection involved in pusher syndrome.

The presence of both isolated thalamic and isolated cortical lesions have been reported in the context of pusher syndrome-a disorder characterized by a disturbed perception of one's own upright body posture, following unilateral left- or right-sided stroke. In recent times, indirect quantification of functional and structural disconnection increases the knowledge derived from focal brain lesions by inferring subsequent brain network damage from the respective lesion. We applied both measures to a sample of 124 stroke patients to investigate brain disconnection in pusher syndrome. Our results suggest a hub-like function of the posterior and lateral portions of the thalamus in the perception of one's own postural upright. Lesion network symptom mapping investigating functional disconnection indicated cortical diaschisis in cerebellar, frontal, parietal and temporal areas in patients with thalamic lesions suffering from pusher syndrome, but there was no evidence for functional diaschisis in pusher patients with cortical stroke and no evidence for the convergence of thalamic and cortical lesions onto a common functional network. Structural disconnection mapping identified posterior thalamic disconnection to temporal, pre-, post- and paracentral regions. Fibre tracking between the thalamic and cortical pusher lesion hotspots indicated that in cortical lesions of patients with pusher syndrome, it is disconnectivity to the posterior thalamus caused by accompanying white matter damage, rather than the direct cortical lesions themselves, that lead to the emergence of pusher syndrome. Our analyses thus offer the first evidence for a direct thalamo-cortical (or cortico-thalamic) interconnection and, more importantly, shed light on the location of the respective thalamo-cortical disconnections. Pusher syndrome seems to be a consequence of direct damage or of disconnection of the posterior thalamus.

Negami: An Augmented Reality App for the Treatment of Spatial Neglect After Stroke.

BACKGROUND: A widely applied and effective rehabilitation method for patients experiencing spatial neglect after a stroke is "visual exploration training." Patients improve their ipsilesional bias of attention and orientation by training exploration movements and search strategies toward the contralesional side of space. In this context, gamification can have a positive influence on motivation for treatment and thus on the success of treatment. In contrast to virtual reality applications, treatment enhancements through augmented reality (AR) have not yet been investigated, although they offer some advantages over virtual reality. OBJECTIVE: This study aimed to develop an AR-based app (Negami) for the treatment of spatial neglect that combines visual exploration training with active, contralesionally oriented rotation of the eyes, head, and trunk. METHODS: The app inserts a virtual element (origami bird) into the real space surrounding the patient, which the patient explores with the camera of a tablet. Subjective reports from healthy elderly participants (n=10) and patients with spatial neglect after stroke (n=10) who trained with the new Negami app were analyzed. Usability, side effects, and game experience were assessed by various questionnaires. RESULTS: Training at the highest defined difficulty level was perceived as differently challenging but not as frustrating by the group of healthy elderly participants. The app was rated with high usability, hardly any side effects, high motivation, and entertainment. The group of patients with spatial neglect after stroke consistently evaluated the app positively on the dimensions of motivation, satisfaction, and fun. CONCLUSIONS: The Negami app represents a promising extension by adding AR to traditional exploration training for spatial neglect. Through participants' natural interaction with the physical surrounding environment during playful tasks, side effects as symptoms of cybersickness are minimized and patients' motivation appeared to markedly increase. The use of AR in cognitive rehabilitation programs and the treatment of spatial neglect seems promising and should receive further investigation.

Spatial neglect in the digital age: Influence of presentation format on patients' test behavior.

OBJECTIVE: Computerized neglect tests could significantly deepen our disorder-specific knowledge by effortlessly providing additional behavioral markers that are hardly or not extractable from existing paper-and-pencil versions. This study investigated how testing format (paper versus digital), and screen size (small, medium, large) affect the Center of cancelation (CoC) in right-hemispheric stroke patients in the Letters and the Bells cancelation task. Our second objective was to determine whether a machine learning approach could reliably classify patients with and without neglect based on their search speed, search distance, and search strategy. METHOD: We compared the CoC measure of right hemisphere stroke patients with neglect in two cancelation tasks across different formats and display sizes. In addition, we evaluated whether three additional parameters of search behavior that became available through digitization are neglect-specific behavioral markers. RESULTS: Patients' CoC was not affected by test format or screen size. Additional search parameters demonstrated lower search speed, increased search distance, and a more strategic search for neglect patients than for control patients without neglect. CONCLUSION: The CoC seems robust to both test digitization and display size adaptations. Machine learning classification based on the additional variables derived from computerized tests succeeded in distinguishing stroke patients with spatial neglect from those without. The investigated additional variables have the potential to aid in neglect diagnosis, in particular when the CoC cannot be validly assessed (e.g., when the test is not performed to completion).

Disconnectomics to unravel the network underlying deficits of spatial exploration and attention.

Spatial attention and exploration are related to a predominantly right hemispheric network structure. However, the areas of the brain involved and their exact role is still debated. Spatial neglect following right hemispheric stroke lesions has been frequently viewed as a model to study these processes in humans. Previous investigations on the anatomical basis on spatial neglect predominantly focused on focal brain damage and lesion-behaviour mapping analyses. This approach might not be suited to detect remote areas structurally spared but which might contribute to the behavioural deficit. In the present study of a sample of 203 right hemispheric stroke patients, we combined connectome lesion-symptom mapping with multivariate support vector regression to unravel the complex and disconnected network structure in spatial neglect. We delineated three central nodes that were extensively disconnected from other intrahemispheric areas, namely the right superior parietal lobule, the insula, and the temporal pole. Additionally, the analysis allocated central roles within this network to the inferior frontal gyrus (pars triangularis and opercularis), right middle temporal gyrus, right temporal pole and left and right orbitofrontal cortices, including interhemispheric disconnection. Our results suggest that these structures-although not necessarily directly damaged-might play a role within the network underlying spatial neglect in humans.

Right hemispheric white matter hyperintensities improve the prediction of spatial neglect severity in acute stroke.

White matter hyperintensities (WMH) are frequently observed in brain scans of elderly people. They are associated with an increased risk of stroke, cognitive decline, and dementia. However, it is unknown yet if measures of WMH provide information that improve the understanding of poststroke outcome compared to only state-of-the-art stereotaxic structural lesion data. We implemented high-dimensional machine learning models, based on support vector regression, to predict the severity of spatial neglect in 103 acute right hemispheric stroke patients. We found that (1) the additional information of right hemispheric or bilateral voxel-based topographic WMH extent indeed yielded a significant improvement in predicting acute neglect severity (compared to the voxel-based stroke lesion map alone). (2) Periventricular WMH appeared more relevant for prediction than deep subcortical WMH. (3) Among different measures of WMH, voxel-based maps as measures of topographic extent allowed more accurate predictions compared to the use of traditional ordinally assessed visual rating scales (Fazekas-scale, Cardiovascular Health Study-scale). In summary, topographic WMH appear to be a valuable clinical imaging biomarker for predicting the severity of cognitive deficits and bears great potential for rehabilitation guidance of acute stroke patients.

Tilted 3D visual scenes influence lateropulsion: A single case study of pusher syndrome.

INTRODUCTION: Hemiparetic stroke patients with so-called "pusher syndrome" (synonyms: contraversive lateropulsion, contraversive pushing) use their non-paretic extremities to push toward their paralyzed side and actively resist external posture correction. The disorder is associated with a distorted perception of postural vertical combined with a maintained, or little deviating perception of visual upright. With the aim of reducing this mismatch, and thus reducing contraversive lateropulsion, we manipulated the orientation of visual input in a virtual reality setup. METHOD: We presented healthy subjects and an acute stroke patient with severe pusher syndrome a 3D visual scene that was either upright or tilted in roll plane by 20°. By moving the sitting participants in roll plane to the left and right, we assessed the occurrence of contraversive lateropulsion, namely the active resistance to external posture manipulation. RESULTS: With the 3D visual scene oriented upright, the patient with pusher syndrome showed the typical active resistance against tilts toward the ipsilesional side. He used his non-paretic arm to block the examiner's attempt to move the body axis toward that side. With the visual scene tilted to the ipsiversive left, his pathological resistance was significantly reduced. Statistically, the tolerated body tilt angles no longer differed from those of healthy subjects. CONCLUSIONS: We conclude that even short presentations of tilted 3D visual input can reduce symptoms of severe contraversive lateropulsion. The technique provides potential for a new treatment method of pusher syndrome and offers a simple, straightforward approach that can be effortlessly integrated in clinical practice. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00026700).

The amnestic syndrome of posterior cerebral artery infarction.

BACKGROUND AND PURPOSE: Little is known about the character and underlying lesions of ischaemic amnesia. Episodic memory functions and brain lesions were therefore studied in 84 patients with acute ischaemic infarcts in the supply territory of the posterior cerebral artery. The aim was also to learn how the neural memory systems are organized. METHODS: Standard neuropsychological tests were used to assess verbal and figural memory. Patients were split into memory-impaired and memory-intact groups. Lesions were demarcated, normalized and anatomically labelled, using standard mapping procedures. RESULTS: Of the 84 patients more than 80% had an amnestic syndrome, mostly with combined memory impairment, less often with figural or verbal memory impairment. Amnesia in subjects with left hemispheric lesions was more frequent and more severe, with significantly lower scores on the verbal memory test. Normal performance or figural amnesia were prevalent after right hemispheric lesions. However, no amnesia subtype was strictly tied to left- or right-sided brain damage. Hippocampal and thalamic lesions were common, but 30% of lesions were extrahippocampal located in the ventral occipito-temporal cortex and long occipital white matter tracts. Most amnestic patients lacked awareness for their memory impairment. CONCLUSIONS: Memory impairment is a key clinical manifestation of acute posterior cerebral artery stroke. Amnesia is more frequent and more severe after left stroke, suggesting a left hemisphere dominance of the two memory systems. Domain specific memory appears not to be strictly lateralized, since deficits in verbal and figural memory were found after lesions of both sides. Extrahippocampal lesions may also cause memory impairment.

Mapping the human praxis network: an investigation of white matter disconnection in limb apraxia of gesture production.

Left hemispheric cerebral stroke can cause apraxia, a motor cognitive disorder characterized by deficits of higher-order motor skills such as the failure to accurately produce meaningful gestures. This disorder provides unique insights into the anatomical and cognitive architecture of the human praxis system. The present study aimed to map the structural brain network that is damaged in apraxia. We assessed the ability to perform meaningful gestures with the hand in 101 patients with chronic left hemisphere stroke. Structural white matter fibre damage was directly assessed by diffusion tensor imaging and fractional anisotropy mapping. We used multivariate topographical inference on tract-based fractional anisotropy topographies to identify white matter disconnection associated with apraxia. We found relevant pathological white matter alterations in a densely connected fronto-temporo-parietal network of short and long association fibres. Hence, the findings suggest that heterogeneous topographical results in previous lesion mapping studies might not only result from differences in study design, but also from the general methodological limitations of univariate topographical mapping in uncovering the structural praxis network. A striking role of middle and superior temporal lobe disconnection, including temporo-temporal short association fibres, was found, suggesting strong involvement of the temporal lobe in the praxis network. Further, the results stressed the importance of subcortical disconnections for the emergence of apractic symptoms. Our study provides a fine-grain view into the structural connectivity of the human praxis network and suggests a potential value of disconnection measures in the clinical prediction of behavioural post-stroke outcome.

The role of ventral stream areas for viewpoint-invariant object recognition.

Object constancy is one of the most crucial mechanisms of the human visual system enabling viewpoint invariant object recognition. However, the neuronal foundations of object constancy are widely unknown. Research has shown that the ventral visual stream is involved in processing of various kinds of object stimuli and that several regions along the ventral stream are possibly sensitive to the orientation of an object in space. To systematically address the question of viewpoint sensitive object perception, we conducted a study with stroke patients as well as an fMRI experiment with healthy participants applying object stimuli in several spatial orientations, for example in typical and atypical viewing conditions. In the fMRI experiment, we found stronger BOLD signals and above-chance classification accuracies for objects presented in atypical viewing conditions in fusiform face sensitive and lateral occipito-temporal object preferring areas. In the behavioral patient study, we observed that lesions of the right fusiform gyrus were associated with lower performance in object recognition for atypical views. The complementary results from both experiments emphasize the contributions of fusiform and lateral-occipital areas to visual object constancy and indicate that visual object constancy is particularly enabled through increased neuronal activity and specific activation patterns for objects in demanding viewing conditions.

A modified Camel and Cactus Test detects presymptomatic semantic impairment in genetic frontotemporal dementia within the GENFI cohort.

Impaired semantic knowledge is a characteristic feature of some forms of frontotemporal dementia (FTD), particularly the sporadic disorder semantic dementia. Less is known about semantic cognition in the genetic forms of FTD caused by mutations in the genes MAPT, C9orf72, and GRN. We developed a modified version of the Camel and Cactus Test (mCCT) to investigate the presence of semantic difficulties in a large genetic FTD cohort from the Genetic FTD Initiative (GENFI) study. Six-hundred-forty-four participants were tested with the mCCT including 67 MAPT mutation carriers (15 symptomatic, and 52 in the presymptomatic period), 165 GRN mutation carriers (33 symptomatic, 132 presymptomatic), and 164 C9orf72 mutation carriers (56 symptomatic, 108 presymptomatic) and 248 mutation-negative members of FTD families who acted as a control group. The presymptomatic mutation carriers were further split into those early and late in the presymptomatic period (more than vs. within 10 years of expected symptom onset). Groups were compared using a linear regression model, adjusting for age and education, with bootstrapping. Performance on the mCCT had a weak negative correlation with age (rho = -0.20) and a weak positive correlation with education (rho = 0.13), with an overall abnormal score (below the 5th percentile of the control population) being below 27 out of a total of 32. All three of the symptomatic mutation groups scored significantly lower than controls: MAPT mean 22.3 (standard deviation 8.0), GRN 24.4 (7.2), C9orf72 23.6 (6.5) and controls 30.2 (1.6). However, in the presymptomatic groups, only the late MAPT and late C9orf72 mutation groups scored lower than controls (28.8 (2.2) and 28.9 (2.5) respectively). Performance on the mCCT correlated strongly with temporal lobe volume in the symptomatic MAPT mutation group (rho > 0.80). In the C9orf72 group, mCCT score correlated with both bilateral temporal lobe volume (rho > 0.31) and bilateral frontal lobe volume (rho > 0.29), whilst in the GRN group mCCT score correlated only with left frontal lobe volume (rho = 0.48). This study provides evidence for presymptomatic impaired semantic knowledge in genetic FTD. The different neuroanatomical associations of the mCCT score may represent distinct cognitive processes causing deficits in different groups: loss of core semantic knowledge associated with temporal lobe atrophy (particularly in the MAPT group), and impaired executive control of semantic information associated with frontal lobe atrophy. Further studies will be helpful to address the longitudinal change in mCCT performance and the exact time at which presymptomatic impairment occurs.