Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders.

OBJECTIVE: To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD. METHODS: Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN-AD = 35). Digital measures of tau, ß-amyloid (Aß), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing. RESULTS: SYN burden was higher in SYN + AD than SYN-AD in each neocortical region (F1, 54 = 5.6-6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F1, 43-49 = 0.7-1.7, p > 0.2). SYN + AD performed worse than SYN-AD on a temporal lobe-mediated naming task (t27 = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = -0.39 to -0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F1, 43 = 12.8-97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t41 = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t41 = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aß compared to AD (F1, 40-43 = 1.6-2.0, p > 0.1). INTERPRETATION: LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1-13 ANN NEUROL 2019;85:259-271.

Implicit Mental Motor Imagery Task Demonstrates a Distortion of the Body Schema in Patients With Eating Disorders.

OBJECTIVES: A rich body of literature has established the role of body image distortion and dissatisfaction in the development and maintenance of eating disorders. However, many of the currently used techniques require explicit comparison of the person's body to an external stimulus. As the body schema is a largely unconscious construct, explicit comparison tasks may reflect a proxy, rather than the body schema itself. METHODS: Here we use an implicit mental motor imagery (MMI) task to interrogate the body schema in healthy control participants (N=40) and participants at a residential eating disorder treatment center (N=42). By comparing the time it takes to imagine making a movement along a part of the body to the time it takes to actually make the same movement, we were able to assess participants' mental image of their body (i.e., body schema). RESULTS: We found that participants with eating disorders, but not healthy controls, exhibited distortions of the body schema such that they believed their abdomen, buttocks, and thighs to be larger than they really are. Additionally, the MMI task used here provided information above and beyond traditional self-report measures (i.e., Body Shape Questionnaire). Together the MMI task and traditional measures provide the most information. CONCLUSIONS: Findings using the novel MMI task are in line with the literature; participants with eating disorders consider themselves to be larger than they truly are. Taken together, results of this study suggest that MMI tasks provide complementary information to traditional self-report measures. (JINS, 2018, 24, 715-723).

Virtual image of a hand displaced in space influences action performance of the real hand.

The rubber hand illusion (RHI) demonstrates that under some circumstances a fake hand can be regarded as part of one's body; the RHI and related phenomena have been used to explore the flexibility of the body schema. Recent work has shown that a sense of embodiment may be generated by virtual reality (VR). In a series of experiments, we used VR to assess the effects of the displacement of the virtual image of subjects' hands on action. Specifically, we tested whether spatial and temporal parameters of action change when participants perform a reaching movement towards the location of their virtual hand, the position of which was distorted on some trials. In different experiments, participants were sometimes provided with incorrect visual feedback regarding the position of the to-be-touched hand (Experiment 1), were deprived of visual feedback regarding the position of the reaching hand when acting (Experiment 2) or reached with the hand, the apparent position of which had been manipulated (Experiment 3). The effect was greatest when participants reached towards (Experiment 1) or with (Experiment 3) the displaced hand when the hand was visible during the reaching, but not when the vision of the hand was removed during the action (Experiment 2). Taken together, these data suggest that visual images of one's hand presented in VR influence the body schema and action performance.

Accurate reaching after active but not passive movements of the hand: evidence for forward modeling.

Converging behavioral findings support recent models of motor control suggesting that estimates of the future positions of a limb as well as the expected sensory consequences of a planned movement may be derived, in part, from efference copies of motor commands. These estimates are referred to as forward models. However, relatively little behavioral evidence has been obtained for proposed forward models that provide on-line estimates of current position. We report data from a patient (JD) who reached accurately to visualized targets with and without vision of her hand despite substantial proprioceptive loss. Additionally, we administered a double-start reaching test to examine the possibility that efference copy information could be used to estimate current limb position. JD reached accurately, without vision, to a final target after actively reaching to a landmark, but exhibited severely impaired reaching after passive movements to the landmark. This finding suggests that forward modeling of efference copy signals may provide relatively accurate estimates of current limb position for the purpose of motor planning. The possibility that such estimates may also contribute to the awareness of body position and to self-recognition is discussed.

Epistasis effects of dopamine genes on interval timing and reward magnitude in humans.

We tested human participants on a modified peak procedure in order to investigate the relation between interval timing and reward processing, and examine the interaction of this relation with three different dopamine-related gene polymorphisms. These gene polymorphisms affected the expression of catechol-o-methyltransferase, which catabolizes synaptic dopamine primarily in the prefrontal cortex (COMT Val158Met polymorphism), D2 dopamine receptors primarily in the striatum (DRD2/ANKK1-Taq1a polymorphism), and dopamine transporters, which clear synaptic dopamine in the striatum (DAT 3' VNTR variant). The inclusion of these polymorphisms allowed us to investigate dissociable aspects of the dopamine system and their interaction with reward magnitude manipulations in shaping timed behavior. These genes were chosen for their roles in reward processing and cortico-striatal information processing that have been implicated for interval timing. Consistent with recent animal studies, human participants initiated their timed anticipatory responding earlier when expecting a larger reward in the absence of any changes in the timing of response termination or perceived time. This effect however was specific to two out of four evaluated COMT and DRD2 polymorphism combinations that lead to high prefrontal dopamine coupled with high D2 density and low prefrontal dopamine coupled with low D2 density. Larger rewards also decreased timing precision indices, some of which interacted with the COMT polymorphism. Furthermore, the COMT polymorphism that leads to higher prefrontal dopamine resulted in weaker manifestation of memory variability (relative to threshold variability) in timed behavior. There was no effect of DAT polymorphisms on any of the core behavioral measures. These results suggest that the reward modulates decision thresholds rather than clock speed, and that these effects are specific to COMT and DRD2 epistasis effects that presumably constitute a balanced prefrontal and striatal dopamine transmission.

Voxel-based lesion-parameter mapping: Identifying the neural correlates of a computational model of word production.

The dual-route interactive two-step model explains the variation in the error patterns of aphasic speakers in picture naming, and word and nonword repetition tasks. The model has three parameters that can vary across individuals: the efficiency of the connections between semantic and lexical representations (s-weight), between lexical and phonological representations (p-weight), and between representations of auditory input and phonological representations (nl-weight). We determined these parameter values in 103 participants with chronic aphasia from left hemisphere stroke whose lesion locations had been determined. Then, using voxel-based lesion-parameter mapping, we mapped the parameters onto the brain, thus determining the neural correlates of the model's mechanisms. The maps and the behavioral findings supported the model's central claim that word repetition is affected by both the p and nl parameters. We propose that these two parameters constitute the model's analogue of the "dorsal stream" component of neurocognitive models of language processing.

Topography of FUS pathology distinguishes late-onset BIBD from aFTLD-U.

BACKGROUND: Multiple neurodegenerative diseases are characterized by the abnormal accumulation of FUS protein including various subtypes of frontotemporal lobar degeneration with FUS inclusions (FTLD-FUS). These subtypes include atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U), basophilic inclusion body disease (BIBD) and neuronal intermediate filament inclusion disease (NIFID). Despite considerable overlap, certain pathologic features including differences in inclusion morphology, the subcellular localization of inclusions, and the relative paucity of subcortical FUS pathology in aFTLD-U indicate that these three entities represent related but distinct diseases. In this study, we report the clinical and pathologic features of three cases of aFTLD-U and two cases of late-onset BIBD with an emphasis on the anatomic distribution of FUS inclusions. RESULTS: The aFTLD-U cases demonstrated FUS inclusions in cerebral cortex, subcortical grey matter and brainstem with a predilection for anterior forebrain and rostral brainstem. In contrast, the distribution of FUS pathology in late-onset BIBD cases demonstrated a predilection for pyramidal and extrapyramidal motor regions with relative sparing of cerebral cortex and limbic regions. CONCLUSIONS: The topography of FUS pathology in these cases demonstrate the diversity of sporadic FUS inclusion body diseases and raises the possibility that late-onset motor neuron disease with BIBD neuropathology may exhibit unique clinical and pathologic features.

A selective working memory impairment after transcranial direct current stimulation to the right parietal lobe.

The role of the posterior parietal cortex in working memory (WM) is poorly understood. We previously found that patients with parietal lobe damage exhibited a selective WM impairment on recognition but not recall tasks. We hypothesized that this dissociation reflected strategic differences in the utilization of attention. One concern was that these findings, and our subsequent interpretation, would not generalize to normal populations because of the patients' older age, progressive disease processes, and/or possible brain reorganization following injury. To test whether our findings extended to a normal population we applied transcranial direct current stimulation (tDCS) to right inferior parietal cortex. tDCS is a technique by which low electric current applied to the scalp modulates the resting potentials of underlying neural populations and can be used to test structure-function relationships. Eleven normal young adults received cathodal, anodal, or sham stimulation over right inferior posterior parietal cortex and then performed separate blocks of an object WM task probed by recall or recognition. The results showed that cathodal stimulation selectively impaired WM on recognition trials. These data replicate and extend our previous findings of preserved WM recall and impaired WM recognition in patients with parietal lobe lesions.

The effect of gaze direction on sound localization in brain-injured and normal adults.

This study examined the effects of eye position on sound localization in normal and brain lesion subjects. On the assumption that cerebral lesions may disrupt the representation of or attention to auditory space in the contralesional hemispace, we predicted that subjects with brain lesions would be less accurate in localizing sounds in the contralesional hemispace. In Experiment 1 we showed that gazing to the midline subjects with brain lesions were indeed impaired in localizing sounds in the contralesional hemispace. On the assumption that spatial attention is deployed at the site to which gaze is directed, we predicted that sound localization would be better on the side to which subjects directed their gaze. In Experiment 2, brain lesion subjects performed significantly better in the contralesional hemispace when they directed gaze to that hemispace. This improvement was accompanied by deterioration of performance in the ipsilesional hemispace. When subjects directed gaze to the ipsilesional hemispace, performance in the contralesional hemispace was further impaired. The effect of gaze was also observed in normal subjects in Experiments 2 and 3, independently of response mode (verbal versus pointing responses). These findings are consistent with the hypothesis that sound location may be mapped in eye-centered coordinates and that directing gaze to one hemispace reduces attentional allocation to the other hemispace.

The man who executed "imagined" movements: evidence for dissociable components of the body schema.

We examined the nature of representations underlying motor imagery and execution in a patient (CW) with bilateral parietal lesions. When imagining hand movements, CW executed the imagined motor act but was unaware of the movements. These movements were significantly more accurate than volitional movements for the left but not right hand. CW also exhibited preserved motor imagery for the left but not right hand. Consistent with previous accounts, these findings suggest that motor imagery may normally involve the inhibition of movements. CW's unawareness of movements during motor imagery may reflect inattention or misattribution of the unexpected sensory feedback. Furthermore, in line with current models of motor control, motor imagery may depend on the integrity of a "forward model" derived from motor outflow information to generate a prediction of the consequences of a motor command. Such predictions appear to be preserved for imagery of left but not right hand movements in CW. Action may additionally depend on precise updating of effector position derived from the comparison of predicted and actual sensory information. We propose that CW's impaired volitional movements may be attributable to the degradation of such an updating mechanism.