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Introduction: As motor imagery is informed by the anticipated sensory consequences of action, including pain, we reasoned that motor imagery could provide a useful indicator of chronic back pain. We tested the hypothesis that mental motor imagery regarding body movements can provide a reliable assessment of low back pain., Methods: Eighty-five subjects with back pain and forty-five age-matched controls were shown two names of body parts and asked to indicate if they could imagine moving so that the named body parts touched. Three types of imagined movements were interrogated: movements of arms, movements of legs and movements requiring flexion and/or rotation of the low back., Results: Accuracy and reaction times were measured. Subjects with back pain were less likely to indicate that they could touch body parts than age-matched controls. The effect was observed only for those movements that required movement of the low back or legs, suggesting that the effect was not attributable to task difficulty or non-specific effects. There was an effect of pain severity. Compared to subjects with mild pain, subjects with severe pain were significantly less likely to indicate that they could move so that named body parts touched. There was a correlation between pain ratings and impaired performance for stimuli that involved the lower but not upper body., Discussion: As the Can They Touch task is quick, easy to administer and does not require an explicit judgment of pain severity, it may provide useful information to supplement the assessment of subjects with chronic pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Coslett, Medina, Goodman, Wang and Burkey.)

Magnified vision of one's body part has been shown to improve tactile discrimination. We used an anesthetic cream (AC) to determine if somesthetic stimulation that alters the perception of the size of one's body would also improve two point-discrimination (2PD). In Experiment 1, application of AC caused an increase in perceived lip size and an improvement in a 2PD. As perceived lip size increased, subjects became more accurate in identifying that they had been touched in two locations. Experiment 2 confirmed this effect in a larger sample and introduced a control condition (no AC) that demonstrated that the change in performance was not attributable to practice or familiarity with the task. In Experiment 3, we showed that both AC and moisturizing cream improved subjects' ability to indicate that they had been touched in 2 locations, but the improvement was modulated by perceived lip size only for AC. These results support the idea that changes in the body representation influence 2PD., (© 2023. The Author(s).)

Transcranial magnetic stimulation (TMS) is used in several FDA-approved treatments and, increasingly, to treat neurological disorders in off-label uses. However, the mechanism by which TMS causes physiological change is unclear, as are the origins of response variability in the general population. Ideally, objective in vivo biomarkers could shed light on these unknowns and eventually inform personalized interventions. Continuous theta-burst stimulation (cTBS) is a form of TMS observed to reduce motor evoked potentials (MEPs) for 60 min or longer post-stimulation, although the consistency of this effect and its mechanism continue to be under debate. Here, we use glutamate-weighted chemical exchange saturation transfer (gluCEST) magnetic resonance imaging (MRI) at ultra-high magnetic field (7T) to measure changes in glutamate concentration at the site of cTBS. We find that the gluCEST signal in the ipsilateral hemisphere of the brain generally decreases in response to cTBS, whereas consistent changes were not detected in the contralateral region of interest (ROI) or in subjects receiving sham stimulation., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Lewy body diseases are pathologically characterized by α-synuclein pathology. Alzheimer's disease (AD) co-pathology can influence phenotypes. In vivo AD biomarkers can suggest the presence of this co-pathology in unusual cases, but pathological validation remains essential., Methods: This patient originally presented with corticobasal syndrome and later developed visual hallucinations and parkinsonism consistent with a synucleinopathy. The patient underwent CSF sampling, 18F-flortaucipir PET scanning, and brain donation with bilateral regions available for digital histological analysis., Results: CSF Aβ42 and t-tau were in the AD range. 18F-flortaucipir scanning showed right-lateralized retention in all lobes (t = 4.3-10.0, P  < .006). Neocortical stage Lewy body pathology and high levels of AD neuropathological changes were present at autopsy. There was right lateralization of α-synuclein and tau pathology ( T value = 3.1, P value = .007 and T value = 3.3, P value = .004 respectively)., Discussion: This case with overlapping tauopathy and synucleinopathy clinical features had in-depth biomarker characterization and rare bilateral post-mortem sampling showing lateralized tau and α-synuclein pathology suggesting possible synergistic relationships., Competing Interests: The authors have no competing interests or conflicts of interest to declare that are relevant to the content of this article., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Phantom limb pain (PLP) is a common and in some cases debilitating consequence of upper- or lower-limb amputation for which current treatments are inadequate., Objective: This small clinical trial tested whether game-like interactions with immersive VR activities can reduce PLP in subjects with transtibial lower-limb amputation., Methods: Seven participants attended 5-7 sessions in which they engaged in a visually immersive virtual reality experience that did not require leg movements (Cool! TM ), followed by 10-12 sessions of targeted lower-limb VR treatment consisting of custom games requiring leg movement. In the latter condition, they controlled an avatar with 2 intact legs viewed in a head-mounted display (HTC Vive TM ). A motion-tracking system mounted on the intact and residual limbs controlled the movements of both virtual extremities independently., Results: All participants except one experienced a reduction of pain immediately after VR sessions, and their pre session pain levels also decreased over the course of the study. At a group level, PLP decreased by 28% after the treatment that did not include leg movements and 39.6% after the games requiring leg motions. Both treatments were successful in reducing PLP., Conclusions: This VR intervention appears to be an efficacious treatment for PLP in subjects with lower-limb amputation.

Background: Increasing perceived hand size with magnifying lenses improves tactile discrimination and induces changes in action performance. We previously demonstrated that motor skills (tested with grip force, finger tapping, and a reach to grasp tasks) improved when actions were performed with magnified compared to normal vision; twenty-eight percent of 25 participants with stroke exhibited significant improvement on a composite measure of motor performance with magnification as compared to a session without magnification., Methods: To investigate the potential implications of magnification of vision for motor rehabilitation, we recruited individuals with stroke from the original cohort who exhibited an improvement of at least 10% in grip force and/or finger tapping for a home training protocol. Six individuals with stroke completed a two-week home-based training program in which they performed a range of activities while looking at their hand magnified. Motor skills were measured before, immediately after, and two weeks after the training., Results: Five of the six participants showed an improvement on motor tasks when tested after the training. In two participants the improvement was evident immediately after the training and persisted in time, while it occurred at two-weeks post-training in the other participants. These results suggest that the magnification of vision is a potential tool for the rehabilitation of post-stroke motor deficits., Competing Interests: The authors declare there are no competing interests.

Closing-in behavior (CIB) is observed in copying tasks (graphic or gestural) when the copy is performed near or on the top of the model. This symptom has been classically considered to be a manifestation of constructional apraxia and is often associated with a visuospatial impairment. More recent work emphasizes the attentional and/or executive nature of the behavior and its association with frontal lobe dysfunction. We describe three patients in whom CIB was associated with posterior parietal deficits of different etiologies (stroke in Patient 1 and dementia in Patients 2 and 3). In copying figures, Patient 1 produced the shape with high accuracy but the rendering overlapped the model, while for Patients 2 and 3 the copies were distorted but overlapping or in close proximity to the target. In gesture imitation, Patient 2 performed the gestures toward the examiner's space, while Patient 1 showed a peculiar form of CIB: when he was asked to place the ipsilesional arm in a position that mirrored the contralesional hand, Patient 1 moved his hand toward his contralesional hand. Patient 3 did not present gestural CIB. While CIB in Patient 1 was associated with selective deficits in executive functions and attention, additional visuospatial deficits were observed in Patients 2 and 3. The latter two patients showed a general visuoconstructional deficit. These case studies support a primary attentional account of CIB but also suggest that visuoconstructional impairments may contribute to the emergence of CIB, in some subjects. This evidence argues for different types of CIB with different cognitive and neural underpinnings. Furthermore, the data support the hypothesis of a differential involvement of fronto-parietal network in CIB.

Changes in the perceived size of a body part using magnifying lenses influence tactile perception and pain. We investigated whether the visual magnification of one's hand also influences the motor system, as indexed by transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs). In Experiment 1, MEPs were measured while participants gazed at their hand with and without magnification of the hand. MEPs were significantly larger when participants gazed at a magnified image of their hand. In Experiment 2, we demonstrated that this effect is specific to the hand that is visually magnified. TMS of the left motor cortex did not induce an increase of MEPs when participants looked at their magnified left hand. Experiment 3 was performed to determine if magnification altered the topography of the cortical representation of the hand. To that end, a 3 × 5 grid centered on the cortical hot spot (cortical location at which a motor threshold is obtained with the lowest level of stimulation) was overlaid on the participant's MRI image, and all 15 sites in the grid were stimulated with and without magnification of the hand. We confirmed the increase in the MEPs at the hot spot with magnification and demonstrated that MEPs significantly increased with magnification at sites up to 16.5 mm from the cortical hot spot. In Experiment 4, we used paired-pulse TMS to measure short-interval intracortical inhibition and intracortical facilitation. Magnification was associated with an increase in short-interval intracortical inhibition. These experiments demonstrate that the visual magnification of one's hand induces changes in motor cortex excitability and generates a rapid remapping of the cortical representation of the hand that may, at least in part, be mediated by changes in short-interval intracortical inhibition.

The neural mechanisms underlying time perception are of vital importance to a comprehensive understanding of behavior and cognition. Recent work has suggested a supramodal role for beta oscillations in measuring temporal intervals. However, the precise function of beta oscillations and whether their manipulation alters timing has yet to be determined. To accomplish this, we first re-analyzed two, separate EEG datasets and demonstrate that beta oscillations are associated with the retention and comparison of a memory standard for duration. We next conducted a study of 20 human participants using transcranial alternating current stimulation (tACS), over frontocentral cortex, at alpha and beta frequencies, during a visual temporal bisection task, finding that beta stimulation exclusively shifts the perception of time such that stimuli are reported as longer in duration. Finally, we decomposed trialwise choice data with a drift diffusion model of timing, revealing that the shift in timing is caused by a change in the starting point of accumulation, rather than the drift rate or threshold. Our results provide evidence for the intrinsic involvement of beta oscillations in the perception of time, and point to a specific role for beta oscillations in the encoding and retention of memory for temporal intervals.

Up to 90% of amputees experience sensations in their phantom limb, often including strong, persistent phantom limb pain (PLP). Standard treatments do not provide relief for the majority of people who experience PLP, but virtual reality (VR) has shown promise. This study provides additional evidence that game-like training with low-cost immersive VR activities can reduce PLP in lower-limb amputees. The user of our system views a real-time rendering of two intact legs in a head-mounted display while playing a set of custom games. The movements of both virtual extremities are controlled by measurements from inertial sensors mounted on the intact and residual limbs. Two individuals with unilateral transtibial amputation underwent multiple sessions of the VR treatment over several weeks. Both participants experienced a significant reduction of pain immediately after each VR session, and their pre-session pain levels also decreased greatly over the course of the study. Although preliminary, these data support the idea that VR interventions like ours may be an effective low-cost treatment of PLP in lower-limb amputees.

Antemortem behavioural and anatomic abnormalities have largely been associated with right hemisphere disease in behavioural-variant frontotemporal dementia, but post-mortem neuropathological examination of bilateral hemispheres remains to be defined. Here we measured the severity of post-mortem pathology in both grey and white matter using a validated digital image analysis method in four cortical regions sampled from each hemisphere in 26 patients with behavioural-variant frontotemporal dementia, including those with frontotemporal degeneration (i.e. tau = 9, TDP-43 = 14, or FUS = 1 proteinopathy) or Alzheimer's pathology (n = 2). We calculated an asymmetry index based on the difference in measured pathology from each left-right sample pair. Analysis of the absolute value of the asymmetry index (i.e. degree of asymmetry independent of direction) revealed asymmetric pathology for both grey and white matter in all four regions sampled in frontototemporal degeneration patients with tau or TDP-43 pathology (P ≤ 0.01). Direct interhemispheric comparisons of regional pathology measurements within-subjects in the combined tauopathy and TDP-43 proteinopathy group found higher pathology in the right orbitofrontal grey matter compared to the left (P < 0.01) and increased pathology in ventrolateral temporal lobe grey matter of the left hemisphere compared to the right (P < 0.02). Preliminary group-wise comparisons between tauopathy and TDP-43 proteinopathy groups found differences in patterns of interhemispheric burden of grey and white matter regional pathology, with greater relative white matter pathology in tauopathies. To test the association of pathology measurement with ante-mortem observations, we performed exploratory analyses in the subset of patients with imaging data (n = 15) and found a direct association for increasing pathologic burden with decreasing cortical thickness in frontotemporal regions on ante-mortem imaging in tauopathy (P = 0.001) and a trend for TDP-43 proteinopathy (P = 0.06). Exploratory clinicopathological correlations demonstrated an association of socially-inappropriate behaviours with asymmetric right orbitofrontal grey matter pathology, and reduced semantically-guided category naming fluency was associated asymmetric white matter pathology in the left ventrolateral temporal region. We conclude that pathologic disease burden is distributed asymmetrically in behavioural-variant frontotemporal dementia, although not universally in the right hemisphere, and this asymmetry contributes to the clinical heterogeneity of the disorder. The basis for this asymmetric profile is enigmatic but may reflect distinct species or strains of tau and TDP-43 pathologies with propensities to spread by distinct cell- and region-specific mechanisms. Patterns of region-specific pathology in the right hemisphere as well as the left hemisphere may play a role in antemortem clinical observations, and these observations may contribute to antemortem identification of molecular pathology in frontotemporal degeneration., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The severity of post-stroke aphasia and the potential for recovery are highly variable and difficult to predict. Evidence suggests that optimal estimation of aphasia severity requires the integration of multiple neuroimaging modalities and the adoption of new methods that can detect multivariate brain-behavior relationships. We created and tested a multimodal framework that relies on three information sources (lesion maps, structural connectivity, and functional connectivity) to create an array of unimodal predictions which are then fed into a final model that creates "stacked multimodal predictions" (STAMP). Crossvalidated predictions of four aphasia scores (picture naming, sentence repetition, sentence comprehension, and overall aphasia severity) were obtained from 53 left hemispheric chronic stroke patients (age: 57.1 ± 12.3 yrs, post-stroke interval: 20 months, 25 female). Results showed accurate predictions for all four aphasia scores (correlation true vs. predicted: r = 0.79-0.88). The accuracy was slightly smaller but yet significant (r = 0.66) in a full split crossvalidation with each patient considered as new. Critically, multimodal predictions produced more accurate results that any single modality alone. Topological maps of the brain regions involved in the prediction were recovered and compared with traditional voxel-based lesion-to-symptom maps, revealing high spatial congruency. These results suggest that neuroimaging modalities carry complementary information potentially useful for the prediction of aphasia scores. More broadly, this study shows that the translation of neuroimaging findings into clinically useful tools calls for a shift in perspective from unimodal to multimodal neuroimaging, from univariate to multivariate methods, from linear to nonlinear models, and, conceptually, from inferential to predictive brain mapping. Hum Brain Mapp 38:5603-5615, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Primary Progressive Aphasia (PPA) is a neurodegenerative condition characterized by insidious irreversible loss of language abilities. Prior studies suggest that transcranial direct current stimulation (tDCS) directed toward language areas of the brain may help to ameliorate symptoms of PPA. In the present sham-controlled study, we examined whether tDCS could be used to enhance language abilities (e.g., picture naming) in individuals with PPA variants primarily characterized by difficulties with speech production (non-fluent and logopenic). Participants were recruited from the Penn Frontotemporal Dementia Center to receive 10 days of both real and sham tDCS (counter-balanced, full-crossover design; participants were naïve to stimulation condition). A battery of language tests was administered at baseline, immediately post-tDCS (real and sham), and 6 weeks and 12 weeks following stimulation. When we accounted for individuals' baseline performance, our analyses demonstrated a stratification of tDCS effects. Individuals who performed worse at baseline showed tDCS-related improvements in global language performance, grammatical comprehension and semantic processing. Individuals who performed better at baseline showed a slight tDCS-related benefit on our speech repetition metric. Real tDCS may improve language performance in some individuals with PPA. Severity of deficits at baseline may be an important factor in predicting which patients will respond positively to language-targeted tDCS therapies. Clinicaltrials.gov ID: NCT02928848.

We examined the effectiveness of a 2-week regimen of a semantic feature training in combination with transcranial direct current stimulation (tDCS) for progressive naming impairment associated with primary progressive aphasia ( N = 4) or early onset Alzheimer's Disease ( N = 1). Patients received a 2-week regimen (10 sessions) of anodal tDCS delivered over the left temporoparietal cortex while completing a language therapy that consisted of repeated naming and semantic feature generation. Therapy targets consisted of familiar people, household items, clothes, foods, places, hygiene implements, and activities. Untrained items from each semantic category provided item level controls. We analyzed naming accuracies at multiple timepoints (i.e., pre-, post-, 6-month follow-up) via a mixed effects logistic regression and individual differences in treatment responsiveness using a series of non-parametric McNemar tests. Patients showed advantages for naming trained over untrained items. These gains were evident immediately post tDCS. Trained items also showed a shallower rate of decline over 6-months relative to untrained items that showed continued progressive decline. Patients tolerated stimulation well, and sustained improvements in naming accuracy suggest that the current intervention approach is viable. Future implementation of a sham control condition will be crucial toward ascertaining whether neurostimulation and behavioral treatment act synergistically or alternatively whether treatment gains are exclusively attributable to either tDCS or the behavioral intervention.

The US Air Force Office of Scientific Research convened a meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine to discuss most pressing issues facing ongoing research in the field of transcranial direct current stimulation (tDCS) and related techniques. In this study, we present opinions prepared by participants of the meeting, focusing on the most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research. Scientific, medical, and ethical considerations support the ongoing testing of tDCS in healthy and clinical populations, provided best protocols are used to maximize safety. Notwithstanding the need for ongoing research, promising applications include enhancing vigilance/attention in healthy volunteers, which can accelerate training and support learning. Commonly, tDCS is used as an adjunct to training/rehabilitation tasks with the goal of leftward shift in the learning/treatment effect curves. Although trials are encouraging, elucidating the basic mechanisms of tDCS will accelerate validation and adoption. To this end, biomarkers (eg, clinical neuroimaging and findings from animal models) can support hypotheses linking neurobiological mechanisms and behavioral effects. Dosage can be optimized using computational models of current flow and understanding dose-response. Both biomarkers and dosimetry should guide individualized interventions with the goal of reducing variability. Insights from other applied energy domains, including ionizing radiation, transcranial magnetic stimulation, and low-level laser (light) therapy, can be prudently leveraged., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CUNY has patents on brain stimulation with Bikson as an inventor. Bikson has equity in Soterix Medical Inc. Nitsche is on the advisory board of neuroelectrics—producing DC stimulators.

The gold standard for identifying stroke lesions is manual tracing, a method that is known to be observer dependent and time consuming, thus impractical for big data studies. We propose LINDA (Lesion Identification with Neighborhood Data Analysis), an automated segmentation algorithm capable of learning the relationship between existing manual segmentations and a single T1-weighted MRI. A dataset of 60 left hemispheric chronic stroke patients is used to build the method and test it with k-fold and leave-one-out procedures. With respect to manual tracings, predicted lesion maps showed a mean dice overlap of 0.696 ± 0.16, Hausdorff distance of 17.9 ± 9.8 mm, and average displacement of 2.54 ± 1.38 mm. The manual and predicted lesion volumes correlated at r = 0.961. An additional dataset of 45 patients was utilized to test LINDA with independent data, achieving high accuracy rates and confirming its cross-institutional applicability. To investigate the cost of moving from manual tracings to automated segmentation, we performed comparative lesion-to-symptom mapping (LSM) on five behavioral scores. Predicted and manual lesions produced similar neuro-cognitive maps, albeit with some discussed discrepancies. Of note, region-wise LSM was more robust to the prediction error than voxel-wise LSM. Our results show that, while several limitations exist, our current results compete with or exceed the state-of-the-art, producing consistent predictions, very low failure rates, and transferable knowledge between labs. This work also establishes a new viewpoint on evaluating automated methods not only with segmentation accuracy but also with brain-behavior relationships. LINDA is made available online with trained models from over 100 patients., (© 2016 Wiley Periodicals, Inc.)

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) presents with a variety of clinical phenotypes including motor impairments such as gait dysfunction, rigidity, tremor and bradykinesia as well as cognitive deficits including personality changes and dementia. In recent years, colony stimulating factor 1 receptor gene (CSF1R) has been identified as the primary genetic cause of HDLS. We describe the clinical and neuropathological features in three siblings with HDLS and the CSF1R p.Arg782His (c.2345G > A) pathogenic mutation. Each case had varied motor symptoms and clinical features, but all included slowed movements, poor balance, memory impairment and frontal deficits. Neuroimaging with magnetic resonance imaging revealed atrophy and increased signal in the deep white matter. Abundant white matter spheroids and CD68-positive macrophages were the predominant pathologies in these cases. Similar to other cases reported in the literature, the three cases described here had varied clinical phenotypes with a pronounced, but heterogeneous distribution of axonal spheroids and distinct microglia morphology. Our findings underscore the critical importance of genetic testing for establishing a clinical and pathological diagnosis of HDLS.

Studies of patients with acquired cognitive deficits following brain damage and studies using contemporary neuroimaging techniques form two distinct streams of research on the neural basis of cognition. In this study, we combine high-quality structural neuroimaging analysis techniques and extensive behavioural assessment of patients with persistent acquired language deficits to study the neural basis of language. Our results reveal two major divisions within the language system-meaning versus form and recognition versus production-and their instantiation in the brain. Phonological form deficits are associated with lesions in peri-Sylvian regions, whereas semantic production and recognition deficits are associated with damage to the left anterior temporal lobe and white matter connectivity with frontal cortex, respectively. These findings provide a novel synthesis of traditional and contemporary views of the cognitive and neural architecture of language processing, emphasizing dual routes for speech processing and convergence of white matter tracts for semantic control and/or integration.

Lesion analysis is a classic approach to study brain functions. Because brain function is a result of coherent activations of a collection of functionally related voxels, lesion-symptom relations are generally contributed by multiple voxels simultaneously. Although voxel-based lesion-symptom mapping (VLSM) has made substantial contributions to the understanding of brain-behavior relationships, a better understanding of the brain-behavior relationship contributed by multiple brain regions needs a multivariate lesion-symptom mapping (MLSM). The purpose of this artilce was to develop an MLSM using a machine learning-based multivariate regression algorithm: support vector regression (SVR). In the proposed SVR-LSM, the symptom relation to the entire lesion map as opposed to each isolated voxel is modeled using a nonlinear function, so the intervoxel correlations are intrinsically considered, resulting in a potentially more sensitive way to examine lesion-symptom relationships. To explore the relative merits of VLSM and SVR-LSM we used both approaches in the analysis of a synthetic dataset. SVR-LSM showed much higher sensitivity and specificity for detecting the synthetic lesion-behavior relations than VLSM. When applied to lesion data and language measures from patients with brain damages, SVR-LSM reproduced the essential pattern of previous findings identified by VLSM and showed higher sensitivity than VLSM for identifying the lesion-behavior relations. Our data also showed the possibility of using lesion data to predict continuous behavior scores., (© 2014 Wiley Periodicals, Inc.)

Numerous functional neuroimaging studies suggest that widespread bilateral parietal, temporal, and frontal regions are involved in tool-related and pantomimed gesture performance, but the role of these regions in specific aspects of gestural tasks remains unclear. In the largest prospective study of apraxia-related lesions to date, we performed voxel-based lesion-symptom mapping with data from 71 left hemisphere stroke participants to assess the critical neural substrates of three types of actions: gestures produced in response to viewed tools, imitation of tool-specific gestures demonstrated by the examiner, and imitation of meaningless gestures. Thus, two of the three gesture types were tool-related, and two of the three were imitative, enabling pairwise comparisons designed to highlight commonalities and differences. Gestures were scored separately for postural (hand/arm positioning) and kinematic (amplitude/timing) accuracy. Lesioned voxels in the left posterior temporal gyrus were significantly associated with lower scores on the posture component for both of the tool-related gesture tasks. Poor performance on the kinematic component of all three gesture tasks was significantly associated with lesions in left inferior parietal and frontal regions. These data enable us to propose a componential neuroanatomic model of action that delineates the specific components required for different gestural action tasks. Thus, visual posture information and kinematic capacities are differentially critical to the three types of actions studied here: the kinematic aspect is particularly critical for imitation of meaningless movement, capacity for tool-action posture representations are particularly necessary for pantomimed gestures to the sight of tools, and both capacities inform imitation of tool-related movements. These distinctions enable us to advance traditional accounts of apraxia., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Recent experimental evidence suggests that the perception of temporal intervals is influenced by the temporal context in which they are presented. A longstanding example is the time-order-error, wherein the perception of two intervals relative to one another is influenced by the order in which they are presented. Here, we test whether the perception of temporal intervals in an absolute judgment task is influenced by the preceding temporal context. Human subjects participated in a temporal bisection task with no anchor durations (partition method). Intervals were demarcated by a Gaussian blob (visual condition) or burst of white noise (auditory condition) that persisted for one of seven logarithmically spaced sub-second intervals. Crucially, the order in which stimuli were presented was first-order counterbalanced, allowing us to measure the carryover effect of every successive combination of intervals. The results demonstrated a number of distinct findings. First, the perception of each interval was biased by the prior response, such that each interval was judged similarly to the preceding trial. Second, the perception of each interval was also influenced by the prior interval, such that perceived duration shifted away from the preceding interval. Additionally, the effect of decision bias was larger for visual intervals, whereas auditory intervals engendered greater perceptual carryover. We quantified these effects by designing a biologically-inspired computational model that measures noisy representations of time against an adaptive memory prior while simultaneously accounting for uncertainty, consistent with a Bayesian heuristic. We found that our model could account for all of the effects observed in human data. Additionally, our model could only accommodate both carryover effects when uncertainty and memory were calculated separately, suggesting separate neural representations for each. These findings demonstrate that time is susceptible to similar carryover effects as other basic stimulus attributes, and that the brain rapidly adapts to temporal context.

While converging evidence implicates the right inferior parietal lobule in audiovisual integration, its role has not been fully elucidated by direct manipulation of cortical activity. Replicating and extending an experiment initially reported by Kamke et al. (2012), we employed the sound-induced flash illusion, in which a single visual flash, when accompanied by two auditory tones, is misperceived as multiple flashes (Wilson, 1987; Shams et al., 2000). Slow repetitive (1 Hz) TMS administered to the right angular gyrus, but not the right supramarginal gyrus, induced a transient decrease in the Peak Perceived Flashes (PPF), reflecting reduced susceptibility to the illusion. This finding independently confirms that perturbation of networks involved in multisensory integration can result in a more veridical representation of asynchronous auditory and visual events and that cross-modal integration is an active process in which the objective is the identification of a meaningful constellation of inputs, at times at the expense of accuracy.

Complex cognitive tasks such as visual working memory (WM) involve networks of interacting brain regions. Several neurotransmitters, including an appropriate dopamine concentration, are important for WM performance. A number of gene polymorphisms are associated with individual differences in cognitive task performance. COMT, for example, encodes catechol-o-methyl transferase the enzyme primarily responsible for catabolizing dopamine in the prefrontal cortex. Striatal dopamine function, linked with cognitive tasks as well as habit learning, is influenced by the Taq-Ia polymorphism of the DRD2/ANKK1 gene complex; this gene influences the density of dopamine receptors in the striatum. Here, we investigated the effects of these polymorphisms on a WM task requiring the maintenance of 4 or 6 items over delay durations of 1 or 5 seconds. We explored main effects and interactions between the COMT and DRD2/ANKK1-Taq-Ia polymorphisms on WM performance. Participants were genotyped for COMT (Val(158)Met) and DRD2/ANKK1-Taq-Ia (A1+, A1-) polymorphisms. There was a significant main effect of both polymorphisms. Participants' WM reaction times slowed with increased Val loading such that the Val/Val homozygotes made the slowest responses and the Met/Met homozygotes were the fastest. Similarly, WM reaction times were slower and more variable for the DRD2/ANKK1-Taq-Ia A1+ group than the A1- group. The main effect of COMT was only apparent in the DRD2/ANKK1-Taq-Ia A1- group. These findings link WM performance with slower dopaminergic metabolism in the prefrontal cortex as well as a greater density of dopamine receptors in the striatum.

Meaningful speech, as exemplified in object naming, calls on knowledge of the mappings between word meanings and phonological forms. Phonological errors in naming (e.g. GHOST named as 'goath') are commonly seen in persisting post-stroke aphasia and are thought to signal impairment in retrieval of phonological form information. We performed a voxel-based lesion-symptom mapping analysis of 1718 phonological naming errors collected from 106 individuals with diverse profiles of aphasia. Voxels in which lesion status correlated with phonological error rates localized to dorsal stream areas, in keeping with classical and contemporary brain-language models. Within the dorsal stream, the critical voxels were concentrated in premotor cortex, pre- and postcentral gyri and supramarginal gyrus with minimal extension into auditory-related posterior temporal and temporo-parietal cortices. This challenges the popular notion that error-free phonological retrieval requires guidance from sensory traces stored in posterior auditory regions and points instead to sensory-motor processes located further anterior in the dorsal stream. In a separate analysis, we compared the lesion maps for phonological and semantic errors and determined that there was no spatial overlap, demonstrating that the brain segregates phonological and semantic retrieval operations in word production.

Background: Given that traumatic brain injury (TBI) results in chronic alteration of baseline cerebral perfusion, a perfusion functional MRI (fMRI) method that dissociates resting- and task-related cerebral blood flow (CBF) changes can be useful in noninvasively investigating the neural correlates of cognitive dysfunction and recovery in TBI., Objective: The authors used continuous arterial spin-labeled (ASL) perfusion fMRI to characterize CBF at rest and during sustained-attention and working-memory tasks., Methods: A total of 18 to 21 individuals with moderate to severe TBI and 14 to 18 demographically matched healthy controls completed 3 continuous 6-minute perfusion fMRI scans (resting, visual sustained attention, and 2-back working memory)., Results: For both tasks, TBI participants showed worse behavioral performance than controls. Voxelwise neuroimaging analysis of the 2-back task found that group differences in task-induced CBF changes were localized to bilateral superior occipital cortices and the left superior temporal cortex. Whereas controls deactivated these areas during task performance, TBI participants tended to activate these same areas. These regions were among those found to be disproportionately hypoperfused at rest after TBI. For both tasks, the control and TBI groups showed different patterns of correlation between performance and task-related CBF changes., Conclusions: ASL perfusion fMRI demonstrated differences between individuals with TBI and healthy controls in resting perfusion and in task-evoked CBF changes as well as different patterns of performance-activation correlation. These results are consistent with the notion that sensory/attentional modulation deficits contribute to higher cognitive dysfunction in TBI.

Previous studies have suggested that contingent negative variation (CNV), as recorded by electroencaphalography (EEG), may serve as an index of temporal encoding. The interpretation of these studies is complicated by the fact that, in a majority of studies, the CNV signal was obtained at a time when subjects were not only registering stimulus duration but also making decisions and preparing to act. Previously, we demonstrated that repetitive transcranial magnetic stimulation (rTMS) of the right supramarginal gyrus (rSMG) in humans lengthened the perceived duration of a visual stimulus (Wiener et al., 2010a), suggesting the rSMG is involved in basic encoding processes. Here, we report a replication of this effect with simultaneous EEG recordings during the encoding of stimulus duration. Stimulation of the rSMG led to an increase in perceived duration and the amplitude of N1 and CNV components recorded from frontocentral sites. Furthermore, the size of the CNV amplitude, but not N1, positively correlated with the size of the rTMS effect but negatively correlated with bias (the baseline tendency to report a comparison stimulus as shorter), suggesting that the CNV indexes stimulus duration. These results suggest that a feedforward mechanism from parietal to prefrontal regions mediates temporal encoding and demonstrate a dissociation between early and late phases of encoding processes.

Evidence from neuroimaging and neuropsychology suggests that portions of the anterior temporal lobes (ATLs) play a critical role in proper name retrieval. We previously found that anodal transcranial direct current stimulation (tDCS) to the ATLs improved retrieval of proper names in young adults (Ross et al., 2010). Here we extend that finding to older adults who tend to experience greater proper-naming deficits than young adults. The task was to look at pictures of famous faces or landmarks and verbally recall the associated proper name. Our results show a numerical improvement in face naming after left or right ATL stimulation, but a statistically significant effect only after left-lateralized stimulation. The magnitude of the enhancing effect was similar in older and younger adults but the lateralization of the effect differed depending on age. The implications of these findings for the use of tDCS as tool for rehabilitation of age-related loss of name recall are discussed.

We used voxel-based lesion-symptom mapping (VLSM) to determine which brain areas are necessary for discriminating time intervals above and below 1 s. VLSM compares behavioral scores of patients that have damage to a given voxel to those that do not on a voxel-by-voxel basis to determine which voxels are critical for the given behavior. Forty-seven subjects with unilateral hemispheric lesions performed a temporal discrimination task in which a standard stimulus was compared on each trial to a test stimulus. In different blocks of trials, standard stimuli were either 600 or 2000 ms. Behavioral measures included the point of subjective equality, a measure of accuracy, and the coefficient of variation, a measure of variability. Lesions of the right middle and inferior frontal gyri were associated with decrements in performance on both durations. In addition, lesions of the left temporal lobe and right precentral gyrus were associated exclusively with impaired performance for subsecond stimuli. In line with results from other studies, these data suggest that different circuits are necessary for timing intervals in these ranges, and that right frontal areas are particularly important to timing.

A number of lines of evidence implicate dopamine in timing [Rammsayer, T. H. Neuropharmacological approaches to human timing. In S. Grondin (Ed.), Psychology of time (pp. 295-320). Bingley, UK: Emerald, 2008; Meck, W. H. Neuropharmacology of timing and time perception. Brain Research, Cognitive Brain Research, 3, 227-242, 1996]. Two human genetic polymorphisms are known to modulate dopaminergic activity. DRD2/ANKK1-Taq1a is a D(2) receptor polymorphism associated with decreased D(2) density in the striatum [Jönsson, E. G., Nothen, M. M., Grunhage, F., Farde, L., Nakashima, Y., Propping, P., et al. Polymorphisms in the dopamine D(2) receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Molecular Psychiatry, 4, 290-296, 1999]; COMT Val158Met is a functional polymorphism associated with increased activity of the COMT enzyme such that catabolism of synaptic dopamine is greater in pFC [Meyer-Lindenberg, A., Kohn, P. D., Kolachana, B., Kippenhan, S., McInerney-Leo, A., Nussbaum, R., et al. Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genotype. Nature Neuroscience, 8, 594-596, 2005]. To investigate the role of dopamine in timing, we genotyped 65 individuals for DRD2/ANKK1-Taq1a, COMT Val158Met, and a third polymorphism, BDNF Val66Met, a functional polymorphism affecting the expression of brain-derived neurotrophic factor [Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257-269, 2003]. Subjects were tested on a temporal discrimination task with sub- and supra-second intervals (500- and 2000-msec standards) as well as a spontaneous motor tempo task. We found a double dissociation for temporal discrimination: the DRD2/ANKK1-Taq1a polymorphism (A1+ allele) was associated with significantly greater variability for the 500-msec duration only, whereas the COMT Val158Met polymorphism (Val/Val homozygotes) was associated with significantly greater variability for the 2000-msec duration only. No differences were detected for the BDNF Vall66Met variant. Additionally, the DRD2/ANKK1-Taq1a polymorphism was associated with a significantly slower preferred motor tempo. These data provide a potential biological basis for the distinctions between sub- and supra-second timing and suggest that BG are integral for the former whereas pFC is implicated in the latter.

It is thought that semantic memory represents taxonomic information differently from thematic information. This study investigated the neural basis for the taxonomic-thematic distinction in a unique way. We gathered picture-naming errors from 86 individuals with poststroke language impairment (aphasia). Error rates were determined separately for taxonomic errors ("pear" in response to apple) and thematic errors ("worm" in response to apple), and their shared variance was regressed out of each measure. With the segmented lesions normalized to a common template, we carried out voxel-based lesion-symptom mapping on each error type separately. We found that taxonomic errors localized to the left anterior temporal lobe and thematic errors localized to the left temporoparietal junction. This is an indication that the contribution of these regions to semantic memory cleaves along taxonomic-thematic lines. Our findings show that a distinction long recognized in the psychological sciences is grounded in the structure and function of the human brain.

A number of conflicting claims have been advanced regarding the role of the left inferior frontal gyrus, inferior parietal lobe and posterior middle temporal gyrus in action recognition, driven in part by an ongoing debate about the capacities of putative mirror systems that match observed and planned actions. We report data from 43 left hemisphere stroke patients in two action recognition tasks in which they heard and saw an action word ('hammering') and selected from two videoclips the one corresponding to the word. In the spatial recognition task, foils contained errors of body posture or movement amplitude/timing. In the semantic recognition task, foils were semantically related (sawing). Participants also performed a comprehension control task requiring matching of the same verbs to objects (hammer). Using regression analyses controlling for both the comprehension control task and lesion volume, we demonstrated that performance in the semantic gesture recognition task was predicted by per cent damage to the posterior temporal lobe, whereas the spatial gesture recognition task was predicted by per cent damage to the inferior parietal lobule. A whole-brain voxel-based lesion symptom-mapping analysis suggested that the semantic and spatial gesture recognition tasks were associated with lesioned voxels in the posterior middle temporal gyrus and inferior parietal lobule, respectively. The posterior middle temporal gyrus appears to serve as a central node in the association of actions and meanings. The inferior parietal lobule, held to be a homologue of the monkey parietal mirror neuron system, is critical for encoding object-related postures and movements, a relatively circumscribed aspect of gesture recognition. The inferior frontal gyrus, on the other hand, was not predictive of performance in any task, suggesting that previous claims regarding its role in action recognition may require refinement.

Non-invasive measurement of resting state cerebral blood flow (CBF) may reflect alterations of brain structure and function after traumatic brain injury (TBI). However, previous imaging studies of resting state brain in chronic TBI have been limited by several factors, including measurement in relative rather than absolute units, use of crude spatial registration methods, exclusion of subjects with substantial focal lesions, and exposure to ionizing radiation, which limits repeated assessments. This study aimed to overcome those obstacles by measuring absolute CBF with an arterial spin labeling perfusion fMRI technique, and using an image preprocessing protocol that is optimized for brains with mixed diffuse and focal injuries characteristic of moderate and severe TBI. Resting state CBF was quantified in 27 individuals with moderate to severe TBI in the chronic stage, and 22 demographically matched healthy controls. In addition to global CBF reductions in the TBI subjects, more prominent regional hypoperfusion was found in the posterior cingulate cortices, the thalami, and multiple locations in the frontal cortices. Diffuse injury, as assessed by tensor-based morphometry, was mainly associated with reduced CBF in the posterior cingulate cortices and the thalami, where the greatest volume losses were detected. Hypoperfusion in superior and middle frontal cortices, in contrast, was associated with focal lesions. These results suggest that structural lesions, both focal and diffuse, are the main contributors to the absolute CBF alterations seen in chronic TBI, and that CBF may serve as a tool to assess functioning neuronal volume. We also speculate that resting reductions in posterior cingulate perfusion may reflect alterations in the default-mode network, and may contribute to the attentional deficits common in TBI.

Models of time perception often describe an "internal clock" that involves at least two components: an accumulator and a comparator. We used functional magnetic resonance imaging to test the hypothesis that distinct distributed neural networks mediate these components of time perception. Subjects performed a temporal discrimination task that began with a visual stimulus (S1) that varied parametrically in duration of presentation. A varying interstimulus interval was followed by a second visual stimulus (S2). After the S2 offset, the subject indicated whether S2 was longer or shorter than S1. We reasoned that neural activity that correlated with S1 duration would represent accumulator networks. We also reasoned that neural activity that correlated with the difficulty of comparisons for each paired-judgment would represent comparator networks. Using anatomically defined regions of interest, we found duration of S1 significantly correlated with left inferior frontal, supplementary motor area (SMA) and superior temporal regions. Furthermore, task difficulty correlated with activity within bilateral inferior frontal gyri. Therefore accumulator and comparator functioning of the internal clock are mediated by distinct as well as partially overlapping neural regions.

Background: The neural basis of timing remains poorly understood. Although controversy persists, many lines of evidence, including studies in animals, functional imaging studies in humans and lesion studies in humans and animals suggest that the basal ganglia are important for temporal processing [1]., Methodology/principal Findings: We report data from a wide range of timing tasks from two subjects with disabling neurologic deficits caused by bilateral lesions of the basal ganglia. Both subjects perform well on tasks assessing time estimation, reproduction and production tasks. Additionally, one subject performed normally on psychophysical tasks requiring the comparison of time intervals ranging from milliseconds to seconds; the second subject performed abnormally on the psychophysical task with a 300ms standard but did well with 600ms, 2000ms and 8000ms standards. Both subjects performed poorly on an isochronous rhythm production task on which they are required to maintain rhythmic tapping., Conclusions/significance: As studies of subjects with brain lesions permit strong inferences regarding the necessity of brain structures, these data demonstrate that the basal ganglia are not crucial for many sub- or supra-second timing operations in humans but are needed for the timing procedures that underlie the production of movements. This dissociation suggests that distinct and dissociable processes may be employed to measure time intervals. Inconsistencies in findings regarding the neural basis of timing may reflect the availability of multiple temporal processing routines that are flexibly implemented in response to task demands.

The neural basis of temporal processing is unclear. We addressed this important issue by performing two experiments in which repetitive transcranial magnetic stimulation (rTMS) was administered in different sessions to the left or right supramarginal gyrus (SMG) or vertex; in both tasks, two visual stimuli were presented serially and subjects were asked to judge if the second stimulus was longer than the first (standard) stimulus. rTMS was presented on 50% of trials. Consistent with a previous literature demonstrating the effect of auditory clicks on temporal judgment, rTMS was associated with a tendency to perceive the paired visual stimulus as longer in all conditions. Crucially, rTMS to the right SMG was associated with a significantly greater subjective prolongation of the associated visual stimulus in both experiments. These findings demonstrate that the right SMG is an important element of the neural system underlying temporal processing and, as discussed, have implications for neural and cognitive models of temporal perception and attention.

Converging evidence from neuroimaging and neuropsychological studies is essential for understanding human frontal cortical function. We introduce a new method for studying the effects of transient disruptions of frontal activity during transcranial magnetic stimulation (TMS). Using a novel combination of TMS and computer-mouse tracking, through two experiments we tested process models of semantic competition in left ventrolateral prefrontal cortex (VLPFC). On TMS stimulation of left mid-VLPFC just after presentation of an ambiguous stimulus, participants' mouse-movement trajectories deviated more toward the incorrect target for weak associate trials than for any other trial type. This effect was extinguished when participants were simultaneously shown both target and cue stimuli. Results suggest that left mid-VLPFC is necessary to resolve semantic competition when a response is underdetermined by the stimulus and the interpretive context of the stimulus is ambiguous. Computer-mouse movements reveal the dynamics of competitive interactions as they resolve, making this technique ideally suited for studying cognitive control processes and a more sensitive index of TMS disruption than reaction time and accuracy alone.

Analysis of error types provides useful information about the stages and processes involved in normal and aphasic word production. In picture naming, semantic errors (horse for goat) generally result from something having gone awry in lexical access such that the right concept was mapped to the wrong word. This study used the new lesion analysis technique known as voxel-based lesion-symptom mapping to investigate the locus of lesions that give rise to semantic naming errors. Semantic errors were obtained from 64 individuals with post-stroke aphasia, who also underwent high-resolution structural brain scans. Whole brain voxel-based lesion-symptom mapping was carried out to determine where lesion status predicted semantic error rate. The strongest associations were found in the left anterior to mid middle temporal gyrus. This area also showed strong and significant effects in further analyses that statistically controlled for deficits in pre-lexical, conceptualization processes that might have contributed to semantic error production. This study is the first to demonstrate a specific and necessary role for the left anterior temporal lobe in mapping concepts to words in production. We hypothesize that this role consists in the conveyance of fine-grained semantic distinctions to the lexical system. Our results line up with evidence from semantic dementia, the convergence zone framework and meta-analyses of neuroimaging studies on word production. At the same time, they cast doubt on the classical linkage of semantic error production to lesions in and around Wernicke's area.

To produce a word, the intended word must be selected from a competing set of other words. In other domains where competition affects the selection process, the left inferior frontal gyrus (LIFG) responds to competition among incompatible representations. The aim of this study was to test whether the LIFG is necessary for resolution of competition in word production. Using a methodological approach applying the same rigorous analytic methods to neuropsychological data as is done with neuroimaging data, we compared brain activation patterns in normal speakers (using fMRI) with the results of lesion-deficit correlations in aphasic speakers who performed the same word production task designed to elicit competition during lexical selection. The degree of activation of the LIFG in normal speakers and damage to the LIFG in aphasic speakers was associated with performance on the production task. These convergent findings provide strong support for the hypothesis that the region of cortex commonly known as Broca's area (i.e., the posterior LIFG) serves to bias competitive interactions during language production.

Abstract Information regarding object identity ("what") and spatial location ("where/how to") is largely segregated in visual processing. Under most circumstances, however, object identity and location are linked. We report data from a simultanagnosic patient (K.E.) with bilateral posterior parietal infarcts who was unable to "see" more than one object in an array despite relatively preserved object processing and normal preattentive processing. K.E. also demonstrated a finding that has not, to our knowledge, been reported: He was unable to report more than one attribute of a single object. For example, he was unable to name the color of the ink in which words were written despite naming the word correctly. Several experiments demonstrated, however, that perceptual attributes that he was unable to report influenced his performance. We suggest that binding of object identity and location is a limited-capacity operation that is essential for conscious awareness for which the posterior parietal lobe is crucial.

Lesion analysis in brain-injured populations complements what can be learned from functional neuroimaging. Voxel-based approaches to mapping lesion-behavior correlations in brain-injured populations are increasingly popular, and have the potential to leverage image analysis methods drawn from functional magnetic resonance imaging. However, power is a major concern for these studies, and is likely to vary regionally due to the distribution of lesion locations. Here, we outline general considerations for voxel-based methods, characterize the use of a nonparametric permutation test adapted from functional neuroimaging, and present methods for regional power analysis in lesion studies.

The spatial neglect syndrome, defined by asymmetric attention and action not attributed to primary motor or sensory dysfunction and accompanied by functional disability, is a major cause of post-stroke morbidity. In this review, we consider the challenges and obstacles facing scientific researches wishing to evaluate the mechanisms and effectiveness of rehabilitation interventions. Spatial neglect is a heterogeneous disorder, for which consensus research definitions are not currently available, and it is unclear which of the deficits associated with the syndrome causes subsequent disability. We review current opinion about methods of assessment, suggest a rational approach to selecting therapies which requires further study, and make systems-level and theoretical recommendations for building theory. We lastly review some creative questions for consideration in future research.

Previous data from single-case and small group studies have suggested distinctions among structural, conceptual, and online sensorimotor representations of the human body. We developed a battery of tasks to further examine the prevalence and anatomic substrates of these body representations. The battery was administered to 70 stroke patients. Fifty-one percent of the patients were impaired relative to controls on at least one body representation measure. Further, principal components analysis of the patient data as well as direct comparisons of patient and control performance suggested a triple dissociation between measures of the 3 putative body representations. Consistent with previous distinctions between the "what" and "how" pathways, lesions of the left temporal lobe were most consistently associated with impaired performance on tasks assessing knowledge of the shape or lexical-semantic information about the body, whereas lesions of the dorsolateral frontal and parietal regions resulted in impaired performance on tasks requiring on-line coding of body posture.