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1.  Multivariate Lesion-Symptom Mapping Using Support Vector Regression 
Human brain mapping  2014;35(12):5861-5876.
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 paper 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 non-linear function, so the inter-voxel 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.
PMCID: PMC4213345  PMID: 25044213
Lesion-symptom mapping; support vector regression; aphasia; total lesion volume control
2.  Voxel-based lesion-parameter mapping: Identifying the neural correlates of a computational model of word production 
Cognition  2013;128(3):380-396.
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.
PMCID: PMC3709005  PMID: 23765000
Aphasia; Language production; Computational models; Voxel-based Lesion Parameter Mapping
3.  Continuous Carryover of Temporal Context Dissociates Response Bias from Perceptual Influence for Duration 
PLoS ONE  2014;9(6):e100803.
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.
PMCID: PMC4071004  PMID: 24963624
4.  Noninvasive Transcranial Direct Current Stimulation Over the Left Prefrontal Cortex Facilitates Cognitive Flexibility in Tool Use 
Cognitive neuroscience  2013;4(2):81-89.
Recent neuroscience evidence suggests that some higher-order tasks might benefit from a reduction in sensory filtering associated with low levels of cognitive control. Guided by neuroimaging findings, we hypothesized that cathodal (inhibitory) transcranial direct current stimulation (tDCS) will facilitate performance in a flexible use generation task. Participants saw pictures of artifacts and generated aloud either the object’s common use or an uncommon use for it, while receiving cathodal tDCS (1.5 mA) either over left or right PFC, or sham stimulation. A forward digit span task served as a negative control for potential general effects of stimulation. Analysis of voice-onset reaction times and number of responses generated showed significant facilitative effects of left PFC stimulation for the uncommon, but not the common use generation task and no effects of stimulation on the control task. The results support the hypothesis that certain tasks may benefit from a state of diminished cognitive control.
PMCID: PMC3719984  PMID: 23894253
semantic memory; creative cognition; transcranial direct current stimulation; prefrontal cortex; cognitive control
5.  Transcranial direct current stimulation accelerates allocentric target detection 
Brain stimulation  2012;6(3):433-439.
Previous research on hemispatial neglect has provided evidence for dissociable mechanisms for egocentric and allocentric processing. Although a few studies have examined whether tDCS to posterior parietal cortex can be beneficial for attentional processing in neurologically intact individuals, none have examined the potential effect of tDCS on allocentric and/or egocentric processing.
Our objective was to examine whether transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique that can increase (anodal) or decrease (cathodal) cortical activity, can affect visuospatial processing in an allocentric and/or egocentric frame of reference.
We tested healthy individuals on a target detection task in which the target – a circle with a gap - was either to the right or left of the viewer (egocentric), or contained a gap on the right or left side of the circle (allocentric). Individuals performed the task before, during, and after tDCS to the posterior parietal cortex in one of three stimulation conditions – right anodal/left cathodal, right cathodal/left anodal, and sham.
We found an allocentric hemispatial effect both during and after tDCS, such that right anodal/left cathodal tDCS resulted in faster reaction times for detecting stimuli with left-sided gaps compared to right-sided gaps.
Our study suggests that right anodal/left cathodal tDCS has a facilitatory effect on allocentric visuospatial processing, and might be useful as a therapeutic technique for individuals suffering from allocentric neglect.
PMCID: PMC3515718  PMID: 22784444
transcranial direct current stimulation; neglect; egocentric; allocentric; current density modeling
6.  Sparse canonical correlation analysis relates network-level atrophy to multivariate cognitive measures in a neurodegenerative population 
NeuroImage  2013;84:698-711.
This study establishes that sparse canonical correlation analysis (SCCAN) identifies generalizable, structural MRI-derived cortical networks that relate to five distinct categories of cognition. We obtain multivariate psychometrics from the domain-specific sub-scales of the Philadelphia Brief Assessment of Cognition (PBAC). By using a training and separate testing stage, we find that PBAC-defined cognitive domains of language, visuospatial functioning, episodic memory, executive control, and social functioning correlate with unique and distributed areas of gray matter (GM). In contrast, a parallel univariate framework fails to identify, from the training data, regions that are also significant in the left-out test dataset. The cohort includes164 patients with Alzheimer’s disease, behavioral-variant frontotemporal dementia, semantic variant primary progressive aphasia, nonfluent/agrammatic primary progressive aphasia, or corticobasal syndrome. The analysis is implemented with open-source software for which we provide examples in the text. In conclusion, we show that multivariate techniques identify biologically-plausible brain regions supporting specific cognitive domains. The findings are identified in training data and confirmed in test data.
PMCID: PMC3911786  PMID: 24096125
Alzheimer disease; Frontotemporal lobar degeneration; Philadelphia Brief Assessment of Cognition; PBAC; MRI; Sparse canonical correlation analysis
7.  The dorsal stream contribution to phonological retrieval in object naming 
Brain  2012;135(12):3799-3814.
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.
PMCID: PMC3525060  PMID: 23171662
aphasia; dual-stream; voxel-based lesion-symptom mapping; naming; phonological errors; semantic errors
8.  The right hemisphere is not unitary in its role in aphasia recovery 
Neurologists and aphasiologists have debated for over a century whether right hemisphere recruitment facilitates or impedes recovery from aphasia. Here we present a well-characterized patient with sequential left and right hemisphere strokes whose case substantially informs this debate. A 72-year-old woman with chronic nonfluent aphasia was enrolled in a trial of transcranial magnetic stimulation (TMS). She underwent 10 daily sessions of inhibitory TMS to the right pars triangularis. Brain activity was measured during picture naming using fMRI prior to TMS exposure and before and after TMS on the first day of treatment. Language and cognition were tested behaviorally three times prior to treatment, and at 2 and 6 months afterwards. Inhibitory TMS to the right pars triangularis induced immediate improvement in naming, which was sustained 2 months later. FMRI confirmed a local reduction in activity at the TMS target, without expected increased activity in corresponding left hemisphere areas. Three months after TMS, the patient suffered a right hemisphere ischemic stroke, resulting in worsening of aphasia without other clinical deficits. Behavioral testing 3 months later confirmed that language function was impacted more than other cognitive domains. The paradoxical effects of inhibitory TMS and the stroke to the right hemisphere demonstrate that even within a single patient, involvement of some right hemisphere areas may support recovery, while others interfere. The behavioral evidence confirms that compensatory reorganization occurred within the right hemisphere after the original stroke. No support is found for interhemispheric inhibition, the theoretical framework on which most therapeutic brain stimulation protocols for aphasia are based.
PMCID: PMC3221765  PMID: 21794852
aphasia; transcranial magnetic stimulation; plasticity; neuromodulation; interhemispheric inhibition
9.  Gone in a flash: manipulation of audiovisual temporal integration using transcranial magnetic stimulation 
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.
PMCID: PMC3769638  PMID: 24062701
transcranial magnetic stimulation; noninvasive brain stimulation; sound-induced flash illusion; audiovisual integration; inferior parietal lobule (IPL); angular gyrus (AG)
10.  Finding the Right Words: Transcranial Magnetic Stimulation Improves Discourse Productivity in Non-fluent Aphasia After Stroke 
Aphasiology  2012;26(9):1153-1168.
Loss of fluency is a significant source of functional impairment in many individuals with aphasia. Repetitive transcranial magnetic stimulation (rTMS) administered to the right inferior frontal gyrus (IFG) has been shown to facilitate naming in persons with chronic left hemisphere stroke and non-fluent aphasia. However, changes in fluency in aphasic subjects receiving rTMS have not been adequately explored.
To determine whether rTMS improves fluency in individuals with chronic nonfluent aphasia, and to identify aspects of fluency that are modulated in persons who respond to rTMS.
Methods & Procedures
Ten individuals with left hemisphere MCA strokes and mild to moderate non-fluent aphasia participated in the study. Before treatment, subjects were asked to describe the Cookie Theft picture in three separate sessions. During treatment, all subjects received 1200 pulses of 1 Hz rTMS daily in 10 sessions over two weeks at a site that had previously been shown to improve naming. Subjects repeated the Cookie Theft description two months after treatment. Five subjects initially received sham stimulation instead of real TMS. Two months after sham treatment, these individuals received real rTMS. Performance both at baseline and after stimulation was coded using Quantitative Production Analysis (Saffran, Berndt & Schwartz, 1989) and Correct Information Unit (Nicholas & Brookshire, 1993) analysis.
Outcomes & Results
Across all subjects (n=10), real rTMS treatment resulted in a significant increase in multiple measures of discourse productivity compared to baseline performance. There was no significant increase in measures of sentence productivity or grammatical accuracy. There was no significant increase from baseline in the sham condition (n=5) on any study measures.
Stimulation of the right IFG in patients with chronic non-fluent aphasia facilitates discourse production. We posit that this effect may be attributable to improved lexical-semantic access.
PMCID: PMC3532848  PMID: 23280015
Language; aphasia; TMS; pars triangularis; fluency; neurorehabilitation
11.  Mental Motor Imagery Indexes Pain: The Hand Laterality Task 
Mental motor imagery is subserved by the same cognitive systems that underlie action. In turn, action is informed by the anticipated sensory consequences of movement, including pain. In light of these considerations, one would predict that motor imagery would provide a useful measure pain-related functional interference. We report a study in which 19 patients with chronic musculoskeletal or radiculopathic arm or shoulder pain, 24 subjects with chronic pain not involving the arm/shoulder and 41 normal controls were asked to indicate if a line drawing was a right or left hand. Previous work demonstrated that this task is performed by mental rotation of the subject’s hand to match the stimulus. Relative to normal and pain control subjects, arm/shoulder pain subjects were significantly slower for stimuli that required greater amplitude rotations. For the arm/shoulder pain subjects only there was a correlation between degree of slowing and the rating of severity of pain with movement but not the non-specific pain rating. The hand laterality task may supplement the assessment of subjects with chronic arm/shoulder pain.
PMCID: PMC2958243  PMID: 20638306
pain assessment; motor imagery; musculoskeletal pain
12.  Contributions of Efference Copy to Limb Localization: Evidence from Deafferentation 
Brain research  2010;1355:104-111.
Previous research with deafferented subjects suggests that efference copy can be used to update limb position. However, the contributions of efference copy to limb localization are currently unclear. We examined the performance of JDY, a woman with severe, longstanding proprioceptive deficits from a sensory peripheral neuropathy, on a reaching task to explore the contribution of efference copy to trajectory control. JDY and eight healthy controls reached without visual feedback to a target that either remained stationary or jumped to a second location after movement initiation. JDY consistently made hypermetric movements to the final target, exhibiting significant problems with amplitude control. Despite this amplitude control deficit, JDY’s performance on jump trials showed that the angle of movement correction (angle between pre- and post-correction movement segments) was significantly correlated with the distance (but not time) of movement from start to turn point. These data suggest that despite an absence of proprioceptive and visual information regarding hand location, JDY derived information about movement distance that informed her movement correction on jump trials. The same type of information that permitted her to correct movement direction on-line, however, was not available for control of final arm position. We propose that efference copy can provide a consistent estimate of limb position that becomes less informative over the course of the movement. We discuss the implications of these data for current models of motor control.
PMCID: PMC2950071  PMID: 20659430
deafferentation; efference copy; motor control; proprioception; reaching
13.  Left lateralizing transcranial direct current stimulation improves reading efficiency 
Brain Stimulation  2011;5(3):201-207.
Poor reading efficiency is the most persistent problem for adults with developmental dyslexia. Previous research has demonstrated a relationship between left posterior temporal cortex (pTC) function and reading ability, regardless of dyslexia status.
In this study, we tested whether enhancing left lateralization of pTC using transcranial direct current stimulation (tDCS) improves reading efficiency in adults without dyslexia.
Twenty-five right-handed adults with no history of learning disorder participated. Real and sham “Left lateralizing” tDCS were applied to the pTC in separate sessions. Standardized word and nonword reading tests were given immediately after stimulation.
Modeling of the induced electrical field confirmed that tDCS was likely to increase left pTC excitability and reduce right pTC excitability as intended. Relative to sham, real tDCS induced improvements in word reading efficiency in below average readers.
Enhancing left lateralization of the pTC using tDCS improves word reading efficiency in below-average readers. This demonstrates that left lateralization of the pTC plays a role in reading ability, and provides stimulation parameters that could be used for a trial of tDCS in adults with developmental dyslexia. Such short-term gains could amplify the effect of appropriate reading interventions when performed in conjunction with them.
PMCID: PMC3346858  PMID: 22305346
dyslexia; alexia; language; reading fluency
14.  Methylphenidate modulates sustained attention and cortical activation in survivors of traumatic brain injury: A perfusion fMRI study 
Psychopharmacology  2011;222(1):47-57.
Methylphenidate (MPH), the most widely prescribed psychostimulant to treat many neuropsychiatric conditions, is reported to improve attention and speed of processing in survivors of traumatic brain injury (TBI). The neural correlate of this efficacy, however, remains unclear.
Using perfusion fMRI as a biomarker of regional neural activity, the current study aimed to examine the neural correlates of single-dose (0.3 mg/kg) MPH administration in a randomized double-blind placebo-controlled cross-over study design.
Twenty-three individuals with moderate to severe TBI were tested on two occasions approximately one week apart. Perfusion fMRI scanning was carried out at rest and while participants performed cognitive tasks requiring sustained attention and working memory.
Behaviorally, MPH significantly improved both accuracy and reaction time (RT) in the sustained attention task, but only RT in the working memory task. A trend of global reduction of cerebral blood flow by MPH was observed in all task conditions including resting. Voxel-wise whole-brain analysis revealed an interaction effect of drug by condition (MPH-placebo X task-rest) for the sustained attention task in the left posterior superior parietal cortex and parieto-occipital junction (BA 7/19). The magnitude of drug-related deactivation of this area during task performance was correlated with improvement in RT.
Suppression of activity in this area during task performance may reflect a compensatory mechanism by which MPH ameliorates attention impairments in TBI.
PMCID: PMC3369011  PMID: 22203319
methylphenidate; traumatic brain injury; CBF; fMRI; sustained attention; working memory
15.  Research with rTMS in the treatment of aphasia 
This review of our research with rTMS to treat aphasia contains four parts: Part 1 reviews functional brain imaging studies related to recovery of language in aphasia with emphasis on nonfluent aphasia. Part 2 presents the rationale for using rTMS to treat nonfluent aphasia patients (based on results from functional imaging studies). Part 2 also reviews our current rTMS treatment protocol used with nonfluent aphasia patients, and our functional imaging results from overt naming fMRI scans, obtained pre- and post- a series of rTMS treatments. Part 3 presents results from a pilot study where rTMS treatments were followed immediately by constraint-induced language therapy (CILT). Part 4 reviews our diffusion tensor imaging (DTI) study that examined white matter connections between the horizontal, midportion of the arcuate fasciculus (hAF) to different parts within Broca’s area (pars triangularis, PTr; pars opercularis, POp), and the ventral premotor cortex (vPMC) in the RH and in the LH. Part 4 also addresses some of the possible mechanisms involved with improved naming and speech, following rTMS with nonfluent aphasia patients.
PMCID: PMC3682778  PMID: 20714075
16.  Topography of FUS pathology distinguishes late-onset BIBD from aFTLD-U 
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.
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.
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.
PMCID: PMC3767453  PMID: 24027631
Frontotemporal dementia; Frontotemporal lobar degeneration; Motor neuron disease; Amyotrophic lateral sclerosis
17.  From Maps to Form to Space: Touch and the Body Schema 
Neuropsychologia  2009;48(3):645.
Evidence from patients has shown that primary somatosensory representations are plastic, dynamically changing in response to central or peripheral alterations, as well as experience. Furthermore, recent research has also demonstrated that altering body posture results in changes in the perceived sensation and localization of tactile stimuli. Using evidence from behavioral studies with brain damaged and healthy subjects, as well as functional imaging, we propose that the traditional concept of the body schema should be divided into three components. First are primary somatosensory representations, which are representations of the skin surface that are typically somatotopically organized, and have been shown to change dynamically due to peripheral (usage, amputation, deafferentation) or central (lesion) modifications. Second, we argue for a mapping from a primary somatosensory representation to a secondary representation of body size and shape (body form representation). Finally, we review evidence for a third set of representations that encodes limb position and is used to represent the location of tactile stimuli relative to the subject using external, non-somatotopic reference frames (postural representations).
PMCID: PMC2813960  PMID: 19699214
18.  Increased Effect of Target Eccentricity on Covert Shifts of Visual Attention in Patients With Neglect 
Debate continues regarding the mechanisms underlying covert shifts of visual attention. We examined the relationship between target eccentricity and the speed of covert shifts of attention in normal subjects and patients with brain lesions using a cued-response task in which cues and targets were presented at 2° or 8° lateral to the fixation point. Normal subjects were slower on invalid trials in the 8° as compared to 2° condition. Patients with right hemisphere stroke with neglect were slower in their responses to left-sided invalid targets compared to valid targets, and demonstrated a significant increase in the effect of target validity as a function of target eccentricity. Additional data from one neglect patient (JM) demonstrated an exaggerated validity × eccentricity × side interaction for contralesional targets on a cued reaction time task with a central (arrow) cue. We frame these results in the context of a continuous ‘moving spotlight’ model of attention, and also consider the potential role of spatial saliency maps. By either account, we argue that neglect is characterized by an eccentricity-dependent deficit in the allocation of attention.
PMCID: PMC2852117  PMID: 19345939
neglect; disengage; attention; eccentricity; validity
19.  Parietal Influence on Temporal Encoding indexed by simultaneous TMS and EEG 
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 feed-forward mechanism from parietal to prefrontal regions mediates temporal encoding, and demonstrate a dissociation between early and late phases of encoding processes.
PMCID: PMC3448365  PMID: 22933807
Temporal Attention; Time Perception; Contingent Negative Variation; Transcranial; Magnetic Stimulation; Electroencephalography; Bias
20.  COMT and ANKK1-Taq-Ia Genetic Polymorphisms Influence Visual Working Memory 
PLoS ONE  2013;8(1):e55862.
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 (Val158Met) 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.
PMCID: PMC3561341  PMID: 23383291
21.  Two-Component Models of Reaching: Evidence from Deafferentation in a Fitts’ Law Task 
Neuroscience letters  2009;451(3):222-226.
Both feedforward and feedback mechanisms are used to ensure accurate movements. Feedback information comes primarily from vision and proprioception; the relative contributions of these modalities to on-line control of action and internal model maintenance remain unclear. We report data from an experiment in which a chronically deafferented subject (JDY) and nine controls were asked to reach to targets of different sizes both with and without vision. Movement times of controls were consistent with Fitts’ Law on trials with and without vision. JDY’s movement times were consistent with Fitts’ Law only with vision. She was inaccurate relative to controls with vision but exhibited a significantly greater decrement in performance than controls without vision. Finally, JDY’s performance on trials with vision deteriorated as a function of the number of preceding trials on which vision was not available. These data provide support for classical models of motor control that divide reaching into an initial ballistic movement guided by efference copy, and a terminal stage where sensory feedback is crucial. Furthermore, these data also demonstrate that proprioception is needed to calibrate and maintain internal models of action.
PMCID: PMC2673692  PMID: 19150390
22.  Cognitive Timing: Neuropsychology and Anatomic Basis 
Brain research  2008;1254:38-48.
We report data from 31 subjects with focal hemisphere lesions (15 left hemisphere) as well as 16 normal controls on a battery of tasks assessing the estimation, production and reproduction of time intervals ranging from 2–12 seconds. Both visual and auditory stimuli were employed for the estimation and production tasks. First, ANOVAs were performed to assess the effect of stimulus modality on estimation and production tasks; a significant effect of stimulus modality was observed for the production but not the estimation task. Second, accuracy was significantly different for the 2 second interval as compared to longer intervals. Subsequent analyses of the data from 4–12 second stimuli demonstrated that patients with brain lesions were more variable than controls on the estimation and reproduction tasks. Additionally, patients with brain lesions but not controls exhibited significant differences in performance on the different tasks; patients with brain lesions under-produced but over-estimated time intervals of 4–12 seconds but performed relatively well on the reproduction task, a pattern of performance consistent with a “fast clock”. There was a significant correlation between impaired performance and lesions of the parietal lobe but there was no effect of laterality of lesion or correlation between lateral frontal lobe lesions and impairment on any task.
PMCID: PMC2701254  PMID: 19046948
Cognitive timing; brain lesion; time estimation; time reproduction; time production
23.  Disruption of Temporal Processing in a Subject with Probable Frontotemporal Dementia 
Neuropsychologia  2008;46(7):1927-1939.
Previous research suggests that the frontal lobes are essential for temporal processing. We report a patient, MN, with probable Frontotemporal Dementia (FTD) who was tested on a battery of timing tasks with stimuli in the sub- and supra-second range. MN demonstrated a substantial over-estimation and under-production of target intervals on estimation and production tasks respectively but was as accurate as controls on a reproduction task. Furthermore, this deficit was markedly different for auditory and visual stimuli on production and estimation tasks; estimates of the duration of auditory stimuli were 3-4 times longer than for comparable visual stimuli. She performed normally on a task requiring her to judge whether a stimulus was longer or shorter than a standard duration with both sub- and supra-second stimuli. She performed well on control tasks involving estimation, production and reproduction of line lengths suggesting that her deficits were not attributable to a generalized cognitive impairment or an inability to make magnitude judgments. These data suggest that bifrontal pathology disrupts the “clock” or memory for time.
PMCID: PMC2494711  PMID: 18329055
Temporal processing; interval timing; Frontotemporal dementia; 0THERS?
24.  Simultanagnosia: Effects of Semantic Category and Repetition Blindness 
Neuropsychologia  2007;46(7):1853-1863.
When confronted with two identical stimuli in a very brief period of time subjects often fail to report the second stimulus, a phenomenon termed “repetition blindness”. The “type-token” account attributes the phenomenon to a failure to individuate the exemplars. We report a subject, KE, who developed simultanagnosia (the inability to see more than one item in an array) as a consequence of bilateral parietal lobe infarctions. With presentation of two words, pictures or letters for an unlimited time, KE typically reported both stimuli on less than half of trials. Performance was significantly influenced by the semantic relationship between items in the array. He reported both items significantly more frequently if they were semantically related; in contrast, when presented either identical or visually different depictions of the same item, he reported both items on only 2-4% of trials. Performance was not influenced by the visual similarity between the stimuli; he reported visually dissimilar objects less frequently than visually similar but different objects. We suggest that KE's bilateral parietal lesions prevent the binding of preserved object representations to a representation computed by the dorsal visual system. More generally, these data are consistent with the claim that the posterior parietal cortex is crucial for individuating a stimulus by computing its unique spatio-temporal characteristics.
PMCID: PMC2494704  PMID: 18514677
repetition blindness; parietal lobe; simultanagnosia; binding; visual attention
25.  Support for Anterior Temporal Involvement in Semantic Error Production in Aphasia: New Evidence from VLSM 
Brain and language  2010;117(3):110-122.
Semantic errors in aphasia (e.g., naming a horse as “dog”) frequently arise from faulty mapping of concepts onto lexical items. A recent study by our group used voxel-based lesion-symptom mapping (VLSM) methods with 64 patients with chronic aphasia to identify voxels that carry an association with semantic errors. The strongest associations were found in the left anterior temporal lobe (L-ATL), in the mid- to anterior MTG region. The absence of findings in Wernicke’s area was surprising, as were indications that ATL voxels made an essential contribution to the post-semantic stage of lexical access. In this follow-up study, we sought to validate these results by re-defining semantic errors in a manner that was less theory dependent and more consistent with prior lesion studies. As this change also increased the robustness of the dependent variable, it made it possible to perform additional statistical analyses that further refined the interpretation. The results strengthen the evidence for a causal relationship between ATL damage and lexically-based semantic errors in naming and lend confidence to the conclusion that chronic lesions in Wernicke’s area are not causally implicated in semantic error production.
PMCID: PMC3037437  PMID: 20961612
aphasia; voxel-based lesion-symptom mapping; naming; semantic; errors

Results 1-25 (44)