Semantic Feature Training in Combination with Transcranial Direct Current Stimulation (tDCS) for Progressive Anomia.

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.

Disrupted structural connectome is associated with both psychometric and real-world neuropsychological impairment in diffuse traumatic brain injury.

Traumatic brain injury (TBI) is likely to disrupt structural network properties due to diffuse white matter pathology. The present study aimed to detect alterations in structural network topology in TBI and relate them to cognitive and real-world behavioral impairment. Twenty-two people with moderate to severe TBI with mostly diffuse pathology and 18 demographically matched healthy controls were included in the final analysis. Graph theoretical network analysis was applied to diffusion tensor imaging (DTI) data to characterize structural connectivity in both groups. Neuropsychological functions were assessed by a battery of psychometric tests and the Frontal Systems Behavior Scale (FrSBe). Local connection-wise analysis demonstrated reduced structural connectivity in TBI arising from subcortical areas including thalamus, caudate, and hippocampus. Global network metrics revealed that shortest path length in participants with TBI was longer compared to controls, and that this reduced network efficiency was associated with worse performance in executive function and verbal learning. The shortest path length measure was also correlated with family-reported FrSBe scores. These findings support the notion that the diffuse form of neuropathology caused by TBI results in alterations in structural connectivity that contribute to cognitive and real-world behavioral impairment.

The image of time: a voxel-wise meta-analysis.

Although there has been an explosion of interest in the neural correlates of time perception during the past decade, substantial disagreement persists regarding the structures that are relevant to interval timing. We addressed this important issue by conducting a comprehensive, voxel-wise meta-analysis using the activation likelihood estimation algorithm; this procedure models each stereotactic coordinate as a 3D Gaussian distribution, then tests the likelihood of activation across all voxels in the brain (Turkeltaub et al., 2002). We included 446 sets of activation foci across 41 studies of timing that report whole-brain analyses. We divided the data set along two dimensions: stimulus duration (sub- vs. supra-second) and nature of response (motor vs. perceptual). Our meta-analyses revealed dissociable neural networks for the processing of duration with motor or perceptual components. Sub-second timing tasks showed a higher propensity to recruit sub-cortical networks, such as the basal ganglia and cerebellum, whereas supra-second timing tasks were more likely to activate cortical structures, such as the SMA and prefrontal cortex. We also detected a differential pattern of activation likelihood in basal ganglia structures, depending on the interval and task design. Finally, a conjunction analysis revealed the SMA and right inferior frontal gyrus as the only structures with significant voxels across all timing conditions. These results suggest that the processing of temporal information is mediated by a distributed network that can be differentially engaged depending on the task requirements.

Fast forward: supramarginal gyrus stimulation alters time measurement.

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.

Neurocognitive contributions to verbal fluency deficits in frontotemporal lobar degeneration.

OBJECTIVE: To test the hypothesis that different neurocognitive networks underlie verbal fluency deficits in frontotemporal lobar degeneration (FTLD). METHODS: Letter ("FAS") and semantic ("animal") fluency tests were administered to patients with a behavioral/dysexecutive disorder (bvFTLD; n = 71), semantic dementia (SemD; n = 21), and progressive nonfluent aphasia (PNFA; n = 26). Tests measuring working memory, naming/lexical retrieval, and semantic knowledge were also obtained. MRI voxel-based morphometry (VBM) studies were obtained on a subset of these patients (bvFTLD, n = 51; PNFA, n = 11; SemD, n = 10). RESULTS: Patients with SemD were disproportionately impaired on the semantic fluency measure. Reduced output on this test was correlated with impaired performance on naming/lexical retrieval tests. VBM analyses related reduced letter and semantic fluency to anterior and inferior left temporal lobe atrophy. Patients with bvFTLD were equally impaired on both fluency tests. Poor performance on both fluency tests was correlated with low scores on working memory and naming/lexical retrieval measures. In this group, MRI-VBM analyses related letter fluency to bilateral frontal atrophy and semantic fluency to left frontal/temporal atrophy. Patients with PNFA were also equally impaired on fluency tests. Reduced semantic fluency output was correlated with reduced performance on naming/lexical retrieval tests. MRI-VBM analyses related semantic fluency to the right frontal lobe and letter fluency to left temporal atrophy. CONCLUSIONS: Distinct neurocognitive networks underlie impaired performance on letter and semantic fluency tests in frontotemporal lobar degeneration subgroups.

Longitudinal decline in autopsy-defined frontotemporal lobar degeneration.

BACKGROUND: The natural history of patients with pathologically proven frontotemporal lobar degeneration (FTLD) is important from clinical and biologic perspectives, but is not well documented quantitatively. METHODS: We examine longitudinal decline in cognitive functioning in an autopsy-proven cohort of patients with the clinical diagnosis of a FTLD spectrum disorder or FTLD pathology using a panel of neuropsychological measures. Patients are categorized according to findings at autopsy into tau-positive FTLD, tau-negative FTLD, and frontal variant-Alzheimer disease (fvAD) subgroups. RESULTS: Patients decline significantly over time on all neuropsychological measures. Moreover, several measures differentiate between histopathologically distinct subgroups throughout the course of the disease process. This includes a significant double dissociation involving relative difficulty on a visual constructional measure in tau-positive patients compared to relatively impaired visual confrontation naming in tau-negative patients. Longitudinal measures of FAS naming fluency and animal naming fluency also distinguish tau-positive patients and tau-negative patients with FTLD from patients with fvAD. Other measures show significant decline but do not distinguish between histopathologic groups longitudinally. CONCLUSION: Our findings suggest different longitudinal patterns of cognitive decline in pathologically defined subgroups of patients. Measures consistently distinguishing between patient subgroups can be used to bolster diagnostic accuracy throughout the course of these diseases, while measures demonstrating undifferentiated longitudinal decline may serve as useful endpoints in treatment trials.

Inconsistency of performance on neglect subtype tests following acute right hemisphere stroke.

Hemispatial neglect has been conceptualized as having dissociable and potentially clinically relevant subtypes. However, the question of whether patient performance on neglect subtype measures is consistent over time remains largely unanswered. We examined changes in performance over time on measures of motor, perceptual, and personal neglect in 21 patients with neglect from acute right hemisphere stroke. Patients were assessed on three occasions, separated by at least one week, using a lateralized target test, lateralized response test, and modified fluff test. Across three testing timepoints, 18 (85.7%) patients changed subtype performance patterns at least once. In 13 (61.9%) of these patients, inconsistency between timepoints was not adequately accounted for by recovery. On initial testing, seven, patients (33.3%) demonstrated more than one neglect subtype symptom; by the third testing timepoint none of the patients demonstrated multiple symptoms. In the setting of acute stroke, performance on three measures of neglect symptoms is inconsistent across time. However, the distribution of neglect subtype symptoms appears to become more discrete over time. These findings complicate our understanding of the pathophysiology and potential prognostic value of neglect subtypes, and suggest that treatment decisions based on subtype performance assessed at a single timepoint, may be of limited utility.

Factors associated with survival probability in autopsy-proven frontotemporal lobar degeneration.

OBJECTIVE: To examine the clinical and pathological factors associated with survival in autopsy-confirmed frontotemporal lobar degeneration (FTLD). METHODS: The final analysis cohort included 71 patients with pathologically proven FTLD, excluding patients with clinical motor neuron disease (MND), evaluated at the University of Pennsylvania or at the University of California, San Francisco. We assessed clinical and demographic features; cognitive functioning at presentation; genetic markers of disease; and graded anatomical distribution of tau, ubiquitin and amyloid pathology. RESULTS: The tau-negative group (n = 35) had a median survival time of 96 months (95% CI: 72-114 months), whereas the tau-positive group (n = 36) had a median survival time of 72 months (95% CI: 60-84 months). Patients with tau-positive pathology across all brain regions had shorter survival than those with tau-negative pathology in univariate Cox regression analyses (Hazard ratio of dying = 2.003, 95% CI = 1.209-3.318, p = 0.007). CONCLUSIONS: Tau-positive pathology represents a significant risk to survival in FTLD, whereas tau-negative pathology is associated with a longer survival time when clinical MND is excluded.

Patterns of spontaneous recovery of neglect and associated disorders in acute right brain-damaged patients.

OBJECTIVES: The evolutionary pattern of spontaneous recovery from acute neglect was studied by assessing cognitive deficits and motor impairments. Detailed lesion reconstruction was also performed to correlate the presence of and recovery from neglect to neural substrates. METHODS: A consecutive series of right brain-damaged (RBD) patients with and without neglect underwent weekly tests in the acute phase of the illness. The battery assessed neglect deficits, neglect-related deficits, and motor impairment. Age-matched normal subjects were also investigated to ascertain the presence of non lateralised attentional deficits. Some neglect patients were also available for later investigation during the chronic phase of their illness. RESULTS: Partial recovery of neglect deficits was observed at the end of the acute period and during the chronic phase. Spatial attention was impaired in acute neglect patients, while non spatial attentional deficits were present in RBD patients with and without acute neglect. A strong association was found between acute neglect and fronto-parietal lesions. Similar lesions were associated with neglect persistence. In the chronic stage, neglect recovery was paralleled by improved motor control of the contralesional upper limb, thus emphasising that neglect is a negative prognostic factor in motor functional recovery. CONCLUSIONS: These findings show that spatial attention deficits partially improve during the acute phase of the disease in less than half the patients investigated. There was an improvement in left visuospatial neglect at a later, chronic stage of the disease, but this recovery was not complete.

Hemispatial neglect: Subtypes, neuroanatomy, and disability.

OBJECTIVE: To assess the relative frequency of occurrence of motor, perceptual, peripersonal, and personal neglect subtypes, the association of neglect and other related deficits (e.g., deficient nonlateralized attention, anosognosia), and the neuroanatomic substrates of neglect in patients with right hemisphere stroke in rehabilitation settings. METHODS: The authors assessed 166 rehabilitation inpatients and outpatients with right hemisphere stroke with measures of neglect and neglect subtypes, attention, motor and sensory function, functional disability, and family burden. Detailed lesion analyses were also performed. RESULTS: Neglect was present in 48% of right hemisphere stroke patients. Patients with neglect had more motor impairment, sensory dysfunction, visual extinction, basic (nonlateralized) attention deficit, and anosognosia than did patients without neglect. Personal neglect occurred in 1% and peripersonal neglect in 27%, motor neglect in 17%, and perceptual neglect in 21%. Neglect severity predicted scores on the Functional Independence Measure and Family Burden Questionnaire more accurately than did number of lesioned regions. CONCLUSIONS: The neglect syndrome per se, rather than overall stroke severity, predicts poor outcome in right hemisphere stroke. Dissociations between tasks assessing neglect subtypes support the existence of these subtypes. Finally, neglect results from lesions at various loci within a distributed system mediating several aspects of attention and spatiomotor performance.

Visual agnosia.

The visual agnosias are an intriguing class of clinical phenomena that have important implications for current theories of high-level vision. Visual agnosia is defined as impaired object recognition that cannot be attributed to visual loss, language impairment, or a general mental decline. At least in some instances, agnostic patients generate an adequate internal representation of the stimulus but fail to recognize it. In this review, we begin by describing the classic works related to the visual agnosias, followed by a description of the major clinical variants and their occurrence in degenerative disorders. In keeping with the theme of this issue, we then discuss recent contributions to this domain. Finally, we present evidence from functional imaging studies to support the clinical distinction between the various types of visual agnosias.

Pain and the body schema: effects of pain severity on mental representations of movement.

Previous research suggests that response times for imagined movements provide a sensitive measure of the integrity of the motor system. In a group of 12 patients with chronic unilateral arm pain, the authors demonstrate that response times for imagined movements are influenced by the severity of pain. Simulated large-amplitude arm movements were slower for the painful as compared with the unaffected arms before, but not after, effective music therapy entrainment, suggesting that mental representations of movement are influenced by the current state of nociceptive feedback.

Pain and the body schema: evidence for peripheral effects on mental representations of movement.

Some accounts of body representations postulate a real-time representation of the body in space generated by proprioceptive, somatosensory, vestibular and other sensory inputs; this representation has often been termed the 'body schema'. To examine whether the body schema is influenced by peripheral factors such as pain, we asked patients with chronic unilateral arm pain to determine the laterality of pictured hands presented at different orientations. Previous chronometric findings suggest that performance on this task depends on the body schema, in that it appears to involve mentally rotating one's hand from its current position until it is aligned with the stimulus hand. We found that, as in previous investigations, participants' response times (RTs) reflected the degree of simulated movement as well as biomechanical constraints of the arm. Importantly, a significant interaction between the magnitude of mental rotation and limb was observed: RTs were longer for the painful arm than for the unaffected arm for large-amplitude imagined movements; controls exhibited symmetrical RTs. These findings suggest that the body schema is influenced by pain and that this task may provide an objective measure of pain.

Specialised structural descriptions for human body parts: Evidence from autotopagnosia.

Previous accounts of autotopagnosia (e.g., Ogden, 1985; Pick, 1908; Semenza, 1988) propose that the disorder is attributable to deficits in "mental images," visual body schema, or semantic representations. A recent account (Sirigu, Grafman, Bressler, & Sunderland, 1991b) posits deficits in visual structural descriptions of the human body and its parts, in the context of spared semantic and proprioceptivespatio-motor body representations, but provides no evidence bearing on the nature or format of the putatively damaged representation. We report data from a man with autotopagnosia consequent to lefthemisphere brain damage which bear directly on the nature of the representation impaired in the disorder. The subject, GL, is unable to localise body parts on himself or others, whether cued by verbal or visual input. In contrast, he uses body parts precisely in reaching and grasping tasks, correctly matches items of clothing to body parts, and localises the parts of animals and man-made objects without error. We also demonstrate that GL is unable to match pictured or real human body parts across shifts in orientation or changes in visual appearance, but can perform analogous matching tasks with animal body parts and man-made object parts. The data extend the account of Sirigu et al. (1991b) in suggesting that human body part localisation depends upon structural descriptions of human (but not animal) bodies that enable viewpoint-independent body part recognition and participate in the calculation of equivalence between the body parts of self and others across transformations in orientation.

Compensatory coding of body part location in autotopagnosia: Evidence for extrinsic egocentric coding.

We report a patient with autotopagnosia (JD) who was unable to code the position of body parts relative to each other and who failed to update the position of body parts after passive movements. JD's performance in Studies 1-4 suggest that her ability to code the dynamic location of body parts with respect to each other ("intrinsic egocentric" spatial coding) was impaired, and that she employed a compensatory strategy by means of which the location of body parts was computed with respect to objects in the environment ("extrinsic egocentric" spatial coding). Studies 5-8 suggest that JD's ability to update hand position information was impaired after passive relative to active movements of her arm. For example, she was impaired in reaching to a target after passive but not active movements of her hand. Taken together, these findings extend previously reported functions of extrinsic egocentric coding to the localisation of body parts and demonstrate a possible dissociation between body part localisation dependent upon proprioceptive and efference copy information.

Acquisition and transfer of new verbal information in amnesia: retrieval and neuroanatomical constraints.

Four experiments examined new associative learning in amnesia by contrasting the performance of 2 amnesic participants-1 (C.C.) with basal forebrain damage and the other (R.H.) with medial temporal lobe damage--and 3 controls. Both amnesic individuals were severely impaired on explicit memory measures but showed intact perceptual priming. On the new associations measures, only C.C., not R.H., exhibited learning by producing correct targets (HIJACKER) in the absence of perceptual cues for them (e.g., STAFF shot ???). When the perceptual cue (e.g., MEDICINE cured _I_C_P) was provided, both C.C. and R.H. showed learning. Transfer to information containing conceptually related targets (e.g., TERRORIST or BELCH) was reliably observed only in C.C. This finding was replicated with further reduction in perceptual overlap across original (LIGHTNING torched JUNGLE) and transfer (LIGHTNING burned WILDERNESS) sentences. Together, these findings delineate the role of experimental conditions, severity of amnesia, and different neuroanatomical structures in mediating new verbal learning in amnesia.

Frequency and duration of inattentive behavior after traumatic brain injury: effects of distraction, task, and practice.

Traumatic brain injury (TBI) is associated with impairments of attention, most typically measured through tests of information processing, or by subjective symptom endorsement by patients, families, and clinicians. We have previously shown increased rates of off-task behavior among patients with TBI versus controls as defined by videotaped records of independent work in distracting environments. In this research, we report on a more detailed method of coding such videotaped records which allows measurement of the precise number of off-task behaviors, their durations, and their relationship to distracting events. Using this method, we studied 20 patients with recent moderate-to-severe TBI and 20 demographically comparable controls as they performed independent work tasks while being subjected to controlled distracting events. This research confirms that patients are markedly less attentive than controls both in the presence of distractions and in their absence, that distractions have an influence on off-task behavior in both groups, and that the disruptive impact of distractors wanes relatively quickly for controls but not for patients. The duration of distraction produced by various classes of distracting events appeared similar for patients and controls, although the power to detect differences in behavioral duration between groups was limited. The pattern of inattentiveness among patients showed minimal relationship to measures of injury severity within this sample.

Acquired dyslexia.

Disorders of reading are frequently encountered in patients with acquired cerebral lesions. Investigations in the past few decades have improved our understanding of these disorders. In this article we review the peripheral dyslexias, including neglect dyslexia, attentional dyslexia, and pure alexia (or alexia without agraphia), as well as the "central" dyslexias, including deep, surface, and phonological dyslexia. Current accounts of acquired dyslexia are also discussed. Finally, we briefly describe the reading tasks that serve to differentiate the different reading disorders.

Spatial influences on motor and language function.

In subjects with parietal lobe lesions, performance on motor and language tasks differed as a function of the side of space to which subjects directed their attention or acted. Subjects with left parietal lesions performed better when attention was directed to stimuli in left hemispace (that is, the left side of their environment), and those with right parietal lesions showed a similar effect when attending to stimuli in right hemispace. Hemispace effects were not observed in subjects with lesions located elsewhere in the cerebral hemispheres, or in subjects with subcortical lesions. These data are consistent with the view that not only motor but also cognitive operations such as language, which do not appear to have any intrinsic spatial organization, are maintained in registration with spatial systems, and that this attention-requiring linkage confers a processing advantage.

Impaired face and word recognition without object agnosia.

A leading account of high-level visual recognition proposes that the recognition of faces, objects, and words is mediated by two processing capacities. Words are assumed to require the capacity to represent numerous parts, whereas faces are processed wholistically. and hence require the representation of complex units. Object recognition requires the capacity to represent both numerous and complex parts. As object recognition depends upon the same processing capacities underlying face and word recognition, this account predicts that patients with severe alexia and prosopagnosia should be deficient in tests of object recognition. We report a patient who is unable to recognize words or faces, yet performs relatively well on tests of object recognition. The two-capacity theory cannot accommodate this pattern of performance without additional assumptions.