Hemorrhagic transformation in patients with acute ischaemic stroke and an indication for anticoagulation.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) can occur in patients following acute ischaemic stroke in the form of hemorrhagic transformation, and results in significant long-term morbidity and mortality. Anticoagulation theoretically increases risk. We evaluated stroke patients with an indication for anticoagulation to determine the factors associated with hemorrhagic transformation. METHODS: Three-hundred and forty-five patients with ICD-9 codes indicating: (i) acute ischaemic stroke; and (ii) an indication for anticoagulation were screened. One-hundred and twenty-three met inclusion criteria. Data were collected retrospectively. Neuroimaging was reviewed for infarct volume and evidence of ICH. Hemorrhages were classified as: hemorrhagic conversion (petechiae) versus intracerebral hematoma (a space occupying lesion); symptomatic versus asymptomatic. Using multivariable logistic regression, we determined the hypothesized factors associated with intracerebral bleeding. RESULTS: Age [odds ratio (OR) = 1.50 per 10-year increment, 95% confidence interval (CI) 1.07-2.08], infarct volume (OR = 1.10 per 10 ccs, 95% CI 1.06-1.18) and worsening category of renal impairment by estimated glomerular filtration rate (eGFR; OR = 1.95, 95% CI 1.04-3.66) were predictors of hemorrhagic transformation. Ninety- nine out of 123 patients were anticoagulated. Hemorrhage rates of patients on and off anticoagulation did not differ (25.3% vs. 20.8%; P = 0.79); however, all intracerebral hematomas (n = 7) and symptomatic bleeds (n = 8) occurred in the anticoagulated group. CONCLUSIONS: The risk of hemorrhagic transformation in patients with acute ischaemic stroke and an indication for anticoagulation is multifactorial, and most closely associated with an individual's age, infarct volume and eGFR.

Action versus animal naming fluency in subcortical dementia, frontal dementias, and Alzheimer's disease.

Accumulating evidence indicates action naming may rely more on frontal-subcortical circuits, and noun naming may rely more on temporal cortex. Therefore, noun versus action fluency might distinguish frontal and subcortical dementias from cortical dementias primarily affecting temporal and/or parietal cortex such as Alzheimer's disease (AD). We hypothesized patients with subcortical dementia, e.g., normal pressure hydrocephalus (NPH) and patients with dementias predominantly affecting frontal cortex, e.g., behavioral variant frontotemporal dementia (bv-FTD) and progressive nonfluent aphasia (PNFA) have more difficulty on action fluency versus noun fluency (e.g., animal naming). Patients with AD, who have temporo parietal cortical dysfunction, should have more difficulty on noun versus verb fluency. A total of 234 participants, including healthy controls (n = 20) and patients diagnosed with NPH (n =144), AD (n = 33), bv-FTD (n = 22) or PNFA (n =15) were administered animal fluency, action fluency, and letter fluency tasks, and the Mini-Mental State Examination (MMSE, to control for dementia severity). NPH and bv-FTD/PNFA patients had significantly higher MMSE scores and animal fluency than AD patients (after adjusting for age), but their action fluency tended to be lower than in AD. Only NPH and bvFTD/PNFA patients showed significantly lower action verb than animal fluency. Results provide novel evidence that action naming relies more on frontal-subcortical circuits while noun naming relies more on temporoparietal cortex, indicating action verb fluency may be more sensitive than noun fluency, particularly for detecting frontal-subcortical dysfunction.

Neural substrates of word generation during stroke recovery: the influence of cortical hypoperfusion.

Several studies have demonstrated reorganization of cognitive and motor function caused by stroke. This study examined the influence of hypoperfused brain regions, in addition to the area of the infarct itself, on reorganization of the cognitive processes underlying word generation in stroke patients. In addition, we also sought to determine the influence of hypoperfusion on the blood oxygen level dependent/(BOLD) effect. Subjects with left and right subacute or chronic subcortical strokes, along with normal controls, were imaged while performing a verbal fluency task (word generation). The study population included six normal subject and six stroke patients with subcortical infarcts and cortical hypoperfusion in the middle cerebral artery territory who had recovered or improved markedly in word fluency. While normal subjects displayed a left-lateralized fronto-temporo-parietal and bilateral cingulo-striatal-thalamic-cerebellar network, the activation pattern of stroke patients was determined both by the hypoperfused regions and infarcted areas of the brain. Specifically, patients showed diminished BOLD effect in the cortical regions that were hypoperfused, even though their infarcts were subcortical, and showed increased BOLD effect in the homologous regions of the normal hemisphere. This finding raises the possibility that cortical hypoperfusion in the absence of infarct can cause shift of language functions to the opposite, intact hemisphere. However, reduced BOLD effect in the task relative to rest was found in hypoperfused regions in two patients, raising the possibility that regional function persisted, even though vascular reactivity was impaired. Results illustrate the complexities of functional imaging studies of recovery in patients with vascular lesions.

Rehabilitation of unilateral spatial neglect and neuroimaging.

We review the literature on current knowledge of the role of unilateral spatial neglect as an independent predictor of poor functional outcome after right brain injury, the neural mechanisms and neural substrates that are responsible for the manifestation of neglect behaviors, and the available rehabilitation techniques for neglect amelioration. We focus on the neuroimaging correlates of these rehabilitation techniques and rehabilitation amelioration, their mode of action and their potential to make a difference in functional outcomes, by assessing their potential to improve patients' performance in activities of daily living. We recognize that there is no consensus on efficacious treatments for neglect rehabilitation, and acknowledge that the lack of complete clarity of the neural substrates and mechanisms underlying neglect phenomena may hinder the development of efficacious rehabilitation techniques. We discuss current opinions on the neural mechanisms of hemispatial neglect and delved into the neural substrates of neglect based on functional and structural imaging. We explore the role of damage or dysfunction within specific right hemisphere structures in generating certain neglect subtypes and discussed how such knowledge may guide treatments for the rehabilitation of unilateral neglect. From this foundation, we proceed to explore the available rehabilitation techniques for neglect amelioration and how neuroimaging may guide the choice of therapies for different forms of unilateral neglect. We discuss cognitive rehabilitation approaches which form the bedrock of most traditional rehabilitation programs and follow with a description of other available, but less well utilized methods of neglect rehabilitation, including sensory stimulation, sensorimotor adaptation to visual perturbations by prism adaptation, and pharmacological agents (mainly dopamine agonists) that might augment rehabilitation. We also discuss the efficacy of these techniques in neglect rehabilitation and compare the potential of these diverse techniques to ameliorate not only the different symptoms of neglect, but also the different subtypes of neglect. Finally, we make suggestions about future research that could enhance the rehabilitation of neglect.

Oscillatory EEG activity induced by conditioning stimuli during fear conditioning reflects Salience and Valence of these stimuli more than Expectancy.

Imaging studies have described hemodynamic activity during fear conditioning protocols with stimulus trains in which a visual conditioned stimulus (CS+) is paired with an aversive unconditioned stimulus (US, painful laser pulse) while another visual stimulus is unpaired (CS-). We now test the hypothesis that CS Event Related Spectral Perturbations (ERSPs) are related to ratings of CS Expectancy (likelihood of pairing with the US), Valence (unpleasantness) and Salience (ability to capture attention). ERSP windows in EEG were defined by both time after the CS and frequency, and showed increased oscillatory power (Event Related Synchronization, ERS) in the Delta/Theta Windows (0-8Hz) and the Gamma Window (30-55Hz). Decreased oscillatory power (Event Related Desynchronization - ERD) was found in Alpha (8-14Hz) and Beta Windows (14-30Hz). The Delta/Theta ERS showed a differential effect of CS+ versus CS- at Prefrontal, Frontal and Midline Channels, while Alpha and Beta ERD were greater at Parietal and Occipital Channels early in the stimulus train. The Gamma ERS Window increased from habituation to acquisition over a broad area from frontal and occipital electrodes. The CS Valence and Salience were greater for CS+ than CS-, and were correlated with each other and with the ERD at overlapping channels, particularly in the Alpha Window. Expectancy and CS Skin Conductance Response were greater for CS+ than CS- and were correlated with ERSP at fewer channels than Valence or Salience. These results suggest that Alpha ERSP activity during fear conditioning reflects Valence and Salience of the CSs more than conditioning per se.

Vigilance behaviors and EEG activity in sustained attention may affect acute pain.

During Sustained Attention to stimuli across many modalities neural activity often decreases over time on task, while Errors in task performance increase (Vigilance Decrement). Sustained Attention to pain has rarely been investigated experimentally despite its clinical significance. We have employed a Sustained Attention protocol (Continuous Performance Task, CPT) in which the subject counts painful laser stimuli (targets) when they occur randomly in a prolonged train of nonpainful nontargets. We hypothesize that the magnitude of the poststimulus oscillatory power divided by baseline power (Event-Related Spectral Perturbation, ERSP - scalp EEG) over Frontoparietal structures will decrease at all frequencies with time on task, while Beta ERSP (14-30Hz) will be correlated with Error Rates in performance of the CPT. During the CPT with a painful target ERSP was found in four separate Windows, as defined by both their frequency band and the time after the stimulus. A Vigilance Decrement was found which confirms that Sustained Attention to pain was produced by this CPT. In addition, Error Rates was correlated inversely with laser energy, and with ratings of pain unpleasantness and salience. Error Rates also were related directly to the Beta ERSP Window at scalp EEG electrodes over the central sulcus. Over time on task, the ERSP magnitude decreased in Alpha (8-14Hz) Window, was unchanged in early and late Delta/Theta Windows (0-8Hz), and increased in the Beta Window. The increase in Beta ERSP and a decrease in the Alpha ERSP occurred at the same EEG electrode over the parietal lobe to a significant degree across subjects. Overall, Beta activity increases with time on task, and with higher Error Rates as in the case of other modalities. In the case of pain increased Errors correspond to misidentification of painful and nonpainful stimuli and so modulate the sensation of pain under the influence of Sustained Attention.

Making sense out of jargon: a neurolinguistic and computational account of jargon aphasia.

OBJECTIVE: To identify the cognitive and neuroanatomic bases of neologistic jargon aphasia with spared comprehension and production of written words. METHODS: Detailed analysis of performance across experiments of naming, reading, writing, repetition, and word/picture matching by a 68-year-old woman (J.B.N.) served to identify which cognitive mechanisms underlying naming and word comprehension were impaired. J.B.N.'s impairments were then simulated by selectively "lesioning" a computer model of word production that has semantic, word form, and subword phonologic levels of representation (described by Dell in 1986). RESULTS: In comprehension experiments, J.B.N. made far more errors with spoken word input than with written word or picture input (chi-square = 40-59; df = 1; p < 0.0001) despite intact auditory discrimination. In naming experiments (with picture, definition, or tactile input), J.B.N. made far more errors in spoken output relative to written output (chi-square = 14-56; df = 1; p < 0.0001). These selective impairments of spoken word processing were simulated by reducing connection strength between word-level and subword-level phonologic units but maintaining full connection strength between word-level and semantic units in Dell's model. The simulation yielded a distribution of error types that was nearly identical to that of J.B.N., and her CT and MRI scans showed a small subarachnoid hemorrhage in the left sylvian fissure without infarct. Cerebral angiogram showed focal vasospasm in sylvian branches of the left middle cerebral artery. CONCLUSION: Focal left perisylvian dysfunction can result in a highly selective "disconnection" between word-level and subword-level phonologic representations manifest as neologistic jargon aphasia with intact understanding and production of written words.

MR perfusion imaging reveals regions of hypoperfusion associated with aphasia and neglect.

OBJECTIVE: To evaluate diffusion-weighted imaging (DWI) and MR perfusion imaging (MRPI) as tools for identifying regions of infarct and hypoperfusion associated with aphasia and neglect in hyperacute stroke. Secondary goal: to establish a functional correlate of a radiologically defined "ischemic penumbra." METHODS: Forty subjects underwent DWI, MRPI, and standardized tests for lexical deficits or hemispatial neglect within 24 hours of stroke onset or progression. Ten patients had repeat DWI, MRPI, and cognitive testing after 3 days (in some cases after reperfusion therapy). Pearson correlations between error rate on cognitive testing and volume of abnormality on DWI versus MRPI were determined at each time period, and regions of hypoperfusion corresponding to specific cognitive deficits were identified. RESULTS: Error rate was more strongly correlated with volume of hypoperfused tissue on MRPI (r = 0.65 to 0.93; p < 0.01 to p < 0.0003) than with volume of lesion on DWI (r = 0.54 to 0.75; p = 0.14 to p < 0.01) for dominant and nondominant hemisphere stroke, at each time point. Forty-eight percent of aphasic patients and 67% of those with hemispatial neglect had either no infarct or only small subcortical infarct on DWI, but had focal cortical hypoperfusion. Patients who had successful reperfusion therapy showed resolution of the hypoperfused territory beyond the infarction on repeat MRPI and showed resolution of corresponding deficits. CONCLUSIONS: MRPI shows regions of hypoperfused cortex associated with lexical deficits or hemispatial neglect, even when DWI shows no infarct or only small subcortical infarct. MRPI-DWI mismatch indicates regions of functionally salvageable tissue.

Restoring blood pressure reperfused Wernicke's area and improved language.

Longitudinal clinical and imaging data from a patient who sustained a left frontal-temporal stroke with hypoperfusion of the adjacent Wernicke's area are reported. His language deficits were partially ameliorated by pharmacologically increasing his blood pressure, and were exacerbated when blood pressure dropped. There was a striking temporal and statistical correlation between mean arterial pressure and language accuracy. MR perfusion imaging showed that language gains were accompanied by improved perfusion of Wernicke's area when mean arterial pressure was increased.

Deficit to stimulus-centered, letter shape representations in a case of "unilateral neglect".

A brain-damaged subject is described whose pattern of performance in various reading tasks can be explained by proposing damage at a level of the word recognition process in which a representation with stimulus-centered, rather than retinal- or word-centered, coordinates is processed. Analysis of her reading performance as a function of topographical arrangement of letters, position of errors in the letter string, and the effects of letter spacing and of adding a prefix or suffix provide evidence not only for the existence of this level of representation (the letter-shape map in a model proposed by Caramazza and Hillis [3]), but also for specific assumptions about its functioning and structure.

Unilateral spatial neglect in dissociable frames of reference: a comment on Farah, Brunn, Wong, Wallace, and Carpenter (1990)

We comment on a paper by Farah et al. in which it is claimed that averaged performance on a letter naming task by a group of patients with left unilateral spatial neglect (USN) provides evidence that spatial allocation of attention is defined by environment-centered and viewer-centred coordinates, but not by object-centred coordinates. We re-analyze the raw data from that paper, and present statistical analyses of the data from individual subjects which show dissociations in the coordinate frames used by the individual subjects with USN. The data from individual cases demonstrate that object-centered USN occurs alone (without evidence of USN in other reference frames) in some cases, and in association with USN in other reference frames other cases. In contrast to the conclusions drawn from the group performance, results from individual subjects provide evidence for the role of dissociable frames of reference, including an object-centred coordinate frame, in the spatial allocation of attention.

Where do semantic errors come from?

We report the performance of two brain-damaged subjects (RGB and HW) whose frequent errors in spoken production are nearly always semantically related to the target word. Both subjects show similar, high rates of these "semantic" errors in oral naming and oral reading; yet neither subject makes semantic errors in comparable written tasks. Further, results of a variety of lexical tasks with the same stimuli demonstrate unimpaired comprehension of printed or spoken words, including those that are orally produced as semantic errors. These patterns of performance are interpreted as resulting from damage to the phonological output lexicon. The postulated deficit is contrasted to the hypothesis of impairment to the lexical-semantic component, required to explain performance by brain-damaged subjects described elsewhere who make seemingly identical types of oral production errors to those of RGB and HW, but, in addition, make comparable errors in writing and comprehension tasks.

When a rose is a rose in speech but a tulip in writing.

We report the pattern of performance on language tasks by a neurologically impaired patient, RCM, who makes semantic errors in writing to dictation and in written naming, but makes very few errors at all (and no semantic errors) in spoken naming, oral reading, or spontaneous speech. RCM also shows a significant effect of concreteness on spelling accuracy and other features of so-called "deep dysgraphia." However, it is shown that, unlike previously reported patients described as deep dysgraphic, RCM has intact semantic processing but impairment in accessing lexical-orthographic representations, at least for the items tested. These results demonstrate that the collection of features labelled as "deep dysgraphia" can arise from damage to different cognitive processes. Detailed analyses of RCM's performance across lexical tasks, at two different time periods of recovery, provide evidence that lexical orthographic representations can be either directly activated by lexical semantic representations, or activated by the interaction of lexical semantic and sublexical information from phonology-to-orthography conversion mechanisms.

Mechanisms of spatial attention revealed by hemispatial neglect.

We report performance by a patient, NG, with hemispatial neglect after nondominant stroke, in detecting briefly (200 msec) presented visual targets. NG's detection of targets (gaps in circles) was determined by the location of the target in the space in which stimuli appeared. Gaps on the neglected side of a circle at fixation were rarely detected when circles of uniform size were always presented at fixation. The same targets in the same location were detected far more often in blocks that also included targets presented on each side of the central circle, or in blocks that included larger target stimuli. In these blocks, the window of space in which stimuli appeared was larger, such that the target fell closer to the center of this "window". These results indicate that the spatial extent of attention, and of hemispatial neglect, can be modified on the the basis of expectations and task requirements.

Mechanisms for accessing lexical representations for output: evidence from a category-specific semantic deficit.

We report the performance of a neurologically impaired patient, JJ, whose oral reading of words exceeded his naming and comprehension performance for the same words--a pattern of performance that has been previously presented as evidence for "direct, nonsemantic, lexical" routes to output in reading. However, detailed analyses of JJ's reading and comprehension revealed two results that do not follow directly from the "direct route" hypothesis: (1) He accurately read aloud all orthophonologically regular words and just those irregular words for which he demonstrated some comprehension (as indicated by correct responses or within-category semantic errors in naming and comprehension tasks); and (2) his reading errors on words that were not comprehended at all (but were recognized as words) were phonologically plausible (e.g., soot read as "suit"). We account for these results by proposing that preserved sublexical mechanisms for converting print to sound, together with partially preserved semantic information, serve to mediate the activation of representations in the phonological output lexicon in the task of reading aloud. We present similar arguments for postulating an interaction between sublexical mechanisms and lexical output components of the spelling process.

The graphemic buffer and attentional mechanisms.

Two patients with acquired dysgraphia were reported. The patients' performance in various written and oral spelling tasks converge in support of the hypothesis that they have selective damage, within the spelling system, to the Graphemic Buffer. Although the patients present with comparable patterns of error types, they differ in the distribution of errors as a function of letter position in words. The patients' patterns of errors are compared to previously reported patterns of spelling errors in dysgraphic patients and are discussed in terms of hypothesized mechanisms that operate on the representations that are stored in the Graphemic Buffer.

The disruption of sentence production: some dissociations.

A patient (M.L.) with selective disruption of sentence production is described. M.L.'s sentence production performance is characterized by the omission (and occasional substitution) of free-standing and bound grammatical morphemes. In contrast to her impaired sentence production performance, M.L. has no difficulties in sentence comprehension or production of single words including functors. Her performance is interpreted as reflecting a functional lesion to the positional level of sentence production.

Reperfusion of specific brain regions by raising blood pressure restores selective language functions in subacute stroke.

We report a series of six single subject studies examining the effects of pharmacological blood pressure elevation on regional brain perfusion and language function. Previous reports indicate that hypoperfusion of specific brain regions, as delineated by magnetic resonance perfusion weighted imaging (PWI), is associated with disruption of selective lexical functions. On this basis, we hypothesized that reperfusion of the same regions, in the absence of infarct in that region, would restore the associated lexical function. We present five patients with impaired lexical-semantics associated with poor perfusion, but not infarction, of Brodmann's area 22 (BA 22), and one patient with impaired lexical-semantics and a superimposed deficit in retrieving the phonological representations of words, associated with poor perfusion Brodmann's area 37 (BA 37) as well as BA 22. Each patient was treated with induced blood pressure elevation to increase perfusion of the ischemic and dysfunctional tissue. Daily testing of naming and comprehension, with stimulus sets matched for frequency, familiarity, and length, showed improved lexical-semantics in the patients who showed reperfusion of BA 22 and improved oral naming (but not lexical-semantics) in the patient who showed reperfusion of BA 37. These cases illustrate that loss of function with hypoperfusion of a circumscribed area of the brain, and recovery of the same function with improved perfusion of that brain region, can reveal brain/language relationships prior to reorganization after brain injury.

An area essential for linking word meanings to word forms: evidence from primary progressive aphasia.

We investigated the relationship between deficits in naming and areas of focal atrophy in primary progressive aphasia (a neurodegenerative disease that specifically affects language processing). We tested patients, across multiple input modalities, on traditional naming tasks (picture naming) and more complex tasks (sentence completion with a name, naming in response to a question) and obtained high resolution MRI. Across most tasks, error rates were correlated with atrophy in the left middle and posterior inferior temporal gyrus. Overall, this result converges with prior literature suggesting that this region plays a major role in modality independent lexical processing.

Atlas-Based Classification of Hyperintense Regions from MR Diffusion-Weighted Images of the Brain: Preliminary Results.

The study of subjects with acquired brain damage in a specific location is important in exploring human brain function. Description of lesion locations within and across subjects is a crucial methodological component that usually involves the distinction of normal from damaged tissue (lesion segmentation) in relation to lesion locations in terms of a standard anatomical reference space (lesion mapping). Our study provides an atlas-based, computer-aided methodology for classification of hyperintense regions on diffusion-weighted images of the brain, representing either ischemic lesions or susceptibility artifacts. We applied a leave-one-out method of cross-validation that computed probabilistic atlases of true lesions and artifacts, based on training data. Our approach accurately classifies lesions and artifacts, but leaves a significant number of regions unclassified, due to the relatively small number of training samples. An initial segmentation step based on a larger sample of data sets is required to automate discrimination of lesions and artifacts.