Reduced Myelin Water in the White Matter Tracts of Patients with Niemann-Pick Disease Type C.

Previous studies using diffusion tensor imaging to examine white matter in Niemann-Pick disease type C have produced mixed results. However, diffusion tensor imaging does not directly measure myelin and may be affected by other structural changes. We used myelin water imaging to more directly examine demyelination in 2 patients with Niemann-Pick disease type C. The results suggest that this technique may be useful for identifying regional changes in myelination in this condition.

Measuring palinopsia: characteristics of a persevering visual sensation from cerebral pathology.

Palinopsia is an abnormal perseverative visual phenomenon, whose relation to normal afterimages is unknown. We measured palinoptic positive visual afterimages in a patient with a cerebral lesion. Positive afterimages were confined to the left inferior quadrant, which allowed a comparison between afterimages in the intact and the affected part of his visual field. Results showed that negative afterimages in the affected quadrant were no different from those in the unaffected quadrant. The positive afterimage in his affected field, however, differed both qualitatively and quantitatively from normal afterimages, being weaker but much more persistent, and displaced from the location of the inducing stimulus. These findings reveal distinctions between pathological afterimages of cerebral origin and physiological afterimages of retinal origin.

Human prosaccades and antisaccades under risk: effects of penalties and rewards on visual selection and the value of actions.

Monkey studies report greater activity in the lateral intraparietal area and more efficient saccades when targets coincide with the location of prior reward cues, even when cue location does not indicate which responses will be rewarded. This suggests that reward can modulate spatial attention and visual selection independent of the "action value" of the motor response. Our goal was first to determine whether reward modulated visual selection similarly in humans, and next, to discover whether reward and penalty differed in effect, if cue effects were greater for cognitively demanding antisaccades, and if financial consequences that were contingent on stimulus location had spatially selective effects. We found that motivational cues reduced all latencies, more for reward than penalty. There was an "inhibition-of-return"-like effect at the location of the cue, but unlike the results in monkeys, cue valence did not modify this effect in prosaccades, and the inhibition-of-return effect was slightly increased rather than decreased in antisaccades. When financial consequences were contingent on target location, locations without reward or penalty consequences lost the benefits seen in noncontingent trials, whereas locations with consequences maintained their gains. We conclude that unlike monkeys, humans show reward effects not on visual selection but on the value of actions. The human saccadic system has both the capacity to enhance responses to multiple locations simultaneously, and the flexibility to focus motivational enhancement only on locations with financial consequences. Reward is more effective than penalty, and both interact with the additional attentional demands of the antisaccade task.

Anomalous global effects induced by 'blind' distractors in visual hemifield defects.

Previous research has revealed that a stimulus presented in the blind visual field of participants with visual hemifield defects can evoke oculomotor competition, in the absence of awareness. Here we studied three cases to determine whether a distractor in a blind hemifield would be capable of inducing a global effect, a shift of saccade endpoint when target and distractor are close to each other, in participants with lesions of the optic radiations or striate cortex. We found that blind field distractors significantly shifted saccadic endpoints in two of three participants with lesions of either the striate cortex or distal optic radiations. The direction of the effect was paradoxical, however, in that saccadic endpoints shifted away from blind field distractors, whereas endpoints shifted towards distractors in the visible hemifields, which is the normal global effect. These results provide further evidence that elements presented in the blind visual field can generate modulatory interactions in the oculomotor system, which may differ from interactions in normal vision.

The contribution of the fusiform gyrus and superior temporal sulcus in processing facial attractiveness: neuropsychological and neuroimaging evidence.

Current cognitive models suggest that the processing of dynamic facial attributes, including social signals such as gaze direction and facial expression, involves the superior temporal sulcus, whereas the processing of invariant facial structure such as the individuals' identity involves the fusiform face area. Where facial attractiveness, a social signal that may emerge from invariant facial structure, is processed within this dual-route model of face perception is uncertain. Here, we present two studies. First, we investigated the explicit judgments of facial attractiveness and attractiveness-motivated behavior in patients with acquired prosopagnosia, a deficit in familiar face recognition usually associated with damage to medial occipitotemporal cortex. We found that both abilities were impaired in these patients, with some weak residual ability for attractiveness judgments found only in those patients with unilateral right occipitotemporal or bilateral anterior temporal lesions. Importantly, deficits in attractiveness perception correlated with the severity of the face recognition deficit. Second, we performed a functional magnetic resonance imaging study in healthy subjects that included an implicit and explicit processing of facial attractiveness. We found increased neural activity when explicitly judging facial attractiveness within a number of cortical regions including the fusiform face area, but not the superior temporal sulcus, indicating a potential contribution of the fusiform face area to this judgment. Thus, converging neuropsychological and neuroimaging evidence points to a critical role of the inferior occipitotemporal cortex in the processing of facial attractiveness.

The use of working memory for task prediction: what benefits accrue from different types of foreknowledge?

The assumption that the deployment of executive processes invariably improves task performance is implicit to cognitive theory. In particular, working memory can be used to retain and update historical information about predictable trial sequences (foreknowledge) so that subjects can anticipate and prepare for the upcoming trial more effectively. We review the effects of different types of foreknowledge on response accuracy and latency, particularly in relation to experiments investigating saccadic eye movements in humans. While it is possible to make all aspects of an impending trial predictable, varying the predictability of different components of the trial independently can reveal which cognitive operations are potentially modifiable by foreknowledge. These operations include stimulus processing, retrieval of task-set rules, and response preparation, among others. The available data suggest that, while response preparation can be completed and the response even executed before the stimulus appears (i.e. anticipation) when the subject possesses complete task-foreknowledge (knowing both the stimulus to appear and the response required), foreknowledge of the task-set alone does not permit advance configuration of the task-set rules. A taxonomy for foreknowledge is proposed, including foreknowledge for timing, stimulus, set, response, and task. Work on differentiating these effects in neurophysiology, neuroimaging, and neuropsychology is still in the early stages.

Deficient saccadic inhibition in Asperger's disorder and the social-emotional processing disorder.

BACKGROUND: Both Asperger's disorder and the social-emotional processing disorder (SEPD), a form of non-verbal learning disability, are associated with executive function deficits. SEPD has been shown to be associated with deficient saccadic inhibition. OBJECTIVE: To study two executive functions in Asperger's disorder and SEPD, inhibition and task switching, using a single saccadic paradigm. METHODS: 22 control subjects and 27 subjects with developmental social processing disorders-SEPD, Asperger's disorder, or both syndromes-performed random sequences of prosaccades and antisaccades. This design resulted in four trial types, prosaccades and antisaccades, that were either repeated or switched. The design allowed the performance costs of inhibition and task switching to be isolated. RESULTS: Subjects with both Asperger's disorder and SEPD showed deficient inhibition, as indicated by increased antisaccade errors and a disproportionate increase in latency for antisaccades relative to prosaccades. In contrast, task switching error and latency costs were normal and unrelated to the costs of inhibition. CONCLUSIONS: This study replicates the finding of deficient saccadic inhibition in SEPD, extends it to Asperger's disorder, and implicates prefrontal cortex dysfunction in these syndromes. The finding of intact task switching shows that executive function deficits in Asperger's disorder and SEPD are selective and suggests that inhibition and task switching are mediated by distinct neural networks.

Oculographic analysis of word reading in hemispatial neglect.

Neglect dyslexia is a disorder in which individuals misread text appearing on the contralateral side of space following an acquired lesion, usually to the right parietal lobe. This disorder is generally attributed to an impairment in representing spatial information. To determine whether the spatial representations underlying reading differ from those mediating other forms of visual behavior, we investigated the co-occurrence of neglect dyslexia with that of neglect, which manifests on tasks such as line bisection or line cancellation. We also examined the correlation between neglect dyslexia, when present, and eye movements in order to characterize the neglect dyslexia disorder further. Whereas there is no clear relationship between the reading disorder and other symptoms of visuospatial neglect, suggesting segregated spatial representations, there is a direct correspondence between the oculomotor performance of patients with neglect dyslexia and their reading behavior. This latter result suggests that the reading deficit may well arise from the failure to register and perceive the contralesional information.

Covert recognition in acquired and developmental prosopagnosia.

BACKGROUND: Some patients with prosopagnosia have covert recognition, meaning that they retain some familiarity or knowledge of facial identity of which they are not aware. OBJECTIVE: To test the hypothesis that prosopagnosic patients with right occipitotemporal lesions and impaired face perception lack covert processing, whereas patients with associative prosopagnosia and bilateral anterior temporal lesions possess it. METHODS: Eight patients with prosopagnosia were tested with a battery of four face recognition tests to determine their ability to discriminate between famous and unknown faces. RESULTS: Measures of overt familiarity revealed better residual discrimination in patients with acquired prosopagnosia than in those with the developmental form. With forced-choice methods using famous faces paired with unknown faces, no patient demonstrated covert familiarity. However, when the semantic cue of the name of the famous face was provided, covert processing was present in all five patients with acquired prosopagnosia, including the three with extensive right-sided lesions and impaired perceptual discrimination of facial configuration. Sorting unrecognized faces by occupation was also performed above chance in three of these five patients. In contrast, none of the three patients with developmental prosopagnosia had covert processing, even though two demonstrated flawless performance on similar tests of name (rather than face) recognition. Overt familiarity correlated highly with the degree of covert recognition. CONCLUSIONS: Extensive right occipitotemporal lesions with significant deficits in face perception are not incompatible with covert face processing. Covert processing is absent in developmental prosopagnosia, because this condition likely precludes the establishment of a store of accurate facial memories. The presence of covert processing correlates with the degree of residual overt familiarity, indicating that these are related phenomena.

Discrimination of spatial relations and features in faces: effects of inversion and viewing duration.

We studied discrimination of changes in eye position, mouth position, and eye colour at viewing durations ranging from 1 second to unlimited time. With upright faces, perception was rapid and did not improve above 2 seconds viewing time. Face inversion impaired discrimination of mouth position significantly, eye position slightly, but not eye colour. The 'inversion effect' for mouth position decreased with increasing stimulus duration, and disappeared when the subject knew that the only change in a trial was in mouth position. A subsequent experiment showed that the inversion impairment in the mouth region was not specific to spatial position but affected mouth colour to a lesser degree. When the mouth region was made more salient by increasing the frequency of mouth change trials, the inversion effect for mouth position decreased, and correlated with an increase in inversion effect for eye position but not eye colour. We conclude that the dominant effect of face inversion upon perception is decreased discrimination in less salient facial regions, that this impairment lessens with increasing viewing time, and that it affects both features and their spatial relations, though the effect on the latter is greater. These results are consistent with greater dependence on a serial component search strategy in inverted faces.

The eye movements of pure alexic patients during reading and nonreading tasks.

We compared the eye-movements of two patients who read letter-by-letter (LBL) following a left occipital lobe lesion with those of normal control subjects and of hemianopic patients in two tasks: a nonreading visual search task and a text reading task. Whereas the LBL readers exhibited similar eye-movement patterns to those of the other two groups on the nonreading task, their eye movements differed significantly during reading, as reflected in the disproportionate increase in the number and duration of fixations per word and in the regressive saccades per word. Importantly, relative to the two control groups, letter-by-letter readers also made more fixations per word as word length increased, especially as word frequency and word imageability decreased. Two critical results emerged from these experiments: First, the alteration in the oculomotor behavior of the LBL readers during reading is similar to that seen in normal readers under difficult reading conditions, as well as in beginning readers and in those with developmental dyslexia, and appears to reflect difficulties in processing the visual stimulus. Second, the interaction of length with frequency and with imageability in determining the eye movement pattern is consistent with an interactive activation model of normal word recognition in which weakened activation of orthographic input can nevertheless engage high-level lexical factors.

A phase II study of combined oral uracil and ftorafur with leucovorin for patients with squamous cell carcinoma of the head and neck.

BACKGROUND: The objective of this Phase II study was to define the response rate, safety profile, and toxicity of oral uracil and ftorafur (UFT) with leucovorin (UFT/LV) as a palliative treatment for patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group performance status < 2 and adequate organ function were enrolled in an institutional review board-approved trial. Prior induction or adjuvant chemotherapy was permitted provided 6 months had elapsed since the last chemotherapy. Patients were treated with UFT 300 mg/m(2) per day and leucovorin 90 mg per day administered in three doses daily for 28 days followed by a 7-day break for a 35-day cycle. Planned intrapatient dose modifications were based on individual toxicity. Patients were removed from the study for progression of disease or unacceptable toxicity. RESULTS: One hundred six cycles of UFT/LV had been administered to 42 patients as of January 1, 2000. The most common toxicities, in descending order of incidence, were anemia, pain, fatigue, diarrhea, nausea, mucositis, and anorexia. Clinically significant toxicities attributable to UFT/ LV were primarily gastrointestinal. On an intent-to-treat basis, three patients (7%) achieved a complete response, and six patients (14%) achieved a partial response. The overall response rate was 21% (95% confidence interval, 10--37%). CONCLUSIONS: UFT/LV therapy is feasible in this patient population and is generally well tolerated. Response rates are similar to the rates expected with continuous-infusion 5-fluorouracil. UFT/LV should be studied further both alone and in combination therapy for patients with SCCHN.

Deficits in cortical visual function.

Lesions of extrastriate cortex cause selective defects in visual function. Damage to portions of the "ventral stream" in medial and inferior occipitotemporal cortex lead to impaired perception of color or various specific visual object recognition defects, such as prospagnosia, the inability to recognize familiar faces, and alexia, the inability to read. The latter must be distinguished from a variety of other reading defects related to primary visual, attentional, linguistic, or ocular motor impairments. Damage to the "dorsal stream" in lateral occipito-temporo-parietal regions impairs visuospatial capabilities, leading to akinetopsia (impaired motion perception) or Balint's syndrome, a loosely bound triad of simultanagnosia, optic ataxia, and ocular motor apraxia. Topographagnosia can occur with ventral or dorsoal lesions for different reasons. Considerable evidence has accumulated showing that residual vision or even "blindsight," which is visual perception in the absence of awareness, can persist after lesion of striate cortex in some patients.

Mode of delivery and risk of respiratory diseases in newborns.

OBJECTIVE: To determine whether there is an increased incidence of persistent pulmonary hypertension in neonates delivered by cesarean, with or without labor, compared with those delivered vaginally. METHODS: We did a computerized retrospective review of 29,669 consecutive deliveries over 7 years (1992-1999). The incidences of persistent pulmonary hypertension of the newborn, transient tachypnea of the newborn, and respiratory distress syndrome (RDS) were tabulated for each delivery mode. Cases of persistent pulmonary hypertension were reviewed individually to determine delivery method and whether labor had occurred. The three groups defined were all cesarean deliveries, all elective cesareans, and all vaginal deliveries. RESULTS: Among 4301 cesareans done, 17 neonates had persistent pulmonary hypertension (four per 1000 live births). Among 1889 elective cesarean deliveries, seven neonates had persistent pulmonary hypertension (3.7 per 1000 live births). Among 21,017 vaginal deliveries, 17 neonates had persistent pulmonary hypertension (0.8 per 1000 live births). chi2 analysis showed an odds ratio 4.6 and P <.001 for comparison of elective cesarean and vaginal delivery for that outcome. CONCLUSION: The incidence of persistent pulmonary hypertension of the newborn was approximately 0.37% among neonates delivered by elective cesarean, almost fivefold higher than those delivered vaginally. The findings have implications for informed consent before cesarean and increased surveillance of neonates after cesarean.

Vertical saccades in superior oblique palsy and Brown's syndrome.

OBJECTIVE: To compare saccadic dynamics in superior oblique palsy and Brown's syndrome. METHODS: Vertical saccades in adduction and in abduction were studied in two subjects with superior oblique palsy and one with Brown's syndrome. Using large numbers of centrifugal saccades over a wide range of amplitudes, we measured peak velocity, duration, and the peak velocity/mean velocity ratio (PV/MV) as a function of saccadic amplitude. We compared vertical saccades in 30 degrees of abduction with those in 30 degrees of adduction. RESULTS: Superior oblique palsy caused a 15-18% reduction in peak velocities in adduction compared with abduction. Saccadic duration was also increased in adduction, with the result that there was no net change in the PV/MV ratio. In the patient with Brown's syndrome, velocities and durations of upward saccades were similar in abduction and adduction, but the PV/MV ratio was significantly elevated in adduction. We also observed an unusual high-speed lateral 'snap' of about 5 degrees that frequently interrupted vertical saccades in the midline but not elsewhere. CONCLUSION: Both paresis and restriction of the superior oblique alter vertical saccades. The effects of restriction on saccadic dynamics are distinct from the effects of paresis.

Unilateral right parietal damage leads to bilateral deficit for high-level motion.

Patients with right parietal damage demonstrate a variety of attentional deficits in their left visual field contralateral to their lesion. We now report that patients with right lesions also show a severe loss in the perception of apparent motion in their "good" right visual field ipsilateral to their lesion. Three tests of attention were conducted, and losses were found only in the contralesional fields for a selective attention and a multiple object tracking task. Losses in apparent motion, however, were bilateral in all cases. The deficit in apparent motion in the parietal patients supports previous claims that this relatively effortless percept is mediated by attention. However, the bilateral deficit suggests that the disruption is due to a bilateral loss in the temporal resolution of attention to transient events that drive the apparent motion percept.

A phase II trial of palliative docetaxel plus 5-fluorouracil for squamous-cell cancer of the head and neck.

PURPOSE: A phase II study to determine the response rate and toxicity of docetaxel and 5-fluorouracil (5-FU) every four weeks ('TF'), in patients with incurable SCCHN. PATIENTS AND METHODS: Patients with metastatic or recurrent SCCHN with an ECOG PS < 3 were enrolled in an institutional review board approved trial. Prior induction or adjuvant chemotherapy was permitted provided six months had elapsed. The regimen was docetaxel 70 mg/m2 i.v., day 1 and 5-FU 800 mg/m2/d x 5 days, days 1-5, as a continuous intravenous infusion, repeated every 28 days. Planned intra-patient dose modifications were based on hematological, cutaneous, and gastrointestinal toxicities. Patients were removed from the study for progression of disease or unacceptable toxicity. RESULTS: Seventeen patients were enrolled. Fourty-six cycles of TF were administered. Reasons for discontinuance of TF included: progressive disease, 12 patients; toxicity, 3 patients; concomitant illness, 1 patient; death, 1 patient. The most common toxicities were neutropenia, mucositis, anemia, fatigue, alopecia, pain, diarrhea and nausea. Evaluation of responses to TF showed that there were four patients of seventeen (24%, 95% exact CI: 6.8-49.9) who achieved a PR or CR. Accrual was terminated after interim analysis of the response rate of the first 17 patients failed to exceed 4 of 17. CONCLUSIONS: The response rate to TF in patients with SCCHN was lower than expected. Trials of other regimens should take precedence over further exploration of the TF regimen.

Ocular aspects of myasthenia gravis.

Ocular myasthenia gravis is a not uncommon autoimmune disorder causing diplopia, ptosis, and weakness of lid closure. The predilection of myasthenia for the ocular muscles may be related to differences between limb and extraocular muscles in either physiological function or antigenicity. Clinically, ocular myasthenia can mimic any form of pupil-sparing ocular motility disorder. Dynamic abnormalities of myasthenic eye movements may reflect the primary hallmarks of the disease, which are fatigability and variability in strength, or secondary adaptive effects by the central nervous system. Tests to confirm the diagnosis include edrophonium challenge, repetitive nerve stimulation, single-fiber electromyography (EMG) of the frontalis, and assays for antibody directed against the acetylcholine receptor: all are less sensitive for ocular myasthenia than for generalized myasthenia. There is a higher incidence of other autoimmune conditions in myasthenia, notably thymoma and thyroid dysfunction. The differential diagnosis includes other diseases of the neuromuscular junction, such as Lambert-Eaton syndrome and botulism. Treatment consists of symptomatic use of acetylcholinesterase inhibitors and immunosuppression with steroids or azathioprine. Between 50 and 70% of patients with ocular myasthenia will eventually develop generalized disease: there is some retrospective data that steroids or azathioprine may reduce this by about 75%. The role of thymectomy in ocular myasthenia remains unclear.