Cognitive interaction after staged callosal section: evidence for transfer of semantic activation.

Sensory and cognitive functions were assessed in a right-handed male before and after partial and complete callosal commissurotomy. After the initial posterior section was made, there was no evidence of interhemispheric sensory transfer, although the left hemisphere did have access to stimulus-related semantic and episodic information from the right hemisphere. After the callosum was completely sectioned, this exchange was no longer observed.

Neuropsychological characterization of the AIDS dementia complex: a preliminary report.

The AIDS dementia complex (ADC) is a frequent complication of advanced HIV infection. In order to better define the neuropsychological character and progression of the ADC, four groups of subjects were studied with a battery of neuropsychological tests: an HIV-seronegative comparison group (n = 20), asymptomatic HIV-seropositive patients (n = 16), newly diagnosed AIDS patients (n = 44) and AIDS patients who were referred for neurological consultation (n = 40). Results showed significant reductions in performance in the two AIDS groups, with impairment being most prominent in tests that assessed motor speed and fine control, concentration, problem solving and visuospatial performance. This pattern of neuropsychological dysfunction is consistent with the characterization of the ADC as a subcortical dementia.

Neurological outcomes in late HIV infection: adverse impact of neurological impairment on survival and protective effect of antiviral therapy. AIDS Clinical Trial Group and Neurological AIDS Research Consortium study team.

OBJECTIVE: In a large multi-center clinical trial of combination reverse transcriptase inhibitors (RTIs), we assessed the impact of antiretroviral therapy on neurological function, the relationship between neurological and systemic benefit, and the prognostic value of neurological performance in late HIV-1 infection. DESIGN: Neurological evaluations incorporated in a randomized, multi-center trial of combination antiretroviral therapy. SETTING: Forty-two AIDS Clinical Trials Group sites and seven National Hemophilia Foundation sites. PATIENTS: Adult HIV-infected patients (n = 1313) with CD4 counts < 50 x 10(6) cells/l. INTERVENTIONS: Four combinations of reverse transcriptase inhibitors consisting of zidovudine (ZDV), alternating monthly with didanosine (ddl), or in combination with zalcitabine (ddC), ddl or ddl and nevirapine. MAIN OUTCOME MEASURES: Mean change from baseline of a four-item quantitative neurological performance battery score, the QNPZ-4, administered to 1031 subjects. RESULTS: Triple therapy and ZDV/ddl combination preserved or improved neurological performance over time compared with the alternating ZDV/ddl and ZDV/ddC regimens (P < 0.001), paralleling their impact on survival in the same trial as previously reported. QNPZ-4 scores were predictive of survival (P < 0.001), after adjusting for CD4 counts and HIV-1 plasma RNA concentrations. CONCLUSIONS: Combination antiretroviral therapy can have a salutary effect on preserving or improving neurological function. Superior systemic treatments may likewise better preserve neurological function. The significant association of poor neurological performance with mortality, independent of CD4 counts and HIV-1 RNA levels indicates that neurological dysfunction is an important cause or a strong marker of poor prognosis in late HIV-1 infection. This study demonstrates the value of adjunctive neurological measures in large therapeutic trials of late HIV-1 infection.

Cerebrospinal fluid beta 2-microglobulin in patients with AIDS dementia complex: an expanded series including response to zidovudine treatment.

OBJECTIVE: To determine the relationship between cerebrospinal fluid (CSF) beta 2-microglobulin (beta 2M) and severity of AIDS dementia complex (ADC), and between CSF beta 2M and response of ADC to zidovudine. DESIGN: A prospective study. SETTING: Tertiary referral hospital. PATIENTS, PARTICIPANTS: Seventy-eight patients with varying stages of ADC were selected from a subgroup of a cohort of HIV-seropositive patients who are being studied prospectively for the neurological complications of HIV-1 infection. To enter our study, patients had to have an ADC stage of at least 0.5 (equivocal symptoms or abnormal neurological signs in the absence of functional impairment). A control group of 11 HIV-1-seropositive, neurologically normal patients was chosen randomly from the patients followed in the Multicenter AIDS Cohort Study. INTERVENTIONS: Patients were assessed neurologically and neuropsychologically and computed tomography of the brain and CSF studies were performed. MAIN OUTCOME MEASURES: Patients were staged according to severity of ADC on clinical criteria. Neuropsychological test scores were converted to an impairment score. CSF beta 2M was quantified in both serum and CSF of all patients and in 10 patients with pre- and post-zidovudine assessments. RESULTS: There was a high correlation between CSF beta 2M concentration and severity of ADC (P less than 0.0001); treatment with zidovudine significantly reduced these concentrations (P = 0.013). CSF beta 2M concentration was independent of CSF white-cell count and blood-brain barrier impairment. Other CSF changes in the same patients (including blood-brain barrier permeability to albumin, intrathecal synthesis of immunoglobulin G and HIV-1-p24-antigen levels) were less useful as objective correlates of ADC severity and response to zidovudine therapy. CONCLUSIONS: CSF beta 2M may be a valuable marker of ADC severity and response to antiviral therapy.

AIDS dementia complex and HIV-1 infection: a view from the clinic.

The AIDS dementia complex (ADC) is a clinical syndrome which characteristically presents as a "subcortical dementia" with cognitive, motor and behavioral changes. While the pathogenesis remains puzzling in a number of critical aspects, ADC likely relates in a fundamental way to HIV-1, itself, rather than to a secondary, opportunistic condition. This review focuses on some of the clinical information which bears on the pathogenesis of this syndrome and its relation to HIV-1 infection. This information derives from studies of the clinical character of ADC, its epidemiology and natural history, cerebrospinal fluid analysis, neuroimaging results, clinical correlates of pathological findings and its response to antiviral therapy.

Scaled subprofile model: a statistical approach to the analysis of functional patterns in positron emission tomographic data.

The data obtained from measurements of regional rCMRglu using [18F]fluorodeoxyglucose (FDG)/positron emission tomographic (PET) data contain more structure than can be identified with group mean rCMRglu profiles or regional correlation coefficients. This additional structure is revealed by a novel mathematical-statistical model of regional metabolic interactions that explicitly represents rCMRglu profiles as a combination of region-independent global effects, a group mean pattern and a mosaic of interacting networks. In its application to FDG/PET data, this model removes global subject effects [global scaling factors (GSFs)] and a group mean pattern (profile) so as to maximize statistical power for the detection and simultaneous discovery of all networks of two or more regions that form a significant and consistent linearly covarying pattern. The model approach presented here was applied to the combined rCMRglu data from 12 demented AIDS patients and 18 normal controls: Two significant metabolic covariance pattern descriptors that together accounted for 71 to 96% of the rCMRglu/GSF variation across subjects for 22/28 regions in the AIDS group were extracted. Each descriptor was found to be highly correlated with performance on several neuropsychological tests, providing independent validation of the analysis technique as a means of discovering and describing behaviorally related components of group rCMRglu profiles.

Absolute quantitation in neurological PET: do we need it?

This article addresses the question posed in the title by examining the effects of parameters traditionally associated with improved absolute quantitation, on the analysis of 12 acquired immune deficiency syndrome dementia complex (ADC) patients compared to a normal control group. Results are discussed within the framework of the subprofile scaling model (SSM) for analyzing patterns of regional covariation. It is demonstrated that the ability to extract measures of group discrimination and disease progression are unaffected by (1) limited improvements in image resolution, (2) the use of transmission scan smoothing, (3) the application of a scatter deconvolution correction, and (4) converting region-of-interest measurements of counts per voxel to measurements of regional CMRglc. This "robustness" of the SSM approach is partly due to the extraction of disease-related subject weights, independent of any subject's global scaling effects. It is argued that other analysis techniques that initially reduce intersubject variation (e.g., using regional ratios or normalizing by global metabolic rates before applying traditional multivariate procedures) lack analytic features that may be important to identify multidimensional, disease-related image patterns. Based on the ADC patient data, it is concluded that measures of group discrimination and disease progression will not necessarily benefit from the organization of parameters traditionally associated with improved absolute quantitation.

Principal component analysis and the scaled subprofile model compared to intersubject averaging and statistical parametric mapping: I. "Functional connectivity" of the human motor system studied with [15O]water PET.

Using [15O]water PET and a previously well studied motor activation task, repetitive finger-to-thumb opposition, we compared the spatial activation patterns produced by (1) global normalization and intersubject averaging of paired-image subtractions, (2) the mean differences of ANCOVA-adjusted voxels in Statistical Parametric Mapping, (3) ANCOVA-adjusted voxels followed by principal component analysis (PCA), (4) ANCOVA-adjustment of mean image volumes (mean over subjects at each time point) followed by F-masking and PCA, and (5) PCA with Scaled Subprofile Model pre- and postprocessing. All data analysis techniques identified large positive focal activations in the contralateral sensorimotor cortex and ipsilateral cerebellar cortex, with varying levels of activation in other parts of the motor system, e.g., supplementary motor area, thalamus, putamen; techniques 1-4 also produced extensive negative areas. The activation signal of interest constitutes a very small fraction of the total nonrandom signal in the original dataset, and the exact choice of data preprocessing steps together with a particular analysis procedure have a significant impact on the identification and relative levels of activated regions. The challenge for the future is to identify those preprocessing algorithms and data analysis models that reproducibly optimize the identification and quantification of higher-order sensorimotor and cognitive responses.

Can left-handed writing posture predict cerebral language laterality?

In terms of cerebral lateralization of function, left-handed persons represent a more heterogeneous group than right-handed persons. Some evidence suggests that left-handed subgroups can be identified on the basis of the following two types of writing posture: (1) inverted posture that indicates ipsilateral hemisphere language capability and (2) straight writing posture that indicates contralateral hemisphere language capability. A direct test of this hypothesis with an intracarotid amobarbital sodium injection failed to support these predictions. For clinical decisions in which the hemisphere subserving language is necessary, one should rely on direct assessment with the use of the amobarbital injection technique.

Evaluation of the AIDS dementia complex in clinical trials.

The AIDS dementia complex (ADC) is one of the most common and important causes of morbidity associated with infection by human immunodeficiency virus type 1 (HIV-1). The evaluation of ADC in clinical trials is significant not only because of the clinical impact of this syndrome, but also because of the value of measuring its cardinal features as an index of drug efficacy and because of its emerging role as a major clinical end point. The objectives of therapy include both prevention of ADC in the presymptomatic patient and alleviation of established disease. At present, the pathogenesis of ADC is incompletely understood in several critical aspects, particularly the processes underlying the clinical manifestations of central nervous system (CNS) HIV-1 infection and, further, how such processes are related to systemic disease. Consequently, it is not yet clear to what extent, or in which patients, it is necessary to achieve "therapeutic" drug levels within the CNS. Nevertheless, the assessment of ADC prevention and treatment relies principally on the complementary approach of neurological examination for diagnosis and neuropsychological testing for quantitative serial measurement of treatment effects. Additionally, surrogate markers in cerebrospinal fluid (CSF) may hold promise for objective, rapid assessment of treatment response and dose adjustment. Other measurements, including more routine CSF analysis, neuroimaging, and neurophysiological assessments, are used principally for differential diagnosis rather than for monitoring ADC status. Accumulating experience with available antiviral agents suggests that ADC can be effectively prevented and treated, at least for some period of time, and that assessment of this condition is indeed a valuable approach for measuring antiviral therapy.

Differential effects of congenital versus acquired unilateral brain injury on dichotic listening performance: evidence for sparing and asymmetric crowding.

We assessed dichotic speech and complex-pitch discrimination in nine young patients with unilateral left-hemisphere injury and eight young patients with unilateral right-hemisphere injury incurred in the pre-perinatal (congenital) period. As in adults with acquired unilateral lesions, both congenital lesion groups demonstrated poor performance on stimuli presented to the ear contralateral to the lesion. In overall performance on speech discrimination, however, the left-hemisphere congenital lesion group performed significantly better than the acquired-lesion group did. On complex-pitch discrimination, the right-hemisphere congenital lesion group performed significantly better than did the acquired-lesion group, but both left- and right-hemisphere congenital lesion groups were significantly worse at complex-pitch discrimination than were their age- and gender-matched normal controls. These results indicate that although congenital damage produces a "lesion effect" in dichotic listening similar to that after damage acquired in adulthood, overall function is relatively spared. To the extent that complex-pitch discrimination is affected by congenital damage to either hemisphere but speech discrimination is not, the present results are consistent with an asymmetric form of crowding during reorganization after congenital unilateral brain damage.

Cortical mechanisms involved in praxis: observations following partial and complete section of the corpus callosum in man.

In patients who have undergone complete section of the corpus callosum for intractable epilepsy, lateralized presentation of visual nonverbal stimulation showed that the coordination of motor acts by either hand is controlled exclusively by the contralateral hemisphere. When two patients had serial operations consisting of an initial division of the splenium and posterior 3 cm, followed by complete callosal division, an opportunity arose to test the explicit cortical pathways involved in ipsilateral control. Between operations, these patients could not coordinate movements of the hand ipsilateral to the hemisphere receiving the command. This suggested that for visual nonverbal stimulation, the posterior 3 cm of corpus callosum is necessary for control of the ipsilateral hand; the rostral callosum cannot transfer sensorimotor commands. Also, contrary to current views, each hemisphere can carry out sequentially dependent motor activity.

Double disconnection effects resulting from infiltrating tumors.

Patients with left hemisphere lesions deep in parietal or parietal-occipital regions close to the lateral ventricles have been reported to have impaired performance on left ear speech stimuli in dichotic listening tests. This loss has been termed "paradoxical" because it presents at the ear ipsilateral to the lesion. Two patients with infiltrating tumors which involved the corpus callosum demonstrated that effect, but also demonstrated right ear extinction on a complex-pitch discrimination test that required right hemisphere processing. Since the side at which the impairment will be demonstrated depends upon the type of test used, the term "paradoxical extinction" does not clearly describe this phenomena. It is suggested that the so-called paradoxical loss is better referred to as callosal extinction.

Abnormal cerebral glucose metabolism in HIV-1 seropositive subjects with and without dementia.

UNLABELLED: This study was undertaken in order to extend our previous finding of relative basal ganglia hypermetabolism in AIDS dementia complex (ADC) and to develop clinically useful metabolic indices of CNS involvement in HIV-seropositive (HIV+) subjects. METHODS: Twenty-one HIV+ subjects (11 with AIDS) underwent FDG-PET scanning; 12 had a follow-up scan at 6 mo and 4 had a third scan at 12 mo. Forty-three age-matched heterosexual volunteers served as controls. FDG-PET scanning was performed with arterial blood sampling, and scan data were analyzed using the Scaled Subprofile Model (SSM) with principal component analysis. RESULTS: SSM/principal component analysis of the combined (HIV+ and controls) FDG-PET dataset extracted two major disease-related metabolic components: (a) a nonspecific indicator of cerebral dysfunction, which was significantly correlated with age, cerebral atrophy and ADC stage and (b) the striatum, which was heavily weighted (relatively hypermetabolic) and appeared to provide a disease-specific measure of early CNS involvement. CONCLUSION: FDG-PET scans provide quantitative measures of abnormal functional connectivity in HIV-seropositives-with or without AIDS or ADC. These measures, which are robust across centers with respect to instrumentation, scanning technique and disease severity, appear to track the progression of CNS involvement in patients with subclinical neurologic or neuropsychologic dysfunction.

Transient ischemic attacks presenting with a loss of pitch perception.

It has been suggested that the non-dominant hemisphere is specialized for receptive and expressive music and prosody. The present report describes a patient who experienced a series of non-dominant hemisphere transient ischemic attacks (TIA's) which included an inability to perceive intonation during one episode, and a failure to perceive melody during another. The perceptual losses during these TIA's are consistent with experimental results which suggest that the non-dominant hemisphere is specialized for complex-pitch processing. In some instances, amusia, dysprosody, and aprosodia reflect a common functional deficit.

Selective loss of complex-pitch or speech discrimination after unilateral lesion.

Twenty-eight right-handed patients who suffered a single cerebrovascular accident in the distribution of either the left or right middle cerebral artery were tested on their ability to discriminate complex-pitch and speech stimuli presented dichotically. Whereas the left hemisphere lesion group was impaired in dichotic speech but not in dichotic complex-pitch discrimination, the right hemisphere lesion group was impaired in dichotic complex pitch but not in dichotic speech discrimination. Complex-pitch phenomena may provide a useful model for the study of auditory function in the nondominant hemisphere.