Working memory in schizophrenia: dynamic visuo-spatial information processing

Working memory, commonly defined as the ability to hold mental representations on line transiently and to manipulate these representations, is known to be a core deficit in schizophrenia. The aim of the present study was to investigate the visuo-spatial component of the working memory in schizophrenia, and more precisely to what extent the dynamic visuo-spatial information processing is impaired in schizophrenia patients. For this purpose we used a computerized paradigm in which 29 patients with schizophrenia (DSMIV, Diagnostic Interview for Genetic Studies) and 29 age and sex matched control subjects (DIGS) had to memorize a plane moving across the computer screen and to identify the observed trajectory among 9 plots proposed together. Each trajectory could be seen max. 3 times if needed. The results showed no difference between schizophrenia patients and controls regarding the number of correct trajectory identified after the first presentation. However, when we determine the mean number of correct trajectories on the basis of 3 trials, we observed that schizophrenia patients are significantly less performant than controls (Mann-Whitney, p _ 0.002). These findings suggest that, although schizophrenia patients are able to memorize some dynamic trajectories as well as controls, they do not profit from the repetition of the trajectory presentation. These findings are congruent with the hypothesis that schizophrenia could induce an unbalance between local and global information processing: the patients may be able to focus on details of the trajectory which could allow them to find the right target (bottom-up processes), but may show difficulty to refer to previous experience in order to filter incoming information (top-down processes) and enhance their visuo-spatial working memory abilities.

HLA class I - associated immunodominance affects CTL responsiveness to an ESO recombinant protein tumor antigen vaccine.

PURPOSE: Vaccination with full-length human tumor antigens aims at inducing or increasing antitumor immune responses, including CD8 CTL in cancer patients across the HLA barrier. We have recently reported that vaccination with a recombinant tumor-specific NY-ESO-1 (ESO) protein, administered with Montanide and CpG resulted in the induction of specific integrated antibody and CD4 T cell responses in all vaccinated patients examined, and significant CTL responses in half of them. Vaccine-induced CTL mostly recognized a single immunodominant region (ESO 81-110). The purpose of the present study was to identify genetic factor(s) distinguishing CTL responders from nonresponders. EXPERIMENTAL DESIGN: We determined the HLA class I alleles expressed by CTL responders and nonresponders using high-resolution molecular typing. Using short overlapping peptides spanning the ESO immunodominant CTL region and HLA class I/ESO peptide tetramers, we determined the epitopes recognized by the majority of vaccine-induced CTL. RESULTS: CTL induced by vaccination with ESO protein mostly recognized distinct but closely overlapping epitopes restricted by a few frequently expressed HLA-B35 and HLA-Cw3 alleles. All CTL responders expressed at least one of the identified alleles, whereas none of the nonresponders expressed them. CONCLUSIONS: Expression of HLA-B35 and HLA-Cw3 is associated with the induction of immunodominant CTL responses following vaccination with recombinant ESO protein. Because recombinant tumor-specific proteins are presently among the most promising candidate anticancer vaccines, our findings indicate that the monitoring of cancer vaccine trials should systematically include the assessment of HLA association with responsiveness.

Postnatal intracerebroventricular administrations of NGF alter spatial memory in adulthood

The present work assessed the effects of intracerebroventricular injections (2x5 mg/2.5 ml) of recombined human nerve growth factor (rhNGF) at postnatal days 2 and 3 upon the development of spatial learning capacities in rats. The treated rats were trained at the age of 22 days to escape onto an invisible platform at a fixed position in space in a Morris navigation task. For half of the subjects, the training position was also cued, a procedure aimed at facilitating escape and reducing attention to the distant spatial cues. At the age of 2 months all the rats were retrained in the same task. Treatment effects were found in both immature and adult rats. The injection of NGF induced a slight alteration of the immature rats' performance. In contrast, a marked impairment of spatial abilities was shown in the 2-month-old rats. The most consistent effects were a significant increase in the escape latency and a decrease bias towards the training platform area during probe trials. The reduction of spatial memory was particularly marked if the subjects had been trained in a cued condition. Taken together, these experiments reveal that an acute pharmacological treatment that leads to transient modifications during early development might induce a behavioural change long after treatment. Thus, the development and the maintenance of an accurate spatial representation are tightly related to the development of brain structures that could be altered by precocious NGF administrations.

Cerebellar lesions: is there a lateralisation effect on memory deficits?

BACKGROUND: Until recently, neurosurgeons eagerly removed cerebellar lesions without consideration of future cognitive impairment that might be caused by the resection. In children, transient cerebellar mutism after resection has lead to a diminished use of midline approaches and vermis transection, as well as reduced retraction of the cerebellar hemispheres. The role of the cerebellum in higher cognitive functions beyond coordination and motor control has recently attracted significant interest in the scientific community, and might change the neurosurgical approach to these lesions. The aim of this study was to investigate the specific effects of cerebellar lesions on memory, and to assess a possible lateralisation effect. METHODS: We studied 16 patients diagnosed with a cerebellar lesion, from January 1997 to April 2005, in the "Centre Hospitalier Universitaire Vaudois (CHUV)", Lausanne, Switzerland. Different neuropsychological tests assessing short term and anterograde memory, verbal and visuo-spatial modalities were performed pre-operatively. RESULTS: Severe memory deficits in at least one modality were identified in a majority (81%) of patients with cerebellar lesions. Only 1 patient (6%) had no memory deficit. In our series lateralisation of the lesion did not lead to a significant difference in verbal or visuo-spatial memory deficits. FINDINGS: These findings are consistent with findings in the literature concerning memory deficits in isolated cerebellar lesions. These can be explained by anatomical pathways. However, the cross-lateralisation theory cannot be demonstrated in our series. The high percentage of patients with a cerebellar lesion who demonstrate memory deficits should lead us to assess memory in all patients with cerebellar lesions.

Visuospatial working memory deficits and visual pursuit impairments are not directly related in schizophrenia.

OBJECTIVE: Patients with schizophrenia show deficits in visuospatial working memory and visual pursuit processes. It is currently unclear, however, whether both impairments are related to a common neuropathological origin. The purpose of the present study was therefore to examine the possible relations between the encoding and the discrimination of dynamic visuospatial stimuli in schizophrenia. METHOD: Sixteen outpatients with schizophrenia and 16 control subjects were asked to encode complex disc displacements presented on a screen. After a delay, participants had to identify the previously presented disc trajectory from a choice of six static linear paths, among which were five incorrect paths. The precision of visual pursuit eye movements during the initial presentation of the dynamic stimulus was assessed. The fixations and scanning time in definite regions of the six paths presented during the discrimination phase were investigated. RESULTS: In comparison with controls, patients showed poorer task performance, reduced pursuit accuracy during incorrect trials and less time scanning the correct stimulus or the incorrect paths approximating its global structure. Patients also spent less time scanning the leftmost portion of the correct path even when making a correct choice. The accuracy of visual pursuit and head movements, however, was not correlated with task performance. CONCLUSIONS: The present study provides direct support for the hypothesis that active integration of visuospatial information within working memory is deficient in schizophrenia. In contrast, a general impairment of oculomotor mechanisms involved in smooth pursuit did not appear to be directly related to lower visuospatial working memory performance in schizophrenia.

A Candidate HIV/AIDS Vaccine (MVA-B) that Enhances the Magnitude and Polyfunctionality of Memory HIV-1-Specific T-Cell Responses

Background: The poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (MVA-B) is currently used as a HIV/AIDS vaccine candidate. A general strategy to try to improve the immunogenicity of poxvirus HIV-1 vaccine candidates is the deletion of known or suggested immunomodulatory vaccinia virus (VACV) genes.Methods: We have generated and characterized the innate immune sensing and the immunogenicity profile of a new HIV-1 vaccine candidate, which contains a deletion in a VACV gene.Results: We show that this VACV protein is expressed early during virus infection and localizes to the cytoplasm of infected cells. Deletion of this VACV gene from the MVA-B had no effect on virus growth kinetics; therefore this VACV protein is not essential for virus replication. The innate immune signals elicited by the MVA-B deletion mutant in human macrophages and monocyte-derived dendritic cells were characterized. In a DNA prime/MVA boost immunization protocol in mice, flow cytometry analysis revealed that the MVA-B deletion mutant enhanced the magnitude and polyfunctionality of the HIV-1-specific CD4 + and CD8 + T-cell memory immune responses, with most of the HIV-1 responses mediated by the CD8 + T-cell compartment with an effector phenotype. Significantly, while MVA-B induced preferentially Env- and Gag-specific CD8 + T-cell responses, the MVA-B deletion mutant induced more GPN-specific CD8 + T-cell responses. Furthermore, the MVA-B deletion mutant enhanced the levels of antibodies against Env in comparison with MVA-B.Conclusion: These findings revealed that this new VACV protein can be considered as an immunomodulator and that deleting this gene in MVA-B confers an immunological benefit by inducing innate immune responses and increasing the magnitude and quality of the T-cell memory immune responses to HIV-1 antigens. Our observations are relevant for the improvement of MVA vectors as HIV-1 vaccines.

Auditory stimulation does not induce implicit memory during anaesthesia

Background and aim of the study: Formation of implicit memory during general anaesthesia is still debated. Perceptual learning is the ability to learn to perceive. In this study, an auditory perceptual learning paradigm, using frequency discrimination, was performed to investigate the implicit memory. It was hypothesized that auditory stimulation would successfully induce perceptual learning. Thus, initial thresholds of the frequency discrimination postoperative task should be lower for the stimulated group (group S) compared to the control group (group C). Material and method: Eighty-seven patients ASA I-III undergoing visceral and orthopaedic surgery during general anaesthesia lasting more than 60 minutes were recruited. The anaesthesia procedure was standardized (BISR monitoring included). Group S received auditory stimulation (2000 pure tones applied for 45 minutes) during the surgery. Twenty-four hours after the operation, both groups performed ten blocks of the frequency discrimination task. Mean of the thresholds for the first three blocks (T1) were compared between groups. Results: Mean age and BIS value of group S and group C are respectively 40 } 11 vs 42 } 11 years (p = 0,49) and 42 } 6 vs 41 } 8 (p = 0.87). T1 is respectively 31 } 33 vs 28 } 34 (p = 0.72) in group S and C. Conclusion: In our study, no implicit memory during general anaesthesia was demonstrated. This may be explained by a modulation of the auditory evoked potentials caused by the anaesthesia, or by an insufficient longer time of repetitive stimulation to induce perceptual learning.

Dissociation between components of spatial memory in rats after recovery from the effects of retrohippocampal lesions

A series of 4 experiments examined the performance of rats with retrohippocampal lesions on a spatial water-maze task. The animals were trained to find and escape onto a hidden platform after swimming in a large pool of opaque water. The platform was invisible and could not be located using olfactory cues. Successful escape performance required the rats to develop strategies of approaching the correct location with reference solely to distal extramaze cues. The lesions encompassed the entire rostro-caudal extent of the lateral and medial entorhinal cortex, and included parts of the pre- and para-subiculum, angular bundle and subiculum. Groups ECR 1 and 2 sustained only partial damage of the subiculum, while Group ECR+S sustained extensive damage. These groups were compared with sham-lesion and unoperated control groups. In Expt 1A, a profound deficit in spatial localisation was found in groups ECR 1 and ECR+S, the rats receiving all training postoperatively. In Expt 1B, these two groups showed hyperactivity in an open-field. In Expt 2, extensive preoperative training caused a transitory saving in performance of the spatial task by group ECR 2, but comparisons with the groups of Expt 1A revealed no sustained improvement, except on one measure of performance in a post-training transfer test. All rats were then given (Expt 3) training on a cueing procedure using a visible platform. The spatial deficit disappeared but, on returning to the normal hidden platform procedure, it reappeared. Nevertheless, a final transfer test, during which the platform was removed from the apparatus, revealed a dissociation between two independent measures of performance: the rats with ECR lesions failed to search for the hidden platform but repeatedly crossed its correct location accurately during traverses of the entire pool. This partial recovery of performance was not (Expt 4) associated with any ability to discriminate between two locations in the pool. The apparently selective recovery of aspects of spatial memory is discussed in relation to O'Keefe and Nadel's (1978) spatial mapping theory of hippocampal function. We propose a modification of the theory in terms of a dissociation between procedural and declarative subcomponents of spatial memory. The declarative component is a flexible access system in which information is stored in a form independent of action. It is permanently lost after the lesion. The procedural component is "unmasked" by the retrohippocampal lesion giving rise to the partial recovery of spatial localisation performance.

Face Short-Term Memory-Related Electroencephalographic Patterns can Differentiate Multi- versus Single-Domain Amnestic Mild Cognitive Impairment.

Amnestic mild cognitive impairment (aMCI) is characterized by memory deficits alone (single-domain, sd-aMCI) or associated with other cognitive disabilities (multi-domain, md-aMCI). The present study assessed the patterns of electroencephalographic (EEG) activity during the encoding and retrieval phases of short-term memory in these two aMCI subtypes, to identify potential functional differences according to the neuropsychological profile. Continuous EEG was recorded in 43 aMCI patients, whose 16 sd-aMCI and 27 md-aMCI, and 36 age-matched controls (EC) during delayed match-to-sample tasks for face and letter stimuli. At encoding, attended stimuli elicited parietal alpha (8-12 Hz) power decrease (desynchronization), whereas distracting stimuli were associated with alpha power increase (synchronization) over right central sites. No difference was observed in parietal alpha desynchronization among the three groups. For attended faces, the alpha synchronization underlying suppression of distracting letters was reduced in both aMCI subgroups, but more severely in md-aMCI cases that differed significantly from EC. At retrieval, the early N250r recognition effect was significantly reduced for faces in md-aMCI as compared to both sd-aMCI and EC. The results suggest a differential alteration of working memory cerebral processes for faces in the two aMCI subtypes, face covert recognition processes being specifically altered in md-aMCI.

Septal lesions impair the acquisition of a cued place navigation task: attentional or memory deficit?

These experiments were designed to analyze how medial septal lesions reducing the cholinergic innervation in the hippocampus might affect place learning. Rats with quisqualic lesions of the medial septal area (MS) were trained in a water maze and on a homing table where the escape position was located at a spatially fixed position and further indicated by a salient cue suspended above it. The lesioned rats were significantly impaired in reaching the cued escape platform during training. In addition rats, did not show any discrimination of the training sector during a probe trial in which no platform or cue was present. This impairment remained significant during further training in the absence of the cue. When the cued escape platform was located at an unpredictable spatial location, the MS-lesioned rats showed no deficit and spent more time under the cue than control rats during the probe trial. On the homing board, with a salient object in close proximity to the escape hole, the MS rats showed no deficit in escape latencies, although a significant reduction in spatial memory was observed. However, this was overcome by additional training in the absence of the cue. Under these conditions, rats with septal lesions were prone to develop a pure guidance strategy, whereas normal rats combined a guidance strategy with a memory of the escape position relative to more distant landmarks. The presence of a salient cue appeared to decrease attention to environmental landmarks, thus reducing spatial memory. These data confirm the general hypothesis that MS lesions reduce the capacity to rely on a representation of the relation between several landmarks with different salience.

Proteasome-assisted identification of a SSX-2-derived epitope recognized by tumor-reactive CTL infiltrating metastatic melanoma.

The tumor Ag SSX-2 (HOM-MEL-40) was found by serological identification of Ags by recombinant expression cloning and was shown to be a cancer/testis Ag expressed in a wide variety of tumors. It may therefore represent a source of CD8(+) T cell epitopes useful for specific immunotherapy of cancer. To identify potential SSX-2-derived epitopes that can be recognized by CD8(+) T cells, we used an approach that combined: 1) the in vitro proteasomal digestion of precursor peptides overlapping the complete SSX-2 sequence; 2) the prediction of SSX-2-derived peptides with an appropriate HLA-A2 binding score; and 3) the analysis of a tumor-infiltrated lymph node cell population from an HLA-A2(+) melanoma patient with detectable anti-SSX-2 serum Abs. This strategy allowed us to identify peptide SSX-2(41-49) as an HLA-A2-restricted epitope. SSX2(41-49)-specific CD8(+) T cells were readily detectable in the tumor-infiltrated lymph node population by multimer staining, and CTL clones isolated by multimer-guided cell sorting were able to lyse HLA-A2(+) tumor cells expressing SSX-2.

Metabolic activation pattern of distinct hippocampal subregions during spatial learning and memory retrieval.

Activation dynamics of hippocampal subregions during spatial learning and their interplay with neocortical regions is an important dimension in the understanding of hippocampal function. Using the (14C)-2-deoxyglucose autoradiographic method, we have characterized the metabolic changes occurring in hippocampal subregions in mice while learning an eight-arm radial maze task. Autoradiogram densitometry revealed a heterogeneous and evolving pattern of enhanced metabolic activity throughout the hippocampus during the training period and on recall. In the early stages of training, activity was enhanced in the CA1 area from the intermediate portion to the posterior end as well as in the CA3 area within the intermediate portion of the hippocampus. At later stages, CA1 and CA3 activations spread over the entire longitudinal axis, while dentate gyrus (DG) activation occurred from the anterior to the intermediate zone. Activation of the retrosplenial cortex but not the amygdala was also observed during the learning process. On recall, only DG activation was observed in the same anterior part of the hippocampus. These results suggest the existence of a functional segmentation of the hippocampus, each subregion being dynamically but also differentially recruited along the acquisition, consolidation, and retrieval process in parallel with some neocortical sites.

The validity of clinical diagnoses of dementia in a group of consecutively autopsied memory clinic patients.

BACKGROUND: Epidemiological studies show that up to 10% of individuals aged 65 years and older suffer from dementia, most commonly from dementia of the Alzheimer Type (DAT) (1). Clinicopathological studies are critical to our understanding of this disease and improving the accuracy of clinical diagnoses. OBJECTIVES: Our objectives were to examine the validity of clinical diagnoses of DAT, to determine the prevalence of different forms of dementia in this sample, and to investigate the relationship between age at death and polymorbidity. SUBJECTS AND METHOD: Clinical data were available from 221 patients who had been examined at the Basel Memory Clinic between 1986 and 1996. From this population, 34% (75 patients) were autopsied in the Department of Pathology, University Hospital Basel, and neuropathological examinations were additionally performed on 62 (83%) of these patients. Clinical and neuropathological data were retrospectively compared. RESULTS: 67.8% of the neuropathologically examined patients received a definitive diagnosis of AD (Alzheimer's disease), vascular dementia (VaD) or mixed dementia (AD and VaD). AD alone or with other histopathological hallmarks of dementia was the most prevalent neuropathological diagnosis (63%). VaD was deemed the only cause of dementia in only 4.8% of patients. The sensitivity for DAT was 75.9%, the specificity 60.6%. Increasing age was associated with an increasing number of clinical and neuropathological diagnoses. CONCLUSION: The sensitivity and specificity of the clinical diagnoses of DAT found in our study are similar to previous reports (2-5). Older patients had more etiologies of their dementia than younger patients. This study reaffirms the need for internationally accepted criteria for clinical and neuropathological diagnoses, as well as further clinical-neuropathological investigations to further refine the clinical diagnostic process.

Antigenicity and immunogenicity of Melan-A/MART-1 derived peptides as targets for tumor reactive CTL in human melanoma.

Some cancer patients mount spontaneous T- and B-cell responses against their tumor cells. Autologous tumor reactive CD8 cytolytic T lymphocyte (CTL) and CD4 T-cell clones as well as antibodies from these patients have been used for the identification of genes encoding the target antigens. This knowledge opened the way for new approaches to the immunotherapy of cancer. In this review, we describe the characterization of the structure-function properties of the melanocyte/melanoma tumor antigen Melan-A/MART-1, the assessment of the T-cell repertoire available against this antigen in healthy individuals, and the analysis of naturally acquired and/or vaccine-induced CTL responses to this antigen in patients with metastatic melanoma.