Generation of immunological memory in tolerant mice.

Adult mice pretreated with dinitrophenylated isologous gamma globulins respond very poorly to the hapten presented in immunogenic form. However, the responses of such tolerized and primed animals, or the spleen cells from such mice on adoptive transfer, to small doses of soluble antigen revealed normal secondary responsiveness in terms of size of response, relative affinities of the antibodies produced and antigenic sensitivity. In contrast, mice tolerized in early life and subsequently primed showed diminished responsiveness to secondary challenge, both in the original animals and on adoptive transfer. In this instance cells producing high affinity antibodies seemed to be preferentially deleted.     

Stimulus- and response-locked neuronal generator patterns of auditory and visual word recognition memory in schizophrenia

Examining visual word recognition memory (WRM) with nose-referenced EEGs, we reported a preserved ERP ‘old-new effect’ (enhanced parietal positivity 300–800 ms to correctly-recognized repeated items) in schizophrenia ([Kayser, J., Bruder, G.E., Friedman, D., Tenke, C.E., Amador, X.F., Clark, S.C., Malaspina, D., Gorman, J.M., 1999. Brain event-related potentials (ERPs) in schizophrenia during a word recognition memory task. Int. J. Psychophysiol. 34(3), 249–265.]). However, patients showed reduced early negative potentials (N1, N2) and poorer WRM. Because group differences in neuronal generator patterns (i.e., sink-source orientation) may be masked by choice of EEG recording reference, the current study combined surface Laplacians and principal components analysis (PCA) to clarify ERP component topography and polarity and to disentangle stimulus- and response-related contributions. To investigate the impact of stimulus modality, 31-channel ERPs were recorded from 20 schizophrenic patients (15 male) and 20 age-, gender-, and handedness-matched healthy adults during parallel visual and auditory continuous WRM tasks. Stimulus- and response-locked reference-free current source densities (spherical splines) were submitted to unrestricted Varimax-PCA to identify and measure neuronal generator patterns underlying ERPs. Poorer (78.2 ± 18.7% vs. 87.8 ± 11.3% correct) and slower (958 ± 226 vs. 773 ± 206 ms) performance in patients was accompanied by reduced stimulus-related left-parietal P3 sources (150 ms pre-response) and vertex N2 sinks (both overall and old/new effects) but modality-specific N1 sinks were not significantly reduced. A distinct mid-frontal sink 50-ms post-response was markedly attenuated in patients. Reductions were more robust for auditory stimuli. However, patients showed increased lateral-frontotemporal sinks (T7 maximum) concurrent with auditory P3 sources. Electrophysiologic correlates of WRM deficits in schizophrenia suggest functional impairments of posterior cortex (stimulus representation) and anterior cingulate (stimulus categorization, response monitoring), primarily affecting memory for spoken words.     

The generation of memory cells. II. Generation of B memory cells with preformed antigen-antibody complexes.

Mice were immunized with preformed complexes of dinitrophenylated haemocyanin (DNP-KLH) and anti-DNP or anti-KLH antibodies, and subsequently assayed for the generation of B memory (BM) cells. Complexes formed at equivalence or in slight antigen excess were far more effective than antigen alone in generating memory: as little as 100 ng DNP-KLH-anti-DNP produced substantial B cell priming. Anti-carrier and anti-hapten antibodies were equally effective. Complexes generated memory more rapidly than antigen alone, and the adjuvant effect was not simply due to aggregation of the antigen. Optimal priming by complexes required the integrity of the Fc portion of the antibody: F(ab')2 antibody fragments were less effective. The capacity of complexes to prime BM cells was abrogated by depriving mice of C3. C3 was also required for localization of complexes within splenic lymphoid follicles; complexes made with F(ab')2 localized in follicles, but less efficiently than those made with intact antibody. These results extend earlier findings (Klaus & Humphrey, 1977) and strongly suggest that the generation of BM cells involves the C3-dependent localization of antigen-antibody complexes within lymphoid follicles and strengthen the concept that germinal centres are the birthplace of BM cells.     

Generation of memory cells. III. Antibody class requirements for the generation of B-memory cells by antigen--antibody complexes.

Immunizing mice with preformed antigen--antibody complexes is a highly effective means of generating B-memory cells. In the present study we have compared the capacity of mouse anti-dinitrophenyl (DNP) IgM, IgG1, IgG2 and IgA antibodies to generate DNP-specific memory, when given in complex with antigen (DNP-KLH: keyhole limpet haemocyanin). Two monoclonal IgM antibodies exerted no adjuvant effect, whereas a monoclonal IgA antibody was effective, IgG2 antibodies were a more powerful adjuvant than IgG1, regardless of whether anti-DNP or anti-KLH antibodies were used. Furthermore, the capacity of DNP-KLH--antibody complexes to localize in splenic lymphoid follicles could be ranked IgG2 greater than IgG1 greater than IgA; IgM complexes did not localize in follicles. These results correlate well with data (presented elsewhere) on the capacity of these different antibodies to activate mouse complement, and confirm that C activation is an essential requirement for both follicular localization of immune complexes, and for the generation of B-memory cells. Although activation of the alternative complement pathway is sufficient to effect both processes, the results with IgG2 antibodies raise the possibility that classical pathway activation may be more effective.     

Generation and maintenance of immunological memory

The key feature of the adaptive immune response is its specificity and the ability to generate and maintain memory. Preexisting antibodies in the circulation and at the mucosa provide the first line of defense against re-infection by extracellular as well as intracellular pathogens. Memory T cells are an important second line of defense against intracellular pathogens, and in particular against microbes that can cause chronic or latent infection. In this article we will review our current understanding of the generation and maintenance of B cell and T cell memory.     

Early sleep triggers memory for early visual discrimination skills

Improvement after practicing visual texture discrimination does not occur until several hours after practice has ended. We show that this improvement strongly depends on sleep. To specify the process responsible for sleep-related improvement, we compared the effects of 'early' and 'late' sleep, dominated respectively by slow-wave and rapid eye movement (REM) sleep. Discrimination skills significantly improved over early sleep, improved even more over a whole night's sleep, but did not improve after late sleep alone. These findings suggest that procedural memory formation is prompted by slow-wave sleep-related processes. Late REM sleep may promote memory formation at a second stage, only after periods of early sleep have occurred.     

Overlapping functional anatomy for working memory and visual search

Recent behavioural findings using dual-task paradigms demonstrate the importance of both spatial and non-spatial working memory processes in inefficient visual search (Anderson et al. in Exp Psychol 55:301–312, 2008). Here, using functional magnetic resonance imaging (fMRI), we sought to determine whether brain areas recruited during visual search are also involved in working memory. Using visually matched spatial and non-spatial working memory tasks, we confirmed previous behavioural findings that show significant dual-task interference effects occur when inefficient visual search is performed concurrently with either working memory task. Furthermore, we find considerable overlap in the cortical network activated by inefficient search and both working memory tasks. Our findings suggest that the interference effects observed behaviourally may have arisen from competition for cortical processes subserved by these overlapping regions. Drawing on previous findings (Anderson et al. in Exp Brain Res 180:289–302, 2007), we propose that the most likely anatomical locus for these interference effects is the inferior and middle frontal cortex of the right hemisphere. These areas are associated with attentional selection from memory as well as manipulation of information in memory, and we propose that the visual search and working memory tasks used here compete for common processing resources underlying these mechanisms.     

The effect of caffeine ingestion on the perceived instability of visual patterns.

The unique cytoarchitecture of the visual cortex, with cells of particular orientation-specificity arranged in vertical columns adjacent to other columns with somewhat different orientation-specificity causes subjective visual instabilities when viewing some repetitive grid patterns for normal subjects. Since caffeine increases cortical arousal by serving as an antagonist to the inhibitory neurotransmitter adenosine, caffeine intake might be expected to increase these subjective disturbances. Twenty subjects were administered a placebo, 100 or 200 mg of caffeine orally. After 40 min subjects rated the level of visual instability on nine subjective dimensions, while viewing grating patterns. Each subject was tested on all levels of caffeine intake, with at least 48 h between tests. With increasing caffeine dosage the level of reported visual disturbances increased. These data suggest that the increased cortical arousal associated with caffeine intake may interact with the structural properties of the visual cortex to increase the perceptual instability associated with viewing grid patterns.     

Role of inferior temporal neurons in visual memory. II. Multiplying temporal waveforms related to vision and memory.

1. In the companion paper we reported on the activity of neurons in the inferior temporal (IT) cortex during a sequential pattern matching task. In this task a sample stimulus was followed by a test stimulus that was either a match or a nonmatch. Many of the neurons encoded information about the patterns of both current and previous stimuli in the temporal modulation of their responses. 2. A simple information processing model of visual memory can be formed with just four steps: 1) encode the current stimulus; 2) recall the code of a remembered stimulus; 3) compare the two codes; 4) and decide whether they are similar or different. The analysis presented in the first paper suggested that some IT neurons were performing the comparison step of visual memory. 3. We propose that IT neurons participate in the comparison of temporal waveforms related to vision and memory by multiplying them together. This product could form the basis of a crosscorrelation-based comparison. 4. We tested our hypothesis by fitting a simple multiplicative model to data from IT neurons. The model generated waveforms in separate memory and visual channels. The waveforms arising from the two channels were then multiplied on a point by point basis to yield the output waveform. The model was fitted to the actual neuronal data by a gradient descent method to find the best fit waveforms that also had the lowest total energy. 5. The multiplicative model fit the neuronal responses quite well. The multiplicative model made consistently better predictions of the actual response waveforms than did an additive model. Furthermore, the fit was better when the actual relationship between the responses and the sample and test stimuli were preserved than when that relationship was randomized. 6. We infer from the superior fit of the multiplicative model that IT neurons are multiplying temporally modulated waveforms arising from separate visual and memory systems in the comparison step of visual memory.     

Event-related potentials during the continuous visual memory test

The Continuous Visual Memory Test (CVMT; Trahan & Larrabee, 1988) is a recognition format assessment of figural memory. It includes 112 ambiguous designs presented sequentially, with a number of designs that recur through the 112 presentations. The patient's task is to identify the recurring figures by responding with the word “old” for recurring stimuli and “new” for non-recurring stimuli. This study examined cortical event-related potentials during discrimination of old vs. new stimuli. While no latency differences between stimuli were found, P300 amplitude was greater during recognition of old stimuli and increasingly prominent at anterior sites. A stimulus by electrode site interaction suggests greater functional involvement in the discrimination by the frontal areas. This points to a degree of psychophysiological validation of the CVMT and cortical specificity of the task. © 1996 John Wiley & Sons, Inc.     

Selective mechanisms for complex visual patterns revealed by adaptation

A great deal is known about the initial steps of visual processing. We know that humans have neural mechanisms selectively tuned to simple patterns of particular spatial frequencies and orientations. We also know that much later in the visual pathway, in inferotemporal cortex, cells respond to extremely complex visual patterns such as images of faces. Very little is known about intermediate levels of visual processing, where early visual signals are presumably combined to represent increasingly complex visual features. Here we show the existence of visual mechanisms in humans, tuned and selective to particular combinations of simple sinusoidal patterns, using a novel method of compound adaptation.     

Studies on B-cell memory. I. Generation and exhaustion of B-cell memory by thymus-dependent antigen in T-cell depleted mice.

Mice depleted of T cells by adult thymectomy, X-irradiation and reconstitution with syngeneic bone marrow cells, either untreated or treated with anti-Thy-1 serum and complement, were immunized intensively with alum-precipitated bovine serum albumin (AP-BSA) along with or without bacterial lipopolysaccharide (LPS), but no significant anti-BSA antibody response was detected. Priming of the T-cell depleted mice, however, either by a single injection of AP-BSA plus LPS or by multiple injections of AP-BSA without LPS, resulted in the generation of immunological memory. A single injection of AP-BSA without LPS was ineffective. The memory required the aid of syngeneic T cells to be recalled by the challenge with AP-BSA plus LPS. On the other hand, multiple injections of AP-BSA plus LPS did not cause the generation of memory and the response of these mice to the challenge was lower than that of unprimed control mice. These results suggest that (1) the anti-BSA response is highly dependent on the helper function of T cells, (2) the degree of T-cell requirement for the memory generation is very low, and (3) priming with too much strong stimulation in the absence of functional T cells leads to the suppression or abortion of previously generated immunological memory.     

Neuronal activity in the substantia nigra in the anaesthetized rat has fractal characteristics. Evidence for firing-code patterns in the basal ganglia

Current models of the basal ganglia assume a firing-rate code for information processing. We have applied five complementary computing methods to assess firing patterns in 188 cells of the substantia nigra in the anaesthetized rat. Fractal firing activity was found in 100% of nigral cells projecting to the superior colliculus, in 51% of cells projecting to the thalamus and in 33% of cells projecting to the pedunculopontine nucleus, but was practically absent in dopaminergic nigrostriatal neurons (3%). The finding of fractal firing patterns may lead to a better understanding of the normal operational mode and pathological manifestations of the basal ganglia.     

Generation and maintenance of memory T cells

Typical immune responses lead to the prominent clonal expansion of antigen-specific T cells followed by their differentiation into effector cells. Most effector cells die at the end of the immune response but some of the responding cells survive and form long-lived memory cells. The factors controlling the formation and survival of memory T cells are discussed. Recent evidence suggests that T memory cells arise from a subset of effector cells. The longevity of T memory cells may require continuous contact with cytokines, notably IL-15 for CD8(+) cells.     

Spatial priming in visual search: memory for body-centred information

Spatial priming allows memory for target locations to be evaluated, whereby when a target appears in the same location across trials, participants become more efficient at locating it and consequently their search times decrease. Previously, we reported priming effects when the location of a target was repeated with respect to the participant’s body but not when it was repeated relative to their eye position; therefore, suggesting that body-centred information is available after a delay of at least a few seconds (Ball et al. in Exp Brain Res 204:585–594, 2010). However, we were unable to rule out the possibility that stable allocentric cues within the room may have contributed to the priming effects that we observed. In this current study, we introduced a condition where despite participants moving to a new location between trials, their position relative to the target was maintained. This movement disrupted any potential room-based cues about the target location. While we replicated our previous finding of priming when the location of the target was repeated relative to the viewer when no movement was required, we also found robust priming effects when participants moved to a new location in between trials. Thus, we provide clear evidence that in our spatial priming task, the location of the target was being coded in a body-centred reference frame and that this information is available after a delay.     

Stimulus specificity and temporal dynamics of working memory for visual motion

When asked to compare two moving stimuli separated by a delay, observers must not only identify stimulus direction but also store it in memory. We examined the properties of this storage mechanism in two macaque monkeys by sequentially presenting two random-dot stimuli, sample and test, in opposite hemifields and introducing a random-motion mask during the delay. The mask interfered with performance only at the precise location of the test, 100-200 ms after the start of the delay, and when its size and speed matched those of the remembered sample. This selective interference suggests that the representation of the motion stimulus in memory preserves its direction, speed, and size and is most fragile shortly after the completion of the encoding phase of the task. This precise preservation of sensory attributes of the motion stimulus suggests that the neural mechanisms involved in the processing of visual motion may also be involved in its storage.     

How MT cells analyze the motion of visual patterns

Neurons in area MT (V5) are selective for the direction of visual motion. In addition, many are selective for the motion of complex patterns independent of the orientation of their components, a behavior not seen in earlier visual areas. We show that the responses of MT cells can be captured by a linear-nonlinear model that operates not on the visual stimulus, but on the afferent responses of a population of nonlinear V1 cells. We fit this cascade model to responses of individual MT neurons and show that it robustly predicts the separately measured responses to gratings and plaids. The model captures the full range of pattern motion selectivity found in MT. Cells that signal pattern motion are distinguished by having convergent excitatory input from V1 cells with a wide range of preferred directions, strong motion opponent suppression and a tuned normalization that may reflect suppressive input from the surround of V1 cells.     

Properties of distortion of the figures in visual short-term memory

We investigated the distortion that occurs during the storage of representations in visual short-term memory by using smooth closed figures with varying stimulus complexity and similarity. In similarity judgments, the results suggested that the psychological similarity between two figures was based on averaging physical similarities of matched features. In a detection experiment, the results showed that the processing of detection was limited in its capacity for the precision of shape, and that it was more difficult to detect the precise shape in the case of complex figures. In a recognition experiment, the results showed that forgetting occurred during a one-second retention interval. These two results showed that internal noise distorts both detection and retention processes. These findings suggested that representations of the complex figures with many features were distorted to a larger degree because each feature was individually masked with internal noise. It is concluded that the psychological similarity between an input pattern and a distorted pattern stored in short-term memory is invariant with stimulus complexity.     

Working memory for complex figures: an fMRI comparison of letter and fractal n-back tasks

n-back letter and fractal tasks were administered to 11 participants during functional magnetic resonance imaging to test process specificity theories of prefrontal cortex (PFC) function and assess task validity. Tasks were matched on accuracy, but fractal n-back responses were slower and more conservative. Maintenance (1-back minus 0-back) activated inferior parietal and dorsolateral PFC, with additional activation in right ventrolateral PFC during letter n-back and left lingual gyrus during fractal n-back. Maintenance plus manipulation (2-back minus 0-back) activated inferior parietal, Broca's area, insula, and dorsolateral and ventral PFC, with greater right dorsolateral PFC activation for letter n-back. Manipulation only (2-back minus 1-back) produced additional and equivalent dorsolateral PFC and anterior cingulate activation in both tasks. Results support fractal n-back validity and indicate substantial overlap in working memory functions of dorsal and ventral PFC.