Complete amnesia induced by ECS and complete recovery of memory following reinstatement treatment

Amnesia of fear conditioning in ECS animals was found to be equal to animals not conditioned. However, memory was shown to recover in ECS animals when different combinations of conditioning cues were presented 96 hr after training. The degree of memory recovered in ECS animals appeared to be a function of the type of reinstatement treatment given with apparent complete recovery obtained under one condition. Modification of retention by the reinstatement procedures was restricted to animals conditioned and made amnesic by ECS. These results are interpreted as indicating that ECS produces amnesia by interfering with memory retrieval processes and that the degree of memory recovered in ECS animals is a function of the type of reinstatement procedure used and the time at which it is administered.     

Interfacing mind and brain: a neurocognitive model of recognition memory

A variety of processes contribute to successful recognition memory, some of which can be associated with spatiotemporally distinct event-related potential old/new effects. An early frontal and a subsequent parietal old/new effect are correlated with the familiarity and recollection subcomponents of recognition memory, respectively, whereas a late, postretrieval old/new effect seems to reflect an ensemble of evaluation processes that are set by the task context in which retrieval occurs. Both the early frontal and the parietal old/new effects are differentially modulated by the informational content (e.g., object forms and spatial locations) of recognition and seem to rely on brain systems damaged in amnesia. The late frontal effect appears to reflect prefrontal cortex activation. A neurophysiologically based model of recognition memory retrieval is presented and it is shown that coupling recognition memory subprocesses with distinct old/new effects allow examination of the time course of the processes that contribute to correct and to illusory memories. In conjunction with event-related functional magnetic resonance imaging activation patterns the brain systems recruited by various aspects of episodic memory retrieval can be identified.     

Monitoring retrieval from long-term memory by slow event-related brain potentials

Slow event-related brain potentials of nine subjects were recorded in an experimentally controlled long-term memory retrieval task (the Fan paradigm) from electrode sites F3, Fz, F4, Cz, P3, Pz, and P4. In all retrieval conditions, a very pronounced DC-like negative potential appeared over the left frontal cortex. This negativity was switched on with the presentation of the probe stimuli and prevailed in some conditions throughout the total recording epoch of 14 s. Particular retrieval conditions became manifest in distinct slow wave effects. The amplitude of a bilaterally distributed frontal negative slow wave increased when a more diversified associative structure had to be searched. The amplitude of another negative slow wave, which peaked bilaterally over parietal areas, was affected by the type of concepts that had to be retrieved. The amplitude was larger with general concepts (category labels) and smaller with specific concepts (category exemplars). These results suggest that distinct strategies are invoked when subjects are required to draw conclusions about different contents stored permanently in an associative network.     

Working memory and preparation elicit different patterns of slow wave event-related brain potentials

Some event-related brain potential (ERP) studies of working memory have used delayed match-to-sample designs in which a stimulus (S1) is held in memory for comparison with a subsequent stimulus (S2). During the S1-S2 interval, ERP slow negativities varied with both the type and amount of material held in working memory. One interpretation is that these slow waves index working memory operations. An alternative explanation is that they only reflect general preparatory processing for the response to S2. To decide between these explanations, we used two visual processing tasks that required similar preparation for S2. In one task, visual memory rehearsal operations were required. During the S1-S2 interval, there were clear differences between the amplitudes, topographies, and the effect of information load on the slow waves in the two tasks, thus ruling out preparation only as an explanation.     

Event-related brain potentials in a varied-set memory search task: A reconsideration

Event-related potentials (ERPs) were recorded in 19 healthy subjects as they completed two Sternberg (1969, American Scientist, 57, 421–457) memory tests. In separate sessions, either single digits (i.e., 0–9) or 10 abstract figures were used as stimuli. In both sessions, memory set sizes were 1 (M1), 2 (M2), or 4 (M4). The amplitude and latency of the parietal P400 and the frontocentral negativity preceding P400 varied significantly with set size, but only between M1 and M2, whereas reaction time increased dramatically from M1 to M2 and from M2 to M4. These findings challenge previous assertions that the ERPs reflect aspects of the exhaustive serial search proposed by Sternberg. A late parietal positivity (P620), which failed to vary with set size, was larger in response to figures than to digits and may represent the search for, or utilization of, semantic traces of the stimuli.     

Training and task-related differences in retrograde amnesia thresholds determined by direct electrical stimulation of the cortex in rats

These experiments investigated the thresholds for producing retrograde amnesia (RA) by direct electrical stimulation of the cortex in rats. In different inhibitory (passive) avoidance tasks the degree of RA varied with the region of cortex (frontal or posterior) stimulated, as well as the motivational and training conditions used: water deprivation lowered the threshold for RA produced by frontal cortex stimulation; familiarization pretraining elevated the threshold for RA produced by posterior cortex stimulation. Brain seizure thresholds and patterns were not influenced by the variations in the motivational and pretraining conditions. These findings indicate that, in rats, the degree of RA produced by direct electrical stimulation of the cortex varies markedly with the training conditions.     

Cortical Imaging on a Head Template: A Simulation Study Using a Resistor Mesh Model (RMM)

The T1 head template model used in Statistical Parametric Mapping Version 2000 (SPM2), was segmented into five layers (scalp, skull, CSF, grey and white matter) and implemented in 2 mm voxels. We designed a resistor mesh model (RMM), based on the finite volume method (FVM) to simulate the electrical properties of this head model along the three axes for each voxel. Then, we introduced four dipoles of high eccentricity (about 0.8) in this RMM, separately and simultaneously, to compute the potentials for two sets of conductivities. We used the direct cortical imaging technique (CIT) to recover the simulated dipoles, using 60 or 107 electrodes and with or without addition of Gaussian white noise (GWN). The use of realistic conductivities gave better CIT results than standard conductivities, lowering the blurring effect on scalp potentials and displaying more accurate position areas when CIT was applied to single dipoles. Simultaneous dipoles were less accurately localized, but good qualitative and stable quantitative results were obtained up to 5% noise level for 107 electrodes and up to 10% noise level for 60 electrodes, showing that a compromise must be found to optimize both the number of electrodes and the noise level. With the RMM defined in 2 mm voxels, the standard 128-electrode cap and 5% noise appears to be the upper limit providing reliable source positions when direct CIT is used. The admittance matrix defining the RMM is easy to modify so as to adapt to different conductivities. The next step will be the adaptation of individual real head T2 images to the RMM template and the introduction of anisotropy using diffusion imaging (DI).     

Electrophysiological markers of cognitive deficits in traumatic brain injury: A review

Event-related potentials (ERPs) and oscillatory activity from the human electroencephalogram (EEG) provides a rich source of data that helps elucidate specific processing impairments in TBI patients. This review will focus on some of the central and disabling cognitive deficits in TBI and how broadband ERP markers and the spectral content of the EEG can help explain abnormalities in brain function that impact upon processing speed, sustained attention, performance monitoring, inhibitory control and cognitive flexibility. Physiological signals also provide useful outcome markers in cognitive intervention studies in conjunction with behavioural endpoints. Potential rehabilitation approaches utilising electrophysiological markers of recovery are also discussed. Progress has been made in recent years in defining key pathophysiological mechanisms in the context of sensitive laboratory paradigms. However, aberrant physiological signals need to be understood more clearly in future studies in terms of the neuroanatomical impact of injury, particularly in relation to the most common type of damage in TBI, disrupting extended white matter fibres.     

A non-arousing test situation abolishes the impairing effects of cortisol on delayed memory retrieval in healthy women

Animal and human studies have repeatedly shown that stress hormones influence memory. Glucocorticoids (GCs) enhance memory consolidation but impair memory retrieval. Studies in rodents indicate that adrenergic activation is necessary for GC induced effects on memory. We have shown, in two previous placebo-controlled double-blind experiments, that memory retrieval is significantly impaired after oral cortisol (30 mg) treatment in healthy young women. Here, we changed the experimental setting before and during the retrieval testing, so that the participants (n=31) experienced a more relaxed test situation. The learning material, the timing and the tester used were identical to the two previous studies. In the relaxed condition no effect of cortisol on memory retrieval occurred (p=0.84). The results indicate that the experimental setting can influence the effect of cortisol on memory. Our findings suggest that glucocorticoid effects on memory retrieval require testing-associated arousal in humans.     

Fractal dimension of the brain in neurodegenerative disease and dementia: A systematic review

Sensitive and specific antemortem biomarkers of neurodegenerative disease and dementia are crucial to the pursuit of effective treatments, required both to reliably identify disease and to track its progression. Atrophy is the structural magnetic resonance imaging (MRI) hallmark of neurodegeneration. However in most cases it likely indicates a relatively advanced stage of disease less susceptible to treatment as some disease processes begin decades prior to clinical onset. Among emerging metrics that characterise brain shape rather than volume, fractal dimension (FD) quantifies shape complexity. FD has been applied in diverse fields of science to measure subtle changes in elaborate structures. We review its application thus far to structural MRI of the brain in neurodegenerative disease and dementia. We identified studies involving subjects who met criteria for mild cognitive impairment, Alzheimer’s Disease, Vascular Dementia, Lewy Body Dementia, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson’s Disease, Huntington’s Disease, Multiple Systems Atrophy, Spinocerebellar Ataxia and Multiple Sclerosis. The early literature suggests that neurodegenerative disease processes are usually associated with a decline in FD of the brain. The literature includes examples of disease-related change in FD occurring independently of atrophy, which if substantiated would represent a valuable advantage over other structural imaging metrics. However, it is likely to be non-specific and to exhibit complex spatial and temporal patterns. A more harmonious methodological approach across a larger number of studies as well as careful attention to technical factors associated with image processing and FD measurement will help to better elucidate the metric’s utility.     

A role for the VLA-4 integrin in the activation of human memory B cells

It is generally recognized that activation through membrane effector molecules such as CD40 or the B cell receptor (BCR) is mandatory to allow B cells to proliferate and differentiate into antibody (Ab)-secreting cells in response to cytokines. We show here that purified tonsillar B cells can be stimulated directly by a cytokine combination to proliferate and secrete immunoglobulins when cultures are performed at high cell density. The contact-mediated activation of B cells in this experimental system is strongly inhibited both by anti-very late antigen (VLA)-4 monoclonal Ab and by a peptide containing the LDV sequence specifically recognized by the α4 integrin binding site. These reagents also significantly suppressed the B cell responses elicited by engagement of the BCR or CD40. Our data reveal that memory B cells but not virgin or germinal center B cells are sensitive to the direct stimulatory effect of cytokines in high-density cultures. Finally, we found that the dual expression of the α and β chains of VLA-4 is a distinctive feature of the memory B cell population. Collectively, our findings support the notion that VLA-4-dependent homotypic B cell interactions can mediate a co-stimulatory signal to human memory B cells and might participate in the B cell activation triggered through the BCR and CD40.     

Reorganization in the auditory cortex of the rat induced by intracortical microstimulation: a multiple single-unit study

Many manipulations are able to change or perturb various aspects of single neuron properties and interneuronal relationships. Changes of cerebral cortex organization have been observed in different cortical areas and at different time scales in relation to peripheral stimulation, peripheral damage, associative learning, and electrical stimulation. Here we describe studies on separable multineuron recordings in the rat's auditory cortex under two different anesthetics. Acoustic stimuli were used as a normal, physiological input, and weak electrical intracortical microstimulation (ICMS) as a perturbation that forces a rapid cortical reorganization. ICMS induced fast changes in the cortical map and in the receptive field properties of cells at the electrically stimulated and adjacent electrodes. In effect there was an enlargement of the cortical domain tuned to the acoustic frequency that had been represented at the stimulating electrode. ICMS also incremented afterdischarge responses; these consisted of an initial response to the auditory stimulus followed by less intense repetitive activity that was stimulus-time locked and had a period of 8–12 Hz, similar to that of the spontaneous synchronous activity. Cortical activity under ketamine differed from that under pentobarbital sodium, although in both situations we observed that cortical neurons were highly synchronous.     

Potentiation of changes in brain electrical activity in A constant magnetic field by means of metrazol

The effect of metrazol on changes in spontaneous and evoked electrical activity of the cerebral cortex, hypothalamus, and cerebellar cortex in a constant magnetic field (CMF) of intensity 500, 1000, and 4000 Oe was studied in experiments on rats. After preliminary injection of metrazol in a subconvulsant dose, the spontaneous rhythmic activity of the rats changes more sharply, the amplitude of the evoked potential increases considerably, and the number of additional phases in its structure rises. Potentiation of the effect of CMP by the analeptic action of metrazol points to the essential importance of the level of activation of the CNS in the response to the action of a magnetic field.(Presented by Academician of the Academy of Medical Sciences of the USSR. P. D. Gorizontov.) Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 87, No. 1, pp. 21–24, January, 1979.     

Saccharin aversion memory in rats: inhibition of cycloheximide-resistant memory by ouabain

Memory for saccharin aversion learning in rats was shown to persist for at least one hour when cerebral protein synthesis was inhibited by cycloheximide. By 4 hours after learning the level of retention had fallen to the amnesic levels seen 24 hours later. The amnesia seen at 24 hours was found to be dose dependent and a mass of 300 μg, administered intraventricularly, was adequate to produce maximum amnesia. When the labile memory inhibitor ouabain was administered 15 min before saccharin and LiCl, amnesia was seen in some rats at 1 hr, at the time when cycloheximide-insusceptible memory was still present. These results compare favorably to those seen in day-old-chickens where a sequentially dependent 3 phase model of memory has been formulated.     

Activation of influenza-specific memory cytotoxic T lymphocytes by Concanavalin A stimulation

Traditionally, the in vitro activation of virus-specific memory cytotoxic T lymphocytes (CTLs) has been achieved by stimulating the CTLs with antigen-presenting cells (APCs) infected with an appropriate virus or pulsed with virus-specific antigenic peptides. Here, we describe the utilization of the polyclonal activator Concanavalin A (ConA) for in vitro restimulation of memory CTLs from virus-primed mice. Using this simple method, the activation of splenocytes with ConA for 3 days (i) eliminates the need to stimulate with virus-pulsed APCs and (ii) generates CD8⁺ CTLs that exhibit virus specificity and MHC-restricted lytic activity similar to CTLs obtained by conventional viral restimulation. In vitro ConA stimulation of splenocytes from BALB/c mice primed with the A/Texas/77 or A/Japanese/57 strain of influenza virus and from C57L/J mice infected with the A/Texas strain, generated CTLs with specific lytic activity. Hence reactivation of memory CTLs by this method is a general phenomenon rather than a mouse or viral strain-specific one. The ConA stimulation method used here had a recall of long-term (1 year) memory CTLs that effectively lysed virally infected targets. Further ConA-stimulated effector lymphocytes from virally primed animals have been shown to recognize and subsequently lyse target cells pulsed with virus or virus-derived peptides. The ConA reactivation of specific anti-viral CTLs may facilitate (i) studying anti-viral CTL responses and (ii) identifying of viral epitopes when unknown or when appropriate viral stimulation is impossible.     

Maintenance of memory CTL responses by T helper cells and CD40-CD40 ligand: antibodies provide the key

Cytotoxic T lymphocytes (CTL) are essential for control of primary infections by many pathogens and in particular by non-cytopathic viruses. It has been proposed that long-term maintenance of CTL memory and control of lymphocytic choriomeningitis virus (LCMV) is dependent upon the presence of T helper cells and interaction of antigen-presenting cells and CTL via CD40 and its ligand CD40L. However, we demonstrate here that CD40-CD40L interaction maintains CTL memory by induction of virus-specific antibodies. In fact, loss of CTL memory responses and spread of virus in mice lacking CD40 or its ligand is prevented by repetitive therapeutic injections of LCMV-specific antibodies. This indicates that antibodies are essential for long-term control of non-cytopathic virus and to maintain protective memory. Transfer of neutralizing antibodies or induction of antibodies by therapeutic vaccination within weeks after infection may therefore prove beneficial for the treatment of chronic virus infections such as HIV, hepatitis B, and hepatitis C. See accompanying article http://dx.doi.org/10.1002/eji.200324844     

A systematic review of the mismatch negativity as an index for auditory sensory memory: From basic research to clinical and developmental perspectives

Auditory sensory memory is an important ability for successful language acquisition and processing. The mismatch negativity (MMN) in response to auditory stimuli has been proposed as an objective tool to measure the existence of auditory sensory memory traces. By increasing interstimulus intervals, attenuation of MMN peak amplitude and increased MMN peak latency have been suggested to reflect duration and decay of sensory memory traces. The aim of the present study is to conduct a systematic review of studies investigating sensory memory duration with MMN. Searches of electronic databases yielded 743 articles. Of these, 37 studies met final eligibility criteria. Results point to maturational changes in the time span of auditory sensory memory from birth on with a peak in young adulthood, as well as to a decrease of sensory memory duration in healthy aging. Furthermore, this review suggests that sensory memory decline is related to diverse neurological, psychiatric, and pediatric diseases, including Alzheimer's disease, alcohol abuse, schizophrenia, and language disorders. This review underlines that the MMN provides a unique window to the cognitive processes of auditory sensory memory. However, further studies combining electrophysiological and behavioral data, and further studies in clinical populations are needed, also on individual levels, to validate the MMN as a clinical tool for the assessment of sensory memory duration.     

Hyaluronan‐binding by CD44 reduces the memory potential of activated murine CD8 T cells

Expansion and death of effector CD8 T cells are regulated to limit immunopathology and cells that escape contraction go on to generate immunological memory. CD44, a receptor for the extracellular matrix component hyaluronan, is a marker of activated and memory T cells. Here, we show with a murine model that the increase in CD44 expression and hyaluronan binding induced upon CD8 T cell activation was proportional to the strength of TCR engagement, thereby identifying the most strongly activated T cells. When CD44^?/? and CD44^+/+ OT‐I CD8 T cells were adoptively transferred into mice challenged with Listeria‐OVA, there was a slight increase in the percentage of CD44^+/+ cells at the effector site. However, CD44^+/+ cells were out‐competed by CD44^?/? cells after the contraction phase in the lymphoid tissues, and the CD44^?/? cells preferentially formed more memory cells. The hyaluronan‐binding CD44^+/+ CD8 effector T cells showed increased pAkt expression, higher glucose uptake, and were more susceptible to cell death during the contraction phase compared to non‐binding CD44^+/+ and CD44^?/? OT‐I CD8 T cells, suggesting that CD44 and its engagement with hyaluronan skews CD8 T cells toward a terminal effector differentiation state that reduces their ability to form memory cells.     

Cross-reactive memory T cells for Epstein-Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major histocompatibility complex-bound peptide by T cells and its role in alloreactivity

In the present report, cytotoxic T lymphocyte (CTL) clones are described that display dual specificity for one of two common human leukocyte antigens (HLA B14 or B35) as alloantigens, and an immunodominant epitope (FLRGRAYGL) from Epstein-Barr virus (EBV) that binds to HLA B8. These T cell clonotypes were isolated from several unrelated HLA B8⁺, EBV-exposed individuals, and each distinct cross-reactivity pattern was associated with a common, public T cell receptor (TCR). In some individuals, CTL cross-reactive with these alloantigens completely dominated the memory response to this EBV epitope. Moreover, these memory T cells to EBV could be reactivated as a significant component of the repertoire of CTL responding to allogeneic stimulator cells expressing either HLA B14 or B35. These data illustrate how a history of infection with an immunogenic virus such as EBV can augment responsiveness to particular alloantigens; such influences may underlie the observed clinical association between herpesvirus infection and both allograft rejection and graft-versus-host disease. We have also explored the molecular basis for T cell cross-reactivity with alloantigens using the HLA B35 allo-reactive CTL clonotype. To elucidate the structural features of peptides that may be cross-recognized by these T cells, mono-substituted analogs of the viral epitope were screened for recognition, revealing broad specificity for major histocompatibility complex (MHC)-bound peptide. Based on the particular amino acid changes tolerated by the CTL at each peptide position, the human protein sequence database was searched for possible sequences that were recognized in association with HLA B35. Four peptides were identified (MPEATVYGL, IPIAPVYGM, KPSPPYFGL, and KPIVVLHGY) that were powerful activating ligands for the CTL when presented on HLA B35 but not B8. Thus, equivalent epitopes, capable of fully activating a single TCR, were formed by peptides with minimal obvious sequence homology bound to either HLA B8 or B35. These data indicate that degenerate peptide recognition by TCR may play an important role in the vigorous response of self-MHC-restricted T cells to alloantigens.