Memory-related Tasks Research Articles

Reduced conditioned fear response in mice that lack Dlx1 and show subtype-specific loss of interneurons.

The inhibitory GABAergic system has been implicated in multiple neuropsychiatric diseases such as schizophrenia and autism. The Dlx homeobox transcription factor family is essential for development and function of GABAergic interneurons. Mice lacking the Dlx1 gene have postnatal subtype-specific loss of interneurons and reduced IPSCs in their cortex and hippocampus. To ascertain consequences of these changes in the GABAergic system, we performed a battery of behavioral assays on the Dlx1 mutant mice, including zero maze, open field, locomotor activity, food intake, rotarod, tail suspension, fear conditioning assays (context and trace), prepulse inhibition, and working memory related tasks (spontaneous alteration task and spatial working memory task). Dlx1 mutant mice displayed elevated activity levels in open field, locomotor activity, and tail suspension tests. These mice also showed deficits in contextual and trace fear conditioning, and possibly in prepulse inhibition. Their learning deficits were not global, as the mutant mice did not differ from the wild-type controls in tests of working memory. Our findings demonstrate a critical role for the Dlx1 gene, and likely the subclasses of interneurons that are affected by the lack of this gene, in behavioral inhibition and associative fear learning. These observations support the involvement of particular components of the GABAergic system in specific behavioral phenotypes related to complex neuropsychiatric diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s11689-009-9025-8) contains supplementary material, which is available to authorized users.

Soya isoflavone supplementation enhances spatial working memory in men

Females perform better in certain memory-related tasks than males. Sex differences in cognitive performance may be attributable to differences in circulating oestrogen acting on oestrogen beta receptors (ERbeta) which are prevalent in brain regions such as the hippocampus, frontal lobe and cortex that mediate cognitive functions. Since soya isoflavones are known to activate ERbeta, chronic isoflavone supplementation in males may improve cognitive performance in memory-related tasks. A 12-week double-blind, placebo-controlled cross-over trial was conducted in thirty-four healthy men to investigate the effect of isoflavone supplementation on cognitive function. Volunteers were randomised to take four capsules/d containing soya isoflavones (116 mg isoflavone equivalents/d: 68 mg daidzein, 12 mg genistein, 36 mg glycitin) or placebo for 6 weeks, and the alternate treatment during the following 6 weeks. Assessments of memory (verbal episodic, auditory and working), executive function (planning, attention, mental flexibility) and visual-spatial processing were performed at baseline and after each treatment period. Isoflavone supplementation significantly improved spatial working memory (P = 0.01), a test in which females consistently perform better than males. Compared with placebo supplementation, there were 18 % fewer attempts (P = 0.01), 23 % fewer errors (P = 0.02) and 17 % less time (P = 0.03) required to correctly identify the requisite information. Isoflavones did not affect auditory and episodic memory (Paired Associate Learning, Rey's Auditory Verbal Learning Task, Backward Digit Span and Letter-Number Sequencing), executive function (Trail Making and Initial Letter Fluency Task) or visual-spatial processing (Mental Rotation Task). Isoflavone supplementation in healthy males may enhance cognitive processes which appear dependent on oestrogen activation.

Androgens and Alzheimer's disease

To discuss the relationship between androgens, cognition and Alzheimer's disease. It has been found that low circulating levels of androgens are a risk factor for Alzheimer's disease. Decreased circulating androgens are also associated with declining cognitive performance, particularly in memory-related tasks. Conversely, androgen supplementation to hypogonadal men results in improved memory performance. It has therefore been hypothesized that androgen supplementation may be beneficial in Alzheimer's disease. In recent studies, animal models have been used to elucidate the molecular mechanism behind this relationship between androgens and Alzheimer's disease. These studies have shown that androgen depletion results in increased levels of beta amyloid and hyperphosphorylated tau, changes which are thought to be associated with subsequent neuronal death. Androgen depletion results in molecular changes associated with Alzheimer's disease. Further human trials are needed to determine whether androgen modulating therapy for Alzheimer's disease has clinical significance.

Effects of chronic manganese exposure on working memory in non-human primates

Human exposure to manganese (Mn) has been associated with a variety of cognitive deficits including learning and memory deficits. However, results from epidemiological studies have been inconsistent in describing the nature of such cognitive deficits. The present study was conducted to evaluate the effects of chronic Mn exposure on memory functioning in non-human primates and to correlate behavioral outcome with brain Mn levels in an attempt to explain outcome variability seen in prior studies. Cynomolgus macaque monkeys were trained to perform memory-related tasks (spatial working memory, non-spatial working memory, reference memory) and exposed to manganese sulfate (15–20 mg/kg/week) over an exposure period lasting 227.5 ± 17.3 days. Blood manganese levels were in the upper range of levels reported for human environmental, medical or occupational exposures. By the end of the manganese exposure period, animals developed mild deficits in spatial working memory, more significant deficits in non-spatial working memory and no deficits in reference memory. Linear regression analyses showed that for most brain regions sampled, there was a significant inverse relationship between working memory task performance and brain Mn concentration. These results suggest that chronic exposure to levels of manganese achieved in this study may have detrimental effects on working memory and that Mn levels achieved in several brain regions are inversely related to working memory performance.

Transverse patterning dissociates human EEG theta power and hippocampal BOLD activation

Theta oscillations (4-8 Hz) are often modulated in human electroencephalogram (EEG) studies of memory, whereas overlapping frequencies dominate rodent hippocampal EEG. An emerging parallelism between theta reactivity and hippocampal functional magnetic resonance imaging activation has suggested a homology between theta activity in humans and rodents, representing a process of cortico-hippocampal interaction involved in memory. In the present study, we investigated EEG reactivity during performance of a relational memory task that induces a negative hippocampal blood oxygenation level dependent (BOLD) signal change, compared to a nonrelational control condition. Relational trials induced theta increases and alpha decreases. Low Resolution Electromagnetic Brain Tomography estimates localized theta and alpha modulation to frontal midline and parietal midline cortices, respectively, both of which exhibit negative BOLD responses in this task. Thus, theta and alpha dynamics are dissociable from positive BOLD activation, and may, in fact, colocalize with negative BOLD responses.

Role of the Central Cholinergic System in the Therapeutics of Schizophrenia

The therapeutic agents currently used to treat schizophrenia effectively improve psychotic symptoms; however, they are limited by adverse effects and poor efficacy when negative symptoms of the illness and cognitive dysfunction are considered. While optimal pharmacotherapy would directly target the neuropathology of schizophrenia neither the underlying neurobiological substrates of the behavioral symptoms nor the cognitive deficits have been clearly established. Abnormalities in the neurotransmitters dopamine, serotonin, glutamate, and GABA are commonly implicated in schizophrenia; however, it is not uncommon for alterations in the brain cholinergic system (e.g., choline acetyltransferase, nicotinic and muscarinic acetylcholine receptors) to also be reported. Further, there is now considerable evidence in the animal literature to suggest that both first and second generation antipsychotics (when administered chronically) can alter the levels of several cholinergic markers in the brain as well as impair memory-related task performance. Given the well-established importance of central cholinergic neurons to information processing and cognition, it is important that cholinergic function in schizophrenia be further elucidated and that the mechanisms of the chronic effects of antipsychotic drugs on this important neurotransmitter system be identified. A better understanding of these mechanisms would be expected to facilitate optimal treatment strategies for schizophrenia as well as the identification of novel therapeutic targets. In this review, the following topics are discussed: 1) the central cholinergic system in schizophrenia 2) effects of antipsychotic drugs on central cholinergic neurons 3) important neurotrophins in schizophrenia, especially those that support central cholinergic neurons; 4) novel strategies to optimize the therapeutics of schizophrenia via the use of cholinergic compounds as primary (i.e., antipsychotic) treatments as well as adjunctive, pro-cognitive agents.

Auditory processing indexed by stimulus-induced alpha desynchronization in children

By means of magnetoencephalography (MEG), we investigated event-related synchronization and desynchronization (ERS/ERD) in auditory cortex activity, recorded from twelve children aged four to six years, while they passively listened to a violin tone and a noise-burst stimulus. Time–frequency analysis using Wavelet Transform was applied to single-trials of source waveforms observed from left and right auditory cortices. Stimulus-induced changes in non-phase-locked activities were evident. ERS in the beta range (13–30 Hz) lasted only for 100 ms after stimulus onset. This was followed by prominent alpha ERD, which showed a clear dissociation between the upper (12 Hz) and lower (8 Hz) alpha range in both left and right auditory cortices for both stimuli. The time courses of the alpha ERD (onset around 300 ms, peak at 500 ms, offset after 1500 ms) were similar to those previously found for older children and adults with auditory memory related tasks. For the violin tone only, the ERD lasted longer in the upper than the lower alpha band. The findings suggest that induced alpha ERD indexes auditory stimulus processing in children without specific cognitive task requirement. The left auditory cortex showed a larger and longer-lasting upper alpha ERD than did the right auditory cortex, likely reflecting hemispheric differences in maturational stages of neural oscillatory mechanisms.

Increased binding potential of [11C]raclopride during unilateral continuous microinjection of nicotine in rat striatum observed by positron emission tomography

Nicotine injections and nicotine skin patches significantly improve attention, memory, and learning in Alzheimer's disease. In animal studies, nicotine improves the performance of various memory-related tasks, an effect that is thought to be mediated by the neuronal dopaminergic system as systemic administration of nicotine decreased [(11)C]raclopride binding in the anesthetized state. Since high doses of systemically administered nicotine are harmful, we administrated it directly into the rat striatum via microdialysis. We then examined the acute effects of continuous central administration of high doses of nicotine on striatal dopamine concentrations by measuring [(11)C]raclopride binding by positron emission tomography. The concentration of dopamine in the dialysates was significantly increased from basal levels when microdialysis with 100 mM nicotine was initiated. However, contrary to expectations, the binding potential (BP) of [(11)C]raclopride in the nicotine-perfused striatum was significantly higher than that in control striatum. Preinjection of mecamylamine (3 mg/kg), a nicotinic antagonist, had no effect on either extracellular dopamine levels or on the BP of [(11)C]raclopride. These findings suggest that the high dose of local nicotine administration induced mecamylamine-insensitive local increases in extracellular dopamine, but might have decreased the total amount of extracellular dopamine in the striatum.

The effects of JWB1-84-1 on memory-related task performance by amyloid Aβ transgenic mice and by young and aged monkeys

JWB1-84-1 is one of 50 tertiary amine analogs of choline synthesized with expectation that they would be high potency compounds for cytoprotection. As one of the more potent analogs in this regard, JWB1-84-1, a piperazine derivative, was selected for testing as a cognition-enhancing agent. The compound was evaluated for efficacy in Alzheimer's disease transgenic mice (B6C3-Tg(APPswe, PSEN1dE9)85Dbo/J). A separate cohort of mice (AD Tg) were first subjected to a behavioral test battery in which the transgenic strain was compared with the wild-type strain. AD Tg mice were shown to exhibit specific deficits in the acquisition of a working memory (5-trial/session radial arm water maze, RAWM) task at a time when the animals exhibited maximal cerebral amyloid burden. JWB1-84-1 produced a dose-dependent decrease in the number of errors made by well trained AD-Tg mice the RAWM task that was maximal after the 20 μg/kg dose. Aged macaques (20–32 y) were trained to proficiency in their performance of a computer-assisted delayed matching-to-sample task. Vehicle (normal saline) or JWB1-84-1 (5–150 μg/kg, i.m.) was administered 10 min before the initiating of testing. On average, JWB1-84-1 treatment significantly improved task accuracy after all but the lowest dose. The maximal degree of improvement was attained after animals received the 100 μg/kg dose. The drug's effects were restricted primarily to Medium and Long delay trials – the most difficult portions of the task, which were improved by up to 18% above control. In young macaques JWB1-84-1 treatment also significantly reversed the decrements in task accuracy associated with the random presentation of a task distractor. Thus JWB1-84-1exhibits the potential for treating the cognitive symptoms associated with neurodegenerative diseases and attention deficit disorders. Its cytoprotective action might also work to slow the progression of Alzheimer's disease.

Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy

To explore the relationship of regional cerebral blood flow and metabolism with cognitive function and past exposure to chemotherapy for breast cancer. Subjects treated for breast cancer with adjuvant chemotherapy remotely (5-10 years previously) were studied with neuropsychologic testing and positron emission tomography (PET), and were compared with control subjects who had never received chemotherapy. [O-15] water PET scans was acquired during performance of control and memory-related tasks to evaluate cognition-related cerebral blood flow, and [F-18] fluorodeoxyglucose (FDG) PET scans were acquired to evaluate resting cerebral metabolism. PET scans were analyzed by statistical parametric mapping and region of interest methods of analysis. During performance of a short-term recall task, modulation of cerebral blood flow in specific regions of frontal cortex and cerebellum was significantly altered in chemotherapy-treated subjects. Cerebral activation in chemotherapy-treated subjects differed most significantly from untreated subjects in inferior frontal gyrus, and resting metabolism in this area correlated with performance on a short-term memory task previously found to be particularly impaired in chemotherapy-treated subjects. In examining drug-class specific effects, metabolism of the basal ganglia was significantly decreased in tamoxifen + chemotherapy-treated patients compared with chemotherapy-only breast cancer subjects or with subjects who had not received chemotherapy, while chemotherapy alone was not associated with decreased basal ganglia activity relative to untreated subjects. Specific alterations in activity of frontal cortex, cerebellum, and basal ganglia in breast cancer survivors were documented by functional neuroimaging 5-10 years after completion of chemotherapy.

Time-Dependent Cognitive Deficits Associated with First and Second Generation Antipsychotics: Cholinergic Dysregulation as a Potential Mechanism

Although cognitive dysfunction is considered one of the more debilitating symptoms of schizophrenia, there is a fundamental gap in our knowledge of how the primary pharmacologic treatments of this disease, first- and second-generation antipsychotics (FGAs and SGAs, respectively), affect cognition, particularly over extended periods of time. Moreover, it has been known for decades that chronic treatment with FGAs can lead to imbalances in cholinergic function in the striatum that result in movement disorders; however, there is a growing body of evidence to suggest that both FGAs and SGAs can lead to cholinergic alterations in brain areas more traditionally considered as memory-related, such as cortical and hippocampal regions. Data from our laboratories in rodents indicate that some SGAs (if administered for sufficient periods of time) can be associated with impairments in memory-related task performance as well as alterations in the cholinergic enzyme choline acetyltransferase, the vesicular acetylcholine transporter, and nicotinic (alpha(7)) and muscarinic (M(2)) acetylcholine receptors. Given the well documented importance of central cholinergic function to information processing and cognitive function, it is important that the mechanisms for such chronic antipsychotic effects be identified. In this review, two potential mechanisms for long-term antipsychotic-related cholinergic alterations in the central nervous system are discussed: 1) antipsychotic antagonist activity at dopaminergic-D(2) receptors on cholinergic neurons and 2) antipsychotic effects on neurotrophins that support cholinergic neurons, such as nerve growth factor and brain derived growth factor. Novel strategies to optimize the therapeutics of schizophrenia and maintain cognitive function via adjunctive cholinergic compounds and antipsychotic crossover approaches are also discussed.

Discrepancy of performance among working memory‐related tasks in autism spectrum disorders was caused by task characteristics, apart from working memory, which could interfere with task execution

Working memory performance has been inconsistently reported in autism spectrum disorders (ASD). Several studies in ASD have found normal performance in digit span and poor performance in digit symbol task although these are closely related with working memory. It is assumed that poor performance in digit symbol could be explained by confirmatory behavior, which is induced due to the vague memory representation of number-symbol association. Therefore it was hypothesized that the performance of working memory task, in which vagueness did not cause confirmatory behavior, would be normal in ASD. For this purpose, the Advanced Trail Making Test (ATMT) was used. The performance of digit span, digit symbol and ATMT was compared between ASD and normal control. The digit span, digit symbol and ATMT was given to 16 ASD subjects and 28 IQ-, age- and sex-matched control subjects. The scores of these tasks were compared. A significantly lower score for ASD was found only in digit symbol compared with control subjects. There were no significant difference in digit span and working memory estimated by ATMT. Discrepancy of scores among working memory-related tasks was demonstrated in ASD. Poor digit symbol performance, normal digit span and normal working memory in ATMT implied that ASD subjects would be intact in working memory itself, and that superficial working memory dysfunction might be observed due to confirmatory behavior in digit symbol. Therefore, to evaluate working memory in ASD, tasks that could stimulate psychopathology specific to ASD should be avoided.

EEG MARKERS FOR COGNITIVE DECLINE IN ELDERLY SUBJECTS WITH SUBJECTIVE MEMORY COMPLAINTS

New treatments for Alzheimer's disease require early detection of cognitive decline. Most studies seeking to identify markers of early cognitive decline have focused on a limited number of measures. We sought to establish the profile of brain function measures which best define early neuropsychological decline. We compared subjects with subjective memory complaints to normative controls on a wide range of EEG derived measures, including a new measure of event-related spatio-temporal waves and biophysical modeling, which derives anatomical and physiological parameters based on subject's EEG measurements. Measures that distinguished the groups were then related to cognitive performance on a variety of learning and executive function tasks. The EEG measures include standard power measures, peak alpha frequency, EEG desynchronization to eyes-opening, and global phase synchrony. The most prominent differences in subjective memory complaint subjects were elevated alpha power and an increased number of spatio-temporal wave events. Higher alpha power and changes in wave activity related most strongly to a decline in verbal memory performance in subjects with subjective memory complaints, and also declines in maze performance and working memory reaction time. Interestingly, higher alpha power and wave activity were correlated with improved performance in reverse digit span in the subjective memory complaint group. The modeling results suggest that differences in the subjective memory complaint subjects were due to a decrease in cortical and thalamic inhibitory gains and slowed dendritic time-constants. The complementary profile that emerges from the variety of measures and analyses points to a nonlinear progression in electrophysiological changes from early neuropsychological decline to late-stage dementia, and electrophysiological changes in subjective memory complaint that vary in their relationships to a range of memory-related tasks.

Temporal dynamics of age-related differences in auditory incidental verbal learning

Auditory response profiles for a group of ten healthy young and ten healthy elderly subjects, evoked by implicit memory and delayed verbal recognition tasks, were evaluated to determine if effects of stimulus repetition could be identified in the superior temporal gyrus (STG) and prefrontal cortical regions. We hypothesized that effects of stimulus repetition should occur both early in time and at early levels of the nervous system (STG) followed by later effects in prefrontal regions. Magnetoencephalographic (MEG) responses were recorded using a whole-head MEG system and automated, multi-start analysis methods were applied to the data in order to characterize the temporal response profiles from distributed but focal, cortical regions engaged in memory-related tasks. The findings revealed a main effect of age for early activity (∼50 ms) in STG which appeared to be nonspecific for Old/New words and an Age × Task interaction for late activity (∼100–800 ms) in STG which was specific to Old/New words. Although the behavioral performance measures did not reveal traditional effects of response priming, the MEG measures did reveal a reduction in amplitude with stimulus repetition in young subjects. The elderly did not reveal a reduction in amplitude concomitant with stimulus repetition for either the global attributes of words or for specific Old/New words. Long duration effects of stimulus repetition noted in the present study raise the possibility that results from sensory gating, mismatch negativity and P300 paradigms may represent a continuum of stimulus repetition effects. Two of these paradigms evoke greater enhancement to novel or infrequent stimuli, or rather, greater reduction of amplitude with repetition.

The temporal context model in spatial navigation and relational learning: toward a common explanation of medial temporal lobe function across domains.

The medial temporal lobe (MTL) has been studied extensively at all levels of analysis, yet its function remains unclear. Theory regarding the cognitive function of the MTL has centered along 3 themes. Different authors have emphasized the role of the MTL in episodic recall, spatial navigation, or relational memory. Starting with the temporal context model (M. W. Howard & M. J. Kahana, 2002a), a distributed memory model that has been applied to benchmark data from episodic recall tasks, the authors propose that the entorhinal cortex supports a gradually changing representation of temporal context and the hippocampus proper enables retrieval of these contextual states. Simulation studies show this hypothesis explains the firing of place cells in the entorhinal cortex and the behavioral effects of hippocampal lesion in relational memory tasks. These results constitute a first step toward a unified computational theory of MTL function that integrates neurophysiological, neuropsychological, and cognitive findings.

Medial prefrontal cortex cells show dynamic modulation with the hippocampal theta rhythm dependent on behavior

Both the hippocampus and the medial prefrontal cortex are essential for successful performance in learning- and memory-related tasks. Within the hippocampus the theta rhythm plays an integral role in the timing of action potentials of hippocampal neurons responding to elements of any given task. Medial prefrontal cortex (mPFC) neurons display firing rate changes to specific facets of behavioral tasks (Jung et al., 1998. Cereb Cortex 8:437--450). We recorded units in the mPFC and field potentials in the hippocampus to determine whether behaviorally correlated mPFC cells fired with phase relationships to the hippocampal theta rhythm. In two different behavioral tasks (running a linear track and foraging in two distinct environments) we found mPFC cells that alternated between theta entrained firing and nonphasic firing depending on the ongoing behavior, while other cells were modulated during all conditions in both tasks. The majority of the mPFC cells with a significant correlation of firing rate changes with behavior were entrained to hippocampal theta. Cells that fired to specific events during only one direction of running were predisposed to theta modulation only in that direction. mPFC neurons have the capability to respond to behaviorally relevant elements by dynamically alternating between hippocampal theta entrained and nonphasic firing.

Novel nonparametric approach to canonical correlation analysis with applications to low CNR functional MRI data.

Detection of activation in functional MRI (fMRI) is often complicated by the low contrast-to-noise ratio (CNR) in the data. The primary source of the difficulty is the fact that for activities that are subtle the signal can be hidden inside the inherent noise in the data. Classical univariate methods based on t-test or F-test are susceptible to noise, as they fail to harness systematic correlations in evoked responses within neighboring voxels. Here the power of a multivariate statistical analysis tool known as canonical correlation analysis (CCA) in fMRI studies is demonstrated where the CNR is low. As a further illustration of the power of the method, a comparative study of CCA and ordinary correlation analysis using simulated data under various noise levels is also performed. A novel nonparametric approach is introduced to calculate the P-values from the distribution of the complicated test statistic. The circumstances under which CCA is a better performer as well as when it is not the case are discussed. As an example, this method is applied to detect hippocampal activation from memory-related tasks.

Neural Mechanism of Implicit and Explicit Memory Retrieval: Functional MR Imaging

Purpose: To identify, using functional MR imaging, distinct cerebral centers and to evaluate the neural mechanism associated with implicit and explicit retrieval of words during conceptual processing. Materials and Methods: Seven healthy volunteers aged 21-25 (mean, 22) years underwent BOLD-based fMR imaging using a 1.5T Signa Horizon Echospeed MR system. To activate the cerebral cortices, a series of tasks was performed as follows: the encoding of two-syllable words, and implicit and explicit retrieval of previously learned words during conceptual processing. The activation paradigm consisted of a cycle of alternating periods of 30 seconds of stimulation and 30 seconds of rest. Stimulation was accomplished by encoding eight twosyllable words and the retrieval of previously presented words, while the control condition was a white screen with a small fixed cross. During the tasks we acquired ten slices (6 mm slice thickness, 1 mm gap) parallel to the AC-PC line, and the resulting functional activation maps were reconstructed using a statistical parametric mapping program (SPM 99). Results: A comparison of activation ratios (percentages), based on the number of volunteers, showed that activation of Rhs-35, PoCiG-23 and ICiG-2630 was associated with explicit retrieval only; other brain areas were activated during the performance of both implicit and explicit retrieval tasks. Activation ratios were higher for explicit tasks than for implicit; in the cingulate gyrus and temporal lobe they were 30% and 10% greater, respectively. During explicit retrieval, a distinct brain activation index (percentage) was seen in the temporal, parietal, and occipital lobe and cingulate gyrus, and PrCeG-4, Pr/PoCeG-43 in the frontal lobe. During implicit retrieval, on the other hand, activity was greater in the frontal lobe, including the areas of SCA-25, SFG/MFG-10, IFG-4445, OrbG-1147, SFG-68, and MFG-946. Overall, activation was lateralized mainly in the left hemisphere during both implicit and explicit retrieval tasks. For explicit retrieval, the lateralization index was more than twice as high as for implicit retrieval. Conclusion: Our findings indicate that there is neuro-anatomical dissociation between implicit and explicit retrieval of words during conceptual processing, suggesting, on the basis of cognitive neuroscience, that the performance of implicit and explicit memory-related tasks involves different mechanisms.

Changes of attention and memory in a group of patients with multiple sclerosis

Cognitive impairment was observed in patients with multiple sclerosis (MS), not only in the later phase of the disease, but also early in the disease [1 /3]. There is no evidence that its occurrence has been a consequence of depression, mood changes, or fatigue after physical exercise. Furthermore, a certain degree of cognitive impairment may occur without any major physical disability symptoms in these patients [4]. The most frequently observed disturbances of cognitive functions in patients with MS were those of shortterm memory and sustaining of attention, followed by conceptual thinking problems and verbal fluency disorder [5]. The nature of attention-related problems in MS has not been definitely explained by previous investigations [5 /9]. Several methods were used to assess different aspects of attention in those patients (paced auditory serial addition test (PASAT), the Stroop test, Sternberg memory scanning test, vigilance tasks auditory As and auditory trails A tests). Working memory, which is a part of short-term memory processes, is closely associated with visual and auditory attention systems [10]. Disturbances of explicit memory in patients in the early and middle phases of MS were observed both on verbal and non-verbal tasks [11]. According to Litvan et al. [12] the short-term memory performance in patients with MS is generally intact, except for the retrieval of data, measured through digit-retention capacity. On the other hand, deficit of digit retention capacity has been reported to exist in patients with less than 2 years’ duration of illness [13]. Few studies on implicit memory [14,15] suggested that patients with MS would perform normally on a motor skill task and priming. The aim of this investigation was to assess the cognitive performance of patients with MS on attentionand memory-related tasks. The contributions of patients’ clinical and demographic characteristics to their cognitive performance were also analyzed in the present study.

Protractive effects of chronic treatment with an acutely sub-toxic regimen of diisopropylflurophosphate on the expression of cholinergic receptor densities in rats

Individuals chronically exposed to low levels of organophosphate insecticides may present with subtle impairments in cognition. In addition, low level diisopropylflurophosphate (DFP) exposure (0.25 mg/kg per day for 2 weeks) in rats resulted in protracted working memory impairment [29]. The current studies attempt to show a temporal relationship between the DFP-induced impairment in performance of a spatial memory task and the protracted decrease in the expression of cholinergic receptors and acetylcholinesterase in specific brain regions. Cholinergic receptors labeled with the ligands [ 3H]epibatidine and [ 3H]AFDX-384 were affected to a much greater extent and for a longer period of time than were both acetylcholinesterase activities and cholinergic receptors labeled with [ 3H]QNB. Pre-testing administration of nicotine was shown to completely reverse this DFP-induced impairment in memory-related task performance. Additionally, prophylaxis with pyridostigmine bromide (PB) caused DFP-treated animals to exhibit near normal levels of memory-related task performance. These results are consistent with the development of a protracted phase of learning impairment to sub-acute DFP exposure, which may involve the loss of hippocampal nicotinic receptors, and may be prevented or reversed by PB or nicotine, respectively.