Differential effects of aging on dendritic spines in visual cortex and prefrontal cortex of the rhesus monkey.

Aging decreases the density of spines and the proportion of thin spines in the non-human primate (NHP) dorsolateral prefrontal cortex (dlPFC). In this study, we used confocal imaging of dye-loaded neurons to expand upon previous results regarding the effects of aging on spine density and morphology in the NHP dlPFC and compared these results to the effects of aging on pyramidal neurons in the primary visual cortex (V1). We confirmed that spine density, and particularly the density of thin spines, decreased with age in the dlPFC of rhesus monkeys. Furthermore, the average head diameter of non-stubby spines in the dlPFC was a better predictor than chronological age of the number of trials required to reach criterion on both the delayed response test of visuospatial working memory and the delayed nonmatching-to-sample test of recognition memory. By contrast, total spine density was lower on neurons in V1 than in dlPFC, and neither total spine density, thin spine density, nor spine size in V1 was affected by aging. Our results highlight the importance and selective vulnerability of dlPFC thin spines for optimal prefrontal-mediated cognitive function. Understanding the nature of the selective vulnerability of dlPFC thin spines as compared to the resilience of thin spines in V1 may be a promising area of research in the quest to prevent or ameliorate age-related cognitive decline.

Time domain measures of inter-channel EEG correlations: a comparison of linear, nonparametric and nonlinear measures.

Correlations between ten-channel EEGs obtained from thirteen healthy adult participants were investigated. Signals were obtained in two behavioral states: eyes open no task and eyes closed no task. Four time domain measures were compared: Pearson product moment correlation, Spearman rank order correlation, Kendall rank order correlation and mutual information. The psychophysiological utility of each measure was assessed by determining its ability to discriminate between conditions. The sensitivity to epoch length was assessed by repeating calculations with 1, 2, 3, …, 8 s epochs. The robustness to noise was assessed by performing calculations with noise corrupted versions of the original signals (SNRs of 0, 5 and 10 dB). Three results were obtained in these calculations. First, mutual information effectively discriminated between states with less data. Pearson, Spearman and Kendall failed to discriminate between states with a 1 s epoch, while a statistically significant separation was obtained with mutual information. Second, at all epoch durations tested, the measure of between-state discrimination was greater for mutual information. Third, discrimination based on mutual information was more robust to noise. The limitations of this study are discussed. Further comparisons should be made with frequency domain measures, with measures constructed with embedded data and with the maximal information coefficient.

Alterations of white matter tracts following neurotoxic hippocampal lesions in macaque monkeys: a diffusion tensor imaging study.

Diffusion tensor imaging (DTI) is a valuable tool for assessing presumptive white matter alterations in human disease and animal models. The current study used DTI to examine the effects of selective neurotoxic lesions of the hippocampus on major white matter tracts and anatomically related brain regions in macaque monkeys. Two years postlesion, structural MRI, and DTI sequences were acquired for each subject. Volumetric assessment revealed a substantial reduction in the size of the hippocampus in experimental subjects, averaging 72% relative to controls, without apparent damage to adjacent regions. DTI images were processed to yield measures of fractional anisotropy (FA), apparent diffusion coefficient (ADC), parallel diffusivity (lADC), and perpendicular diffusivity (tADC), as well as directional color maps. To evaluate potential changes in major projection systems, a region of interest (ROI) analysis was conducted including the corpus callosum, fornix, temporal stem, cingulum bundle, ventromedial prefrontal white matter, and optic radiations. Lesion-related abnormalities in the integrity of the fiber tracts examined were limited to known hippocampal circuitry, including the fornix and ventromedial prefrontal white matter. These findings are consistent with the notion that hippocampal damage results in altered interactions with multiple memory-related brain regions, including portions of the prefrontal cortex.

Statistical validation of mutual information calculations: comparison of alternative numerical algorithms.

Given two time series X and Y , their mutual information, I (X,Y) = I (Y,X) , is the average number of bits of X that can be predicted by measuring Y and vice versa. In the analysis of observational data, calculation of mutual information occurs in three contexts: identification of nonlinear correlation, determination of an optimal sampling interval, particularly when embedding data, and in the investigation of causal relationships with directed mutual information. In this contribution a minimum description length argument is used to determine the optimal number of elements to use when characterizing the distributions of X and Y . However, even when using partitions of the X and Y axis indicated by minimum description length, mutual information calculations performed with a uniform partition of the XY plane can give misleading results. This motivated the construction of an algorithm for calculating mutual information that uses an adaptive partition. This algorithm also incorporates an explicit test of the statistical independence of X and Y in a calculation that returns an assessment of the corresponding null hypothesis. The previously published Fraser-Swinney algorithm for calculating mutual information includes a sophisticated procedure for local adaptive control of the partitioning process. When the Fraser and Swinney algorithm and the algorithm constructed here are compared, they give very similar numerical results (less than 4% difference in a typical application). Detailed comparisons are possible when X and Y are correlated jointly Gaussian distributed because an analytic expression for I (X,Y) can be derived for that case. Based on these tests, three conclusions can be drawn. First, the algorithm constructed here has an advantage over the Fraser-Swinney algorithm in providing an explicit calculation of the probability of the null hypothesis that X and Y are independent. Second, the Fraser-Swinney algorithm is marginally the more accurate of the two algorithms when large data sets are used. With smaller data sets, however, the Fraser-Swinney algorithm reports structures that disappear when more data are available. Third, the algorithm constructed here requires about 0.5% of the computation time required by the Fraser-Swinney algorithm.

Dynamical analysis reveals individuality of locomotion in goldfish.

Goldfish swimming was analysed quantitatively to determine if it exhibits distinctive individual spatio-temporal patterns. Due to the inherent variability in fish locomotion, this hypothesis was tested using five nonlinear measures, complemented by mean velocity. A library was constructed of 75 trajectories, each of 5 min duration, acquired from five fish swimming in a constant and relatively homogeneous environment. Three nonlinear measures, the 'characteristic fractal dimension' and 'Richardson dimension', both quantifying the degree to which a trajectory departs from a straight line, and 'relative dispersion', characterizing the variance as a function of the duration, have coefficients of variation less than 7%, in contrast to mean velocity (30%). A discriminant analysis, or classification system, based on all six measures revealed that trajectories are indeed highly individualistic, with the probability that any two trajectories generated from different fish are equivalent being less than 1%. That is, the combination of these measures allows a given trajectory to be assigned to its source with a high degree of confidence. The Richardson dimension and the 'Hurst exponent', which quantifies persistence, were the most effective measures.

Contribution of ovarian steroid production to urinary estrone conjugate concentrations in Macaca mulatta.

This study was designed to test the hypothesis that basal estrone conjugate (E1C) profiles do not accurately detect ovarian function when ovarian estrogen production is low or absent. We employed surgical removal of active ovaries from laboratory rhesus macaques to simulate an acute decline in ovarian estrogen production. In the first experiment, urine samples collected prior to and following ovariectomy (Ovx) were subjected to high-performance liquid chromatography (HPLC) separation. Eluates were then assayed for E1C immunoreactive components. The results indicated a modest decrease in total immunoreactive polar conjugates following ovariectomy, with no substantial change in the overall retention profile. In the second experiment, estradiol (E2) cypionate injections were used to replace the E2 component of ovarian estrogen production in the treated (Tx) group, while the control group (C) received only vehicle. Urine samples were hydrolyzed and individual estrogens were separated by celite chromatography prior to immuno-assay. Both the Tx and C groups exhibited similar urinary excretion levels of estrone (E1), E2, and E1C prior to Ovx (Pre-Ovx) and after Ovx (Post-Ovx), but there were significant differences between groups after treatment (Post-Tx). Significant differences were observed in the Tx group's excretion of E1, E2, and E1C in the Pre- vs. Post-Ovx samples and in the Post-Ovx and Post-Tx samples. The C group also showed the expected significant differences in the Pre- vs. Post-Ovx samples, as well as in the Pre-Ovx and Post-Tx samples. The results indicate that the use of E1C measurements is clearly a suitable method for monitoring ovarian function in intact, cycling animals, but urinary E2 measurements are required to verify loss of follicular activity.

[Bilateral uveitis with definitive hypotony caused by systemic cidofovir]. / Uvéite bilatérale et hypotonie définitive due au cidofovir intraveineux. A propos d'un cas.

We report the case of a 52-year-old man with AIDS and CMV bilateral retinitis, treated first with ganciclovir (cymevan) and then with cidofovir. During the treatment, the patient complained of a sharp decrease in visual acuity. Cycloplegics and topical corticosteroids were given. Then cidofovir was stopped and replaced with intravenous Foscavir because of the clinical inefficacy. The anterior uveitis resolved but the ciliary secretion has not stopped after 12 months of follow-up. The patient presented +11 hypermetropia with a choroidal edema and bilateral cataract. This case is interesting for its permanent hypotony and bilateral uveitis. A literature search has brought out a rate of only 3% of chronic hypotony. We hypothesize bilateral iatrogenic ciliary body necrosis, as described in the animal models.

The algorithmic complexity of multichannel EEGs is sensitive to changes in behavior.

Symbolic measures of complexity provide a quantitative characterization of the sequential structure of symbol sequences. Promising results from the application of these methods to the analysis of electroencephalographic (EEG) and event-related brain potential (ERP) activity have been reported. Symbolic measures used thus far have two limitations, however. First, because the value of complexity increases with the length of the message, it is difficult to compare signals of different epoch lengths. Second, these symbolic measures do not generalize easily to the multichannel case. We address these issues in studies in which both single and multichannel EEGs were analyzed using measures of signal complexity and algorithmic redundancy, the latter being defined as a sequence-sensitive generalization of Shannon's redundancy. Using a binary partition of EEG activity about the median, redundancy was shown to be insensitive to the size of the data set while being sensitive to changes in the subject's behavioral state (eyes open vs. eyes closed). The covariance complexity, calculated from the singular value spectrum of a multichannel signal, was also found to be sensitive to changes in behavioral state. Statistical separations between the eyes open and eyes closed conditions were found to decrease following removal of the 8- to 12-Hz content in the EEG, but still remained statistically significant. Use of symbolic measures in multivariate signal classification is described.

Comparative study of embedding methods.

Embedding experimental data is a common first step in many forms of dynamical analysis. The choice of appropriate embedding parameters (dimension and lag) is crucial to the success of the subsequent analysis. We argue here that the optimal embedding of a time series cannot be determined by criteria based solely on the time series itself. Therefore we base our analysis on an examination of systems that have explicit analytic representations. A comparison of analytically obtained results with those obtained by an examination of the corresponding time series provides a means of assessing the comparative success of different embedding criteria. The assessment also includes measures of robustness to noise. The limitations of this study are explicitly delineated. While bearing these limitations in mind, we conclude that for the examples considered here, the best identification of the embedding dimension was achieved with a global false nearest neighbors argument, and the best value of lag was identified by the mutual information function.

Multiphasic kinetics of transformation of 1,2,4-trichlorobenzene at nano- and micromolar concentrations by Burkholderia sp. strain PS14.

The transformation of 1,2,4-trichlorobenzene (1,2,4-TCB) at initial concentrations in nano- and micromolar ranges was studied in batch experiments with Burkholderia sp. strain PS14. 1,2,4-TCB was metabolized from nano- and micromolar concentrations to below its detection limit of 0.5 nM. At low initial 1,2,4-TCB concentrations, a first-order relationship between specific transformation rate and substrate concentration was observed with a specific affinity (a(0)(A)) of 0.32 liter. mg (dry weight)(-1). h(-1) followed by a second one at higher concentrations with an a(o)(A) of 0.77 liter. mg (dry weight)(-1). h(-1). This transition from the first-order kinetics at low initial 1,2,4-TCB concentrations to the second first-order kinetics at higher 1,2,4-TCB concentrations was shifted towards higher initial 1,2,4-TCB concentrations with increasing cell mass. At high initial concentrations of 1,2,4-TCB, a maximal transformation rate of approximately 37 nmol. min(-1). mg (dry weight)(-1) was measured, irrespective of the cell concentration.

Effective normalization of complexity measurements for epoch length and sampling frequency.

The algorithmic complexity of a symbol sequence is sensitive to the length of the message. Additionally, in those cases where the sequence is constructed by the symbolic reduction of an experimentally observed wave form, the corresponding value of algorithmic complexity is also sensitive to the sampling frequency. In this contribution, we present definitions of algorithmic redundancy that are sequence-sensitive generalizations of Shannon's original definition of information redundancy. In contrast with algorithmic complexity, we demonstrate that algorithmic redundancy is not sensitive to message length or to observation scale (sampling frequency) when stationary systems are examined.

Hippocampal dependent learning ability correlates with N-methyl-D-aspartate (NMDA) receptor levels in CA3 neurons of young and aged rats.

Hippocampal N-methyl-D-Aspartate (NMDA) receptors mediate mechanisms of cellular plasticity critical for spatial learning in rats. The present study examined the relationship between spatial learning and NMDA receptor expression in discrete neuronal populations, as well as the degree to which putative age-related changes in NMDA receptors are coupled to the effects of normal aging on spatial learning. Young and aged Long-Evans rats were tested in a Morris water maze task that depends on the integrity of the hippocampus. Levels of NR1, the obligatory subunit for a functional NMDA receptor, were subsequently quantified both biochemically by Western blot in whole homogenized hippocampus, and immunocytochemically by using a high-resolution confocal laser scanning microscopy method. The latter approach allowed comprehensive, regional analysis of discrete elements of excitatory hippocampal circuitry. Neither method revealed global changes, nor were there region-specific differences in hippocampal NR1 levels between young and aged animals. However, across all subjects, individual differences in spatial learning ability correlated with NR1 immunofluorescence levels selectively in CA3 neurons of the hippocampus. Parallel confocal microscopic analysis of the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor failed to reveal reliable differences as a function of age or spatial learning ability. This analysis linking age, performance, and NR1 levels demonstrates that although dendritic NR1 is generally preserved in the aged rat hippocampus, levels of this receptor subunit in selective elements of hippocampal circuitry are linked to spatial learning. These findings suggest that NMDA receptor abundance in CA3 bears a critical relationship to learning mediated by the hippocampus throughout the life span.

Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats.

The present study examined the long-standing concept that changes in hippocampal circuitry contribute to age-related learning impairment. Individual differences in spatial learning were documented in young and aged Long-Evans rats by using a hippocampal-dependent version of the Morris water maze. Postmortem analysis used a confocal laser-scanning microscopy method to quantify changes in immunofluorescence staining for the presynaptic vesicle glycoprotein, synaptophysin (SYN), in the principal relays of hippocampal circuitry. Comparisons based on chronological age alone failed to reveal a reliable difference in the intensity of SYN staining in any region that was examined. In contrast, aged subjects with spatial learning deficits displayed significant reductions in SYN immunoreactivity in CA3 lacunosum-moleculare (LM) relative to either young controls or age-matched rats with preserved learning. SYN intensity values for the latter groups were indistinguishable. In addition, individual differences in spatial learning capacity among the aged rats correlated with levels of SYN staining selectively in three regions: outer and middle portions of the dentate gyrus molecular layer and CA3-LM. The cross-sectional area of SYN labeling, by comparison, was not reliably affected in relation cognitive status. These findings are the first to demonstrate that a circuit-specific pattern of variability in the connectional organization of the hippocampus is coupled to individual differences in the cognitive outcome of normal aging. The regional specificity of these effects suggests that a decline in the fidelity of input to the hippocampus from the entorhinal cortex may play a critical role.

Degradation of chlorobenzenes at nanomolar concentrations by Burkholderia sp. strain PS14 in liquid cultures and in soil.

The utilization of 1,2,4,5-tetrachloro-, 1,2,4-trichloro-, the three isomeric dichlorobenzenes and fructose as the sole carbon and energy sources at nanomolar concentrations was studied in batch experiments with Burkholderia sp. strain PS14. In liquid culture, all chlorobenzenes were metabolized within 1 h from their initial concentration of 500 nM to below their detection limits of 0.5 nM for 1,2,4,5-tetrachloro- and 1,2,4-trichlorobenzene and 7.5 nM for the three dichlorobenzene isomers, with 63% mineralization of the tetra- and trichloroisomers. Fructose at the same initial concentration was, in contrast, metabolized over a 4-h incubation period down to a residual concentration of approximately 125 nM with 38% mineralization during this time. In soil microcosms, Burkholderia sp. strain PS14 metabolized tetrachlorobenzene present at 64.8 ppb and trichlorobenzene present at 54.4 ppb over a 72-h incubation period to below the detection limits of 0.108 and 0.09 ppb, respectively, with approximately 80% mineralization. A high sorptive capacity of Burkholderia sp. strain PS14 for 1,2,4, 5-tetrachlorobenzene was found at very low cell density. The results demonstrate that Burkholderia sp. strain PS14 exhibits a very high affinity for chlorobenzenes at nanomolar concentrations.

Morphometric studies of the aged hippocampus: I. Volumetric analysis in behaviorally characterized rats.

The present investigation examined the structural integrity of the aged hippocampus by using computer-aided morphometry to quantify the volume of principal hippocampal circuits in young, mature adult, and aged Long-Evans rats. A key feature of the experimental design was that the status of hippocampal-dependent learning and memory was documented prior to histologic evaluation. The following regions, which were visualized by using Timm staining, were included in the analysis: 1) outer portions of the dentate gyrus molecular layer (OML) innervated by the lateral entorhinal cortex, 2) middle portions of the molecular layer (MML) that receive input from the medial entorhinal cortex, 3) the commissural/associational zone (IML) immediately adjacent to the granule cell layer, and 4) the hilus and mossy fiber projection to the CA3 pyramidal cell field (MF). To identify morphometric changes that emerge during the same segment of the life span as age-related learning impairment, analysis of the volumetric results focused on comparisons between the mature adult group and the aged group. Among the individual regions that were analyzed, age-related decreases in total volume were restricted to the MML. This effect, however, occurred against a background of other, subtle changes that, together, reflected substantial reorganization in the normal balance of hippocampal circuitry. Age-related decreases in the proportion of the molecular layer (ML) that comprises the MML were accompanied by a corresponding increase in relative IML volume. The ratio between the volumes of the MML and the MF also displayed significant age-related decline. Overall, aging affected septal levels of the hippocampus disproportionately, and, with the exception of MML/MF volume ratio, the temporal hippocampus was spared. Finally, the status of spatial learning among the aged animals correlated selectively with decreases in the MML/ML and MML/MF ratios. These results demonstrate that the effects of aging are regionally selective and circuit specific, and they suggest that connectional reorganization may contribute to age-related decline in the computational functions of the hippocampus.

Preservation of prefrontal cortical volume in behaviorally characterized aged macaque monkeys.

Normal aging is frequently accompanied by a decline in cognitive capacities supported by the prefrontal cortex. The principal aim of the present study was to determine whether these impairments are coupled to morphometric alterations affecting the volume of the prefrontal cortex in an established nonhuman primate model. A large sample of 19 young (4-11 years old) and 40 aged (20-32 years old) rhesus monkeys was tested using a delayed response procedure known to require the functional integrity of area 46 of the prefrontal cortex. Aged monkeys displayed robust delayed response deficits that were specifically related to the demands of testing on memory. Modern stereological methods were then used to estimate the total volume of area 46 and the volume of layer I in brains from 21 young and aged monkeys. Prefrontal cortex volume was entirely preserved in the aged monkeys as a group and among the subset of aged subjects that displayed the most severe behavioral impairment. These findings indicate that gross morphometric alterations affecting cortical volume are unlikely to account for age-related decline in the information processing capacities of area 46 in primates. Taken together, current evidence instead suggests that changes in the functional connectivity of critical cortical circuits may contribute to normal cognitive aging.