Differential effects of aging on executive and automatic inhibition

One of the major accounts of cognitive aging states that age effects are related to a deficiency of inhibitory mechanisms (Hasher & Zacks, 1988). Given that inhibition has traditionally been associated with the frontal cortex, and that the frontal cortex deteriorates early with age (Raz, 2000), this is consistent with the frontal hypothesis of aging (West, 1996). However, not all inhibitory processes require executive control, and so they are not all equally supported by the frontal cortex. As a consequence, one would expect dissociations between inhibitory tasks in the sense of a greater susceptibility of executive/frontal inhibition to aging. Based on Nigg's (2000) working inhibition taxonomy, we tested this hypothesis by combining inhibitory paradigms with different levels of executive control within the same participants. The results showed that age affects Stroop interference but not negative priming (Experiment 1) and stop signal responsiveness but not negative priming (Experiment 2). These findings suggest that tasks with a high executive (or effortful) inhibitory control are more sensitive to aging than tasks with a lower executive (more automatic) inhibitory control. The results are discussed in relation to the inhibitory and frontal accounts of aging.     

Differential effects of absent visual feedback control on gait variability during different locomotion speeds

Healthy persons exhibit relatively small temporal and spatial gait variability when walking unimpeded. In contrast, patients with a sensory deficit (e.g., polyneuropathy) show an increased gait variability that depends on speed and is associated with an increased fall risk. The purpose of this study was to investigate the role of vision in gait stabilization by determining the effects of withdrawing visual information (eyes closed) on gait variability at different locomotion speeds. Ten healthy subjects (32.2 ± 7.9 years, 5 women) walked on a treadmill for 5-min periods at their preferred walking speed and at 20, 40, 70, and 80 % of maximal walking speed during the conditions of walking with eyes open (EO) and with eyes closed (EC). The coefficient of variation (CV) and fractal dimension (α) of the fluctuations in stride time, stride length, and base width were computed and analyzed. Withdrawing visual information increased the base width CV for all walking velocities (p < 0.001). The effects of absent visual information on CV and α of stride time and stride length were most pronounced during slow locomotion (p < 0.001) and declined during fast walking speeds. The results indicate that visual feedback control is used to stabilize the medio-lateral (i.e., base width) gait parameters at all speed sections. In contrast, sensory feedback control in the fore-aft direction (i.e., stride time and stride length) depends on speed. Sensory feedback contributes most to fore-aft gait stabilization during slow locomotion, whereas passive biomechanical mechanisms and an automated central pattern generation appear to control fast locomotion.     

Differential effects of normal aging on recollection of concrete and abstract words

Verbal memory is known to be affected by word features. Concrete words are remembered better than abstract words (concreteness effect), presumably due to the concurrent activation of image-based and/or semantic associations. Vivid remembering during recognition (recollection) has been linked to the hippocampus and is thought to be more affected by healthy aging than familiarity-based recognition. Recent evidence also implicated the hippocampus in the processing of concrete words. Based on these observations, we hypothesized age-related changes in recollection to affect concrete words more than abstract words. This prediction was tested in a cross-sectional design with three consecutive age groups (mean ages 21 years, 42 years, and 61 years). Changes in recollection, but not familiarity, across ages were significantly modulated by word concreteness. Recollection of concrete words showed a steady decline across age, while recollection of abstract words decreased only from young to middle age, leading to a reduced concreteness effect in the oldest group. These findings are consistent with the idea that changes in hippocampally mediated recollective processes during aging affect concrete words more than abstract words.     

Differential effects of aging on the functions of the corpus callosum

Several structural imaging studies have revealed atrophy in regions of the corpus callosum due to normal aging. We examined the performance of young and senior adults on 2 behavioral measures of interhemispheric interactions to test for possible functional consequences of callosal decline. In a simple reaction time task, the efficiency of sensorimotor transfer was assessed by comparing response times from conditions that required interhemispheric transfer (e.g., the left hand responding to a right visual field light) to those from conditions that did not require transfer (e.g., the left hand responding to a left visual field light). Older adults were selectively slower when interhemispheric transfer was required. In the second task, participants matched letters presented within the same visual field or in opposite visual fields. This task is thought to index attentional functions of the corpus callosum, in particular, callosal contributions to resource allocation (Banich, 1998). For more difficult tasks, older participants showed a performance advantage on bilateral conditions requiring transfer compared to unilateral conditions that did not require transfer. This advantage equaled or exceeded that observed in younger adults. Together these results suggest that age does not have uniform effects on callosal function. Whereas sensorimotor functions show age-related decline, attentional functions of the corpus callosum may be relatively preserved and assume a more prominent role in the aging brain.     

Differential effects of nucleus basalis lesions in young adult and aging rats

To characterize age-related changes in frontal cortical plasticity, we assessed maze learning and frontal cortical pharmacology in young adult, middle-aged, and aged rats. Rats received either ibotenic acid or sham lesions of the nucleus basalis magnocellularis (NBM) and were then trained on a radial maze task. After training, we assessed [3H]desmethylimipramine (DMI), [3H]muscimol, [3H]AMPA, and [3H]QNB binding using quantitative autoradiography. Both middle-aged and aged rats were impaired on the radial maze task. DMI binding was increased in both middle-aged and aged rats, while QNB binding was decreased in aged rats. While lesions impaired maze performance at all ages, middle-aged and aged rats showed more profound lesion-induced deficits. Lesions increased GABA, and AMPA receptor binding in young adult rats only. These lesion-induced changes may reflect a compensatory response that is lost with advancing age.     

COMT genotype and cognitive ability: a longitudinal aging study

Dopaminergic neurotransmission in the pre-frontal cortex (PFC) contributes to individual cognitive differences in animals and humans. Catechol-O-methyltransferase (COMT) influences dopamine concentration in the PFC. Functional variation in the human COMT gene occurs at a single nucleotide polymorphism (SNP)--472G>A--that results in a valine (Val) to methionine (Met) amino acid substitution (Val158Met). The Met/Met form is less active resulting in higher dopamine concentrations and thus may enhance cognitive function. We applied repeated measures mixed general linear modelling over three waves between ages 64 and 68 years to optimise cognitive phenotype characterisation in a cohort of 473 community volunteers who had validated childhood IQ data. After adjusting for childhood IQ, wave of testing and specific test type, COMT Val158Met genotype polymorphism had a significant overall effect on cognition (F(2,935.7)=7.92, p<.001) with adjusted means of all cognitive test scores taken together being: Val/Val 33.0 (95% C.I. 32.2-33.8), Val/Met 34.9 (95% C.I. 34.3-35.5), and Met/Met 34.9 (95% C.I. 34.1-35.8). This study adds to the evidence that the Val/Val polymorphism has a detrimental effect on cognition, extending upwards the age range in which such an effect has been detected.     

Age effects on executive ability

Heterogeneity of executive tasks has made it difficult to determine whether there are age-related declines in executive functioning. To address this issue, 112 individuals, 20-79 years old, took the California Trail Making Test (CTMT) and the California Stroop Test (CST), subtests of the Delis-Kaplan Executive Function Scale (D. C. Delis, E. Kaplan, & J. H. Kramer, in press) that include measurement of component skills embedded in the executive function tasks. Multiple regression analyses revealed that after controlling for component skills, age had a significant effect on the executive requirement of the CST, namely speed on the interference condition. Age did not affect switching performance on the letter-number condition of the CTMT. Additional analyses revealed that age was significantly associated with commission of certain types of errors. This study confirms the importance of partialing out components in the assessment of multidimensional cognitive tasks, particularly when making age comparisons. It also emphasizes specificity over generalizability when examining the impact of age on cognition.     

Differential effects of aging on NMDA receptors in the intermediate versus the dorsal hippocampus

There are discrepancies in the literature about the effects of aging on NMDA receptor expression in the hippocampus. The present study was designed to determine whether there are regional differences in how NMDA receptors are affected by aging. Brains from male C57BL/6 mice from three different age groups (3, 10, and 30 months of age) were sectioned coronally through the dorsal hippocampus and horizontally through the intermediate hippocampus. Sections were processed and analyzed for [3H]glutamate binding to NMDA receptors using receptor autoradiography and for mRNA for the zeta1 (NR1), epsilon1 (NR2A), and epsilon2 (NR2B) subunits of the NMDA receptor using in situ hybridization. There were more significant effects of aging within the intermediate hippocampus in NMDA-displaceable [3H]glutamate binding and epsilon2 mRNA densities than were seen in the dorsal hippocampus. There was no significant effect of age on densities of either the zeta1 or epsilon1 subunit mRNA. These results suggest that the aging process affects NMDA receptors more in the intermediate hippocampus than the dorsal.     

The val158met COMT polymorphism's effect on atrophy in healthy aging and Parkinson's disease

We investigated whether the val(158)met functional polymorphism of catechol-o-methyltransferase influenced age-related changes in grey matter density and volume, both in healthy individuals (n=80, ages 18-79) and those with Parkinson's disease (n=50). Global grey matter volumes and voxelwise estimates of grey matter volume and density were determined from structural magnetic resonance images at 3T. Male and female ValVal homozygotes (low prefrontal cortical dopamine) had more grey matter in early adulthood, but this difference disappeared with increasing age. The insula and ventral prefrontal cortex had higher grey matter volume in younger, but not older, ValVal homozygotes. Conversely, the dominant premotor cortex revealed genotypic differences in grey matter density in later life. There were no global or local interactions between Parkinson's disease and COMT val(158)met genotype on morphometry. Since the val(158)met polymorphism is associated with differences in cortical dopamine metabolism, our data suggest a role for dopamine in cortical development followed by differential vulnerability to cortical atrophy across the adult life span.     

Alerting, orienting and executive control: the effects of sleep deprivation on attentional networks

Sleep deprivation alters attentional functions like vigilance or tonic alerting (i.e., sustaining an alert state over a period of time). However, the effects of sleep loss on both orienting and executive control are still not clear, and no study has assessed whether sleep deprivation might affect the relationships among these three attentional systems. In order to investigate the efficiency of the three attentional networks—alerting, orienting and executive control—within a single task, we used the Attention Network Test (ANT). Eighteen right-handed male participants took part in the experiment, which took place on two consecutive days. On the first day, each participant performed a 20 min training session of the ANT. On the second day, participants remained awake for 24 h during which time the ANT was performed once at 5:00 p.m. and once at 4:00 a.m. Results showed an overall slowing of reaction times in the nocturnal session, indicating a strong decrease in vigilance. Furthermore, sleep deprivation did affect attentional orienting and executive control. Results are consistent with the hypothesis that the tonic component of alerting interacts with both attentional orienting and executive functions.     

Differential effects of aging and Alzheimer's disease on medial temporal lobe cortical thickness and surface area

The volume of parcellated cortical regions is a composite measure related to both thickness and surface area. It is not clear whether volumetric decreases in medial temporal lobe (MTL) cortical regions in aging and Alzheimer's disease (AD) are due to thinning, loss of surface area, or both, nor is it clear whether aging and AD differ in their effects on these properties. Participants included 28 Younger Normals, 47 Older Normals, and 29 patients with mild AD. T1-weighted MRI data were analyzed using a novel semi-automated protocol (presented in a companion article) to delineate the boundaries of entorhinal (ERC), perirhinal (PRC), and posterior parahippocampal (PPHC) cortical regions and calculate their mean thickness, surface area, and volume. Compared to Younger Normals, Older Normals demonstrated moderately reduced ERC and PPHC volumes, which were due primarily to reduced surface area. In contrast, the expected AD-related reduction in ERC volume was produced by a large reduction in thickness with minimal additional effect (beyond that of aging) on surface area. PRC and PPHC also showed large AD-related reductions in thickness. Of all these MTL morphometric measures, ERC and PRC thinning were the best predictors of poorer episodic memory performance in AD. Although the volumes of MTL cortical regions may decrease with both aging and AD, thickness is relatively preserved in normal aging, while even in its mild clinical stage, AD is associated with a large degree of thinning of MTL cortex. These differential morphometric effects of aging and AD may reflect distinct biologic processes and ultimately may provide insights into the anatomic substrates of change in memory-related functions of MTL cortex.     

Differential effects of control and antigen-specific T cells on intracellular mycobacterial growth

We investigated the effects of peripheral blood mononuclear cells expanded with irrelevant control and mycobacterial antigens on the intracellular growth of Mycobacterium bovis bacillus Calmette-Guérin (BCG) in human macrophages. More than 90% of the cells present after 1 week of in vitro expansion were CD3(+). T cells were expanded from purified protein derivative-negative controls, persons with latent tuberculosis, and BCG-vaccinated individuals. T cells expanded with nonmycobacterial antigens enhanced the intracellular growth of BCG in suboptimal cultures of macrophages. T cells expanded with live BCG or lysates of Mycobacterium tuberculosis directly inhibited intracellular BCG. Recent intradermal BCG vaccination significantly enhanced the inhibitory activity of T cells expanded with mycobacterial antigens (P < 0.02), consistent with the induction of memory-immune inhibitory T-cell responses. Selected mycobacterial antigens (Mtb41 > lipoarabinomannan > 38kd > Ag85B > Mtb39) expanded inhibitory T cells, demonstrating the involvement of antigen-specific T cells in intracellular BCG inhibition. We studied the T-cell subsets and molecular mechanisms involved in the memory-immune inhibition of intracellular BCG. Mycobacteria-specific gammadelta T cells were the most potent inhibitors of intracellular BCG growth. Direct contact between T cells and macrophages was necessary for the BCG growth-enhancing and inhibitory activities mediated by control and mycobacteria-specific T cells, respectively. Increases in tumor necrosis factor alpha, interleukin-6, transforming growth factor beta, and vascular endothelial growth factor mRNA expression were associated with the enhancement of intracellular BCG growth. Increases in gamma interferon, FAS, FAS ligand, perforin, granzyme, and granulysin mRNA expression were associated with intracellular BCG inhibition. These culture systems provide in vitro models for studying the opposing T-cell mechanisms involved in mycobacterial survival and protective host immunity.     

Differential effects of deep cerebellar nuclei inactivation on reaching and adaptive control

This study examined the effects of selective inactivation of the cerebellar nuclei in the cat on the control of multijoint trajectories and trajectory adaptation to avoid obstacles. Animals were restrained in a hammock and trained to perform a prehension task in which they reached to grasp a small cube of meat from a narrow food well. To examine trajectory adaptation, reaching was obstructed by placing a horizontal bar in the limb's path. Inactivation was produced by microinjection of the GABA agonist muscimol (0.25-1.0 microg in 1 microL saline). Fastigial nucleus inactivation produced a severe impairment in balance and in head and trunk control but no effect on reaching and grasping. Dentate inactivation slowed movements significantly and produced a significant increase in tip path curvature but did not impair reaching and grasping. Selective inactivation of the anterior and posterior interpositus nuclei did not impair grasping but severely decreased the accuracy of reaching movements and produced different biases in wrist and paw paths. Anterior interpositus inactivation produced movement slowing (wrist speed) and under-reaching to the food well. Wrist and tip paths showed anterior biases and became more curved. Also animals could no longer make anticipatory adjustments in limb kinematics to avoid obstructions but sensory-evoked corrective responses were preserved. Posterior interpositus inactivation produced a significant increase in wrist speed and overreaching. Wrist and tip paths showed a posterior bias and became more curved, although in a different way than during anterior interpositus inactivation. Posterior interpositus inactivation did not impair trajectory adaptation to reach over the obstacle. During inactivation of either interpositus nucleus, all measures of kinematic temporal and spatial variability increased with somewhat greater effects being produced by anterior interpositus inactivation. We discuss our results in relation to the hypothesis that anterior and posterior interpositus have different roles in trajectory control, related possibly to feed-forward use of cutaneous and proprioceptive inputs, respectively. The loss of adaptive reprogramming during anterior interpositus inactivation further suggests a role in motor learning. Comparison with results from our earlier motor cortical study shows that the distinctive impairments produced by inactivation of these two nuclei are similar to those produced by selective inactivation of different zones in the forelimb area of rostral motor cortex. Our findings are consistent with the hypothesis that there are separate functional output channels from the anterior and posterior interpositus nuclei to rostral motor cortex for distinct aspects of trajectory control and, from anterior interpositus alone, for trajectory adaptation.     

Differential effects of aging on spatial contrast sensitivity to linear and polar sine-wave gratings

Changes in visual function beyond high-contrast acuity are known to take placeduring normal aging. We determined whether sensitivity to linear sine-wavegratings and to an elementary stimulus preferentially processed in extrastriateareas could be distinctively affected by aging. We measured spatial contrastsensitivity twice for concentric polar (Bessel) and vertical linear gratings of0.6, 2.5, 5, and 20 cycles per degree (cpd) in two age groups (20-30 and 60-70years). All participants were free of identifiable ocular disease and had normalor corrected-to-normal visual acuity. Participants were more sensitive toCartesian than to polar gratings in all frequencies tested, and the youngeradult group was more sensitive to all stimuli tested. Significant differencesbetween sensitivities of the two groups were found for linear (only 20 cpd;P<0.01) and polar gratings (all frequencies tested; P<0.01). The youngadult group was significantly more sensitive to linear than to circular gratingsin the 20 cpd frequency. The older adult group was significantly more sensitiveto linear than to circular gratings in all spatial frequencies, except in the 20cpd frequency. The results suggest that sensitivity to the two kinds of stimuliis affected differently by aging. We suggest that neural changes in the agingbrain are important determinants of this difference and discuss the resultsaccording to current models of human aging.     

Differential effects of methamphetamine and haloperidol on the control of an internal clock

Humans and animals process temporal information as if they were using an internal stopwatch that can be stopped and reset, and whose speed is adjustable. Previous data suggest that dopaminergic drugs affect the speed of this internal stopwatch. Using a paradigm in which rats have to filter out the gaps that (sometimes) interrupted timing, the authors found that methamphetamine and haloperidol also affect the stop and reset mechanism of the internal clock, possibly by modulating attentional components that are dependent on the content and salience of the timed events. This is the first report of both clock and attentional effects of dopaminergic drugs on interval timing in the same experimental setting.     

Differential effects of aging on the distribution of calcium-binding proteins in a pretectal nucleus of the chicken brain

The nucleus pretectalis (PT) of birds is an ovoid-shaped visuomotor cell group of the pretectum that receives tectal input and projects back to the optic tectum. We performed immunohistochemical single- and double-labeling to determine the distribution and abundance of neurons containing three calcium-binding proteins, parvalbumin (PV), calretinin (CR), and calbindin (CB), in the PT in chickens at three ages. We found that PV-positive and CR-positive cells co-localize and are largely found in the outer part of PT at all ages. The GluR4 subunit of the AMPA-type glutamate receptor was selectively localized to these neurons. CB-positive neurons, however, were largely absent from the PT in young and adult chickens. The abundance of PV-positive and CR-positive neurons in PT in old birds was indistinguishable from that in the younger birds, but CB-positive perikarya were 10-20-fold more common than in young birds, and were again mainly found in the outer part of PT. The overall abundance of neurons in PT was reduced to about 50% of its former abundance in the old birds, with this loss restricted to the central part of the nucleus. These data indicate that a cell loss process develops in PT as birds age, that parvalbuminergic and calretinergic neurons resist this process, and that this process is associated with increased expression of CB.