Placebo effects in cognitive training.

Although a large body of research shows that general cognitive ability is heritable and stable in young adults, there is recent evidence that fluid intelligence can be heightened with cognitive training. Many researchers, however, have questioned the methodology of the cognitive-training studies reporting improvements in fluid intelligence: specifically, the role of placebo effects. We designed a procedure to intentionally induce a placebo effect via overt recruitment in an effort to evaluate the role of placebo effects in fluid intelligence gains from cognitive training. Individuals who self-selected into the placebo group by responding to a suggestive flyer showed improvements after a single, 1-h session of cognitive training that equates to a 5- to 10-point increase on a standard IQ test. Controls responding to a nonsuggestive flyer showed no improvement. These findings provide an alternative explanation for effects observed in the cognitive-training literature and the brain-training industry, revealing the need to account for confounds in future research.

A cognitive phenotype for a polymorphism in the nicotinic receptor gene CHRNA4.

Drawing on converging behavioral, electrophysiological, and imaging evidence, we advance an hypothesis for a cognitive phenotype of a SNP in the CHRNA4 gene encoding the α(4) subunit of α(4)ß(2) nicotinic receptors. First, we review evidence that visuospatial attention can be decomposed into several component processes. Secondly, we consider evidence that one component, redirection of attention, is modulated by the nicotinic cholinergic system. Third, we review evidence that nicotinic stimulation exerts effects at the network level. Fourth, we consider evidence that normal variation in this SNP exerts nicotine-like modulatory effects on visuospatial attention. Fifth, we hypothesize that the cognitive phenotype of the CHRNA4 rs1044396 SNP is characterized by greater ability of T allele carriers to preferentially process events in the attentional focus compared to events outside the attentional focus. Finally, we consider effects of the CHNRA4 rs1044396 SNP on brain activity and cognition in light of our hypothesized cognitive phenotype. This hypothesis makes an important contribution to the development of cognitive phenomics by arguing for a cognitive phenotype of CHRNA4.

Synergistic effects of genetic variation in nicotinic and muscarinic receptors on visual attention but not working memory.

It is widely appreciated that neurotransmission systems interact in their effects on human cognition, but those interactions have been little studied. We used genetics to investigate pharmacological evidence of synergisms in nicotinic/muscarinic interactions on cognition. We hypothesized that joint influences of nicotinic and muscarinic systems would be reflected in cognitive effects of normal variation in known SNPs in nicotinic (CHRNA4 rs1044396) and muscarinic (CHRM2 rs8191992) receptor genes. Exp. 1 used a task of cued visual search. The slope of the cue size/reaction time function showed a trend level effect of the muscarinic CHRM2 SNP, no effect of the nicotinic CHRNA4 SNP, but a significant interaction between the 2 SNPs. Slopes were steepest in individuals who were both CHRNA4 C/C and CHRM2 T/T homozygotes. To determine the specificity of this synergism, Exp. 2 assessed working memory for 1-3 locations over 3 s and found no significant effects on either SNP. Interpreting these results in light of Sarter's [Briand LA, et al. (2007) Modulators in concert for cognition: Modulator interactions in the prefrontal cortex. Prog Neurobiol 83:69-91] claims of tonic and phasic modes of cholinergic activity, we argue that reorienting attention to the target after invalid cues requires a phasic response, dependent on the nicotinic system, whereas orienting attention to valid cues requires a tonic response, dependent on the muscarinic system. Consistent with that, shifting and scaling after valid cues (tonic) were strongest in CHRNA4 C/C homozygotes who were also CHRM2 T/T homozygotes. This shows synergistic effects within the human cholinergic system.

Functional plasticity in cognitive aging: review and hypothesis.

Cognitive aging reflects not only loss but also adaptation to loss. The adult brain is capable of plastic change, including change in cortical representation. This has been seen in association not only with frank lesions but also in healthy individuals as a function of experience and training. This review considers the potential for adult plasticity together with evidence of a relation in old age between regional cortical atrophy/shrinkage and increased activation in neuroimaging. Those cortical regions shown most consistently to shrink in adulthood--prefrontal and parietal cortices--are the same regions showing increased regional activation in aging. Combining several strands of behavioral and neuroimaging evidence, the author argues that functional plasticity alters the course of cognitive aging. The author advances the hypothesis that losses in regional brain integrity drive functional reorganization through changes in processing strategy and makes specific predictions from that hypothesis.

Scaling of visuospatial attention undergoes differential longitudinal change as a function of APOE genotype prior to old age: results from the NIMH BIOCARD study.

The effect of apolipoprotein E (APOE) genotype on longitudinal cognitive decline in midlife was investigated with attentional scaling. Healthy individuals (mean age 59.6 years) genotyped for APOE were tested at 3 12-month intervals on a cued visual search task. A random effects model revealed significant interaction in effect of precue size on search speed between APOE-epsilon4 gene dose and assessment, with longitudinal increases in noncarriers and heterozygotes but longitudinal decreases in homozygotes. Association of APOE-epsilon4 with cognitive decline in midlife is consistent with an Alzheimer's disease (AD) prodrome, albeit a decade or more before average age of AD diagnosis. However, cognitive decline in midlife associated with a gene modulating neuronal response to insult argues that the concept of an AD prodrome includes factors that allow as well as cause AD.

Effects of apolipoprotein E genotype on spatial attention, working memory, and their interaction in healthy, middle-aged adults: results From the National Institute of Mental Health's BIOCARD study.

The cognitive consequences of the apolipoprotein E-epsilon4 (APOE-epsilon4) allele were examined in middle age, before likely onset of symptoms of Alzheimer's disease. The authors identified 3 cognitive processes--visuospatial attention, spatial working memory, and the effect of visuospatial attention on working memory--and devised "behavioral assays" of the integrity of components of these processes. Redirecting visuospatial attention, retention of memory for location, and attentional modulation of memory of target location were affected by APOE genotype. Visuospatial attention showed additive effects of epsilon4 gene dose; each additional epsilon4 allele inherited further slowed disengagement from invalidly cued space. In contrast, working memory performance was affected only in epsilon4 homozygotes. Effect sizes for the APOE gene were moderate to large, ranging from 14% to 24%. Effects of APOE genotype on component processes of cognition in healthy, middle-aged adults is consistent with the emergence in adulthood of an APOE-epsilon4 cognitive phenotype.

The scaling of spatial attention in visual search and its modification in healthy aging.

A model of visual search (Greenwood & Parasuraman, 1999) postulating that visuospatial attention is composed of two processing components--shifting and scaling of a variable-gradient attentional focus--was tested in three experiments. Whereas young participants are able to dynamically constrict or expand the focus of visuospatial attention on the basis of prior information, in healthy aging individuals visuospatial attention becomes a poorly focused beam, unable to be constricted around one array element. In the present work, we sought to examine predictions of this view in healthy young and older participants. An attentional focus constricted in response to an element-sized precue had the strongest facilitatory effect on visual search. However, this was true only when the precue correctly indicated the location of a target fixed in size. When precues incorrectly indicated target location or when target size varied, the optimal spatial scale of attention for search was larger, encompassing a number of array elements. Healthy aging altered the deployment of attentional scaling: The benefit of valid precues on search initially (in participants 65-74 years of age) was increased but later (in those 75-85 years of age) was reduced. The results also provided evidence that cue size effects are attentional, not strategic. This evidence is consistent with the proposed model of attentional scaling in visual search.

Normal genetic variation, cognition, and aging.

This article reviews the modulation of cognitive function by normal genetic variation. Although the heritability of "g" is well established, the genes that modulate specific cognitive functions are largely unidentified. Application of the allelic association approach to individual differences in cognition has begun to reveal the effects of single nucleotide polymorphisms on specific and general cognitive functions. This article proposes a framework for relating genotype to cognitive phenotype by considering the effect of genetic variation on the protein product of specific genes within the context of the neural basis of particular cognitive domains. Specificity of effects is considered, from genes controlling part of one receptor type to genes controlling agents of neuronal repair, and evidence is reviewed of cognitive modulation by polymorphisms in dopaminergic and cholinergic receptor genes, dopaminergic enzyme genes, and neurotrophic genes. Although allelic variation in certain genes can be reliably linked to cognition--specifically to components of attention, working memory, and executive function in healthy adults--the specificity, generality, and replicability of the effects are not fully known.

Dynamics of the spatial scale of visual attention revealed by brain event-related potentials.

The temporal dynamics of the spatial scaling of attention during visual search were examined by recording event-related potentials (ERPs). A total of 16 young participants performed a search task in which the search array was preceded by valid cues that varied in size and hence in precision of target localization. The effects of cue size on short-latency (P1 and N1) ERP components, and the time course of these effects with variation in cue-target stimulus onset asynchrony (SOA), were examined. Reaction time (RT) to discriminate a target was prolonged as cue size increased. The amplitudes of the posterior P1 and N1 components of the ERP evoked by the search array were affected in opposite ways by the size of the precue: P1 amplitude increased whereas N1 amplitude decreased as cue size increased, particularly following the shortest SOA. The results show that when top-down information about the region to be searched is less precise (larger cues), RT is slowed and the neural generators of P1 become more active, reflecting the additional computations required in changing the spatial scale of attention to the appropriate element size to facilitate target discrimination. In contrast, the decrease in N1 amplitude with cue size may reflect a broadening of the spatial gradient of attention. The results provide electrophysiological evidence that changes in the spatial scale of attention modulate neural activity in early visual cortical areas and activate at least two temporally overlapping component processes during visual search.

Genetics and visual attention: selective deficits in healthy adult carriers of the epsilon 4 allele of the apolipoprotein E gene.

The epsilon4 allele of the apolipoprotein E (APOE) gene is associated with altered brain physiology in healthy adults before old age, but concomitant deficits in cognition on standardized tests of cognitive function have not been consistently demonstrated. We hypothesized that sensitive and specific assessment of basic attentional functions that underlie complex cognition would reveal evidence of impairment in otherwise asymptomatic individuals. We found that as early as middle age, nondemented carriers of the varepsilon4 allele of the APOE gene showed deficits when visual attention was spatially directed by cues in tasks of visual discrimination and visual search, in comparison to those without the epsilon4 allele (epsilon2 and epsilon3 carriers). Two component attentional operations were selectively affected: (i) shifting spatial attention following invalid location cues, and (ii) adjusting the spatial scale of attention during visual search. These changes occurred only in the presence of the epsilon4 allele and without decline in other aspects of attention (vigilance), memory, or general cognition. The results show that specific components of visual attention are affected by APOE genotype and that the course of cognitive aging is subject to selective alteration by a genetic trait.

The frontal aging hypothesis evaluated.

That the human frontal lobes are particularly vulnerable to age-related deterioration has been frequently invoked as an explanation of functional decline in aging. This "frontal aging hypothesis" is evaluated in this review by examining evidence of selectively reduced frontal lobe function in aging. The frontal aging hypothesis predicts that functions largely dependent on frontal regions would decline in aging, while functions largely independent of frontal lobes would remain relatively spared. The hypothesis further predicts that age-related brain change would selectively impact frontal regions. The literatures on working memory, visuospatial attention, face recognition, and implicit memory were reviewed as exemplars of functions dependent on prefrontal, parietal, temporal and occipitotemporal cortices, respectively, with a view to establishing mediating structures and effects of aging. Age sensitivity was seen both in functions dependent on frontal integrity as well as in functions apparently independent of frontal integrity. Further, although prefrontal areas exhibit age-related decreases in regional volume, blood flow and metabolism, nonfrontal cortical regions undergo similar declines. It is concluded that while the frontal lobes are subject to age-related changes reflected in both behavior and pathology, there is only weak and conflicting evidence that frontal regions are selectively and differentially affected by aging. It is argued that a network-based theory of cognitive aging has advantages over the localizationist approach inherent in the frontal aging hypothesis.

Alzheimer disease constricts the dynamic range of spatial attention in visual search.

A cued visual search task was used to examine the dynamic range over which spatial attention affects target identification during visual search. Precues varied in validity (valid, invalid, or neutral) and in precision (cue size) of target localization. Participants were "young-old" (65-74 years) and "old-old" (75-85 years) elderly adults and individuals in the mild stage of dementia of the Alzheimer type (DAT). For all participants, search was speeded as the precision with which a precue surrounding the location of a subsequently appearing target increased (precue size decreased). The cue size effect was evident in both feature and conjunction search, but was greatly reduced in both old-old and DAT groups compared to the young-old. However, whereas all non-demented adults showed a progressive modulation of search efficiency over the entire range of cue sizes, the dynamic range of spatial attention was restricted to the most precise cue in the DAT group. The restriction in the dynamic range of spatial attention may represent an underlying component of the impairment in perceptual and memory functioning found in early-stage DAT.

Acetylcholine affects the spatial scale of attention: evidence from Alzheimer's disease.

Location precues were used to manipulate the spatial scale of attention in visual search for a target in an array of letters in patients with dementia of the Alzheimer type (DAT) and in age-matched older controls. Cue size varied in the amount of spatial precision conferred. Scopolamine, a muscarinic antagonist, decreased overall arousal and broadened spatial attention after a precise precue (small and valid) to target location for DAT patients but not for controls, suggesting a selective effect for attentional impairment induced by cholinergic blockade. In contrast, physostigmine, a cholinesterase inhibitor, did not alter the distribution of spatial attention relative to no-drug baseline testing for patients. Results support a differential role for cholinergic mechanisms in the modulation of the spatial scale of visual attention.

Scale of attentional focus in visual search.

The effects of the spatial scale of attention on feature and conjunction search were examined in two experiments. Adult participants in three age groups--young, young-old, and old-old--were given precues of varying validity and precision in indicating the location of a target letter subsequently presented in a visual array. Systematic decreases in the size of a valid precue (toward the size of the target) progressively facilitated both feature and conjunction search, with a greater benefit accruing to conjunction search. Age-related slowing in conjunction search was mitigated by precise (small and valid) precues, presumably because they reduced the need for participants in the young-old group to focus and to shift attention. Nevertheless, this benefit was reduced in the old-old group. The effects of valid location precue size varied with cue-target stimulus onset asynchrony (SOA) in a manner that interacted with search difficulty: Effects of cue size developed more rapidly in feature search but more slowly in conjunction search. Finally, when precues were invalid for target location, search was faster with larger sized precues. Thus, in both easy feature search and hard conjunction search, the scale of visuospatial attention modulates the speed of visual search. Furthermore, when the SOA is sufficiently long for cue effects to develop, the ability to dynamically adjust the scale of visuospatial attention appears to decline in advanced age. These results go beyond current models in suggesting that visuospatial attention possesses two dynamic properties--shifting in space and varying in scale--that are deployed independently, depending on task demands.

Age-related reduction in 3-D visual motion priming.

In 3 experiments, younger and older adults judged the perceived motion of three-dimensional (3-D) figures that rotated in depth either unambiguously or ambiguously. Both groups were found to be equivalent in judging the direction of single rotations of the simulated 3-D objects (Experiment 1). In Experiments 2 and 3, a single unambiguous rotation (prime) was followed 0-3200 ms later by an ambiguous rotation (target). Motion priming was indicated by the disambiguation of the second rotation by the first rotation. 3-D motion priming was initially found to be similar in young and old, but it rapidly reduced in the older participants compared to the younger ones. Using a nonluminance depth cue--occlusion--to induce 3-D motion, diminished contrast sensitivity in the elderly was ruled out as a cause of the reduced priming. The results show that 3-D motion priming exhibits robust age-related decline. An age-related decrease in temporal persistence may account for the reduction in 3-D motion priming in older adults.

Controlling the focus of spatial attention during visual search: effects of advanced aging and Alzheimer disease.

It was hypothesized that slowed visual search in healthy adult aging arises from reduced ability to adjust the size of the attentional focus. A novel, cued-visual search task manipulated the scale of spatial attention in a complex field in healthy elderly individuals and patients with dementia of the Alzheimer type (DAT). Precues indicated with varying validity the size and location of the area to be searched. Location precues exerted the strongest effects on conjunction search and the weakest effects on feature search. As the size of valid location cues decreased, conjunction search was facilitated. These effects declined progressively with advanced age and the onset of DAT. As the size of invalid cues increased, conjunction search was first facilitated, then slowed, but neither age nor DAT altered this effect. These results indicate that both Alzheimer's disease and, to a lesser degree, advanced aging, reduce control of the spatial focus of attention.

Selective impairment of spatial attention during visual search in Alzheimer's disease.

Spatial attention during visual search was examined in 14 persons with mild Alzheimer's disease (AD) and 28 healthy older subjects, 14 aged 65-74 (young-old), and 14 aged 75-85 (old-old). Subjects searched for single feature (color) or conjunction (color + letter) targets in displays of 10 or 15 letters. Precues of differing sizes were used to provide localizing information of varying precision. Effects of display size and cue size on reaction time (RT) for color search were similar in AD subjects and controls. For color + letter search, however, AD patients showed minimal effects of cue size, pointing to an impairment in AD in the spatial focusing of attention during visual search. Pathology affecting the association parietal and extrastriate areas may mediate impairment of spatial attention and visual search in AD.

Changes in visuospatial attention over the adult lifespan.

Shifts of visual attention elicited by spatial cues were examined for detection and letter-discrimination tasks in 90 normal adults ranging in age over each decade from the 20s to the 70s. Spatial cues were valid, invalid, or neutral in indicating probable target location and were presented either centrally at fixation or peripherally 6.7 degrees to the left or right of fixation. Stimulus-onset asynchrony (SOA) between cue and target was varied between 200, 500 and 2000 msec. Reaction time (RT) costs and benefits associated with spatial cueing did not vary with age for: (1) the detection task; (2) the letter-discrimination task with peripheral cues; and (3) the letter-discrimination task with central cues at a short (200 msec) SOA. RT costs and benefits increased with age only for SOAs greater than 200 msec with central cueing in the discrimination task. In general, the efficiency of cue-based shifts of visuospatial attention appears relatively resistant to the effects of adult age up to 79 years. When an age effect was found, RT costs and benefits increased steadily across all age decades, the correlation with age being 0.25 and 0.38 for the 500 and 2000 msec SOAs, respectively. The findings suggest a qualitative difference in the influence of normal adult aging and effects of dementia noted in previous studies; normal aging has only a weak influence on voluntary attention shifts, whereas dementia affects both voluntary and involuntary modes of attention shifting.

Visuospatial attention in dementia of the Alzheimer type.

Cue-directed shifts of spatial attention were examined for a letter-discrimination task in 15 patients with mild to moderate dementia of the Alzheimer type (DAT) and 15 healthy, age-matched controls. Spatial cues were valid, invalid or neutral in indicating probable target location and were presented either centrally at fixation or peripherally 6.7 degrees to the left or right of fixation. Stimulus-onset asynchrony (SOA) between cue and target was varied between 200 ms and 2000 ms. Reaction time (RT) benefits conferred by valid cues did not differ between the DAT group and the controls. However, RT costs incurred by invalid cues were significantly greater in the DAT group than in the control group. Group differences in RT costs plus benefits occurred at short SOAs (less than 500 ms) for peripheral cues and at long SOAs (greater than 500 ms) for central cues. Reaction time costs plus benefits were correlated with right-left asymmetry in resting levels of cerebral glucose metabolism in the superior parietal lobe for DAT patients but not for controls. The results indicate that focusing of attention to spatial location is intact in early DAT, whereas the disengagement of visuospatial attention is impaired. Automatic attention shifts elicited by peripheral cues reveal abnormalities earlier than attention shifts initiated 'effortfully' by central cues. Intact focusing and impaired disengagement of visuospatial attention may be linked to dysfunction in early DAT of cortico-cortical networks linking the posterior parietal and frontal lobes.

Modification of median nerve somatic evoked potentials by prior median nerve, peroneal nerve, and auditory stimulation.

In a recovery function design, changes were measured in the somatic evoked potential (SEP) to right median nerve (RMN) shocks preceded by stimulation of: the same nerve (RMN-RMN); the left median nerve having primary input to the homologous sensory area in the contralateral hemisphere (LMN-RMN); the right peroneal nerve having primary input to a different region of the same hemisphere (RPN-RMN); and the auditory nerve with primary input to a different sensory modality (AUD-RMN). Eight inter-stimulus intervals ranged from zero (simultaneous) to 2.5 sec. It was assumed that the degree of interaction between evoked potentials would be related to the degree to which common neural structures are activated or modulated in response to the stimuli. Results were: (a) the primary somatosensory response N20-P30 was little influenced by other somatic or auditory stimulation, interaction occurring predominantly in the RMN-RMN condition; (b) with increasing latency, components showed increasing interaction across modalities; (c) preceding homolateral stimulation (RPN-RMN) showed no greater interaction than preceding contralateral stimulation (LMN-RMN); (d) N55-P100 differed from the primary somatosensory response N20-P30 by showing greater interaction with other somatic stimuli; and (e) N140-P190 showed similarly shaped recovery functions across stimulus pairs but significant differences in magnitude of interaction. These results show that components with similar wave form and topographical characteristics can have different neurophysiological properties.