Effect of the BDNF V166M polymorphism on working memory in healthy adolescents.

Brain-derived neurotrophic factor (BDNF) may play a role in modulating memory function and there is growing evidence that the BDNF V166M polymorphism may influence episodic memory in humans. However, previous association studies examining this polymorphism and working memory are inconsistent. The current study examined this association in a large sample of adolescent twin-pairs and siblings (785 individuals from 439 families). A range of measures (event-related potential, general performance and reaction time) was obtained from a delayed-response working-memory task and total association was examined using the quantitative transmission disequilibrium tests (QTDT) program. Analyses had approximately 93-97% power (alpha= 0.05) to detect an association accounting for as little as 2% of the variance in the phenotypes examined. Results indicated that the BDNF V166M polymorphism is not associated with variation in working memory in healthy adolescents.

Genome-wide scan of IQ finds significant linkage to a quantitative trait locus on 2q.

A genome-wide linkage scan of 795 microsatellite markers (761 autosomal, 34 X chromosome) was performed on Multidimensional Aptitude Battery subtests and verbal, performance and full scale scores, the WAIS-R Digit Symbol subtest, and two word-recognition tests (Schonell Graded Word Reading Test, Cambridge Contextual Reading Test) highly predictive of IQ. The sample included 361 families comprising 2-5 siblings who ranged in age from 15.7 to 22.2 years; genotype, but not phenotype, data were available for 81% of parents. A variance components analysis which controlled for age and sex effects showed significant linkage for the Cambridge reading test and performance IQ to the same region on chromosome 2, with respective LOD scores of 4.15 and 3.68. Suggestive linkage (LOD score>2.2) for various measures was further supported on chromosomes 6, 7, 11, 14, 21 and 22. Where location of linkage peaks converged for IQ subtests within the same scale, the overall scale score provided increased evidence for linkage to that region over any individual subtest. Association studies of candidate genes, particularly those involved in neural transmission and development, will be directed to genes located under the linkage peaks identified in this study.

Linkage analyses of event-related potential slow wave phenotypes recorded in a working memory task.

Working memory is an essential component of wide-ranging cognitive functions. It is a complex genetic trait probably influenced by numerous genes that individually have only a small influence. These genes may have an amplified influence on phenotypes closer to the gene action. In this study, event-related potential (ERP) phenotypes recorded during a working-memory task were collected from 656 adolescents from 299 families for whom genotypes were available. Univariate linkage analyses using the MERLIN variance-components method were conducted on slow wave phenotypes recorded at multiple sites while participants were required to remember the location of a target. Suggestive linkage (LOD > 2.2) was found on chromosomes 4, 5, 6, 10, 17, and 20. After correcting for multiple testing, suggestive linkage remained on chromosome 10. Empirical thresholds were computed for the most promising phenotypes. Those on chromosome 10 remained suggestive. A number of genes reported to regulate neural differentiation and function (i.e. NRP1, ANK3, and CHAT) were found under these linkage peaks and may influence the levels of neural activity occurring in individuals participating in a spatial working-memory task.

Genetic covariation between event-related potential (ERP) and behavioral non-ERP measures of working-memory, processing speed, and IQ.

The aim of this study was to identify genetic covariants for fundamental measures of brain function (event-related potentials (ERPs): P300 latency and slow wave amplitude recorded in a working-memory task) and more complex cognitive measures (behavioral non-ERP measures: working-memory performance, information processing speed, IQ). Data were collected from 252 monozygotic and 297 dizygotic twin pairs aged 16. Multivariate modeling identified two independent genetic factors associated with processing speed that also influenced working-memory performance (one reflected the duration of neural activity required to evaluate target information, the other reflected more general cognitive and speed-related abilities). However, the allocation of neural resources, as assessed by ERP slow wave amplitude measures, was not associated with the other cognitive measures investigated. Thus, of the ERP measures examined, P300 latency, but not slow wave amplitude, may be an informative measure to include (i.e., with working-memory performance) in future multivariate linkage and association analyses of cognitive function.

The n-back as a dual-task: P300 morphology under divided attention.

The n-back task was hypothesized to be a dual task, permitting the imposition of parametrically increasing attentional and working memory demands, while keeping constant the demands of an embedded matching subtask. Visual targets were presented for 200 ms every 2.2 s at pseudorandomly varying positions on a computer screen. Participants were required to remember the most recent 0, 1, 2, or 3 positions and responded with a choice button push to whether the current target position matched the position presented n items previously. P300 peak latency was constant across n-back tasks, reflecting constant perceptual and cognitive demands of the matching subtask. P300 peak amplitude decreased with increasing memory load, reflecting reallocation of attention and processing capacity away from the matching subtask to working memory activity. These data support a dual-task nature of the n-back, which should be considered when employing this paradigm.

Genetic influence on the variance in P3 amplitude and latency.

The P3(00) event-related potential (ERP) component is widely used as a measure of cognitive functioning and provides a sensitive electrophysiological index of the attentional and working memory demands of a task. This study investigated what proportion of the variance in the amplitude and latency of the P3, elicited in a delayed response working memory task, could be attributed to genetic factors. In 335 adolescent twin pairs and 48 siblings, the amplitude and latency of the P3 were examined at frontal, central, and parietal sites. Additive genetic factors accounted for 48% to 61% of the variance in P3 amplitude. Approximately one-third of the genetic variation at frontal sites was mediated by a common genetic factor that also influenced the genetic variation at parietal and central sites. Familial resemblance in P3 latency was due to genetic influence that accounted for 44% to 50% of the variance. Genetic covariance in P3 latency across sites was substantial, with a large part of the variance found at parietal, central, and frontal sites attributed to a common genetic factor. The findings provide further evidence that the P3 is a promising phenotype of neural activity of the brain and has the potential to be used in linkage and association analysis in the search for quantitative trait loci (QTLs) influencing cognition.

Genetic covariance among measures of information processing speed, working memory, and IQ.

The genetic relationship between lower (information processing speed), intermediate (working memory), and higher levels (complex cognitive processes as indexed by IQ) of mental ability was studied in a classical twin design comprising 166 monozygotic and 190 dizygotic twin pairs. Processing speed was measured by a choice reaction time (RT) task (2-, 4-, and 8-choice), working memory by a visual-spatial delayed response task, and IQ by the Multidimensional Aptitude Battery. Multivariate analysis, adjusted for test-retest reliability, showed the presence of a genetic factor influencing all variables and a genetic factor influencing 4- and 8-choice RTs, working memory, and IQ. There were also genetic factors specific to 8-choice RT, working memory, and IQ. The results confirmed a strong relationship between choice RT and IQ (phenotypic correlations: -0.31 to -0.53 in females, -0.32 to -0.56 in males; genotypic correlations: -0.45 to -0.70) and a weaker but significant association between working memory and IQ (phenotypic: 0.26 in females, 0.13 in males; genotypic: 0.34). A significant part of the genetic variance (43%) in IQ was not related to either choice RT or delayed response performance, and may represent higher order cognitive processes.

Genetic influence on ERP slow wave measures of working memory.

Individual differences in the variance of event-related potential (ERP) slow wave (SW) measures were examined. SW was recorded at prefrontal and parietal sites during memory and sensory trials of a delayed-response task in 391 adolescent twin pairs. Familial resemblance was identified and there was a strong suggestion of genetic influence. A common genetic factor influencing memory and sensory SW was identified at the prefrontal site (accounting for an estimated 35%-37% of the reliable variance) and at the parietal site (51%-52% of the reliable variance). Remaining reliable variance was influenced by unique environmental factors. Measurement error accounted for 24% to 30% of the total variance of each variable. The results show genetic independence for recording site, but not trial type, and suggest that the genetic factors identified relate more directly to brain structures, as defined by the cognitive functions they support, than to the cognitive networks that link them.

Concussion in contact sports: reliable change indices of impairment and recovery.

This paper reports a follow-up study to an article on the sensitivity of three tests of speed of information processing to impairment after concussion (Hinton-Bayre, Geffen, & McFarland, 1997). Group analyses showed that practice effects can obscure the effects of concussion on information processing, thereby making the assessment of functional impairment and recovery after injury unreliable. A Reliable Change Index (RCI) was used to assess individual variations following concussion. It was found that 16 of the 20 concussed professional rugby league players were impaired 1-3 days following injury. It was also demonstrated that 7 players still displayed cognitive deficits at 1-2 weeks, before returning to preseason levels at 3-5 weeks. The RCI permits comparisons between different tests, players, and repeated assessments, thereby providing a quantitative basis for decisions regarding return to play.

Effects of memory load and distraction on performance and event-related slow potentials in a visuospatial working memory task.

Brain electrical activity related to working memory was recorded at 15 scalp electrodes during a visuospatial delayed response task. Participants (N = 18) touched the remembered position of a target on a computer screen after either a 1 or 8 sec delay. These memory trials were compared to sensory trials in which the target remained present throughout the delay and response periods. Distractor stimuli identical to the target were briefly presented during the delay on 30% of trials. Responses were less accurate in memory than sensory trials, especially after the long delay. During the delay slow potentials developed that were significantly more negative in memory than sensory trials. The difference between memory and sensory trials was greater at anterior than posterior electrodes. On trials with distractors, the slow potentials generated by memory trials showed further enhancement of negativity, whereas there were minimal effects on accuracy of performance. The results provide evidence that engagement of visuospatial working memory generates slow wave negativity with a timing and distribution consistent with frontal activation. Enhanced brain activity associated with working memory is required to maintain performance in the presence of distraction.

ERP measures of stimulus processing during an auditory oddball task in Parkinson's disease: Evidence for an early information processing deficit.

Seventeen non-demented patients with idiopathic Parkinson's disease were compared with an age and sex matched control group on an auditory oddball task. Low probability target tones were either counted silently or responded to by a button press. N1 amplitude in the Parkinson group was attenuated to both target and non-target tones suggesting an impairment in early information processing. In contrast amplitudes of P2, N2 and P3 did not differentiate patients from controls. Several peak latencies (P2, N2 and P3) were increased in the Parkinson group when targets were counted, whereas only N2 was delayed when targets were identified by a button press. The longer N2 latency is suggestive of an increase in the time needed to categorize stimuli. The amplitude and latency changes of early ERP components provide evidence for impairment in early information processing in Parkinson's disease.

Event related potentials during covert orientation of visual attention: effects of cue validity and directionality.

Covert orientation of attention was studied in 30 adults who fixated warning cues and pressed a button at target onset. Directional cues (arrows) indicated the most probable (p = 0.8) side of target occurrence. Subjects responded fastest when validly cued, slowest to invalidly cued targets, and at an intermediate rate when the cue (a cross) was not directional. Directional cues took longer to evaluate (increased N1 and P2 latencies) and produced more focussed attention and greater response preparation (enhanced CNV and P3 amplitude) than non-directional cues. These findings indicate that the expectancy of a target can be manipulated by a spatial cue at three levels, sensory, attention, and response preparation, and lead to changes in the sensory perceptual processing of the target. Validly cued targets produced an increase in P1 amplitude reflecting attention enhanced sensory processing whereas invalidly cued targets increased N1 and P3 amplitudes reflecting the re-orientation of attention, and further processing and updating of information required of low probability stimuli respectively. P3 latency to invalidly cued targets was also delayed reflecting the additional processes required to shift attention to a new location. The P3 latency validity effect was smaller than that found for response time suggesting response execution may also be affected by spatial attention.

Interhemispheric control of manual motor activity.

The interhemispheric control of manual motor processes is reviewed, focusing on the clinical evidence from patients with commissurotomies and with agenesis of the corpus callosum. There is little evidence for a role of the corpus callosum in transferring explicit motor commands. Rather, the corpus callosum seems important for transferring lateralised information (such as verbal or visuospatial activity) of the pre-motor variety. Also, the corpus callosum may become very significant when movement begins: there appears to be a transcallosal passage of corollary motor signals and feedback sensory signals that are used to control asychronous bimanual movements and to inhibit the opposite hemisphere from interfering when a simple unimanual movement is required.

Event-related potential indices of visual attention following moderate to severe closed head injury.

Covert orientation of visual attention was studied in eight closed head injury (CHI) subjects who fixated warning cues and pressed a button at peripheral target onset. Directional cues (arrows) indicated the most probable (p = 0.8) side of target occurrence while neutral cues (crosses) gave no directional information. A NoGo cue (vertical bar) indicated no response was required. Compared to eight matched controls the CHI subjects displayed slowed processing of all cues (increased P2, N2 and P3 latencies). Also, evidence was found for very early impairment (increased P2 amplitude) in directing attention. Further, the CHI group did not show the normal attenuated CNV after NoGo signals, suggesting perseverative behaviour. Finally, the amplitude and latency of the P3 component (post-cue and post-target) approached normal as time since injury increased.

Test-retest reliability of a new form of the auditory verbal learning test (AVLT).

The equivalence between the original form (Form 1) of the Auditory Verbal Learning Test (AVLT), and a new form (Form 4) was examined in 51 normal adult subjects (20-67 years) of average estimated intelligence who were assessed in two separate sessions. Performance on the new form was equivalent to that on the original and most measures on the two tests showed significant positive correlations. Test-retest reliability of AVLT scores between sessions was also assessed, both globally and separately for Form 1 followed by Form 4 and for the reverse order. The most reliable measures on the AVLT were the total number of words learned over the five learning trials, (r =.77), and performance on the retention trial of the learning list following the presentation and performance of the distractor list (r =.70). These measures are sufficiently robust for use in clinical serial assessments.

Auditory verbal learning test components as measures of the severity of closed-head injury.

Auditory verbal learning and memory was assessed in 18 patients with moderate-severe closed-head injury (CHI). Compared to a matched control group, performance of the CHI subjects on all measures of the Auditory Verbal Learning Test (AVLT) was significantly worse. Discriminant function analysis correctly classified 90% of subjects as CHI or control using the three most reliable measures of the AVLT. Retention of the learning list following the distractor trial varied with severity of injury as indexed by duration of post-traumatic amnesia (PTA). The more severe the injury (longer PTA), the fewer words were recalled after interference (r = -0.72). Susceptibility of verbal memory to retroactive interference is sensitive to the presence and severity of CHI.

Persistent visuospatial attention deficits following mild head injury in Australian Rules football players.

The ability to direct visuospatial attention covertly was studied in two groups of Australian Rules football players who had sustained mild head injuries (MHI) during competition. Their performance was compared to 12 non-injured sportsmen using a cued reaction time (RT) task which measured the RT benefit of valid directional cueing and the RT cost of miscueing. In Experiment 1, nine footballers tested within 2 weeks of sustaining their injury showed the same cost as normals in speed of response to targets in the unexpected visual field. However, their responses to targets in the expected location (following valid cues) showed only a minor benefit compared to controls. Moderate to severely injured patients also show a normal cost but a reduced or absent benefit (Cremona-Meteyard and Geffen, Neuropsychologia 30, 123-132, 1992). When subjects were retested 1 year later their pattern of performance had not altered but overall RT had improved. Experiment 2 replicated these findings in another eight footballers tested at least 1 year after sustaining their MHI. A persistent consequence of MHI might be an inability to take action quickly in response to expected events.

Event-related potentials associated with covert orientation of visual attention in Parkinson's disease.

Event-related potentials (ERPs) were measured in a group of patients with idiopathic Parkinson's disease and compared with a matched control group during a task involving covert orientation of visual attention. Central warning cues directed attention to the probable location of a lateralized signal that required a button-press response. Parkinson patients had enhanced post-cue P1 (at Oz) and P2 (at Cz) amplitudes, delayed N1 (at Oz) latencies, and diminished CNV amplitudes. Post-target amplitudes were similar to controls, except for an enhanced P1 to invalidly cued targets, and delayed N1 and P3 target latencies. These results indicate that Parkinson patients, in addition to their motor deficits, process spatial cues more effortfully and slowly, have impaired response preparation, and process imperative stimuli more slowly.

Event-related potential measurement of deficits in information processing following moderate to severe closed head injury.

Event-related potentials may offer more precision than behavioural measures for understanding the extent and timing of information processing difficulties that follow closed head injury (CHI). Behavioural tests consistently indicate a general reduction in cognitive function but lack adequate diagnostic or prognostic function. This study compares a group of seven CHI patients, in which time since injury varied between 1 and 5 years following injury, with 10 matched controls on a three-tone discrimination task. Abnormality in the processing of tones as early as 200 ms following their onset, as measured by the P2 and N2 components of the event-related potential, indicated a general difficulty with tone discrimination. This abnormality was obtained despite differing damage profiles over patients and is likely to be due to the diffuse aspects of damage normal in CHI. These results also indicate that functional deficits in CHI patients can extend up to 5 years or more. A correlation between P2/N2 amplitudes and time since injury, however, suggests that both these components normalize with the passage of time and offers the prospect of a sensitive, non-behavioural measure of recovery in cognitive processing.

Covert orientation of visual attention after closed head injury.

The ability to orient visual attention covertly was studied in 11 patients who had suffered a moderate or severe closed head injury (CHI) at least 1 year previously. Their performance was compared to nine matched controls using a cued reaction time (RT) task which measured the RT benefit of valid directional cueing and the RT cost of miscueing. The CHI and control groups did not differ in overall RT. Relative to controls, the CHI group showed normal cost but hardly any benefit, indicating that the normal capacity to pre-align attention with a cued location was impaired.