Ciara M. Greene

Imaging the genetics of executive function

Recent advances in neuroimaging technologies have allowed ever more detailed studies of the human brain. The combination of neuroimaging techniques with genetics may provide a more sensitive measure of the influence of genetic variants on cognitive function than behavioural measures alone. Here we present a review of functional magnetic resonance imaging (fMRI) studies of genetic links to executive functions, focusing on sustained attention, working memory and response inhibition. In addition to studies in the normal population, we also address findings from three clinical populations: schizophrenia, ADHD and autism spectrum disorders. While the findings in the populations studied do not always converge, they all point to the usefulness of neuroimaging techniques such as fMRI as potential endophenotypes for parsing the genetic aetiology of executive function.

Interplay between affect and arousal in recognition memory.

Background Emotional states linked to arousal and mood are known to affect the efficiency of cognitive performance. However, the extent to which memory processes may be affected by arousal, mood or their interaction is poorly understood. Methodology/Principal Findings Following a study phase of abstract shapes, we altered the emotional state of participants by means of exposure to music that varied in both mood and arousal dimensions, leading to four different emotional states: (i) positive mood-high arousal; (ii) positive mood-low arousal; (iii) negative mood-high arousal; (iv) negative mood-low arousal. Following the emotional induction, participants performed a memory recognition test. Critically, there was an interaction between mood and arousal on recognition performance. Memory was enhanced in the positive mood-high arousal and in the negative mood-low arousal states, relative to the other emotional conditions. Conclusions/Significance Neither mood nor arousal alone but their interaction appears most critical to understanding the emotional enhancement of memory.

Behaviour of spectral entropy, spectral edge frequency 90%, and alpha and beta power parameters during low-dose propofol infusion

BACKGROUND In this study we analyse the behaviour, potential clinical application and optimal cortical sampling location of the spectral parameters: (i) relative alpha and beta power; (ii) spectral edge frequency 90%; and (iii) spectral entropy as monitors of moderate propofol-induced sedation. METHODS Multi-channel EEG recorded from 12 ASA 1 (American Society of Anesthesiologists physical status 1) patients during low-dose, target effect-site controlled propofol infusion was used for this analysis. The initial target effect-site concentration was 0.5 microg ml(-1) and increased at 4 min intervals in increments of 0.5 to 2 microg ml(-1). EEG parameters were calculated for 2 s epochs in the frequency ranges 0.5-32 and 0.5-47 Hz. All parameters were calculated in the channels: P4-O2, P3-O1, F4-C4, F3-C3, F3-F4, and Fp1-Fp2. Sedation was assessed clinically using the OAA/S (observers assessment of alertness/sedation) scale. RESULTS Relative beta power and spectral entropy increased with increasing propofol effect-site concentration in both the 0.5-47 Hz [F(18, 90) = 3.455, P<0.05 and F(18, 90) = 3.33, P<0.05, respectively] and 0.5-32 Hz frequency range. This effect was significant in each individual channel (P<0.05). No effect was seen of increasing effect-site concentration on relative power in the alpha band. Averaged across all channels, spectral entropy did not outperform relative beta power in either the 0.5-32 Hz [Pk=0.79 vs 0.814 (P>0.05)] or 0.5-47 Hz range [Pk=0.81 vs 0.82 (P>0.05)]. The best performing indicator in any single channel was spectral entropy in the frequency range 0.5-47 Hz in the frontal channel F3-F4 (Pk=0.85). CONCLUSIONS Relative beta power and spectral entropy when considered over the propofol effect-site range studied here increase in value, and correlate well with clinical assessment of sedation.

Neural effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253†

The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains‐1 (CSMD1) gene on 8p23.2 has been identified as genome‐wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel‐based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk “A” allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified “A” risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk.

The Effect of the Neurogranin Schizophrenia Risk Variant rs12807809 on Brain Structure and Function

A single nucleotide polymorphism rs12807809 located upstream of the neurogranin (NRGN) gene has been identified as a risk variant for schizophrenia in recent genome-wide association studies. To date, there has been little investigation of the endophenotypic consequences of this variant, and our own investigations have suggested that the effects of this gene are not apparent at the level of cognitive function in patients or controls. Because the impact of risk variants may be more apparent at the level of brain, the aim of this investigation was to delineate whether NRGN genotype predicted variability in brain structure and/or function. Healthy individuals participated in structural (N = 140) and/or functional (N = 36) magnetic resonance imaging (s/fMRI). Voxel-based morphometry was used to compare gray and white matter volumes between carriers of the non-risk C allele (i.e., CC/CT) and those who were homozygous for the risk T allele. Functional imaging data were acquired during the performance of a spatial working memory task, and were also analyzed with respect to the difference between C carriers and T homozygotes. There was no effect of the NRGN variant rs12807809 on behavioral performance or brain structure. However, there was a main effect of genotype on brain activity during performance of the working memory task, such that while C carriers exhibited a load-independent decrease in left superior frontal gyrus/BA10, TT individuals failed to show a similar decrease in activity. The failure to disengage this ventromedial prefrontal region, despite preserved performance, may be indicative of a reduction in processing efficiency in healthy TT carriers. Although it remains to be established whether this holds true in larger samples and in patient cohorts, if valid, this suggests a potential mechanism by which NRGN variability might contribute to schizophrenia risk.

Functional connectivity between ventral and dorsal frontoparietal networks underlies stimulus-driven and working memory-driven sources of visual distraction.

We investigate the neural basis of two routes to visual distraction: salient stimuli capture attention in a bottom-up fashion and the reappearance of task-irrelevant items that are being actively maintained in working memory can lead to distraction via top-down, but automatic, guidance of attention. Bottom-up, stimulus-driven distraction has typically been associated with a ventral network incorporating the inferior frontal gyrus and temporoparietal junction. A dorsal network including the superior frontal gyrus, superior parietal cortex and intraparietal sulcus is known to underlie the voluntary, top-down control of attention. Here we show that the ventral attention network may be modulated in a top-down manner by task-irrelevant memory signals. Furthermore, we delineate how the biasing of attention by these bottom-up and top-down sources of visual distraction is modulated by changes in connectivity among critical nodes of ventral and dorsal frontoparietal regions. The findings further our understanding of the neural circuitry that mediates the control of human visual attention.

Neural repetition effects in the medial temporal lobe complex are modulated by previous encoding experience

It remains an intriguing question why the medial temporal lobe (MTL) can display either attenuation or enhancement of neural activity following repetition of previously studied items. To isolate the role of encoding experience itself, we assessed neural repetition effects in the absence of any ongoing task demand or intentional orientation to retrieve. Experiment 1 showed that the hippocampus and surrounding MTL regions displayed neural repetition suppression (RS) upon repetition of past items that were merely attended during an earlier study phase but this was not the case following re-occurrence of items that had been encoded into working memory (WM). In this latter case a trend toward neural repetition enhancement (RE) was observed, though this was highly variable across individuals. Interestingly, participants with a higher degree of neural RE in the MTL complex displayed higher memory sensitivity in a later, surprise recognition test. Experiment 2 showed that massive exposure at encoding effected a change in the neural architecture supporting incidental repetition effects, with regions of the posterior parietal and ventral-frontal cortex in addition to the hippocampus displaying neural RE, while no neural RS was observed. The nature of encoding experience therefore modulates the expression of neural repetition effects in the MTL and the neocortex in the absence of memory goals.

Perceptual Load Affects Eyewitness Accuracy and Susceptibility to Leading Questions.

Load Theory (Lavie, 1995, 2005) states that the level of perceptual load in a task (i.e., the amount of information involved in processing task-relevant stimuli) determines the efficiency of selective attention. There is evidence that perceptual load affects distractor processing, with increased inattentional blindness under high load. Given that high load can result in individuals failing to report seeing obvious objects, it is conceivable that load may also impair memory for the scene. The current study is the first to assess the effect of perceptual load on eyewitness memory. Across three experiments (two video-based and one in a driving simulator), the effect of perceptual load on eyewitness memory was assessed. The results showed that eyewitnesses were less accurate under high load, in particular for peripheral details. For example, memory for the central character in the video was not affected by load but memory for a witness who passed by the window at the edge of the scene was significantly worse under high load. High load memories were also more open to suggestion, showing increased susceptibility to leading questions. High visual perceptual load also affected recall for auditory information, illustrating a possible cross-modal perceptual load effect on memory accuracy. These results have implications for eyewitness memory researchers and forensic professionals.

Distinct parietal sites mediate the influences of mood, arousal, and their interaction on human recognition memory

The two dimensions of emotion, mood valence and arousal, have independent effects on recognition memory. At present, however, it is not clear how those effects are reflected in the human brain. Previous research in this area has generally dealt with memory for emotionally valenced or arousing stimuli, but the manner in which interacting mood and arousal states modulate responses in memory substrates remains poorly understood. We investigated memory for emotionally neutral items while independently manipulating mood valence and arousal state by means of music exposure. Four emotional conditions were created: positive mood/high arousal, positive mood/low arousal, negative mood/high arousal, and negative mood/low arousal. We observed distinct effects of mood valence and arousal in parietal substrates of recognition memory. Positive mood increased activity in ventral posterior parietal cortex (PPC) and orbitofrontal cortex, whereas arousal condition modulated activity in dorsal PPC and the posterior cingulate. An interaction between valence and arousal was observed in left ventral PPC, notably in a parietal area distinct from the those identified for the main effects, with a stronger effect of mood on recognition memory responses here under conditions of relative high versus low arousal. We interpreted the PPC activations in terms of the attention-to-memory hypothesis: Increased arousal may lead to increased top-down control of memory, and hence dorsal PPC activation, whereas positive mood valence may result in increased activity in ventral PPC regions associated with bottom-up attention to memory. These findings indicate that distinct parietal sites mediate the influences of mood, arousal, and their interplay during recognition memory.

Dynamic states in working memory modulate guidance of visual attention: Evidence from an n-back paradigm

Items held in working memory (WM) can automatically bias attention when they reappear in visual displays. Recent evidence, however, suggests that WM biases of attention may be reduced under certain conditions, for example with increasing memory load. We employed a dual task paradigm to investigate how WM biases are affected by dynamic updating of memory contents. 1-back and 2-back versions of a memory task with colour stimuli were interrupted at intervals by an unrelated visual search task. Reappearance in the search display of the item that was currently active in WM guided attention, while suppressed or inactive items did not. We conclude that the rapid updating of memory contents facilitates the shifting of memory representations into different activity states on a moment-to-moment basis. The finding is consistent with models that propose that only one item can be “active” in WM at any one time to guide attention.