Edited by: Sebastian Heinzel, Hertie-Institute for Clinical Brain Research (HIH), Germany
Reviewed by: Alexander Strobel, Technische Universitaet Dresden, Germany; Karolina Kauppi, University of Oslo, Norway
*Correspondence: Björn H. Schott, Leibniz-Institut für Neurobiologie, Brenneckestr. 6, 39118 Magdeburg, Germany e-mail:
This article was submitted to the journal Frontiers in Human Neuroscience.
†These authors share senior authorship.
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The guanine nucleotide exchange factor
The Ras pathway (Ambrosini et al.,
Ras activation is controlled by inhibitory GTPase-activating proteins (GAPs) and activating guanine nucleotide exchange factors (GEFs) (Mizuno-Yamasaki et al.,
Given the combined ocular and hippocampal phenotype of
We investigated the potential effect of
Genomic DNA was extracted from EDTA-anticoagulated venous whole blood using the GeneMole automated DNA extraction system (Mole Genetics, Lysaker, Norway) according to the manufacturer's protocol. Genotyping of
The participants were recruited from a cohort investigated at the Department of Psychology, University of Magdeburg, described in detail previously (Richter et al.,
The cohort consisted of 719 young (age mean ±
119 young (age mean ±
63 young (mean age ±
All experiments were programmed and conducted by means of the Presentation® software (version 0.71, Neurobehavioral Systems Inc.,
All subjects of the first and second cohort performed a computer-based version of the VLMT, adapted with slight modifications from (Helmstaedter et al.,
All subjects of the first and second cohort took part in a computer-based German auditory version of the WMS for logical memory. The testing procedure had been adapted and slightly modified from (Härting et al.,
To examine the influence of
Due to the observed ceiling effects (see Results section, Trial 3 in both cohorts) particularly in the second cohort, both cohorts were divided into three groups, based on the total value of memory performance (sum value of all trials). The upper quartile formed the group of
During the fMRI session the subjects performed an incidental encoding task. Eighty-eight novel images (44 indoor and 44 outdoor) and 22 repetitions of each of two familiar images (one indoor and one outdoor scene) were presented in a pseudo-randomized order. The two familiar images (“master pictures”) had been familiarized over five repetitions each directly before MRI acquisition. During the actual experiment, stimuli were shown for 2.5 s, each with an average inter-stimulus interval (ISI) of 1000 ms (jittered around the average ISI with an SD of 600 ms), during which a fixation cross was shown. The order of stimulus presentation was optimized for event-related fMRI time series sampling (Hinrichs et al.,
Approximately 90 min after the start of the fMRI session, participants performed a recognition memory task with a five-step confidence rating during which the 90 images from the fMRI session were presented randomly intermixed with 44 distractors that had not been presented before (22 indoor–22 outdoor). The task was performed outside the MR tomograph. Subjects rated their recognition confidence on a scale ranging from 1 to 5 (“1”: definitely new; “2”: likely new; “3”: unsure; “4”: likely old; “5”: definitely old). Based on these confidence ratings fMRI data were modeled.
MRI data were acquired using a Verio Syngo 3T MR system (Siemens Medical Systems, Erlangen) with a 32-channel head coil. Prior to the functional MRI session, a T1-weigthed 3D Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) image was acquired (192 sagittal slices, image matrix = 256 × 256, field of view (FOV) = 256 × 256 mm2, slice thickness = 1 mm,
Data were analyzed using Statistical Parametric Mapping (SPM8, Wellcome Department of Imaging Neuroscience, Institute of Neurology, London, UK). EPIs were corrected for acquisition delay and head motion. EPIs were co-registered to the mean image obtained from motion correction and used to determine normalization parameters for spatial normalization to the Montreal Neurological Institute (MNI) stereotactic coordinate system (voxel size = 2 × 2 × 2 mm3). Data were smoothed using an isotropic Gaussian kernel of 6 mm full width at half maximum.
Statistical analysis was performed using a two-stage mixed effects model. At the first stage, the stimulus-specific BOLD responses were modeled by convolving a delta function at stimulus onset with a canonical hemodynamic response function (HRF; Friston et al.,
After being positioned in the MR scanner, participants were given a short demonstration of the task and completed a practice session lasting 2:54 min (20 trials). This practice session should minimize learning effects during functional data acquisition and was intended to lead to a switching of reward responses from the moment of reward receipt to the time of reward anticipation (Wittmann et al.,
Each of the two reward sessions consisted of 100 trials lasting 14:06 min (50 reward and 50 no-reward trials). A modified version of the monetary incentive delay task described previously (Wittmann et al.,
Approximately 24 h after the start of the fMRI session, participants performed a recognition memory task with a five-step confidence rating during which the 200 cue images from the fMRI session were presented randomly intermixed with 100 distracters that had not been presented before. The task was performed outside the MRI scanner. Subjects rated their recognition confidence on a scale ranging from 1 to 5 (“5”: definitely new; “4”: likely new; “3”: unsure; “2”: likely old; “1”: definitely old). These confidence ratings were used to model the relationship between individual behavior and brain response during first-level fMRI data analysis. See Supporting Information for details on used reward stimuli and cues signaling reward.
fMRI was performed using a 3 Tesla Siemens Magnetom Trio Scanner (SIEMENS Medical Systems, Erlangen, Germany) and a 12-channel phased array head coil. We collected structural (T1-weighted MPRAGE: 256 × 256 matrix; FOV = 256 mm; 96 2-mm sagittal slices) and functional images (Gradient-Echo-EPI-sequence;
Image processing and statistical analyses were performed using SPM8 (
Among the 355 study participants in the first cohort, we identified 95 individuals homozygous for the T allele of rs8027411, 186 heterozygotes, and 74 G homozygotes. The genotype distribution was in Hardy-Weinberg equilibrium (HWE) (χ2 = 0.94,
Women/Men | 53/42 | 96/90 | 39/35 | χ2 = 0.44; |
Mean age | 23.0 ± 3.1 | 23.1 ± 2.9 | 22.4 ± 2.7 | |
Women/Men | 110/83 | 175/159 | 90/102 | χ2 = 3.96; |
Mean age | 23.8 ± 2.9 | 23.9 ± 2.6 | 23.5 ± 2.9 | |
Ametropia/no ametropia | 89/74 | 151/136 | 76/90 | χ2 = 2.93; |
Women/Men | 16/15 | 30/24 | 12/22 | χ2 = 3.57; |
Mean age | 24.0 ± 2.7 | 24.4 ± 2.6 | 24.6 ± 2.5 | |
Women/Men | 3/9 | 19/12 | 9/11 | χ2 = 4.77; |
Mean age | 24.9 ± 1.9 | 24.0 ± 2.4 | 25.2 ± 3.6 |
The numbers of correctly recalled words (VLMT) and correctly recalled story items (WMS, logical memory) are displayed in Figures
Trial 1 | 10.1 ± 2.2 | 9.8 ± 2.3 | 10.1 ± 2.3 |
Trial 2 | 13.0 ± 1.6 | 12.5 ± 1.9 | 12.1 ± 2.2 |
Trial 3 | 13.8 ± 1.4 | 13.4 ± 1.7 | 12.9 ± 2.1 |
Recall 24 h | 10.7 ± 2.7 | 10.4 ± 2.6 | 10.3 ± 2.8 |
Trial 1 | 10.2 ± 2.3 | 10.2 ± 2.3 | 9.9 ± 2.5 |
Trial 2 | 13.3 ± 1.6 | 13.2 ± 1.8 | 12.8 ± 2.1 |
Trial 3 | 14.0 ± 1.2 | 14.1 ± 1.2 | 13.9 ± 1.4 |
Trial 4 | 14.3 ± 1.0 | 14.3 ± 1.1 | 14.3 ± 1.2 |
Trial 5 | 14.6 ± 0.7 | 14.6 ± 0.9 | 14.5 ± 0.9 |
Distractor trial | 10.4 ± 2.6 | 10.4 ± 2.5 | 10.4 ± 2.7 |
Trial 6 | 14.2 ± 1.3 | 14.4 ± 1.1 | 14.1 ± 1.6 |
Recall 30 min | 14.4 ± 1.1 | 14.4 ± 1.0 | 14.2 ± 1.3 |
Recall 24 h | 13.8 ± 1.8 | 13.7 ± 1.7 | 13.5 ± 2.1 |
Immediate recall | 15.7 ± 3.8 | 15.1 ± 3.3 | 14.7 ± 3.8 |
Recall 24 h | 11.5 ± 5.8 | 10.4 ± 3.5 | 10.0 ± 3.6 |
Immediate recall | 33.7 ± 5.7 | 33.0 ± 5.6 | 32.6 ± 6.1 |
Recall 30 min | 32.1 ± 5.9 | 31.6 ± 5.7 | 30.9 ± 6.3 |
Recall 24 h | 31.6 ± 6.3 | 31.0 ± 5.7 | 30.9 ± 6.3 |
A two-way ANCOVA for repeated measures with memory (number of correctly recalled items in trials 1–3 and in 24-h free recall trial) as within-subject factor,
A detailed overview of all significant effects is given in Supplementary Table
A two-way ANCOVA for repeated measures with memory performance (number of correctly recalled items in immediate recall and 24 h delayed recall) as within-subject factor,
To assess the effects of
The reaction times (RTs) of the indoor/outdoor decision during the encoding phase in the MRI scanner were comparable across the
Independently of genotype, the analysis of the novelty contrast (BOLD responses to novel stimuli that were later correctly recognized compared to the highly familiar “master” pictures) revealed significant activations in a temporo-occipital network including the right hippocampus [(x, y, z) = (28, −42, −12);
To further substantiate the role of the
We performed two ANCOVAs for repeated measures (separately for each reward type) with corrected hit rate for reward predicting cues and corrected hit rate for no reward predicting cues as within-subject factor,
Group level analysis of the effect of
In our two independent study cohorts of young, healthy participants (
We observed a relationship between a genetic variation in the
In accordance with the positive relationship between T allele carrier status and memory performance we observed a modifying effect of
Our observation that a genetic variant in a putative
In fMRI experiment 2, the behavioral and neural effect of
As a nucleotide exchange factor that activates Ras (Raaijmakers and Bos,
The present data, along with the previously published GWAS, suggest that the same genetic variation, rs8027411 T, adversely affects vision, but exerts beneficial effects on memory performance. Therefore, rs8027411 may serve as an example that certain variants with apparently deleterious effects are present in the population if they are potentially advantageous in other biological processes. Given the small effect sizes, this interpretation remains, however, tentative. The relationship between refractive error and human cognitive function is complex. Myopia is overrepresented in individuals with high intelligence (for review see Czepita et al.,
Our results provide evidence for a role of
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors would like to thank Ina Schanze for help with obtaining blood samples. We further thank Catherine Libeau and Carola Nath for assistance with data analysis, Annika Schult for support in designing the stimulus set in fMRI experiment 2 and Katja Neumann, Renate Blobel, Kerstin Möhring, Denise Scheermann, Ilona Wiedenhöft, and Claus Tempelmann for assistance with MRI acquisition. This project was supported by the Leibniz Graduate School Synaptogenetics (Ph.D. stipend to Adriana Barman; Master stipend to Marieke Klein and Anni Richter) and the Deutsche Forschungsgemeinschaft (SFB 779, TP A8 and A7).
The Supplementary Material for this article can be found online at: