Guillén Fernández’s research while affiliated with Radboud University Medical Centre (Radboudumc) and other places

Stressful events are typically well remembered, but their effects on memory for surrounding neutral events and the underlying mechanisms remain less clear. We hypothesized that stress would enhance memory for events surrounding the stressor, contingent on the memory of the stressor itself. Additionally, we predicted that memory for neutral events would be modulated by pairing them with stressor-related cues. To test these hypotheses, 122 healthy participants encoded a series of images before and after experiencing a stressful or control episode. During encoding, images were preceded by cues from stressor or control contexts. Memory for the stress or control episode and the encoded images was tested 24 h later. Our results showed enhanced memory prioritization, reflected in better memory for central versus peripheral features, for the stressful compared to the control episode. Exposure to the stressful episode further enhanced memory for neutral images preceding the stressor. However, this memory boost occurred only in participants with enhanced memory prioritization for the stressor. Memory for stimuli encoded after the stressor remained unaffected, and there was no evidence for the proposed cueing mechanism. These findings indicate that stressful events enhance memory consolidation only when these events themselves are distinctly represented in memory.

In this study, we explored the relationship between developmental differences in gray matter structure and grammar learning ability in 159 Dutch-speaking individuals (8 to 25 yr). The data were collected as part of a recent large-scale functional MRI study (Menks WM, Ekerdt C, Lemhöfer K, Kidd E, Fernández G, McQueen JM, Janzen G. Developmental changes in brain activation during novel grammar learning in 8-25-year-olds. Dev Cogn Neurosci. 2024;66:101347. https://doi.org/10.1016/j.dcn.2024.101347) in which participants implicitly learned Icelandic morphosyntactic rules and performed a grammaticality judgment task in the scanner. Behaviorally, Menks et al. (2024) showed that grammaticality judgment task performance increased steadily from 8 to 15.4 yr, after which age had no further effect. We show in the current study that this age-related grammaticality judgment task performance was negatively related to cortical gray matter volume and cortical thickness in many clusters throughout the brain. Hippocampal volume was positively related to age-related grammaticality judgment task performance and L2 (English) vocabulary knowledge. Furthermore, we found that grammaticality judgment task performance, L2 grammar proficiency, and L2 vocabulary knowledge were positively related to gray matter maturation within parietal regions, overlapping with the functional MRI clusters that were reported previously in Menks et al. (2024) and which showed increased brain activation in relation to grammar learning. We propose that this overlap in functional and structural results indicates that brain maturation in parietal regions plays an important role in second language learning.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson’s disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

Children and adults are excellent word learners. Increasing evidence suggests that the neural mechanisms that allow us to learn words change with age. In a recent fMRI study from our group, several brain regions exhibited age-related differences when accessing newly learned words in a second language (L2; Takashima et al. Dev Cogn Neurosci 37, 2019). Namely, while the Teen group (aged 14–16 years) activated more left frontal and parietal regions, the Young group (aged 8–10 years) activated right frontal and parietal regions. In the current study we analyzed the structural connectivity data from the aforementioned study, examining the white matter connectivity of the regions that showed age-related functional activation differences. Age group differences in streamline density as well as correlations with L2 word learning success and their interaction were examined. The Teen group showed stronger connectivity than the Young group in the right arcuate fasciculus (AF). Furthermore, white matter connectivity and memory for L2 words across the two age groups correlated in the left AF and the right anterior thalamic radiation (ATR) such that higher connectivity in the left AF and lower connectivity in the right ATR was related to better memory for L2 words. Additionally, connectivity in the area of the right AF that exhibited age-related differences predicted word learning success. The finding that across the two age groups, stronger connectivity is related to better memory for words lends further support to the hypothesis that the prolonged maturation of the prefrontal cortex, here in the form of structural connectivity, plays an important role in the development of memory.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signalling and brain ageing-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson’s disease and ADHD. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Appraisal refers to the evaluation of stimuli or situations with respect to an individual’s goals and needs. Stimuli or situations that are appraised as a threat to one’ goals and needs (‘stressors’) induce stress responses (‘stress’). Stressor appraisal occurs on various dimensions, of which the magnitude or cost of a potential adverse outcome, the probability of the outcome, and an individual’s coping potential are the most important. Individuals show subjective biases on each of these dimensions, which can range from extremely unrealistically negative to extremely unrealistically positive. Positive appraisal style (PAS) is an integrative construct. Individuals with a PAS have an average tendency to appraise stressors in a realistic to mildly unrealistically positive fashion across the different stressor appraisal dimensions; hence, they typically avoid both negative and also delusionally positive appraisals. Positive appraisal style theory of resilience (PASTOR) posits that this global bias is key for stress resilience, as it enables individuals to generate stress responses when needed but also to avoid unnecessary and over-shooting stress responses that will exhaust one’s resources and prevent resource replenishment during times of severe or lasting stressor exposure. We here use data from three prospective-longitudinal studies to compare recently validated self-report instruments for PAS with existing measures of appraisal biases in single dimensions in their relative predictive potential for resilience, using regularized regression methodology. We find that one PAS instrument, reflecting a tendency to produce general positive appraisal contents (PASS-content), and an optimism instrument, supposed to reflect a positive appraisal bias on the probability dimension, are consistent predictors of resilience over long time frames and superior in this quality to the other instruments (measures of positive appraisal processes, self-efficacy, and control). Generally, our results confirm the important role of appraisal biases in resilience. Item and nomological network analyses further indicate that the PASS-content instrument may more closely reflect individual differences in appraisal than the optimism instrument and thus be well suited for mechanistically interpretable prediction models based on well-defined psychological constructs. By contrast, the optimism instrument may reflect differences in life perspectives in addition to differences in appraisal. This makes the instrument less mechanistically interpretable; however, it may be better suited for clinical prediction models aiming at individual-level prognosis on the basis of maximized explained variance.