Leo Gschwind

Working memory training in patients with multiple sclerosis – comparison of two different training schedules

PURPOSE Evaluation of two different training schedules of a computer based working memory training (BrainStim) in patients with multiple sclerosis (MS). METHOD Forty-five MS outpatients were allocated to two different training groups and a control group without training. Patients with treatment received 16 training sessions scheduled either as a high intensity training (4 times per week for 4 weeks) or as a distributed training (2 times per week for 8 weeks). A neuropsychological test battery including self-report measures was applied at baseline and at retest. The baseline assessment was performed twice at an interval of two weeks to control for possible learning effects. RESULTS In the outcome measures training for both intervention groups led to significantly improved fatigue symptoms as well as working memory -, and mental speed performances. Log files recorded during training showed a similar increase in levels of difficulty for both intervention groups as training progressed. No effects were found on short term memory, quality of life or depression. CONCLUSIONS Since comparable improvements were observed in both training groups, BrainStim can be applied as a therapeutic intervention adjusted to the personal agenda of MS patients.

Epigenetic Modification of the Glucocorticoid Receptor Gene Is Linked to Traumatic Memory and Post-Traumatic Stress Disorder Risk in Genocide Survivors

Recent evidence suggests that altered expression and epigenetic modification of the glucocorticoid receptor gene (NR3C1) are related to the risk of post-traumatic stress disorder (PTSD). The underlying mechanisms, however, remain unknown. Because glucocorticoid receptor signaling is known to regulate emotional memory processes, particularly in men, epigenetic modifications of NR3C1 might affect the strength of traumatic memories. Here, we found that increased DNA methylation at the NGFI-A (nerve growth factor-induced protein A) binding site of the NR3C1 promoter was associated with less intrusive memory of the traumatic event and reduced PTSD risk in male, but not female survivors of the Rwandan genocide. NR3C1 methylation was not significantly related to hyperarousal or avoidance symptoms. We further investigated the relationship between NR3C1 methylation and memory functions in a neuroimaging study in healthy subjects. Increased NR3C1 methylation–which was associated with lower NR3C1 expression–was related to reduced picture recognition in male, but not female subjects. Furthermore, we found methylation-dependent differences in recognition memory-related brain activity in men. Together, these findings indicate that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to interindividual and gender-specific differences in memory functions and PTSD risk.

PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors

Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα (PRKCA) was associated with memory capacity—including aversive memory—in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD.

A peripheral epigenetic signature of immune system genes is linked to neocortical thickness and memory

Increasing age is tightly linked to decreased thickness of the human neocortex. The biological mechanisms that mediate this effect are hitherto unknown. The DNA methylome, as part of the epigenome, contributes significantly to age-related phenotypic changes. Here, we identify an epigenetic signature that is associated with cortical thickness (P=3.86 × 10−8) and memory performance in 533 healthy young adults. The epigenetic effect on cortical thickness was replicated in a sample comprising 596 participants with major depressive disorder and healthy controls. The epigenetic signature mediates partially the effect of age on cortical thickness (P<0.001). A multilocus genetic score reflecting genetic variability of this signature is associated with memory performance (P=0.0003) in 3,346 young and elderly healthy adults. The genomic location of the contributing methylation sites points to the involvement of specific immune system genes. The decomposition of blood methylome-wide patterns bears considerable potential for the study of brain-related traits.

Testosterone levels in healthy men are related to amygdala reactivity and memory performance

Testosterone is a steroid hormone thought to influence both emotional and cognitive functions. It is unknown, however, if testosterone also affects the interaction between these two domains, such as the emotional arousal-induced enhancement of memory. Healthy subjects (N=234) encoded pictures taken from the International Affective Picture System (IAPS) during functional magnetic resonance imaging (fMRI) and underwent a free recall test 10 min after memory encoding. We show that higher endogenous testosterone levels at encoding were associated with higher arousal ratings of neutral pictures in men. fMRI analysis revealed that higher testosterone levels were related to increased brain activation in the amygdala during encoding of neutral pictures. Moreover, endogenous testosterone levels were positively correlated with the number of freely recalled neutral pictures. No such relations were found in women. These findings point to a male-specific role for testosterone in enhancing memory by increasing the biological salience of incoming information.

A genome-wide survey of human short-term memory

Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the α subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory.

Dynamic modulation of amygdala-hippocampal connectivity by emotional arousal

Positive and negative emotional events are better remembered than neutral events. Studies in animals suggest that this phenomenon depends on the influence of the amygdala upon the hippocampus. In humans, however, it is largely unknown how these two brain structures functionally interact and whether these interactions are similar between positive and negative information. Using dynamic causal modeling of fMRI data in 586 healthy subjects, we show that the strength of the connection from the amygdala to the hippocampus was rapidly and robustly increased during the encoding of both positive and negative pictures in relation to neutral pictures. We also observed an increase in connection strength from the hippocampus to the amygdala, albeit at a smaller scale. These findings indicate that, during encoding, emotionally arousing information leads to a robust increase in effective connectivity from the amygdala to the hippocampus, regardless of its valence.

A role for α-adducin (ADD-1) in nematode and human memory

Identifying molecular mechanisms that underlie learning and memory is one of the major challenges in neuroscience. Taken the advantages of the nematode Caenorhabditis elegans, we investigated α‐adducin (add‐1) in aversive olfactory associative learning and memory. Loss of add‐1 function selectively impaired short‐ and long‐term memory without causing acquisition, sensory, or motor deficits. We showed that α‐adducin is required for consolidation of synaptic plasticity, for sustained synaptic increase of AMPA‐type glutamate receptor (GLR‐1) content and altered GLR‐1 turnover dynamics. ADD‐1, in a splice‐form‐ and tissue‐specific manner, controlled the storage of memories presumably through actin‐capping activity. In support of the C. elegans results, genetic variability of the human ADD1 gene was significantly associated with episodic memory performance in healthy young subjects. Finally, human ADD1 expression in nematodes restored loss of C. elegans add‐1 gene function. Taken together, our findings support a role for α‐adducin in memory from nematodes to humans. Studying the molecular and genetic underpinnings of memory across distinct species may be helpful in the development of novel strategies to treat memory‐related diseases.

A genome-wide survey and functional brain imaging study identify CTNNBL1 as a memory-related gene.

Unbiased genome-wide screens combined with imaging data on brain function may identify novel molecular pathways related to human cognition. Here we performed a dense genome-wide screen to identify episodic memory-related gene variants. A genomic locus encoding the brain-expressed beta-catenin-like protein 1 (CTNNBL1) was significantly (P=7 × 10−8) associated with verbal memory performance in a cognitively healthy cohort from Switzerland (n=1073) and was replicated in a second cohort from Serbia (n=524; P=0.003). Gene expression studies showed CTNNBL1 genotype-dependent differences in beta-catenin-like protein 1 mRNA levels in the human cortex. Functional magnetic resonance imaging in 322 subjects detected CTNNBL1 genotype-dependent differences in memory-related brain activations. Converging evidence from independent experiments and different methodological approaches suggests a role for CTNNBL1 in human memory.

The association of the BDNF Val66Met polymorphism and the hippocampal volumes in healthy humans: A joint meta-analysis of published and new data

BACKGROUND The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (refSNP Cluster Report: rs6265) is a common and functionally relevant single nucleotide polymorphism (SNP). The gene itself, as well as the SNP rs6265, have been implicated in hippocampal learning and memory. However, imaging genetic studies have produced controversial results about the impact of this SNP on hippocampal volumes in healthy subjects. METHODS We examined the association between the rs6265 polymorphism and hippocampal volume in 643 healthy young subjects using automatic segmentation and subsequently included these data in a meta-analysis based on published studies with 5298 healthy subjects in total. RESULTS We found no significant association between SNP rs6265 and hippocampal volumes in our sample (g=0.05, p=0.58). The meta-analysis revealed a small, albeit significant difference in hippocampal volumes between genotype groups, such that Met-carriers had slightly smaller hippocampal volumes than Val/Val homozygotes (g=0.09, p=0.04), an association that was only evident when manual (g=0.22, p=0.01) but not automatic tracing approaches (g=0.04, p=0.38) were used. Studies using manual tracing showed evidence for publication bias and a significant decrease in effect size over the years with increasing sample sizes. CONCLUSIONS This study does not support the association between SNP rs6265 and hippocampal volume in healthy individuals. The weakly significant effect observed in the meta-analysis is mainly driven by studies with small sample sizes. In contrast, our original data and the meta-analysis of automatically segmented hippocampal volumes, which was based on studies with large samples sizes, revealed no significant genotype effect. Thus, meta-analyses of the association between rs6265 and hippocampal volumes should consider possible biases related to measuring technique and sample size.