Region- and time- specific effects of ketamine on cerebral blood flow: a randomized controlled trial.

There is intriguing evidence suggesting that ketamine might have distinct acute and delayed neurofunctional effects, as its acute administration transiently induces schizophrenia-like symptoms, while antidepressant effects slowly emerge and are most pronounced 24 h after administration. Studies attempting to characterize ketamine's mechanism of action by using blood oxygen level dependent (BOLD) imaging have yielded inconsistent results regarding implicated brain regions and direction of effects. This may be due to intrinsic properties of the BOLD contrast, while cerebral blood flow (CBF), as measured with arterial spin labeling, is a single physiological marker more directly related to neural activity. As effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release, a combination of these approaches should be particularly suited to offer novel insights. In total, 75 healthy participants were investigated in a double blind, placebo-controlled, randomized, parallel-group study and underwent two scanning sessions (acute/post 24 h.). Acute ketamine administration was associated with higher perfusion in interior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC), but no other investigated brain region. Inhibition of glutamate release by pretreatment with lamotrigine abolished ketamine's effect on perfusion. At the delayed time point, pretreatment with lamotrigine was associated with lower perfusion in IFG. These findings underscore the idea that regionally selective patterns of CBF changes reflect proximate effects of modulated glutamate release on neuronal activity. Furthermore, region- specific sustained effects indicate both a swift restoration of disturbed homeostasis in DLPFC as well changes occurring beyond the immediate effects on glutamate signaling in IFG.

Modulatory Effects of Ketamine and Lamotrigine on Cognition: Emotion Interaction in the Brain.

INTRODUCTION: Cognition and emotion are fundamentally integrated in the brain and mutually contribute to behavior. The relation between working memory (WM) and emotion is particularly suited to investigate cognition-emotion interaction since WM is an essential component of many higher cognitive functions. Ketamine affects not only WM but also has a profound impact on emotional processing. Effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Accordingly, a combination of these approaches should be particularly suited to investigate cognition-emotion interaction. METHODS: Seventy five healthy subjects were investigated in a double-blind, placebo-controlled, randomized, single-dose, parallel-group study with three treatment conditions. All subjects underwent two scanning sessions (acute/post 24 h). RESULTS: Compared to placebo, acute ketamine administration induced significant dissociative, psychotomimetic, and cognitive effects, as well as an increase in neural activity during WM for positive stimuli. Inhibition of glutamate release by pretreatment with lamotrigine did not influence ketamine's subjective effects, but significantly attenuated its impact on emotional WM and associated neural activity. There was no effect on these measures 24 h after ketamine administration. CONCLUSION: Our results demonstrate differential acute effects of modulated glutamate release and a swift restoration of disturbed neurobehavioral homeostasis in healthy subjects.

The effects of transient receptor potential cation channel inhibition by BI 1358894 on cortico-limbic brain reactivity to negative emotional stimuli in major depressive disorder.

Abnormal emotional processing in major depressive disorder (MDD) has been associated with increased activation to negative stimuli in cortico-limbic brain regions. The authors investigated whether treatment with BI 1358894, a small-molecule inhibitor of the transient receptor potential cation channel subfamily C leads to attenuated activity in these areas in MDD patients. 73 MDD patients were randomized to receive a single oral dose of BI 1358894 (100 mg), citalopram (20 mg), or matching placebo. Brain responses to emotional faces and scenes were investigated using functional magnetic resonance imaging. Primary endpoints were BOLD signal changes in response to negative faces in cortico-limbic brain regions, i.e. bilateral amygdala (AMY), dorsolateral prefrontal cortex, anterior insula (AI), and anterior cingulate cortex. Secondary endpoints were BOLD signal changes in response to negative scenes. For each region, separate ANOVA models were computed for the comparison of treatments (BI 1358894 or citalopram) vs. placebo. The adjusted treatment differences in the % BOLD signal changes in the faces task showed that BI 1358894 induced signal reduction in bilateral AMY and left AI. In the scenes task, BI 1358894 demonstrated significant signal reduction in bilateral AMY, AI, anterior cingulate cortex and left dorsolateral prefrontal cortex. Citalopram failed to induce any significant reductions in BOLD signal in both tasks. BI 1358894-mediated inhibition of the transient receptor potential cation channel subfamily resulted in strong signal reduction in cortico-limbic brain regions, thereby supporting development of this mechanism of action for MDD patients.

Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker.

BACKGROUND: Growing evidence underscores the utility of ketamine as an effective and rapid-acting treatment option for major depressive disorder (MDD). However, clinical outcomes vary between patients. Predicting successful response may enable personalized treatment decisions and increase clinical efficacy. METHODS: We here explored the potential of pregenual anterior cingulate cortex (pgACC) activity to predict antidepressant effects of ketamine in relation to ketamine-induced changes in glutamatergic metabolism. Prior to a single i.v. infusion of ketamine, 24 patients with MDD underwent functional magnetic resonance imaging during an emotional picture-viewing task and magnetic resonance spectroscopy. Changes in depressive symptoms were evaluated using the Beck Depression Inventory measured 24 hours pre- and post-intervention. A subsample of 17 patients underwent a follow-up magnetic resonance spectroscopy scan. RESULTS: Antidepressant efficacy of ketamine was predicted by pgACC activity during emotional stimulation. In addition, pgACC activity was associated with glutamate increase 24 hours after the ketamine infusion, which was in turn related to better clinical outcome. CONCLUSIONS: Our results add to the growing literature implicating a key role of the pgACC in mediating antidepressant effects and highlighting its potential as a multimodal neuroimaging biomarker of early treatment response to ketamine.

Subjective and objective difficulty of emotional facial expression perception from dynamic stimuli.

This study aimed to discover predictors of subjective and objective difficulty in emotion perception from dynamic facial expressions. We used a multidimensional emotion perception framework, in which observers rated the perceived emotion along a number of dimensions instead of choosing from traditionally-used discrete categories of emotions. Data were collected online from 441 participants who rated facial expression stimuli in a novel paradigm designed to separately measure subjective (self-reported) and objective (deviation from the population consensus) difficulty. We targeted person-specific (sex and age of observers and actors) and stimulus-specific (valence and arousal values) predictors of those difficulty scores. Our findings suggest that increasing age of actors makes emotion perception more difficult for observers, and that perception difficulty is underestimated by men in comparison to women, and by younger and older adults in comparison to middle-aged adults. The results also yielded an increase in the objective difficulty measure for female observers and female actors. Stimulus-specific factors-valence and arousal-exhibited quadratic relationships with subjective and objective difficulties: Very positive and very negative stimuli were linked to reduced subjective and objective difficulty, whereas stimuli of very low and high arousal were linked to decreased subjective but increased objective difficulty. Exploratory analyses revealed low relevance of person-specific variables for the prediction of difficulty but highlighted the importance of valence in emotion perception, in line with functional accounts of emotions. Our findings highlight the need to complement traditional emotion recognition paradigms with novel designs, like the one presented here, to grasp the "big picture" of human emotion perception.

Acute effects of ketamine on the pregenual anterior cingulate: linking spontaneous activation, functional connectivity, and glutamate metabolism.

Ketamine exerts its rapid antidepressant effects via modulation of the glutamatergic system. While numerous imaging studies have investigated the effects of ketamine on a functional macroscopic brain level, it remains unclear how altered glutamate metabolism and changes in brain function are linked. To shed light on this topic we here conducted a multimodal imaging study in healthy volunteers (N = 23) using resting state fMRI and proton (1H) magnetic resonance spectroscopy (MRS) to investigate linkage between metabolic and functional brain changes induced by ketamine. Subjects were investigated before and during an intravenous ketamine infusion. The MRS voxel was placed in the pregenual anterior cingulate cortex (pgACC), as this region has been repeatedly shown to be involved in ketamine's effects. Our results showed functional connectivity changes from the pgACC to the right frontal pole and anterior mid cingulate cortex (aMCC). Absolute glutamate and glutamine concentrations in the pgACC did not differ significantly from baseline. However, we found that stronger pgACC activation during ketamine was linked to lower glutamine concentration in this region. Furthermore, reduced functional connectivity between pgACC and aMCC was related to increased pgACC activation and reduced glutamine. Our results thereby demonstrate how multimodal investigations in a single brain region could help to advance our understanding of the association between metabolic and functional changes.

How Much of Me Do I See in Other Minds? Modulating Egocentricity in Emotion Judgments by tDCS.

When inferring the mental states of others, individuals' judgments are influenced by their own state of mind, an effect often referred to as egocentricity. Self-other differentiation is key for an accurate interpretation of other's mental states, especially when these differ from one's own states. It has been suggested that the right supramarginal gyrus (rSMG) is causally involved in overcoming egocentricity in the affective domain. In a double-blind randomized study, 47 healthy adults received anodal (1 mA, 20 min) or sham transcranial direct current stimulation (tDCS) to the rSMG prior to performing a newly developed paradigm, the self-other facial emotion judgment (SOFE) task. In this task, participants made judgments of facial emotional expressions while having been previously confronted with congruent or incongruent emotion-inducing situations. To differentiate between emotional and cognitive egocentricity, participants additionally completed an established visual perspective-taking task. Our results confirmed the occurrence of emotional egocentric biases during the SOFE task. No conclusive evidence of a general role of the rSMG in emotional egocentricity was found. However, active as compared to sham tDCS induced descriptively lower egocentric biases when judging incongruent fearful faces, and stronger biases when judging incongruent happy faces, suggesting emotion-specific tDCS effects on egocentric biases. Further, we found significant tDCS effects on cognitive egocentricity. Results of the present study expanded our understanding of emotional egocentricity and point towards emotion-specific patterns of the underlying functionality.

Comparison of Four fMRI Paradigms Probing Emotion Processing.

Previous fMRI research has applied a variety of tasks to examine brain activity underlying emotion processing. While task characteristics are known to have a substantial influence on the elicited activations, direct comparisons of tasks that could guide study planning are scarce. We aimed to provide a comparison of four common emotion processing tasks based on the same analysis pipeline to suggest tasks best suited for the study of certain target brain regions. We studied an n-back task using emotional words (EMOBACK) as well as passive viewing tasks of emotional faces (FACES) and emotional scenes (OASIS and IAPS). We compared the activation patterns elicited by these tasks in four regions of interest (the amygdala, anterior insula, dorsolateral prefrontal cortex (dlPFC) and pregenual anterior cingulate cortex (pgACC)) in three samples of healthy adults (N = 45). The EMOBACK task elicited activation in the right dlPFC and bilateral anterior insula and deactivation in the pgACC while the FACES task recruited the bilateral amygdala. The IAPS and OASIS tasks showed similar activation patterns recruiting the bilateral amygdala and anterior insula. We conclude that these tasks can be used to study different regions involved in emotion processing and that the information provided is valuable for future research and the development of fMRI biomarkers.

Light-Dependent Effects of Prefrontal rTMS on Emotional Working Memory.

Growing evidence suggests that colored light exposure can affect several brain functions in addition to conscious visual perception. Blue as compared to green light has especially been shown to enhance alertness and vigilance, as well as cognitive functions. However, the role of light exposure in studies using non-invasive brain stimulation remains unclear. Here, we examined the impact of light on cognitive-emotional effects of prefrontal repetitive transcranial magnetic stimulation (rTMS). In a randomized within-subjects design, twenty participants (12 males, 26 ± 4 years) were exposed to blue or green light prior and concomitant to active or sham rTMS (1Hz, 15min, 110% of the resting motor threshold), applied over the right dorsolateral prefrontal cortex (DLPFC). In each condition, an emotional working memory task (EMOBACK) was presented pre- and post-intervention. Stimuli of the EMOBACK task were positive, negative and neutral words. Our results revealed valence-specific stimulation effects in dependence of colored light exposure. More specifically, task accuracy was significantly increased for positive stimuli under blue light and for negative stimuli under green light exposure. Our findings highlight the importance of state-dependency in studies using non-invasive brain stimulation and show blue light exposure to be a potential adjunctive technique to rTMS for enhancing cognitive-emotional modulation.

Affective states influence emotion perception: evidence for emotional egocentricity.

Research in social cognition has shown that our own emotional experiences are an important source of information to understand what other people are feeling. The current study investigated whether individuals project their own affective states when reading other's emotional expressions. We used brief autobiographical recall and audiovisual stimuli to induce happy, neutral and sad transient states. After each emotion induction, participants made emotion judgments about ambiguous faces displaying a mixture of happiness and sadness. Using an adaptive psychophysics procedure, we estimated the tendency to perceive the faces as happy under each of the induced affective states. Results demonstrate the occurrence of egocentric projections, such that faces were more likely judged as happy when participants reported being happy as compared to when they were sad. Moreover, the degree of emotional egocentricity was associated with individual differences in perspective-taking, with smaller biases being observed in individuals with higher disposition to take the perspective of others. Our findings extend previous literature on emotional egocentricity by showing that self-projection occurs when we make emotion attributions based on the other's emotional expressions, and supports the notion that perspective-taking tendencies play a role in the ability to understand the other's affective states.

Using Brain Imaging to Improve Spatial Targeting of Transcranial Magnetic Stimulation for Depression.

Transcranial magnetic stimulation (TMS) is an effective treatment for depression but is limited in that the optimal therapeutic target remains unknown. Early TMS trials lacked a focal target and thus positioned the TMS coil over the prefrontal cortex using scalp measurements. Over time, it became clear that this method leads to variation in the stimulation site and that this could contribute to heterogeneity in antidepressant response. Newer methods allow for precise positioning of the TMS coil over a specific brain location, but leveraging these precise methods requires a more precise therapeutic target. We review how neuroimaging is being used to identify a more focal therapeutic target for depression. We highlight recent studies showing that more effective TMS targets in the frontal cortex are functionally connected to deep limbic regions such as the subgenual cingulate cortex. We review how connectivity might be used to identify an optimal TMS target for use in all patients and potentially even a personalized target for each individual patient. We address the clinical implications of this emerging field and highlight critical questions for future research.

Feasibility of Computerized Cognitive-Behavioral Therapy Combined With Bifrontal Transcranial Direct Current Stimulation for Treatment of Major Depression.

BACKGROUND: Cognitive behavioral therapy (CBT) is effective in the treatment of major depressive disorder (MDD). Transcranial Direct Current Stimulation (tDCS) has demonstrated preliminary antidepressant effects and beneficial effects on cognitive function. OBJECTIVE: We investigated the feasibility and acceptability of using tDCS to enhance the effects of computer-based CBT for treatment of MDD. MATERIALS AND METHODS: In a randomized, double-blind, sham-controlled study, 14 patients with MDD on stable or no pharmacotherapy received active or sham bifrontal tDCS for four weeks with concurrent CBT. RESULTS: Ten participants completed the protocol. Three withdrew from the study because of lack of efficacy or dislike of the eCBT program. One was discontinued from the protocol by the investigators. Treatment was well tolerated, and most side-effects were mild and consistent with prior tDCS research. Pooled data from both groups showed significant baseline to endpoint improvement in depression (p = 0.008). Overall percent change on the HAMD-21 was 28.98%. The study was underpowered to detect differences in tDCS treatment groups. CONCLUSIONS: Combining tDCS with computer-based CBT is feasible for MDD. Further work is needed to evaluate potential synergistic effects of combined tDCS and CBT.

Interaction of HPA axis genetics and early life stress shapes emotion recognition in healthy adults.

BACKGROUND: Early life stress (ELS) affects facial emotion recognition (FER), as well as the underlying brain network. However, there is considerable inter-individual variability in these ELS-caused alterations. As the hypothalamic-pituitary-adrenal (HPA) axis is assumed to mediate neural and behavioural sequelae of ELS, the genetic disposition towards HPA axis reactivity might explain differential vulnerabilities. METHODS: An additive genetic profile score (GPS) of HPA axis reactivity was built from 6 SNPs in 3 HPA axis-related genes (FKBP5, CRHR1, NR3C1). We studied two independent samples. As a proof of concept, GPS was tested as a predictor of cortisol increase to a psychosocial challenge (MIST) in a healthy community sample of n = 40. For the main study, a sample of n = 170 completed a video-based FER task and retrospectively reported ELS experiences in the Childhood Trauma Questionnaire (CTQ). RESULTS: GPS positively predicted cortisol increase in the stress challenge over and above covariates. CTQ and genetic profile scores interacted to predict facial emotion recognition, such that ELS had a detrimental effect on emotion processing only in individuals with higher GPS. Post-hoc moderation analyses revealed that, while a less stress-responsive genetic profile was protective against ELS effects, individuals carrying a moderate to high GPS were affected by ELS in their ability to infer emotion from facial expressions. DISCUSSION: These results suggest that a biologically informed genetic profile score can capture the genetic disposition to HPA axis reactivity and moderates the influence of early environmental factors on facial emotion recognition. Further research should investigate the neural mechanisms underlying this moderation. The GPS used here might prove a powerful tool for studying inter-individual differences in vulnerability to early life stress.

Prospective Validation That Subgenual Connectivity Predicts Antidepressant Efficacy of Transcranial Magnetic Stimulation Sites.

BACKGROUND: The optimal target in the dorsolateral prefrontal cortex for treating depression with repetitive transcranial magnetic stimulation (rTMS) remains unknown. Better efficacy has been associated with stimulation sites that are 1) more anterior and lateral and 2) more functionally connected to the subgenual cingulate. Here we prospectively test whether these factors predict response in individual patients. METHODS: A primary cohort (Boston, n = 25) with medication-refractory depression underwent conventional open-label rTMS to the left dorsolateral prefrontal cortex. A secondary cohort (Michigan, n = 16) underwent 4 weeks of sham followed by open-label rTMS for nonresponders (n = 12). In each patient, the location of the stimulation site was recorded with frameless stereotaxy. Connectivity between each patient's stimulation site and the subgenual cingulate was assessed using resting-state functional connectivity magnetic resonance imaging from a cohort of healthy subjects (n = 1000) and confirmed using connectivity from patients with depression (n = 38). RESULTS: In our primary cohort, antidepressant efficacy was predicted by stimulation sites that were both more anterolateral (r = .51, p < .01) and more negatively correlated with the subgenual cingulate (r = -.55, p < .005). However, subgenual connectivity was the only independent predictor of response and the only factor to predict response to active (r = -.52, p < .05) but not sham rTMS in our secondary cohort. CONCLUSIONS: This study provides prospective validation that functional connectivity between an individual's rTMS cortical target and the subgenual cingulate predicts antidepressant response. Implications for improving the cortical rTMS target for depression are discussed.

The interaction of corticotropin-releasing hormone receptor gene and early life stress on emotional empathy.

Early life stress (ELS) is associated with increased vulnerability for depression, changes to the corticotropin-releasing hormone (CRH) system and structural and functional changes in hippocampus. Single nucleotide polymorphisms in the CRH receptor 1 (CRHR1) gene interact with ELS to predict depression, cognitive functions and hippocampal activity. Social cognition has been related to hippocampal function and might be crucial for maintaining mental health. However, the interaction of CRHR1 gene variation and ELS on social cognition has not been investigated yet. We assessed social cognition in 502 healthy subjects to test effects of ELS and the CRHR1 gene. Participants were genotyped for rs110402 and rs242924. ELS was assessed by Childhood Trauma Questionnaire, social cognition was measured via Multifaceted Empathy Test and Empathy Quotient. Severity of ELS was associated with decreased emotional, but not cognitive empathy. Subjects with the common homozygous GG GG genotype showed decreased implicit emotional empathy after ELS exposure regardless of its severity. The results reveal that specific CRHR1 polymorphisms moderate the effect of ELS on emotional empathy. Exposure to ELS in combination with a vulnerable genotype results in impaired emotional empathy in adulthood, which might represent an early marker of increased vulnerability after ELS.

Effects of ketamine on cognition-emotion interaction in the brain.

Cognition-emotion interaction in the brain can be investigated by incorporating stimuli with emotional content into cognitive tasks. Emotional stimuli in the context of a working memory (WM) task yield increased activation in WM-related lateral prefrontal regions, whereas cognitive effort enhances deactivation in emotion-related cortical midline regions. N-methyl-d-aspartate glutamate receptors (NMDA-Rs) are critically involved in WM, and NMDA-R antagonists, such as ketamine, accordingly affect WM but also have a profound impact on emotional processing, as underscored by the rapid reduction of depressive symptoms after administration of a single dose of ketamine. The effect of ketamine on both cognitive and emotional processing therefore makes it a useful tool to further explore cognition-emotion interaction in the brain. Twenty-three healthy subjects were administered ketamine to investigate whether its effects on WM performance and brain reactivity depend on emotional content or emotional valence of stimuli. Furthermore, we aimed at investigating how ketamine affects the integration of emotion and WM processes in emotion-related cortical midline regions and WM-related lateral prefrontal regions. Results show that ketamine modulates cognition-emotion interaction in the brain by inducing lateralized and valence-specific effects in emotion-related cortical midline regions, WM-related lateral prefrontal regions and insula. In emotion-related cortical midline regions ketamine abolishes enhancement of deactivation normally observed during cognitive effort, while in the right DLPFC and the left insula the previously described pattern of increased activation due to emotional content is abrogated exclusively for negative stimuli. Our data therefore shows a specific effect of ketamine on cognition-emotion interaction in the brain and indicates that its effect on amelioration of negative biases in MDD patients might be related to less interference of cognitive processing by negative emotional content.

Oxytocin improves mentalizing - pronounced effects for individuals with attenuated ability to empathize.

The ability to predict the behavior of others based on their mental states is crucial for social functioning. Previous studies have provided evidence for the role of Oxytocin (OXT) in enhancing the ability to mentalize. It has also been demonstrated that the effect of OXT seems to strongly depend on socio-cognitive skills with more pronounced effects in individuals with lower socio-cognitive skills. Although recent studies indicate that mentalizing is related to empathy, no study has yet examined whether the effects of OXT on mentalizing depend on the ability to empathize. 71 male participants participated in a double-blind, between-subjects, placebo-controlled experiment. The Reading the Mind in the Eye Test (RMET) was used to investigate mentalizing abilities. We analyzed the effect of OXT on easy and difficult items of the RMET depending on differential empathy scores of the participants as assessed with the Empathy Quotient (EQ). Our results showed that OXT improves mentalizing for difficult but not for easy items. We generally observed increased mentalizing accuracy in participants with higher empathy scores. Importantly, however, whereas the performance in participants with higher empathy scores was comparable in both OXT and placebo condition, OXT specifically enhanced mentalizing accuracy in participants with lower empathy scores. Our findings suggest that OXT enhances mentalizing abilities. However, we also demonstrate that not all participants benefited from OXT application. It seems that the effects of OXT strongly depend on baseline social-cognitive skills such as empathy.

Causal Influence of Articulatory Motor Cortex on Comprehending Single Spoken Words: TMS Evidence.

Classic wisdom had been that motor and premotor cortex contribute to motor execution but not to higher cognition and language comprehension. In contrast, mounting evidence from neuroimaging, patient research, and transcranial magnetic stimulation (TMS) suggest sensorimotor interaction and, specifically, that the articulatory motor cortex is important for classifying meaningless speech sounds into phonemic categories. However, whether these findings speak to the comprehension issue is unclear, because language comprehension does not require explicit phonemic classification and previous results may therefore relate to factors alien to semantic understanding. We here used the standard psycholinguistic test of spoken word comprehension, the word-to-picture-matching task, and concordant TMS to articulatory motor cortex. TMS pulses were applied to primary motor cortex controlling either the lips or the tongue as subjects heard critical word stimuli starting with bilabial lip-related or alveolar tongue-related stop consonants (e.g., "pool" or "tool"). A significant cross-over interaction showed that articulatory motor cortex stimulation delayed comprehension responses for phonologically incongruent words relative to congruous ones (i.e., lip area TMS delayed "tool" relative to "pool" responses). As local TMS to articulatory motor areas differentially delays the comprehension of phonologically incongruous spoken words, we conclude that motor systems can take a causal role in semantic comprehension and, hence, higher cognition.

Variation in the corticotropin-releasing hormone receptor 1 (CRHR1) gene modulates age effects on working memory.

Decline in working memory (WM) functions during aging has been associated with hippocampal dysfunction mediated by age-related changes to the corticotropin-releasing hormone (CRH) system. Recent reports suggest that GG-homozygous individuals of single nucleotide polymorphisms (rs110402 and rs242924) in the CRH receptor 1 (CRHR1) gene show increased stress vulnerability and decreased BOLD responses in WM relevant regions. However, until now, no study investigated the interaction effects of variation in the CRHR1 gene and age on individual differences in WM. Here, young, middle-aged and old subjects (N = 466) were genotyped for rs110402 and rs242924 within the CRHR1 gene and an n-back task was used to investigate the hypothesis that vulnerable genotypes (GG-homozygotes) would show impaired WM functions that might be magnified by increased CRH production with advancing age. Our results show an impact of genotype already in middle-age with significantly better performance in AT-carriers. Working memory performance in AT-carriers did not differ between young and middle-aged subjects, but was significantly impaired in old age. In GG-homozygotes, severe working memory dysfunction occurred already in middle age. Our data indicate that GG-homozygotes of CRHR1 rs110402 and rs242924 represent a genetically driven subtype of early WM impairments due to alterations in hippocampal CRHR1 activation. Early interventions that have proven effective in delaying cognitive decline appear to be particularly important for these subjects at risk for premature memory decline, who are in the prime of their personal and professional lives.