A perspective on epigenomic aging processes in the human brain and their plasticity in patients with mental disorders - a systematic review.

The debate surrounding nature versus nurture remains a central question in neuroscience, psychology, and in psychiatry, holding implications for both aging processes and the etiology of mental illness. Epigenetics can serve as a bridge between genetic predisposition and environmental influences, thus offering a potential avenue for addressing these questions. Epigenetic clocks, in particular, offer a theoretical framework for measuring biological age based on DNA methylation signatures, enabling the identification of disparities between biological and chronological age. This structured review seeks to consolidate current knowledge regarding the relationship between mental disorders and epigenetic age within the brain. Through a comprehensive literature search encompassing databases such as EBSCO, PubMed, and ClinicalTrials.gov, relevant studies were identified and analyzed. Studies that met inclusion criteria were scrutinized, focusing on those with large sample sizes, analyses of both brain tissue and blood samples, investigation of frontal cortex markers, and a specific emphasis on schizophrenia and depressive disorders. Our review revealed a paucity of significant findings, yet notable insights emerged from studies meeting specific criteria. Studies characterized by extensive sample sizes, analysis of brain tissue and blood samples, assessment of frontal cortex markers, and a focus on schizophrenia and depressive disorders yielded particularly noteworthy results. Despite the limited number of significant findings, these studies shed light on the complex interplay between epigenetic aging and mental illness. While the current body of literature on epigenetic aging in mental disorders presents limited significant findings, it underscores the importance of further research in this area. Future studies should prioritize large sample sizes, comprehensive analyses of brain tissue and blood samples, exploration of specific brain regions such as the frontal cortex, and a focus on key mental disorders. Such endeavors will contribute to a deeper understanding of the relationship between epigenetic aging and mental illness, potentially informing novel diagnostic and therapeutic approaches.

Anxiety and depression in patients with breast cancer undergoing radiotherapy: the role of intelligence, life history, and social support-preliminary results from a monocentric analysis.

PURPOSE: It is known that the diagnosis of breast cancer often causes anxiety and depression. Radiotherapy of the breast as an obligatory part of a breast-conserving treatment concept can markedly increase these psychological symptoms in many, but not all patients. In this clinical observational study, we aimed at identifying cognitive, health-related and social factors that may either enhance or reduce the emergence of anxiety and depression. METHODS: Using a longitudinal study design with 25 women (mean age: 52.9 years; SD = 10.6; age range 29-70 years) with a first diagnosis of nonmetastatic breast cancer, measures of anxiety, depression, situational emotional states, intelligence, and aspects of social frameworks were assessed before, during, and after radiotherapy of the breast. At 4 time-points, standard and self-constructed questionnaires were used to assess the course of anxiety and depressive symptoms across the radiotherapy intervention. RESULTS: We found that anxiety is highest immediately before the start of radiation therapy, while the anxiety level was lowest on the day that therapy was completed. Anxiety and depression were enhanced in women with a lifetime history of chronic diseases at all time points of measurement. Moreover, women with high intelligence and low social support had stronger symptoms of depression than women with low intelligence and a stable family background at some time points of measurement. The degree of anxiety was neither related to intelligence nor to social support. CONCLUSION: For the first time, we demonstrate empirical pilot data on cognitive and social modulators of anxiety and depression in women with breast cancer over the course of radiotherapy. Our results may help to optimize clinical procedures and thereby reduce symptoms of anxiety and depression in these patients.

Acute social stress before the planning phase improves memory performance in a complex real life-related prospective memory task.

Successful execution of intentions, but also the failure to recall are common phenomena in everyday life. The planning, retention, and realization of intentions are often framed as the scientific concept of prospective memory. The current study aimed to examine the influence of acute stress on key dimensions of complex "real life" prospective memory. To this end, we applied a prospective memory task that involved the planning, retention, and performance of intentions during a fictional holiday week. Forty healthy males participated in the study. Half of the subjects were stressed with the Socially Evaluated Cold Pressor Test (SECPT) before the planning of intentions, and the other half of the participants underwent a control procedure at the same time. Salivary cortisol was used to measure the effectiveness of the SECPT stress induction. Stressed participants did not differ from controls in planning accuracy. However, when we compared stressed participants with controls during prospective memory retrieval, we found statistically significant differences in PM across the performance phase. Participants treated with the SECPT procedure before the planning phase showed improved prospective memory retrieval over time, while performance of controls declined. Particularly, there was a significant difference between the stress and control group for the last two days of the holiday week. Interestingly, control participants showed significantly better performance for early than later learned items, which could be an indicator of a primacy effect. This differential effect of stress on performance was also found in time- and event-dependent prospective memory. Our results demonstrate for the first time, that acute stress induced before the planning phase may improve prospective memory over the time course of the performance phase in time- and event-dependent prospective memory. Our data thus indicate that prospective memory can be enhanced by acute stress.

Disturbed spatial cognitive processing of body-related stimuli in a case of a lesion to the right fusiform gyrus.

The fusiform gyrus (FG) is well known as one of the main neural sites of human face and body processing. We report the case of a young male patient with epilepsy and a circumscribed lesion in the right FG who presented with isolated impairments in spatial cognitive processing of body-related stimuli. However, he did not show any clinical signs of prosopagnosia. In particular, handling/processing of body and face stimuli was impaired, when stimuli were presented in unconventional views and orientations, thus requiring additional spatial cognitive operations. In this case study, we discuss the patient's selective impairment from the view of current empirical and theoretical work on the segregation of functions in the FG.

The Bergen left-right discrimination test: practice effects, reliable change indices, and strategic performance in the standard and alternate form with inverted stimuli.

Several authors pointed out that left-right discrimination (LRD) tasks may be entangled with differential demands on mental rotation (MR). However, studies considering this interrelationship are rare. To differentially assess LRD of stimuli with varying additional demands on MR, we constructed and evaluated an extended version of the Bergen right-left discrimination (BRLD) test including additional subtests with inverted stickmen stimuli in 174 healthy participants (50♂, 124♀) and measured subjective reports on participants' strategies to accomplish the task. Moreover, we analyzed practice effects and reliable change indices (RCIs) on BRLD performance, as well as gender differences. Performance significantly differed between subtests with high and low demands on MR with best scores on subtests with low demands on MR. Participants' subjective strategies corroborate these results: MR was most frequently reported for subtests with highest MR demands (and lowest test performance). Pronounced practice effects were observed for all subtests. Sex differences were not observed. We conclude that our extended version of the BRLD allows for the differentiation between LRD with high and low demands on MR abilities. The type of stimulus materials is likely to be critical for the differential assessment of MR and LRD. Moreover, RCIs provide a basis for the clinical application of the BRLD.

A double-blind randomized clinical trial on the suggestive effect of anxiety management questionnaires in dental emergencies.

Objective: Dental anxiety is widespread among both children and adults. To diagnose dental anxiety, standardized anxiety questionnaires are recommended. Based on the suggestive nature of the questionnaires, the study aimed to find out whether asking respondents about personal coping strategies before dental treatment influences their anxiety. Methods: This prospective, double-blind, randomized controlled clinical trial included a total of 158 patients of a university dental clinic on emergency service. The intervention group (n = 82) received the Coping with Anxiety Questionnaire (CAQ) and the control group (n = 76) the Hierarchical Anxiety Questionnaire (HAF). State anxiety scores were assessed by using the State-Trait Anxiety Inventory (STAI) before and after the completion of each questionnaire. Results: Anxiety decreased in the intervention group (CAQ) (p < 0.001) and increased in the control group (HAF) (p < 0.001). Conclusion: Within the limitations of the current study, a diagnostic tool of a standardized questionnaire for the assessment to assess personal coping strategies decreased state anxiety in comparison to a questionnaire assessing anxiety. Clinical trial registration: https://www.drks.de, German Trials Register (DRKS00032450).

Learning real-life cognitive abilities in a novel 360°-virtual reality supermarket: a neuropsychological study of healthy participants and patients with epilepsy.

BACKGROUND: To increase the ecological validity of neuropsychological instruments the use of virtual reality (VR) applications can be considered as an effective tool in the field of cognitive neurorehabilitation. Despite the growing use of VR programs, only few studies have considered the application of everyday activities like shopping or travelling in VR training devices. METHODS: We developed a novel 360°-VR supermarket, which is displayed on a circular arrangement of 8 touch-screens--the "OctaVis". In this setting, healthy human adults had to memorize an auditorily presented shopping list (list A) and subsequently buy all remembered products of this list in the VR supermarket. This procedure was accomplished on three consecutive days. On day four, a new shopping list (list B) was introduced and participants had to memorize and buy only products of this list. On day five, participants had to buy all remembered items of list A again, but without new presentation of list A. Additionally, we obtained measures of participants' presence, immersion and figural-spatial memory abilities. We also tested a sample of patients with focal epilepsy with an extended version of our shopping task, which consisted of eight days of training. RESULTS: We observed a comprehensive and stable effect of learning for the number of correct products, the required time for shopping, and the length of movement trajectories in the VR supermarket in the course of the training program. Task performance was significantly correlated with participants' figural-spatial memory abilities and subjective level of immersion into the VR. CONCLUSIONS: Learning effects in our paradigm extend beyond mere verbal learning of the shopping list as the data show evidence for multi-layered learning (at least visual-spatial, strategic, and verbal) on concordant measures. Importantly, learning also correlated with measures of figural-spatial memory and the degree of immersion into the VR. We propose that cognitive training with the VR supermarket program in the OctaVis will be efficient for the assessment and training of real-life cognitive abilities in healthy subjects and patients with epilepsy. It is most likely that our findings will also apply for patients with cognitive disabilities resulting from other neurological and psychiatric syndromes.

COVID-19 stress syndrome in the German general population: Validation of a German version of the COVID Stress Scales.

The COVID Stress Scales (CSS) are a new self-report instrument for multidimensional assessment of psychological stress in the context of the pandemic. The CSS have now been translated and validated in over 20 languages, but a validated German version has not yet been available. Therefore, the aim was to develop a German version of the CSS, to test its factor structure, reliability, and validity, and to compare it with international studies. In an online survey (08/2020-06/2021), N = 1774 individuals from the German general population (71.5% female; Mage = 41.2 years, SD = 14.2) completed the CSS as well as questionnaires on related constructs and psychopathology. After eight weeks, participants were asked to participate again for the purpose of calculating retest reliability (N = 806). For the German version, the 6-factor structure with good model fit (Root Mean Square Error of Approximation, RMSEA = 0.06) was confirmed, with the six subscales: Danger, Socio-Economic Consequences, Xenophobia, Contamination, Traumatic Stress, and Compulsive Checking. Internal consistencies ranged from ω = .82-.94 (except Compulsive Checking ω = .70), and retest reliability from rtt = .62-.82. Convergent and discriminant validity were confirmed for the German version. Related constructs such as health anxiety, general xenophobia, obsessive-compulsive behavior, and posttraumatic stress disorder symptoms correlated moderately with the respective subscale and lower with the other scales. With anxiety and depression, Traumatic Stress showed the strongest correlation. Overall, there was a high degree of agreement in an international comparison. The CSS can help to identify pandemic-related psychological stress and to derive appropriate interventions.

Mental health during the COVID-19 pandemic: Stress and strain profiles in the German population.

Clinical observations indicate that people frequently display stress-related behavior during the COVID-19 pandemic. Although numerous studies have been published concerning pandemic-related psychological distress, systematic data on the interrelationships between stress sensitivity, personality, and behavioral characteristics of people are still lacking. In the present cross-sectional online survey study, we applied a German version of the COVID Stress Scales (CSS) and standard psychological questionnaires to systematically identify the complex interplay between stress sensitivity, gender, and personality in the modulation of quality of life and mental health in the German population (N = 1774; age ≥ 16 years). A CSS-based cluster analysis revealed two clusters characterized by higher and lower stress levels. Study participants in each cluster differed significantly with respect to neuroticism, extraversion, agreeableness, quality of life, depression, and anxiety. Females were significantly overrepresented in the higher stress cluster, while there was an overrepresentation of males in the lower stress cluster. Neuroticism was identified as a risk factor and extraversion as a protective factor for enhanced pandemic-related stress responses. For the first time our data show a taxonomy of factors, which modulate pandemic-related stress sensitivity and warrant consideration as key indicators of quality of life and psychological distress during the COVID-19 pandemic. We suggest that our data may advise governmental regulation of pandemic-related public health measures, to optimize quality of life and psychological health in different groups of the population.

Computer-assisted analysis of spontaneous speech: quantification of basic parameters in aphasic and unimpaired language.

Although generally accepted as an important part of aphasia assessment, detailed analysis of spontaneous speech is rarely carried out in clinical practice mostly due to time limitations. The Aachener Sprachanalyse (ASPA; Aachen Speech Analysis) is a computer-assisted method for the quantitative analysis of German spontaneous speech that allows for a detailed assessment by means of linguistic basic parameters in an acceptable amount of time. It has previously been proven sensitive for monitoring changes over time. In this study, we present data of 52 aphasic participants whose spontaneous speech was analyzed retrospectively before and after an intensive therapy program. The measured changes are evaluated with reference to normative data of 60 non-brain-damaged speakers. Results confirm good sensitivity to document changes over time. Clinical relevance of changes is assessed with reference to critical score ranges derived from the normative data. Findings provide further evidence of the clinical applicability and usefulness of ASPA.

Modulatory effects of levodopa on cognitive control in young but not in older subjects: a pharmacological fMRI study.

Older individuals show decline of prefrontal cortex (PFC) functions which may be related to altered dopaminergic neurotransmission. We investigated the effects of aging and dopaminergic stimulation in 15 young and 13 older healthy subjects on the neural correlates of interference control using fMRI. In a double-blind, placebo-controlled within-subject design, subjects were measured after levodopa (100 mg) or placebo administration. In each session, subjects performed a visual-spatial interference task based on a Stroop/Simon-like paradigm. Across age groups, interference (incongruent relative to congruent trials) was associated with activations in the presupplementary motor area, ACC, and intraparietal cortex. Increased interference was found behaviorally in older volunteers. Differential activation in left dorsolateral PFC in young subjects and bilateral PFC activity in older subjects was observed to be associated with interference control. Performance deteriorated under levodopa only in young subjects. This was accompanied by an increase of neural activity in ACC (p < .05; small-volume correction for multiple comparisons). Worsening of performance under levodopa in young subjects and the associated effect on ACC may indicate that overstimulation of the dopaminergic system compromises interference control. This supports the inverted-U-shaped model of neurotransmitter action.

Cognitive training in an everyday-like virtual reality enhances visual-spatial memory capacities in stroke survivors with visual field defects.

OBJECTIVES: Visual field defects due to hemi- or quadrantanopia after stroke represent an under-recognized neurological symptom with inefficient instruments for neurorehabilitation to date. We here examined the effects of training in a virtual reality (VR) supermarket on cognitive functions, depressive symptoms, and subjective cognitive complaints in patients with hemianopia/quadrantanopia and healthy controls. METHODS: During a 14-day rehabilitation program, 20 patients and 20 healthy controls accomplished a real-life-like shopping task in a VR supermarket. A comparison between pre- and post-training standard neuropsychological measures, depressive symptoms, and subjective memory complaints allowed us to assess a putative transfer of rehabilitation effects from the training tasks to specific cognitive functions. RESULTS: The results indicate that VR training may improve performance not only in the trained task but also in specific neuropsychological functions. After the training, both patients and controls showed improved performances in visual scanning, mental rotation, visuoconstruction, and cognitive flexibility. Moreover, depressive symptoms were attenuated in both groups. In the patient group compared to the control group, the training particularly resulted in improved visual memory retrieval and reduced memory complaints. CONCLUSIONS: The results of the current study suggest that VR training can improve particularly visual-spatial skills in patients with hemianopia or quadrantanopia. Our study thus introduces an interesting novel treatment approach to improve cognitive functions relevant to daily life in stroke patients with visual field defects.

Neurofunctional modulation of brain regions by distinct forms of motor cognition and movement features.

Extrastriate, parietal, and frontal brain regions are differentially involved in distinct kinds of body movements and motor cognition. Using functional magnetic resonance imaging, we investigated the neural mechanisms underlying the observation and mental imagery of meaningful face and limb movements with or without objects. The supplementary motor area was differentially recruited by the mental imagery of movements while there were differential responses of the extrastriate body area (EBA) during the observation conditions. Contrary to most previous reports, the EBA responded to face movements, albeit to a lesser degree than to limb movements. The medial wall of the intraparietal sulcus and adjacent intraparietal cortex was selectively recruited by the processing of meaningful upper limb movements, irrespective of whether these were object-related or not. Besides reach and grasp movements, the intraparietal sulcus may thus be involved in limb gesture processing, that is, in an important aspect of human social communication. We conclude that subregions of a frontal-parietal network differentially interact during the cognitive processing of body movements according to the specific motor-related task at hand and the particular movement features involved.

Loxapine for Treatment of Patients With Refractory, Chemotherapy-Induced Neuropathic Pain: A Prematurely Terminated Pilot Study Showing Efficacy But Limited Tolerability.

Neuropathic pain is a debilitating and commonly treatment-refractory condition requiring novel therapeutic options. Accumulating preclinical studies indicate that the potassium channel Slack (KNa1.1) contributes to the processing of neuropathic pain, and that Slack activators, when injected into mice, ameliorate pain-related hypersensitivity. However, whether Slack activation might reduce neuropathic pain in humans remains elusive. Here, we evaluated the tolerability and analgesic efficacy of loxapine, a first-generation antipsychotic drug and Slack activator, in neuropathic pain patients. We aimed to treat 12 patients with chronic chemotherapy-induced, treatment-refractory neuropathic pain (pain severity ≥ 4 units on an 11-point numerical rating scale) in a monocentric, open label, proof-of-principle study. Patients received loxapine orally as add-on analgesic in a dose-escalating manner (four treatment episodes for 14 days, daily dose: 20, 30, 40, or 60 mg loxapine) depending on tolerability and analgesic efficacy. Patient-reported outcomes of pain intensity and/or relief were recorded daily. After enrolling four patients, this study was prematurely terminated due to adverse events typically occurring with first-generation antipsychotic drugs that were reported by all patients. In two patients receiving loxapine for at least two treatment episodes, a clinically relevant analgesic effect was found at a daily dose of 20-30 mg of loxapine. Another two patients tolerated loxapine only for a few days. Together, our data further support the hypothesis that Slack activation might be a novel strategy for neuropathic pain therapy. However, loxapine is no valid treatment option for painful polyneuropathy due to profound dopamine and histamine receptor-related side effects. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02820519.

Gender differences in brain networks supporting empathy.

Females frequently score higher on standard tests of empathy, social sensitivity, and emotion recognition than do males. It remains to be clarified, however, whether these gender differences are associated with gender specific neural mechanisms of emotional social cognition. We investigated gender differences in an emotion attribution task using functional magnetic resonance imaging. Subjects either focused on their own emotional response to emotion expressing faces (SELF-task) or evaluated the emotional state expressed by the faces (OTHER-task). Behaviorally, females rated SELF-related emotions significantly stronger than males. Across the sexes, SELF- and OTHER-related processing of facial expressions activated a network of medial and lateral prefrontal, temporal, and parietal brain regions involved in emotional perspective taking. During SELF-related processing, females recruited the right inferior frontal cortex and superior temporal sulcus stronger than males. In contrast, there was increased neural activity in the left temporoparietal junction in males (relative to females). When performing the OTHER-task, females showed increased activation of the right inferior frontal cortex while there were no differential activations in males. The data suggest that females recruit areas containing mirror neurons to a higher degree than males during both SELF- and OTHER-related processing in empathic face-to-face interactions. This may underlie facilitated emotional "contagion" in females. Together with the observation that males differentially rely on the left temporoparietal junction (an area mediating the distinction between the SELF and OTHERS) the data suggest that females and males rely on different strategies when assessing their own emotions in response to other people.

The neurofunctional mechanisms of traumatic and non-traumatic memory in patients with acute PTSD following accident trauma.

Neurofunctional alterations in acute posttraumatic stress disorder (PTSD) and changes thereof during the course of the disease are not well investigated. We used functional magnetic resonance imaging to assess the functional neuroanatomy of emotional memory in surgical patients with acute PTSD. Traumatic (relative to non-traumatic) memories increased neural activity in the amygdala, hippocampus, lateral temporal, retrosplenial, and anterior cingulate cortices. These regions are all implicated in memory and emotion. A comparison of findings with data on chronic PTSD suggests that brain circuits affected by the acute disorder are extended and unstable while chronic disease is characterized by circumscribed and stable neurofunctional abnormalities.

Memory performance of patients with major depression in an everyday life situation.

Although patients with major depressive disorder (MDD) report severe memory impairment in their everyday life, memory tests indicate only moderate deficits. In order to clarify these conflicting observations, the present study aimed at the investigation of MDD patients' memory performance in a real everyday life situation. The study included 20 MDD patients and 20 healthy control subjects. Nonverbal memory was assessed by means of the Rey Complex Figure Test whereas verbal memory was assessed by the recall of a 20-item wordlist with supermarket products. For the assessment of everyday life memory, subjects had to purchase as many products as possible of the 20-item wordlist in a real supermarket. Furthermore, subjects were asked for memory complaints. MDD patients' performance in the supermarket resembled memory test results and was not significantly impaired. MDD patients' self-reports, however, indicated severe memory problems that clearly fell below their performance in the supermarket. This study helped to identify everyday life-related factors that do not impair MDD patients' cognitive performance beyond their performance in standard laboratory testing situations. These factors may not be relevant for remediation programs that are specifically developed for depressed patients.

Recollections of one's own past: the effects of aging and gender on the neural mechanisms of episodic autobiographical memory.

Episodic autobiographical recollection is the most complex form of human memory. It relies on interactions between episodic memory, associated emotions, and a sense of self-continuity along the time axis of one's personal life history. Evidence exists that autobiographical memory performance as well as its underlying brain mechanisms are influenced by genetic, physiological, psychological, situational, and social-cultural factors. In particular, age (normal cognitive aging as well as age of memories, as defined by the time interval elapsed since information encoding) and gender affect both the performance level and the neural substrates of autobiographical recollection. In this review, studies concerned with aging and gender effects on autobiographical memory are discussed with reference to other age- and gender-related influences on human cognition, as well as clinical data on demented patients. Both age and gender act upon the functional hemispheric lateralization of autobiographical recollection and the prefrontal, hippocampal and parahippocampal engagement in information processing. On the performance level, re-collective qualities such as episodic detail and emotional intensity of autobiographical memories are modulated by both factors. Although the effects of aging and gender on human brain function are built upon different genetic and physiological mechanisms, they influence at least in part the same neurofunctional and behavioral dimensions of autobiographical recollection. Interestingly, age- and gender-related specificities in the neural mechanisms of autobiographical recollection need not be reflected on the performance level.

Posttraumatic stress disorder and fMRI activation patterns of traumatic memory in patients with borderline personality disorder.

BACKGROUND: Early traumatization and additional posttraumatic stress disorder are frequent in patients with borderline personality disorder (BPD). The purpose of this study was to investigate neural correlates of traumatic memory in BPD with and without posttraumatic stress disorder (PTSD) using functional magnetic resonance imaging (fMRI). METHODS: We studied 12 traumatized female patients BPD, 6 of them with and 6 without PTSD. According to an autobiographical interview key words (cues) were defined for traumatic and for negative but nontraumatic episodes. In a block-designed fMRI task patients recalled these episodes. Contrasts between trauma condition and nontrauma condition were analyzed. RESULTS: Analyses for all subjects revealed activation of orbitofrontal cortex areas in both hemispheres, anterior temporal lobes, and occipital areas. In the subgroup without PTSD, activation of orbitofrontal cortex on both sides and Broca's area predominated. In the subgroup with additional PTSD, we observed right more than left activation of anterior temporal lobes, mesiotemporal areas, amygdala, posterior cingulate gyrus, occipital areas, and cerebellum. CONCLUSIONS: Dependent on absence or presence of additional PTSD different neural networks seem to be involved in the traumatic memory of patients with BPD.

A Bayesian latent group analysis for detecting poor effort in a sample of cognitively impaired patients.

Using a Bayesian latent group analysis in a simulation design, we recently showed a high diagnostic accuracy when assessing effort in the context of malingered memory deficits. We here further evaluate our Bayesian model in a sample of cognitively impaired patients. The main analysis showed both high sensitivity and specificity, thus corroborating a high diagnostic accuracy of the model. Additional analysis showed variations on effort estimates after changes in malingering base rates. Variations affected sensitivity, but not specificity, which is in line with typical findings in malingering research. These data suggest that Bayesian analyses may complement and improve existing effort measures.