Neurobiological mechanisms of ECT and TMS treatment in depression: study protocol of a multimodal magnetic resonance investigation.

BACKGROUND: Noninvasive neurostimulation treatments are increasingly being used to treat major depression, which is a common cause of disability worldwide. While electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are both effective in treating depressive episodes, their mechanisms of action are, however, not completely understood. ECT is given under general anesthesia, where an electrical pulse is administered through electrodes placed on the patient's head to trigger a seizure. ECT is used for the most severe cases of depression and is usually not prescribed before other options have failed. With TMS, brain stimulation is achieved through rapidly changing magnetic fields that induce electric currents underneath a ferromagnetic coil. Its efficacy in depressive episodes has been well documented. This project aims to identify the neurobiological underpinnings of both the effects and side effects of the neurostimulation techniques ECT and TMS. METHODS: The study will utilize a pre-post case control longitudinal design. The sample will consist of 150 subjects: 100 patients (bipolar and major depressive disorder) who are treated with either ECT (N = 50) or TMS (N = 50) and matched healthy controls (N = 50) not receiving any treatment. All participants will undergo multimodal magnetic resonance imaging (MRI) as well as neuropsychological and clinical assessments at multiple time points before, during and after treatment. Arterial spin labeling MRI at baseline will be used to test whether brain perfusion can predict outcomes. Signs of brain disruption, potentiation and rewiring will be explored with resting-state functional MRI, magnetic resonance spectroscopy and multishell diffusion weighted imaging (DWI). Clinical outcome will be measured by clinician assessed and patient reported outcome measures. Memory-related side effects will be investigated, and specific tests of spatial navigation to test hippocampal function will be administered both before and after treatment. Blood samples will be stored in a biobank for future analyses. The observation time is 6 months. Data will be explored in light of the recently proposed disrupt, potentiate and rewire (DPR) hypothesis. DISCUSSION: The study will contribute data and novel analyses important for our understanding of neurostimulation as well as for the development of enhanced and more personalized treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05135897.

Laterality indices consensus initiative (LICI): A Delphi expert survey report on recommendations to record, assess, and report asymmetry in human behavioural and brain research.

Laterality indices (LIs) quantify the left-right asymmetry of brain and behavioural variables and provide a measure that is statistically convenient and seemingly easy to interpret. Substantial variability in how structural and functional asymmetries are recorded, calculated, and reported, however, suggest little agreement on the conditions required for its valid assessment. The present study aimed for consensus on general aspects in this context of laterality research, and more specifically within a particular method or technique (i.e., dichotic listening, visual half-field technique, performance asymmetries, preference bias reports, electrophysiological recording, functional MRI, structural MRI, and functional transcranial Doppler sonography). Experts in laterality research were invited to participate in an online Delphi survey to evaluate consensus and stimulate discussion. In Round 0, 106 experts generated 453 statements on what they considered good practice in their field of expertise. Statements were organised into a 295-statement survey that the experts then were asked, in Round 1, to independently assess for importance and support, which further reduced the survey to 241 statements that were presented again to the experts in Round 2. Based on the Round 2 input, we present a set of critically reviewed key recommendations to record, assess, and report laterality research for various methods.

Eliciting false auditory perceptions using speech frequencies and semantic priming: a signal detection approach.

INTRODUCTION: Individuals experiencing auditory hallucinations (AH) tend to perceive voices when exposed to random noise. However, the factors driving this tendency remain unclear. The present study examined the interaction of a top-down (expectations) and bottom-up (type of noise) process to better understand the mechanisms that underlie AH. METHODS: Fifty-two healthy individuals (29 with high proneness and 23 with low proneness to AH) completed a signal detection task, in which they listened to pre-recorded sentences. The last word was either masked by noise or only noise was presented without the word. Two types of noise existed (speech-related versus speech-unrelated frequencies) and words were characterised by either high or low levels of semantic expectation. RESULTS: Participants with high proneness to AH showed a more liberal decision bias (i.e., they were more likely to report having heard a word) and poorer discrimination ability as compared to participants with low proneness to AH - but only when the word was masked by speech-related noises and the level of expectation was high. Further, the more liberal decision bias correlated negatively with the tendency to experience AH. CONCLUSION: This novel paradigm demonstrated an interaction between top-down (level of expectation) and bottom-up (type of noise) processes, supporting current theoretical models of AH.

A multimodal study of the effects of tDCS on dorsolateral prefrontal and temporo-parietal areas during dichotic listening.

The underlying neural mechanisms of transcranial direct current stimulation (tDCS), especially beyond the primary motor cortex, remain unclear. Several studies examined tDCS effects on either functional activity, neurotransmitters or behavior but few investigated those aspects together to reveal how the brain responds to tDCS. The objective is to elucidate the underlying mechanisms of tDCS using a multimodal approach that extends from behavioral to neurotransmitter levels of explanation. Thirty-two healthy participants performed an auditory dichotic listening task at two visits, one session with sham and one session with real tDCS (2 mA) while simultaneously undergoing functional magnetic resonance imaging (fMRI). The anode and cathode were placed over the left temporo-parietal cortex (TPC) and dorsolateral prefrontal cortex, respectively. Before and after simultaneous dichotic listening/fMRI/tDCS, combined glutamate and glutamine (Glx) and myo-inositol levels were assessed in the stimulated areas. While fMRI and dichotic listening showed expected functional activity and behavioral effects, neither method demonstrated differences between real and sham stimulation. Glx only showed a statistical trend towards higher levels after real tDCS in both stimulated brain areas. There were no significant correlations between behavior and Glx. Despite a reasonable sample size, electrical field strength, and replication of behavioral and functional activity results, tDCS had little to no effect on dichotic listening, Glx, and functional activity. The study emphasizes that findings about the underlying neural mechanisms of the primary motor cortex cannot simply be generalized to other brain areas. Particularly, the TPC might be less sensitive to tDCS. Moreover, the study demonstrates the general feasibility of multimodal approaches.

Gender stereotypes and incremental beliefs in STEM and non-STEM students in three countries: relationships with performance in cognitive tasks.

Women's underrepresentation in science, technology, engineering and mathematics (STEM) has been linked, among others, to gender stereotypes and ability-related beliefs as well as gender differences in specific cognitive abilities. However, the bulk of studies focused on gender stereotypes related to mathematics. The present study, therefore, aimed to map gender stereotypes and incremental beliefs (i.e., the conviction about modifiability) with respect to a wide range of stereotypical male-favouring and female-favouring abilities. Gender stereotypes and incremental beliefs were assessed with self-report questionnaires in 132 STEM students (65 women) and 124 non-STEM students (73 women) in three European countries ranked in the top, middle, and bottom of the Global Gender Gap Report. Moreover, a mental rotation and a verbal fluency test were completed. Men endorsed male-favouring stereotypes more than women, and women endorsed female-favouring stereotypes more than men, an effect that was most pronounced in the country with the larger gender gap. Male STEM students endorsed male-favouring stereotypes more strongly than male non-STEM and female STEM students. Male non-STEM students endorsed female-favouring stereotypes less than female and male STEM students. Female STEM students reported higher incremental beliefs than female non-STEM students, especially in the country with the lowest gender gap. Men outperformed women, and STEM students outperformed non-STEM in mental rotation, while women outperformed men in verbal fluency. Male STEM students' stronger endorsement of male-favouring stereotypes might reflect genuine group differences, at least in mental rotation. While potentially such gender stereotypes can help creating a "chilly climate" where women in academic STEM degrees are expected to perform poorly, those women believed more in the possibility to change and improve in male-favouring abilities which could help them to overcome the potential negative effect of stereotyping.

Mapping psychotic-like experiences: Results from an online survey.

Suggestions have been made that psychotic-like experiences (PLEs), such as hallucinatory and delusional experiences, exist on a continuum from healthy individuals to patients with a diagnosis of schizophrenia. We used the screening questions of the Questionnaire for Psychotic Experiences (QPE), an interview that captures the presence and phenomenology of various psychotic experiences separately, to assess PLEs in Norway. Based on data from an online survey in a sample of more than 1,400 participants, we demonstrated that the QPE screening questions show satisfactory psychometric properties. Participants with mental disorders reported more frequent lifetime and current hallucinatory experiences than participants without mental disorders. Childhood experiences were rather low and ranged from 0.7% to 5.2%. We further replicated findings that young age, illegal drug use, lower level of education, and having parents with a mental disorder are associated with higher endorsement rates of PLEs. Finally, a binomial regression revealed that the mere presence of PLEs does not discriminate between individuals with and without a mental disorder. Taken together, the findings of the present study support existing models that both hallucinations and delusions exist on a structural and phenomenological continuum. Moreover, we demonstrated that the QPE screening questions can be used by themselves as a complementary tool to the full QPE interview.

Universal Patterns in Color-Emotion Associations Are Further Shaped by Linguistic and Geographic Proximity.

Many of us "see red," "feel blue," or "turn green with envy." Are such color-emotion associations fundamental to our shared cognitive architecture, or are they cultural creations learned through our languages and traditions? To answer these questions, we tested emotional associations of colors in 4,598 participants from 30 nations speaking 22 native languages. Participants associated 20 emotion concepts with 12 color terms. Pattern-similarity analyses revealed universal color-emotion associations (average similarity coefficient r = .88). However, local differences were also apparent. A machine-learning algorithm revealed that nation predicted color-emotion associations above and beyond those observed universally. Similarity was greater when nations were linguistically or geographically close. This study highlights robust universal color-emotion associations, further modulated by linguistic and geographic factors. These results pose further theoretical and empirical questions about the affective properties of color and may inform practice in applied domains, such as well-being and design.

No sex difference in an everyday multitasking paradigm.

According to popular beliefs and anecdotes, females best males when handling multiple tasks at the same time. However, there is relatively little empirical evidence as to whether there truly is a sex difference in multitasking and the few available studies yield inconsistent findings. We present data from a paradigm that was specifically designed to test multitasking abilities in an everyday scenario, the computerized meeting preparation task (CMPT), which requires participants to prepare a room for a meeting and handling various tasks and distractors in the process. Eighty-two males and 66 females with a wide age range (18-60 years) and a wide educational background completed the CMPT. Results revealed that none of the multitasking measures (accuracy, total time, total distance covered by the avatar, a prospective memory score, and a distractor management score) showed any sex differences. All effect sizes were d ≤ 0.18 and thus not even considered "small" by conventional standards. The findings are in line with other studies that found no or only small gender differences in everyday multitasking abilities. However, there is still too little data available to conclude if, and in which multitasking paradigms, gender differences arise.

Cognitive sex differences and hemispheric asymmetry: A critical review of 40 years of research.

According to a longstanding view, sex differences in cognitive abilities such as mental rotation or verbal memory arise from sex differences in hemispheric asymmetry: males are thought to be more lateralized than females which boosts their spatial but hampers their verbal skills. This idea sparked great interest and, even though it lost support in the 1990s, it is still put forward in contemporary (popular) scientific papers and textbooks. We aimed to provide a comprehensive review that summarizes the last 40 years of research. First, we confirm previous findings that the stronger hemispheric asymmetry in males is very small but robust. Second, we conclude that stronger hemispheric asymmetry, in general, does not enhance spatial and reduce verbal performance. Crucially, we carried out a systematic literature review showing that cognitive sex differences often emerge in the absence of sex differences in hemispheric asymmetry (and vice versa), implying the two phenomena are at least partly independent of each other. At present, there is insufficient data to conclude that sex differences in hemispheric asymmetry and cognitive performance are uncorrelated. However, we can conclude that sex differences in hemispheric asymmetry are certainly not the driving force behind sex differences in cognitive functioning.

Sex- and sex hormone-related variations in energy-metabolic frontal brain asymmetries: A magnetic resonance spectroscopy study.

Creatine is a key regulator of brain energy homeostasis, and well-balanced creatine metabolism is central in healthy brain functioning. Still, the variability of brain creatine metabolism is largely unattended in magnetic resonance spectroscopy (MRS) research. In the human brain, marginal sex differences in creatine levels have been found in the prefrontal cortex. It is however not known to what degree these sex differences are stable or change with varying gonadal hormone levels. The current study therefore investigated creatine in the prefrontal cortex across the menstrual cycle. In addition, we explored cerebral asymmetries. Creatine, Choline (Cho), N-acetylaspartate (NAA), Myo inositol (mI), and glutamate + glutamine (Glx) were assessed three times in 15 women and 14 men using MRS. Women were tested in cycle phases of varying hormone levels (menstrual, follicular, and luteal phase). Prefrontal creatine was found to change across the menstrual cycle, in a hemisphere-specific manner. Women in the follicular phase showed increased left prefrontal creatine accompanied with reduced right prefrontal creatine, while this asymmetry was not present in the luteal phase. In men, the creatine levels remained stable across three testing sessions. In general, both men and women were found to have higher creatine levels in the left as compared to the right prefrontal cortex. Exploratory analyses of other metabolites showed similar asymmetries in NAA, Cho, and mI, while Cho also showed a menstrual cycle effect. This is the first time that sex hormone-related changes in creatine metabolism have been demonstrated in the human brain. These findings may have important methodological implications for MRS research, as it supports previous concerns against uncritical usage of creatine as a reference measure for other metabolites, assumed to be invariant across individuals and conditions.

The neural correlates of sex differences in left-right confusion.

Difficulties in left-right discrimination (LRD) are commonly experienced in everyday life situations. Here we investigate the neurocognitive mechanisms of LRD and the specific role of left angular gyrus. Given that previous behavioral research reported women to be more susceptible to left-right confusion, the current study focuses particularly on the neural basis of sex differences in LRD while controlling for potential menstrual cycle effects (repeated measures design). 16 women and 15 men were presented pictures of pointing hands in various orientations (rotated versus non-rotated) and were asked to identify them as left or right hands. Results revealed that LRD was particularly associated with activation in inferior parietal regions, extending into the right angular gyrus. Irrespective of menstrual cycle phase, women, relative to men, recruited more prefrontal areas, suggesting higher top-down control in LRD. For the subset of rotated stimuli as compared to the non-rotated, we found leftward asymmetry for both men and women, although women scored significantly lower. We conclude that there are sex differences in the neurocognitive mechanisms underlying LRD. Although the angular gyrus is involved in LRD, several other parietal areas are at least as critical. Moreover, the hypothesis that more left-right confusion is due to more bilateral activation (in women) can be rejected.

Excess of non-right-handedness in schizophrenia: meta-analysis of gender effects and potential biases in handedness assessment.

BACKGROUND: The notion that schizophrenia is characterised by increased non-right-handedness is a cornerstone of the theory that schizophrenia arises from, and is genetically linked to, abnormal brain lateralisation. Reviews and meta-analyses have reported higher rates of non-right-handers in patients with schizophrenia. However, this was suggested to be the result of a gender artefact or a hidden bias in self-report handedness questionnaires. AIMS: To investigate using a meta-analytical approach whether the excess of non-right-handedness is seen in both females and males, and also when handedness is assessed behaviourally. METHOD: Electronic databases were searched for studies that reported (a) the rate of female and male non-right-handers in schizophrenia compared with controls and (b) the rate of non-right-handers in schizophrenia (regardless of gender) based on behavioural handedness assessment. RESULTS: The odds ratios (ORs) for females (OR = 1.63; based on 621 patients, 3747 controls) and males (OR = 1.50; based on 1213 patients, 3800 controls) differed significantly from 1.0, indicating both female and male patients were more often non-right-handed than controls. Moreover, there was an excess of non-right-handedness in patients with schizophrenia when handedness was assessed behaviourally: OR = 1.84 (1255 patients, 6260 controls). Even when both gender and behavioural handedness assessment were controlled for simultaneously, the excess of non-right-handedness persisted. CONCLUSIONS: The findings clearly demonstrate that the excess of non-right-handedness in schizophrenia does not result from a gender artefact or from biased handedness questionnaires. It is a true empirical effect and may indeed reflect a genetic link between schizophrenia and brain lateralisation.

Gender-stereotyping and cognitive sex differences in mixed- and same-sex groups.

Sex differences in specific cognitive abilities are well documented, but the biological, psychological, and sociocultural interactions that may underlie these differences are largely unknown. We examined within a biopsychosocial approach how gender stereotypes affect cognitive sex differences when adult participants were tested in mixed- or same-sex groups. A total of 136 participants (70 women) were allocated to either mixed- or same-sex groups and completed a battery of sex-sensitive cognitive tests (i.e., mental rotation, verbal fluency, perceptual speed) after gender stereotypes or gender-neutral stereotypes (control) were activated. To study the potential role of testosterone as a mediator for group sex composition and stereotype boost/threat effects, saliva samples were taken before the stereotype manipulation and after cognitive testing. The results showed the typical male and female advantages in mental rotation and verbal fluency, respectively. In general, men and women who were tested in mixed-sex groups and whose gender stereotypes had not been activated performed best. Moreover, a stereotype threat effect emerged in verbal fluency with reduced performance in gender stereotyped men but not women. Testosterone levels did not mediate the effects of group sex composition and stereotype threat nor did we find any relationship between testosterone and cognitive performance in men and women. Taken together, the findings suggest that an interaction of gender stereotyping and group sex composition affects the performance of men and women in sex-sensitive cognitive tasks. Mixed-sex settings can, in fact, increase cognitive performance as long as gender-stereotyping is prevented.

A comparative analysis of colour-emotion associations in 16-88-year-old adults from 31 countries.

As people age, they tend to spend more time indoors, and the colours in their surroundings may significantly impact their mood and overall well-being. However, there is a lack of empirical evidence to provide informed guidance on colour choices, irrespective of age group. To work towards informed choices, we investigated whether the associations between colours and emotions observed in younger individuals also apply to older adults. We recruited 7393 participants, aged between 16 and 88 years and coming from 31 countries. Each participant associated 12 colour terms with 20 emotion concepts and rated the intensity of each associated emotion. Different age groups exhibited highly similar patterns of colour-emotion associations (average similarity coefficient of .97), with subtle yet meaningful age-related differences. Adolescents associated the greatest number but the least positively biased emotions with colours. Older participants associated a smaller number but more intense and more positive emotions with all colour terms, displaying a positivity effect. Age also predicted arousal and power biases, varying by colour. Findings suggest parallels in colour-emotion associations between younger and older adults, with subtle but significant age-related variations. Future studies should next assess whether colour-emotion associations reflect what people actually feel when exposed to colour.

The consequences of the new European reclassification of non-invasive brain stimulation devices and the medical device regulations pose an existential threat to research and treatment: An invited opinion paper.

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment.

Auditory hallucinations and reduced language lateralization in schizophrenia: a meta-analysis of dichotic listening studies.

Reduced left-hemispheric language lateralization has been proposed to be a trait marker for schizophrenia, but the empirical evidence is ambiguous. Recent studies suggest that auditory hallucinations are critical for whether a patient shows reduced language lateralization. Therefore, the aim of the study was to statistically integrate studies investigating language lateralization in schizophrenia patients using dichotic listening. To this end, two meta-analyses were conducted, one comparing schizophrenia patients with healthy controls (n = 1407), the other comparing schizophrenia patients experiencing auditory hallucinations with non-hallucinating controls (n = 407). Schizophrenia patients showed weaker language lateralization than healthy controls but the effect size was small (g = -0.26). When patients with auditory hallucinations were compared to non-hallucinating controls, the effect size was substantially larger (g = -0.45). These effect sizes suggest that reduced language lateralization is a weak trait marker for schizophrenia as such and a strong trait marker for the experience of auditory hallucinations within the schizophrenia population.

Sex/Gender Differences in Verbal Fluency and Verbal-Episodic Memory: A Meta-Analysis.

Women are thought to fare better in verbal abilities, especially in verbal-fluency and verbal-memory tasks. However, the last meta-analysis on sex/gender differences in verbal fluency dates from 1988. Although verbal memory has only recently been investigated meta-analytically, a comprehensive meta-analysis is lacking that focuses on verbal memory as it is typically assessed, for example, in neuropsychological settings. On the basis of 496 effect sizes and 355,173 participants, in the current meta-analysis, we found that women/girls outperformed men/boys in phonemic fluency (ds = 0.12-0.13) but not in semantic fluency (ds = 0.01-0.02), for which the sex/gender difference appeared to be category-dependent. Women/girls also outperformed men/boys in recall (d = 0.28) and recognition (ds = 0.12-0.17). Although effect sizes are small, the female advantage was relatively stable over the past 50 years and across lifetime. Published articles reported stronger female advantages than unpublished studies, and first authors reported better performance for members of their own sex/gender. We conclude that a small female advantage in phonemic fluency, recall, and recognition exists and is partly subject to publication bias. Considerable variance suggests further contributing factors, such as participants' language and country/region.

Analysis of distributions reveals real differences on dichotic listening scores between left- and right-handers.

About 95% of right-handers and 70% of left-handers have a left-hemispheric specialization for language. Dichotic listening is often used as an indirect measure of this language asymmetry. However, while it reliably produces a right-ear advantage (REA), corresponding to the left-hemispheric specialization of language, it paradoxically often fails to obtain statistical evidence of mean differences between left- and right-handers. We hypothesized that non-normality of the underlying distributions might be in part responsible for the similarities in means. Here, we compare the mean ear advantage scores, and also contrast the distributions at multiple quantiles, in two large independent samples (Ns = 1,358 and 1,042) of right-handers and left-handers. Right-handers had an increased mean REA, and a larger proportion had an REA than in the left-handers. We also found that more left-handers are represented in the left-eared end of the distribution. These data suggest that subtle shifts in the distributions of DL scores for right- and left-handers may be at least partially responsible for the unreliability of significantly reduced mean REA in left-handers.

An online survey on clinical and healthy individuals with auditory verbal hallucinations: Abuse did not lead to more negative voice content.

Despite the clinical and theoretical importance of the negative content in auditory verbal hallucinations (AVHs), little research has been conducted on the topic. A handful of studies suggest that trauma or adverse life events contribute to negative content. The findings are somewhat inconsistent, however, possibly due to methodological limitations. Moreover, only trauma occurring in childhood has been investigated so far. In the present study, we studied the effect of abuse, experienced in either child- or adulthood, and clinical status on negative content of AVHs in four groups of participants that were assessed as part of a large, previously published online survey: Individuals with a psychotic disorder and AVHs (total n = 33), who had experienced abuse (n = 21) or not (n = 12) as well as a group of healthy individuals with AVHs (total n = 53), who had experienced abuse (n = 31) or not (n = 22). We hypothesized that having experienced abuse was associated with a higher degree of negative content. The clinical group collectively reported significantly higher degrees of negative AVHs content compared to the healthy group, but there was no effect of abuse on the degree of negative AVHs content. The presence of AVHs was more common amongst individuals who reported a history of abuse compared to individuals with no history of abuse, both in clinical and healthy participants with AVHs. This implies that at group level, being subjected to traumatic events increases an individual's vulnerability to experiencing AVHs. However, it does not necessarily account for negative content in AVHs.