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.

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.

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.

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.

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.

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.

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.

Pilot-RCT Finds No Evidence for Modulation of Neuronal Networks of Auditory Hallucinations by Transcranial Direct Current Stimulation.

BACKGROUND: Transcranial direct current stimulation (tDCS) is used as treatment for auditory verbal hallucinations (AVH). The theory behind the treatment is that tDCS increases activity in prefrontal cognitive control areas, which are assumed to be hypoactive, and simultaneously decreases activity in temporal speech perception areas, which are assumed to be hyperactive during AVH. We tested this hypofrontal/hypertemporal reversal theory by investigating anatomical, neurotransmitter, brain activity, and network connectivity changes over the course of tDCS treatment. METHODS: A double-blind, randomized controlled trial was conducted with 21 patients receiving either sham or real tDCS treatment (2 mA) twice daily for 5 days. The anode was placed over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the left temporo-parietal cortex (TPC). Multimodal neuroimaging as well as clinical and neurocognitive functioning assessment were performed before, immediately after, and three months after treatment. RESULTS: We found a small reduction in AVH severity in the real tDCS group, but no corresponding neuroimaging changes in either DLPFCD or TPC. LIMITATIONS: The study has a small sample size. CONCLUSION: The results suggest that the currently leading theory behind tDCS treatment of AVH may need to be revised, if confirmed by studies with larger N. Tentative findings point to the involvement of Broca's area as a critical structure for tDCS treatment.

From core schemas about the self and others to voice phenomenology: Anxiety and depression affect voice hearers differently.

OBJECTIVES: Auditory verbal hallucinations (AVHs) occur as a symptom in various mental disorders, and show different phenomenological aspects, depending on their underlying psychopathology. Anxiety and depression, which are known to be involved in the development of AVHs, are suggested to amplify a vicious cycle in which negative interpretations of daily experiences feed into the formation of negative core schemas about the self and others. However, the way in which these variables interrelate is still unknown. Therefore, our aim was to determine the specific roles of anxiety and depression in the relationship between core schemas and emotional aspects of AVHs for three groups (non-clinical voice hearers, affective voice hearers and non-affective voice hearers). METHODS: Positive and negative core schemas of the self and others were tested as predictors of emotional distress due to AVHs, examining anxiety and depression separately as potential mediators. RESULTS: Results showed full mediating effects of depression in non-affective voice hearers in the relationship between negative core schemas and AVH distress, but not in affective voice hearers. Anxiety was not a mediator in any of the groups. CONCLUSIONS: These findings suggest different emotional mechanisms depending on the underlying psychopathology.

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.

Sex/gender differences in the brain are not trivial-A commentary on Eliot et al. (2021).

In this commentary to the comprehensive review by Eliot et al. (2021), we fully comply with rejecting the 'sexual dimorphism' concept in its extreme, binary form. However, we criticise the authors' extreme position and argue that sex/gender differences in the brain are far from being 'trivial' and 'unlikely to be meaningful'. Our key arguments refer to the importance of small effects which can have meaningful behavioural consequences, and to several non-binary sex/gender-related factors which might explain individual differences better than sex/gender per se and which have shown to play important roles as risk factors in the aetiology of many mental and neurodevelopmental disorders. We conclude that the biopsychosocial approach is key to understanding sex/gender differences in the brain better than we currently do.

Transcranial direct current stimulation (tDCS) enhances internal source monitoring abilities in healthy participants.

Source monitoring refers to the ability to identify the origin of a memory, for example, whether you remember saying something or thinking about it, and confusions of these sources have been associated with the experience of auditory verbal hallucinations (AVHs). Both AVHs and source confusions are reported to originate from dysfunctional brain activations in the prefrontal cortex (PFC) and the superior temporal gyrus (STG); specifically, it is assumed that a hypoactive PFC and a hyperactive STG gives rise to AVHs and source confusions. We set out to test this assumption by trying to mimic this hypertemporal/hypofrontal model in healthy individuals with transcranial direct current stimulation (tDCS): the inhibitory cathode was placed over the left PFC and the excitatory anode over the left dorsolateral STG. Participants completed a reality monitoring task (distinguishing between external and internal memory sources) and an internal source monitoring task (distinguishing between two or more internal memory sources) in two separate experiments (offline vs. online tDCS). In the offline experiment (n = 34), both source monitoring tasks were completed after tDCS stimulation, and in the online experiment (n = 27) source monitoring tasks were completed while simultaneously being stimulated with tDCS. We found that internal source monitoring abilities were significantly enhanced during active online tDCS, while reality monitoring abilities were unaffected by stimulation in both experiments. We speculate, based on combining the present findings with previous studies, that there might be different brain areas involved in reality and internal source monitoring. While internal source monitoring seems to involve speech production areas, specifically Broca's area, as suggested in the present study, reality monitoring seems to rely more on the STG and DLPFC, as shown in other studies of the field.

Olfactory hallucinations in a population-based sample.

Olfactory hallucinations referring to olfactory perceptions in the absence of chemical stimuli, occur in non-clinical and clinical populations. Few studies have investigated their prevalence in the general population and little is known about factors triggering and maintaining them such as substance use, severe life events, and mood. We analyzed self-report data from 2500 community dwelling Norwegians, aged 18-96 years, for occurrence of olfactory hallucinations and co-occurring hallucinations in other modalities (auditory, visual, tactile). Analyses included age, sex, self-reported symptoms of depression and anxiety, mental health status, and experience of severe life-events. The results show that 4.2% (95% CI 3.5-5.1%) reported having experienced olfactory hallucinations, and 56% of individuals experiencing olfactory hallucinations also reported these in combination with hallucinations in other modalities. Prevalence varied significantly in terms of age and sex, in that olfactory hallucinations were most frequently reported by young individuals and females. Self-reported symptoms of anxiety and experience of stressful life events were significantly associated with olfactory hallucinations, suggesting that experiencing olfactory hallucinations may negatively affect functioning and may increase the likelihood of developing psychopathology. Findings underline the need to continue to examine olfactory hallucinations albeit with a more comprehensive assessment in order to increase knowledge on this experience.

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.

Personal resilience factors protect against distressing auditory hallucinations: A study comparing psychotic patients with auditory hallucinations, non-patients with auditory hallucinations, and healthy controls.

Although studies have identified several risk factors for the development of psychotic disorders, potential protective factors - such as resilience - have rarely been examined. Studies suggest that the negative beliefs people hold about their Auditory Hallucinations (AH) may be an indicator of a need for care. However, the reason why certain people do not develop negative beliefs is unclear but may be related to resilience. The present study aimed to examine the role of resilience in AH by comparing psychotic patients with AH, non-patients with AH, and healthy controls without AH. Another aim was to explore whether resilience is related to the beliefs people hold about their AH. Results revealed that patients with AH and non-patients with AH had similarly weak interpersonal resilience factors compared to healthy controls without AH. In contrast, patients with AH showed weak personal factors of resilience compared to both non-patients with AH and healthy controls without AH. Patients with AH had more negative and fewer positive beliefs about their AH than non-patients with AH. Finally, the personal factors of resilience were related to the beliefs about AH. These results showed that personal factors of resilience are decisive variables influencing the need for care in people experiencing AH and thus represent an important treatment target.