Handedness in schizophrenia and affective disorders: a large-scale cross-disorder study.

While most people are right-handed, a minority are left-handed or mixed-handed. It has been suggested that mental and developmental disorders are associated with increased prevalence of left-handedness and mixed-handedness. However, substantial heterogeneity exists across disorders, indicating that not all disorders are associated with a considerable shift away from right-handedness. Increased frequencies in left- and mixed-handedness have also been associated with more severe clinical symptoms, indicating that symptom severity rather than diagnosis explains the high prevalence of non-right-handedness in mental disorders. To address this issue, the present study investigated the association between handedness and measures of stress reactivity, depression, mania, anxiety, and positive and negative symptoms in a large sample of 994 healthy controls and 1213 patients with DSM IV affective disorders, schizoaffective disorders, or schizophrenia. A series of complementary analyses revealed lower lateralization and a higher percentage of mixed-handedness in patients with major depression (14.9%) and schizophrenia (24.0%) compared to healthy controls (12%). For patients with schizophrenia, higher symptom severity was associated with an increasing tendency towards left-handedness. No associations were found for patients diagnosed with major depression, bipolar disorder, or schizoaffective disorder. In healthy controls, no association between hand preference and symptoms was evident. Taken together, these findings suggest that both diagnosis and symptom severity are relevant for the shift away from right-handedness in mental disorders like schizophrenia and major depression.

Clinical implications of brain asymmetries.

No two human brains are alike, and with the rise of precision medicine in neurology, we are seeing an increased emphasis on understanding the individual variability in brain structure and function that renders every brain unique. Functional and structural brain asymmetries are a fundamental principle of brain organization, and recent research suggests substantial individual variability in these asymmetries that needs to be considered in clinical practice. In this Review, we provide an overview of brain asymmetries, variations in such asymmetries and their relevance in the clinical context. We review recent findings on brain asymmetries in neuropsychiatric and neurodevelopmental disorders, as well as in specific learning disabilities, with an emphasis on large-scale database studies and meta-analyses. We also highlight the relevance of asymmetries for disease symptom onset in neurodegenerative diseases and their implications for lateralized treatments, including brain stimulation. We conclude that alterations in brain asymmetry are not sufficiently specific to act as diagnostic biomarkers but can serve as meaningful symptom or treatment response biomarkers in certain contexts. On the basis of these insights, we provide several recommendations for neurological clinical practice.

Measuring paw preferences in dogs, cats and rats: Design requirements and innovations in methodology.

Studying behavioural lateralization in animals holds great potential for answering important questions in laterality research and clinical neuroscience. However, comparative research encounters challenges in reliability and validity, requiring new approaches and innovative designs to overcome. Although validated tests exist for some species, there is yet no standard test to compare lateralized manual behaviours between individuals, populations, and animal species. One of the main reasons is that different fine-motor abilities and postures must be considered for each species. Given that pawedness/handedness is a universal marker for behavioural lateralization across species, this article focuses on three commonly investigated species in laterality research: dogs, cats, and rats. We will present six apparatuses (two for dogs, three for cats, and one for rats) that enable an accurate assessment of paw preference. Design requirements and specifications such as zoometric fit for different body sizes and ages, reliability, robustness of the material, maintenance during and after testing, and animal welfare are extremely important when designing a new apparatus. Given that the study of behavioural lateralization yields crucial insights into animal welfare, laterality research, and clinical neuroscience, we aim to provide a solution to these challenges by presenting design requirements and innovations in methodology across species.

Emotional cues reduce Pavlovian interference in feedback-based go and nogo learning.

It is easier to execute a response in the promise of a reward and withhold a response in the promise of a punishment than vice versa, due to a conflict between cue-related Pavlovian and outcome-related instrumental action tendencies in the reverse conditions. This robust learning asymmetry in go and nogo learning is referred to as the Pavlovian bias. Interestingly, it is similar to motivational tendencies reported for affective facial expressions, i.e., facilitation of approach to a smile and withdrawal from a frown. The present study investigated whether and how learning from emotional faces instead of abstract stimuli modulates the Pavlovian bias in reinforcement learning. To this end, 137 healthy adult participants performed an orthogonalized Go/Nogo task that fully decoupled action (go/nogo) and outcome valence (win points/avoid losing points). Three groups of participants were tested with either emotional facial cues whose affective valence was either congruent (CON) or incongruent (INC) to the required instrumental response, or with neutral facial cues (NEU). Relative to NEU, the Pavlovian bias was reduced in both CON and INC, though still present under all learning conditions. Importantly, only for CON, the reduction of the Pavlovian bias effect was adaptive by improving learning performance in one of the conflict conditions. In contrast, the reduction of the Pavlovian bias in INC was completely driven by decreased learning performance in non-conflict conditions. These results suggest a potential role of arousal/salience in Pavlovian-instrumental regulation and cue-action congruency in the adaptability of goal-directed behavior. Implications for clinical application are discussed.

A late-life neurogenetic signature of exposure to combat stress - A monozygotic discordant twin study.

Animal models suggest that experiencing high-stress levels induces changes in amygdalar circuitry and gene expression. In humans, combat exposure has been shown to alter amygdalar responsivity and connectivity, but abnormalities have been indicated to normalize at least partially upon the termination of stress exposure. In contrast, other evidence suggests that combat exposure continues to exert influence on exposed individuals well beyond deployment and homecoming, as indicated by longitudinal psychosocial evidence from veterans, and observation of greater health decline in veterans late in life. Accordingly, the experience of combat stress early in life may affect amygdalar responsivity late in life, a possibility requiring careful consideration of the confounding effects of aging, genetic factors, and symptoms of post-traumatic stress disorder. Here, we investigated amygdalar responsivity in a unique sample of 16 male monozygotic (MZ) twin pairs in their sixties, where one but not the other sibling had been exposed to combat stress in early adulthood. Forty years after combat experience, a generally blunted amygdalar response was observed in combat-exposed veterans compared to their non-exposed twin siblings. Spatial associations between these phenotypical changes and patterns of gene expression in the brain were found for genes involved in the synaptic organization and chromatin structure. Protein-protein interactions among the set of identified genes pointed to histone modification mechanisms. We conclude that exposure to combat stress early in life continues to impact brain function beyond the termination of acute stress and appears to exert prolonged effects on amygdalar function later in life via neurogenetic mechanisms.

Behavioral lateralization in bipolar disorders: a systematic review.

BACKGROUND: Bipolar disorder (BD) is often seen as a bridge between schizophrenia and depression in terms of symptomatology and etiology. Interestingly, hemispheric asymmetries as well as behavioral lateralization are shifted towards a tendency of left-side or mixed-side bias in schizophrenia whereas no shift is observed in subjects with depression. Given the role of BD with both, (hypo)manic and depressive episodes, investigating hemispheric asymmetries in subjects with BD is an interesting objective. METHOD: A systematic review of studies including measures of behavioral lateralization in the form of handedness, footedness, eyedness, and language lateralization was performed resulting in 25 suitable studies. RESULTS: A broad variety of methods was used to assess behavioral lateralization, especially for eyedness, footedness, and language lateralization hindering the integration of results. Additionally, for hand preference, studies frequently used different cut-off scores and classification systems. Overall, studies do not support alteration in side preference in BD subjects. Studies focusing on differences in handedness demonstrate that subjects show equal rates of right- and non-right-handedness as the general population. Few studies focusing on manic episodes point towards increased left-side bias in ear and eye dominance, but the small sample sizes and conflicting results warrant further investigation. CONCLUSION: The results reinforce that some disorders, such as BD, should not be treated as a homogenous group but sub-groups should be analyzed within the patient's population. Particularly, clinical implications resulting from neuroimaging studies highlight the need to study hemispheric asymmetries given that they may be important to consider for brain stimulation protocols.

Hand Preference in Stuttering: Meta-Analyses.

Reduced hemispheric asymmetries, as well as their behavioral manifestation in the form of atypical handedness (i.e., non-right, left-, or mixed-handedness), are linked to neurodevelopmental disorders, such as autism spectrum disorder, and several psychiatric disorders, such as schizophrenia. One neurodevelopmental disorder that is associated with reduced hemispheric asymmetries, but for which findings on behavioral laterality are conflicting, is stuttering. Here, we report a series of meta-analyses of studies that report handedness (assessed as hand preference) levels in individuals who stutter (otherwise healthy) compared to controls. For this purpose, articles were identified via a search in PubMed, Scopus, and PsycInfo (13 June 2023). On the basis of k = 52 identified studies totaling n = 2590 individuals who stutter and n = 17,148 controls, five random effects meta-analyses were conducted: four using the odds ratio [left-handers (forced choice); left-handers (extreme); mixed-handers; non-right-handers vs. total)] and one using the standardized difference in means as the effect size. We did not find evidence of a left (extreme)- or mixed-handedness difference or a difference in mean handedness scores, but evidence did emerge, when it came to left-handedness (forced-choice) and (inconclusively for) non-right-handedness. Risk-of-bias analysis was not deemed necessary in the context of these meta-analyses. Differences in hand skill or strength of handedness could not be assessed as no pertinent studies were located. Severity of stuttering could not be used s a moderator, as too few studies broke down their data according to severity. Our findings do not allow for firm conclusions to be drawn on whether stuttering is associated with reduced hemispheric asymmetries, at least when it comes to their behavioral manifestation.

The role of the cerebellum in internet gaming disorder-A systematic review.

Recent studies increasingly highlight involvement of the cerebellum in drug craving and addiction. However, its exact role, that is, whether the cerebellum is a critical component of a brain network underlying addictive behaviour, or whether it rather is a facilitator or mediator, is still unclear. Findings concerning the newly recognized internet gaming disorder (IGD) suggest that changes in cerebellar connectivity and functioning are associated with behavioural/non-substance addiction. Here, we systematically review the literature on IGD and cerebellar involvement following the PRISMA guidelines. A total of 13 neuroimaging studies met the inclusion criteria. Studies utilized a broad range of diagnostic instruments and resulting cut-off criteria, rendering it difficult to compare findings. Results on altered cerebro-cerebellar connectivity in patients with IGD are mixed; most studies report altered or increased functional connectivity. Moreover, decreased cerebellar grey matter volume is reported. Studies have further indicated that differential activation patterns in the cerebellum may enable discrimination between healthy subjects and subjects with IGD, even allowing for prediction of treatment outcomes. Given the strong connectivity between the cerebellum and cerebral regions, the cerebellum may act as an intermediary between regions involved in craving and addiction and consequently affect symptoms of IGD. Results suggest differential involvement of the cerebellar lobes, emphasizing a need for high-resolution parcellation of the cerebellum in future studies. However, the studies included in the present review have small sample sizes and include mostly male participants. Thus, results may have limited generalizability yet highlight a crucial role of the cerebellum in IGD that needs further investigation.

Handedness and anxiety: a review.

Handedness is a core phenotype in clinical laterality research and several different disorders such as schizophrenia and autism spectrum disorders have been linked to a higher prevalence of non-right-handedness. Moreover, subclinical personality traits like schizotypy have been linked to a higher prevalence of non-right-handedness. The association with handedness is poorly understood for generalized anxiety disorder and specific phobias, as well as for state and trait anxiety and fear of specific stimuli in nonclinical samples. Therefore, we performed a narrative review of studies investigating handedness in anxiety disorders patients and studies that compared anxiety scores between different handedness groups. Unlike schizophrenia and autism spectrum disorders, there seems to be no strong association between anxiety disorders and handedness in adult patients, except for specific phobias. Studies often had small sample sizes and therefore a high risk to report spurious findings. Similar findings were reported in most non-clinical studies. Importantly, familial handedness affects phobia risk and antenatal maternal anxiety increased the probability of mixed-handedness. This suggests that a transgenerational, developmental perspective is essential to better understand the complex interrelations between handedness and anxiety. Familial and especially maternal handedness and anxiety disorders should be integrated into future studies on handedness and anxiety whenever possible.

Maternal separation and its developmental consequences on anxiety and parvalbumin interneurons in the amygdala.

The early postnatal period represents an exceptionally vulnerable phase for the development of neurobiological alterations, aberrant behavior, and psychiatric disorders. Altered GABAergic activity in the hippocampus and the amygdala have been identified in humans diagnosed with depression or anxiety disorders, as well as in respective animal models. Changes in GABAergic activity can be visualized by immunohistochemical staining of parvalbumin (PV) protein. Therewith, alterations in PV intensity as well as in the integrity of the perineural net surrounding PV positive (PV+) interneurons have been reported as consequences of early stress. In the current study, maternal separation (MS) was used to induce early life stress. Female and male Sprague-Dawley rats were subjected to MS over 4 h from postnatal days 2-20. Then, anxiety behavior and PV+ interneurons in the amygdala were analyzed using immunohistochemistry in adolescence or adulthood. MS induced increased anxiety behavior in the marble-burying test in adolescence as well as in the elevated plus maze in adulthood. No effect of sex was found. Concerning alterations of parvalbumin expression in the amygdala, a trend towards a lower number of parvalbumin-positive inhibitory interneurons was shown in the amygdala after MS in adolescence, with no differences in the total number of cells. The current study offers a developmental perspective, suggesting that the kind of anxiety behavior expressed by rats following MS changes over time from active to passive avoidance, indicating that effects of MS are highly dependent on developmental state. Moreover, a cell-type-specific effect of MS on the cellular composition of the amygdala is discussed. The presented study demonstrates the long-lasting consequences of early stress on behavior, offers a possible neurobiological correlate, and discusses possible mediators in the development of these alterations.

Oligodendrocytes matter: a review of animal studies on early adversity.

Exposure to adversities in early life appears to affect the development of white matter, especially oligodendrocytes. Furthermore, altered myelination is present in regions subjected to maturation during the developmental time when early adversities are experienced. In this review, studies applying two well-established animal models of early life adversity, namely maternal separation and maternal immune activation, focusing on oligodendrocyte alterations and resulting implications for psychiatric disorders are discussed. Studies revealed that myelination is reduced as a result of altered oligodendrocyte expression. Furthermore, early adversity is associated with increased cell death, a simpler morphology, and inhibited oligodendrocyte maturation. However, these effects seem to be region- specific as some brain regions show increased expression while others show decreased expression of oligodendroglia-related genes, and they occur especially in regions of ongoing development. Some studies furthermore suggest that early adversity leads to premature differentiation of oligodendrocytes. Importantly, especially early exposure results in stronger oligodendrocyte-related impairments. However, resulting alterations are not restricted to exposure during the early pre- and postnatal days as social isolation after weaning leads to fewer internodes and branches and shorter processes of oligodendrocytes in adulthood. Eventually, the found alterations may lead to dysfunction and long-lasting alterations in structural brain development associated with psychiatric disorders. To date, only few preclinical studies have focused on the effects of early adversity on oligodendrocytes. More studies including several developmental stages are needed to further disentangle the role of oligodendrocytes in the development of psychiatric disorders.

Stress exposure, hand preference, and hand skill: A deep phenotyping approach.

ABSTRACTStress exposure and reactivity may show differential associations with handedness, but shallow phenotyping may influence the current knowledge. Importantly, different handedness measures do not necessarily show high correlations with each other and should not be used interchangeably as they may reflect different dimensions of laterality. Here, data on handedness from 599 participants in the population-based, longitudinal Dortmund Vital Study was used to determine various asymmetry indices. Hand preference was assessed with the Edinburgh Handedness Inventory (EHI) and the lateral preference inventory (LPI) measuring handedness, footedness, earedness, and eyedness. Hand performance was determined using the pegboard test. In addition, data on several dimensions of stress exposure and reactivity, including hair cortisol, and mental well-being was analysed to determine associations with handedness. All handedness measures correlated significantly with each other, with the strongest correlation between the EHI and the LPI handedness score. The EHI and LPI hand measures resulted in the highest effect sizes and most consistent correlations with stress or mental well-being. In contrast, the pegboard test only showed very little association with the stress and mental well-being measures. This highlights the importance of handedness phenotyping. Including preference measures is recommended to disentangle the link between handedness and mental health.

Hemispheric asymmetries in mental disorders: evidence from rodent studies.

The brain is built with hemispheric asymmetries in structure and function to enable fast neuronal processing. In neuroimaging studies, several mental disorders have been associated with altered or attenuated hemispheric asymmetries. However, the exact mechanism linking asymmetries and disorders is not known. Here, studies in animal models of mental disorders render important insights into the etiology and neuronal alterations associated with both disorders and atypical asymmetry. In this review, the current literature of animal studies in rats and mice focusing on anxiety and fear, anhedonia and despair, addiction or substance misuse, neurodegenerative disorders as well as stress exposure, and atypical hemispheric asymmetries is summarized. Results indicate overall increased right-hemispheric neuronal activity and a left-sided behavioral bias associated with symptoms of anxiety, fear, anhedonia, behavioral despair as well as stress exposure. Addiction behavior is associated with right-sided bias and transgenic models of Alzheimer's disease indicate an asymmetrical accumulation of fibrillar plaques. Most studies focused on changes in the bilateral amygdala and frontal cortex. Across studies, two crucial factors influencing atypical asymmetries arose independently of the disorder modeled: sex and developmental age. In conclusion, animal models of mental disorders demonstrate atypical hemispheric asymmetries similar to findings in patients. Particularly, increased left-sided behavior and greater right-hemispheric activity were found across models applying stress-based paradigms. However, sex- and age-dependent effects on atypical hemispheric asymmetries are present that require further investigation. Animal models enable the analysis of hemispheric changes on the molecular level which may be most effective to detect early alterations.

Unraveling the mystery of white matter in depression: A translational perspective on recent advances.

BACKGROUND: Numerous cortical and subcortical structures have been studied extensively concerning alterations of their integrity as well as their neurotransmitters in depression. However, connections between these structures have received considerably less attention. OBJECTIVE: This systematic review presents results from recent neuroimaging as well as neuropathologic studies conducted on humans and other mammals. It aims to provide evidence for impaired white matter integrity in individuals expressing a depressive phenotype. METHODS: A systematic database search in accordance with the PRISMA guidelines was conducted to identify imaging and postmortem studies conducted on humans with a diagnosis of major depressive disorder, as well as on rodents and primates subjected to an animal model of depression. RESULTS: Alterations are especially apparent in frontal gyri, as well as in structures establishing interhemispheric connectivity between frontal regions. Translational neuropathological findings point to alterations in oligodendrocyte density and morphology, as well as to alterations in the expression of genes related to myelin synthesis. An important role of early life adversities in the development of depressive symptoms and white matter alterations across species is thereby revealed. Data indicating that stress can interfere with physiological myelination patterns is presented. Altered myelination is most notably present in regions that are subject to maturation during the developmental stage of exposure to adversities. CONCLUSION: Translational studies point to replicable alterations in white matter integrity in subjects suffering from depression across multiple species. Impaired white matter integrity is apparent in imaging as well as neuropathological studies. Future studies should focus on determining to what extent influencing white matter integrity is able to improve symptoms of depression in animals as well as humans.

It's About Time: The Circadian Network as Time-Keeper for Cognitive Functioning, Locomotor Activity and Mental Health.

A variety of organisms including mammals have evolved a 24h, self-sustained timekeeping machinery known as the circadian clock (biological clock), which enables to anticipate, respond, and adapt to environmental influences such as the daily light and dark cycles. Proper functioning of the clock plays a pivotal role in the temporal regulation of a wide range of cellular, physiological, and behavioural processes. The disruption of circadian rhythms was found to be associated with the onset and progression of several pathologies including sleep and mental disorders, cancer, and neurodegeneration. Thus, the role of the circadian clock in health and disease, and its clinical applications, have gained increasing attention, but the exact mechanisms underlying temporal regulation require further work and the integration of evidence from different research fields. In this review, we address the current knowledge regarding the functioning of molecular circuits as generators of circadian rhythms and the essential role of circadian synchrony in a healthy organism. In particular, we discuss the role of circadian regulation in the context of behaviour and cognitive functioning, delineating how the loss of this tight interplay is linked to pathological development with a focus on mental disorders and neurodegeneration. We further describe emerging new aspects on the link between the circadian clock and physical exercise-induced cognitive functioning, and its current usage as circadian activator with a positive impact in delaying the progression of certain pathologies including neurodegeneration and brain-related disorders. Finally, we discuss recent epidemiological evidence pointing to an important role of the circadian clock in mental health.

Hemispheric asymmetries in the amygdala: A comparative primer.

The amygdala is a core structure in the neuronal network underlying emotion processing in the vertebrate brain. Its structure and function have been extensively studied in both neuroimaging studies in human volunteers and comparative studies in animal models. Across different studies and research questions regarding the amygdala, one often-encountered finding is that the left and the right amygdala are not equivalent in terms of function and structure. Hemispheric asymmetries in the amygdala have been reported on many different levels, yet a systematic integration of these findings has been missing from the literature. Researchers in both cognitive and clinical neurosciences are often puzzled why they find a specific effect or association for the left but not the right amygdala, or vice versa. In this review article, we provide an integrated overview of existing basic and clinical findings regarding amygdala asymmetries in structure, connections, and functions. Importantly, the literature suggests that functional amygdala lateralization is determined by temporal characteristics, emotional valence, and perceptual properties. Furthermore, we highlight alterations of amygdala asymmetries reported in different patient groups, thereby allowing for a deeper understanding of atypical amygdala asymmetries. Lastly, we aim to provide guidelines and approaches concerning the interpretation of results for researchers investigating amygdala asymmetries.

Maternal separation: Does it hold the potential to model consequences of postpartum depression?

The postpartum period is a sensitive time where women are especially vulnerable to develop postpartum depression (PPD), with 10%-15% of women affected. This review investigates whether the maternal separation (MS) paradigm in rodents holds the potential to help to understand mothers suffering from PPD. MS is a well-established stress model to investigate effects on infants, whereas effects on the dam are often overlooked. The database PubMed was searched for studies investigating effects of daily MS within the first weeks after parturition on dams in rats and mice and compared to findings in PPD mothers. MS was categorized as brief MS (5-45 min) with or without handling of pups and long MS (3-4 h and longer). MS alters maternal care, depressive-like behavior, anxiety, and aggression; leads to alterations in neuronal gene expression; and affects hormone and neurotransmitter levels similar to observations in PPD patients. Even though there are disparities between human and rodent mothers, with some results differing in directionality, as well as the reason for separation (self-induced in PPD, externally induced in MS), the overall effects found on neurobiological, hormonal, and behavioral levels mostly coincide. Thus, the MS paradigm can add relevant knowledge to existing PPD animal models, further advancing the study of PPD.

Asymmetry in the Central Nervous System: A Clinical Neuroscience Perspective.

Recent large-scale neuroimaging studies suggest that most parts of the human brain show structural differences between the left and the right hemisphere. Such structural hemispheric asymmetries have been reported for both cortical and subcortical structures. Interestingly, many neurodevelopmental and psychiatric disorders have been associated with altered functional hemispheric asymmetries. However, findings concerning the relation between structural hemispheric asymmetries and disorders have largely been inconsistent, both within specific disorders as well as between disorders. In the present review, we compare structural asymmetries from a clinical neuroscience perspective across different disorders. We focus especially on recent large-scale neuroimaging studies, to concentrate on replicable effects. With the notable exception of major depressive disorder, all reviewed disorders were associated with distinct patterns of alterations in structural hemispheric asymmetries. While autism spectrum disorder was associated with altered structural hemispheric asymmetries in a broader range of brain areas, most other disorders were linked to more specific alterations in brain areas related to cognitive functions that have been associated with the symptomology of these disorders. The implications of these findings are highlighted in the context of transdiagnostic approaches to psychopathology.