Meta-Analysis of Cognitive Ability Differences by Apolipoprotein E Genotype in Young Humans Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-08-17 Gali H. Weissberger, Daniel A. Nation, Caroline P. Nguyen, Mark W. Bondi, S. Duke Han
The apolipoprotein (APOE) ε4 allele has been proposed as an example of an antagonistic pleiotropy gene, conferring a beneficial effect on cognition in early life and a detrimental impact on cognition during later years. However, findings on the cognitive associations of the ε4 allele in younger persons are mixed. This PRISMA conforming study aimed to investigate APOE genotype (e4/non-e4) associations across seven cognitive domains (intelligence/achievement, attention/working memory, executive functioning, memory, language, processing speed and visuospatial abilities) in younger humans using a meta-analytic approach. Of 689 records reviewed, 29 studies (34 data-points) were selected for the quantitative synthesis. Participants’ ages ranged from 2-40. Results showed that young ε4 carriers did not statistically differ from non-ε4 carriers across any cognitive domains. Overall, findings do not provide compelling support for an antagonistic pleiotropic effect of the ε4 allele across the lifespan.
Balancing between the two: are freezing of gait and postural instability in Parkinson’s disease connected? Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-08-17 E.M.J. Bekkers, B.W. Dijkstra, E. Heremans, S.M.P. Verschueren, B.R. Bloem, A. Nieuwboer
Postural instability and freezing of gait (FoG) are key features of Parkinson’s disease (PD) closely related to falls. Growing evidence suggests that co-existing postural deficits could influence the occurrence and severity of FoG. To date, the exact nature of this interrelationship remains largely unknown. We analyzed the complex interaction between postural instability and gait disturbance by comparing the findings available in the posturographic literature between patients with and without FoG. Results showed that FoG and postural instability are intertwined, can influence each other behaviorally and may coincide neurologically. The most common FoG-related postural deficits included weight-shifting impairments, and inadequate scaling and timing of postural responses most apparent at forthcoming postural changes under time constraints. Most likely, a negative cycle of combined and more severe postural deficits in people with FoG will enhance postural stability breakdown. As such, the wide brain network deficiencies involved in FoG may also concurrently influence postural stability. Future work needs to examine whether training interventions targeting both symptoms will have extra clinical benefits on fall frequency.
“Pure apathy” and cognitive dysfunctions in Parkinson’s disease: A meta-analytic study Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-08-13 Alfonsina D’Iorio, Gianpaolo Maggi, Carmine Vitale, Luigi Trojano, Gabriella Santangelo
Parkinson’s Disease (PD) is characterized by motor and non-motor symptoms such as cognitive deficit and behavioural disturbances. Apathy seems to be related to cognitive impairment, but some studies failed to confirm the relationship due to different methodological procedures across studies. A meta-analysis on 8 studies was performed to explore the cognitive correlates of apathy without depression and dementia (pure apathy). Global cognitive function, memory, executive functions, processing speed/attention/working memory, visuospatial abilities and language were the outcomes. The effect size of the relationship between “pure apathy” and reduced global cognitive functioning, executive functions, processing speed/attention/working memory, visuospatial functions, long-term verbal memory was moderate, whereas apathy was strongly associated with inhibition dysfunctioning. Our results revealed a strong association between “pure apathy” and cognitive dysfunctions, particularly deficit of memory and executive functions related to altered prefronto-subcortical circuitries.
The PRISM Project: Social Withdrawal from an RDoC Perspective Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-08-11 Bruce N. Cuthbert
The PRISM (Psychiatric Ratings using Intermediate Stratified Markers) project was funded under the auspices of the European Union Innovative Medicine Initiative (EU-IMI) to explore quantitative approaches to the biological and behavioral aspects of neuropsychiatric disorders. PRISM focuses specifically on social withdrawal, although its principles are applicable to a wide range of disorders. This commentary explores some of the major aspects of the PRISM design from the perspective of the Research Domain Criteria (RDoC) project initiated by the National Institute of Mental Health. PRISM represents an apt exemplar of the principles developed in the RDoC framework, with the potential to contribute palpable advances in precision diagnosis and innovative approaches to treatment development.
Advanced Biomarkers of Pediatric Mild Traumatic Brain Injury: Progress and Perils Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-08-09 Andrew R. Mayer, Mayank Kaushal, Andrew B. Dodd, Faith M. Hanlon, Nicholas A. Shaff, Rebekah Mannix, Christina L. Master, John J. Leddy, David Stephenson, Christopher J. Wertz, Elizabeth M. Suelzer, Kristy B. Arbogast, Timothy B. Meier
There is growing public concern about neurodegenerative changes (e.g., Chronic Traumatic Encephalopathy) that may occur chronically following clinically apparent and clinically silent (i.e., subconcussive blows) pediatric mild traumatic brain injury (pmTBI). However, there are currently no biomarkers that clinicians can use to objectively diagnose patients or predict those who may struggle to recover. Non-invasive neuroimaging, electrophysiological and neuromodulation biomarkers have promise for providing evidence of the so-called “invisible wounds” of pmTBI. Our systematic review, however, belies that notion, identifying a relative paucity of high-quality, clinically impactful, diagnostic or prognostic biomarker studies in the sub-acute injury phase (36 studies on unique samples in 28 years), with the majority focusing on adolescent pmTBI. Ultimately, well-powered longitudinal studies with appropriate control groups, as well as standardized and clearly-defined inclusion criteria (time post-injury, injury severity and past history) are needed to truly understand the complex pathophysiology that is hypothesized (i.e., still needs to be determined) to exist during the acute and sub-acute stages of pmTBI and may underlie post-concussive symptoms.
Neural Correlates of Action: Comparing Meta-Analyses of Imagery, Observation, and Execution Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-08-09 Robert M. Hardwick, Svenja Caspers, Simon B Eickhoff, Stephan P Swinnen
Several models propose Motor Imagery, Action Observation, and Movement Execution recruit the same brain regions. There is, however, no quantitative synthesis of the literature that directly compares their respective networks. Here we summarized data from neuroimaging experiments examining Motor Imagery (303 experiments, 4,902 participants), Action Observation (595 experiments, 11,032 participants), and related control tasks involving Movement Execution (142 experiments, 2,302 participants). Comparisons across these networks showed that Motor Imagery and Action Observation recruited similar premotor-parietal cortical networks. However, while Motor Imagery recruited a similar subcortical network to Movement Execution, Action Observation did not consistently recruit any subcortical areas. These data quantify and amend previous models of the similarities in the networks for Motor Imagery, Action Observation, and Movement Execution, while highlighting key differences in their recruitment of motor cortex, parietal cortex, and subcortical structures.
Cerebral correlates of Imitation of Intransitive Gestures: An Integrative Review of Neuroimaging Data and Brain Lesion Studies Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-08-04 Mathieu Lesourd, François Osiurak, Josselin Baumard, Angela Bartolo, Tim Vanbellingen, Emanuelle Reynaud
The aim of the present review is to investigate the cerebral correlates, more particularly the role of the parietal lobe, when imitating intransitive gestures, a task highly sensitive to apraxic errors. By providing an integrative review of functional imaging and brain lesion studies, we focused our attention on the meaning of gestures (meaningful and meaningless) and the body parts (finger and hand). We found that imitation of intransitive gestures is relying upon a bilateral brain network including fronto-parietal areas irrespective of meaning or body parts. Moreover, we observed that while imitation of meaningful and meaningless gestures is predominantly impacted following left parietal lesions, more brain areas are engaged during meaningless gesture imitation. Concerning body parts, whereas imitation of hand postures is relying upon the left parietal lobe (angular gyrus), imitation of finger postures is more likely to be impaired following lesions in the frontal lobe, insula and basal ganglia. These results question neuropsychological theories on apraxia and open promising avenues for a better understanding of apraxia.
Systematic review of Drosophila short-term-memory genetics: Meta-analysis reveals robust reproducibility Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-08-02 Tayfun Tumkaya, Stanislav Ott, Adam Claridge-Chang
Geneticists use olfactory conditioning in Drosophila to identify learning genes; however, little is known about how these genes are integrated into short-term memory (STM) pathways. Here, we investigated the hypothesis that the STM evidence base is weak. We performed systematic review and meta-analysis of the field. Using metrics to quantify variation between discovery articles and follow-up studies, we found that seven genes were both highly replicated, and highly reproducible. However, ~80% of STM genes have never been replicated. While only a few studies investigated interactions, the reviewed genes could account for >1000% memory. This large summed effect size could indicate irreproducibility, many shared pathways, or that current assay protocols lack the specificity needed to identify core plasticity genes. Mechanistic theories of memory will require the convergence of evidence from system, circuit, cellular, molecular, and genetic experiments; systematic data synthesis is an essential tool for integrated neuroscience.
KETOGENIC DIET AS A METABOLIC THERAPY FOR MOOD DISORDERS: EVIDENCE AND DEVELOPMENTS Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-31 Elisa Brietzke, Rodrigo B. Mansur, Mehala Subramaniapillai, Vicent Balanzá Martinez, Maj Vinberg, Ana González-Pinto, Joshua D. Rosenblat, Roger Ho, Roger S. McIntyre
Despite significant advances in pharmacological and non-pharmacological treatments, mood disorders remain a significant source of mental capital loss, with high rates of treatment resistance, requiring a coordinated effort in investigation and development of efficient, tolerable and accessible novel interventions. Ketogenic diet (KD) is a low-carb diet that substantially changes the energetic matrix of the body including the brain. It has been established as an effective anticonvulsant treatment, and more recently, the role of KD for mental disorders has been explored. Ketogenic diet has profound effects in multiple targets implicated in the pathophysiology of mood disorders, including but not limited to, glutamate/GABA transmission, monoamine levels, mitochondrial function and biogenesis, neurotrophism, oxidative stress, insulin dysfunction and inflammation. Preclinical studies, case reports and case series have demonstrated antidepressant and mood stabilizing effects of KD, however, to date, no clinical trials for depression or bipolar disorder have been conducted. Because of its potential pleiotropic benefits, KD should be considered as a promising intervention in research in mood disorder therapeutics, especially in treatment resistant presentations.
Hungry Brains: A Meta-Analytical Review of Brain Activation Imaging Studies On Food Perception and Appetite in Obese Individuals Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-30 F. Devoto, L. Zapparoli, R. Bonandrini, M. Berlingeri, A. Ferrulli, L. Luzi, G. Banfi, E. Paulesu
The dysregulation of food intake in chronic obesity has been explained by different theories. To assess their explanatory power, we meta-analyzed 22 brain-activation imaging studies. We found that obese individuals exhibit hyper-responsivity of the brain regions involved in taste and reward for food-related stimuli. Consistent with a Reward Surfeit Hypothesis, obese individuals exhibit a ventral striatum hyper-responsivity in response to pure tastes, particularly when fasting. Furthermore, we found that obese subjects display more frequent ventral striatal activation for visual food cues when satiated: this continued processing within the reward system, together with the aforementioned evidence, is compatible with the Incentive Sensitization Theory. On the other hand, we did not find univocal evidence in favor of a Reward Deficit Hypothesis nor for a systematic deficit of inhibitory cognitive control. We conclude that the available brain activation data on the dysregulated food intake and food-related behavior in chronic obesity can be best framed within an Incentive Sensitization Theory. Implications of these findings for a brain-based therapy of obesity are briefly discussed.
The Role of Epigenetic Modifications in Neurodevelopmental Disorders: A Systematic Review Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-29 Lorenza Dall’Aglio, Taulant Muka, Charlotte A.M. Cecil, Wichor M. Bramer, Michael M.P.J. Verbiest, Jana Nano, Andrea Cortes Hidalgo, Oscar H. Franco, Henning Tiemeier
Epigenetic processes have been suggested as key mechanisms in the etiology of neurodevelopmental disorders. This systematic review summarizes the current evidence for an association between epigenetics and Autism Spectrum Disorder (ASD) and Attention/Deficit-Hyperactivity Disorder (ADHD). Six databases were searched until the 24th of October 2017. Of the 2169 retrieved articles, 29 met our inclusion criteria. While generally associations between epigenetics and neurodevelopmental disorders were reported, only a few findings were consistent across independent analyses. Differential epigenetic markers were repeatedly identified in OR2L13, C11orf21/TSPAN32, PRRT1 and H3K27 for autism, and in VIPR2 for ADHD. Overall, evidence of an association between epigenetic modifications and ASD or ADHD should be considered preliminary and based on studies suffering from numerous caveats. We highlight the need for carefully designed investigations and for greater homogeneity and provide specific recommendations for future research. Despite our current limited understanding, the suggestive findings and the rapid advances in the field hold the promise of a forthcoming elucidation of the role of epigenetic modifications in neurodevelopmental disorders.
Functional neuroanatomy of peripheral inflammatory physiology: A meta-analysis of human neuroimaging studies Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-29 Thomas E. Kraynak, Anna L. Marsland, Tor D. Wager, Peter J. Gianaros
Communication between the brain and peripheral mediators of systemic inflammation is implicated in numerous psychological, behavioral, and physiological processes. Functional neuroimaging studies have identified brain regions that associate with peripheral inflammation in humans, yet there are open questions about the consistency, specificity, and network characteristics of these findings. The present systematic review provides a meta-analysis to address these questions. Multilevel kernel density analysis of 24 studies (37 statistical maps; 264 coordinates; 457 participants) revealed consistent effects in the amygdala, hippocampus, hypothalamus, striatum, insula, midbrain, and brainstem, as well as prefrontal and temporal cortices. Effects in some regions were specific to particular study designs and tasks. Spatial pattern analysis revealed significant overlap of reported effects with limbic, default mode, ventral attention, and corticostriatal networks, and co-activation analyses revealed functional ensembles encompassing the prefrontal cortex, insula, and midbrain/brainstem. Together, these results characterize brain regions and networks associated with peripheral inflammation in humans, and they provide a functional neuroanatomical reference point for future neuroimaging studies on brain-body interactions.
CANNABIS USE AND THE DEVELOPMENT OF TOLERANCE: A SYSTEMATIC REVIEW OF HUMAN EVIDENCE Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-26 Marco Colizzi, Sagnik Bhattacharyya
Where in the serotonergic system does it go wrong? Unravelling the route by which the serotonergic system affects feather pecking in chickens Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-25 Elske N. de Haas, Jerine A.J. van der Eijk
Vision dominates audition in adults but not children: A meta-analysis of the Colavita effect Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-23 Rebecca J. Hirst, Lucy Cragg, Harriet A. Allen
The Colavita effect occurs when participants respond only to the visual element of an audio-visual stimulus. This visual dominance effect is proposed to arise from asymmetric facilitation and inhibition between modalities. It has also been proposed that, unlike adults, children appear predisposed to auditory information. We provide the first quantitative synthesis of studies exploring the Colavita effect, combining data from 70 experiments across 14 studies. A mixed-meta-regression model was applied to assess whether the Colavita effect is influenced by methodological factors and age group tested. Studies reporting response time data were used to test for the presence of asymmetrical facilitation between modalities. Studies with adult participants yielded a medium, approaching large, effect size. Studies exploring the Colavita effect in children yielded no Colavita effect. Across adult and child studies, no methodological factors influenced the effect. Contrary to asymmetrical facilitation, response time data suggested a general slowing under bimodal conditions. These findings suggest that whilst vision dominates in adults, this effect is absent in childhood.
Behavioral Tagging: Plausible involvement of PKMζ, Arc and role of neurotransmitter receptor systems Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-20 Shruti Vishnoi, Mehar Naseem, Sheikh Raisuddin, Suhel Parvez
There are many evidences in support of Behavioral Tagging hypothesis that relies on the setting of a learning tag and the synthesis of plasticity related proteins (PRPs). It explains that how a learning tag produced as a result of weak training can be paired up with PRPs that arrive as a result of novelty and consequently lead to long lasting memories. In the following review we have focused on possible involvement of PKMζ, Arc as PRPs and neurotransmitter receptor systems ACh, metabotropic glutamate in behavioral tagging along with evidences in support of involvement of dopamine, NMDA glutamate and β-adrenergic receptor systems in behavioral tagging.
Mind wandering perspective on ADHD Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-20 Natali Bozhilova, Giorgia Michelini, Jonna Kuntsi, Philip Asherson
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder associated with a range of mental health, neurocognitive and functional problems. Although the diagnosis is based on descriptions of behaviour, individuals with ADHD characteristically describe excessive spontaneous mind wandering (MW). MW in individuals with ADHD reflects constant mental activity which lacks topic stability and content consistency. Based on this review of the neural correlates of ADHD and mind wandering, we outline a new perspective on ADHD: the MW hypothesis. We propose that altered deactivation of the default mode network, and dysfunctional interaction with the executive control network, leads to excessive and spontaneous MW, which underpins symptoms and impairments of ADHD. We highlight that processes linked to the normal neural regulation of MW (context regulation, sensory decoupling, salience thresholds) are deficient in ADHD. MW-related measures could serve as markers of the disease process, as MW can be experimentally manipulated, as well as measured using rating scales, and experience sampling during both cognitive tasks and daily life. MW may therefore be a potential endophenotype.
Investigating the influence of social support on experimental pain and related physiological arousal: A systematic review and meta-analysis Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-10 Xianwei Che, Cash Robin, Chung Sungwook, B Fitzgerald Paul, M. Fitzgibbon Bernadette
Social support is demonstrated to have mixed effects on both pain and related physiological arousal. In this study, a meta-analysis was conducted to characterise these effects. A total of 2416 studies were identified in a systematic search, among which 21 were eligible for the quantitative review. The mere presence of another person was not sufficient to modulate pain perception. However, stranger presence was identified to decrease pain-related arousal (SMD = -0.31), and the presence of a significant other increased facial expression of pain (SMD = 0.21). We further found verbal support to decrease pain (SMD = -0.69) and arousal (SMD = -0.99), and we demonstrated moderate to large analgesic effects of intimate relationships through touching (SMD = -0.95) and viewing (SMD = -0.60) of a romantic partner. Finally, we presented evidence of publication bias for pain-related arousal but not for behavioural pain outcomes. Together, our findings suggest that the impact of social support on pain is context-dependent with clear communications of support and intimate relationships being of particular importance.
Environmental stressors and alcoholism development: focus on molecular targets and their epigenetic regulation Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-11 Mariangela Pucci, Maria Vittoria Micioni Di Bonaventura, Aranza Wille-Bille, Macarena Soledad Fernández, Mauro Maccarrone, Ricardo Marcos Pautassi, Carlo Cifani, Claudio D’Addario
Alcohol exposure and stressful events in life can induce long-lasting changes in physiology, behavior and gene expression patterns, eventually facilitating the development of psychiatric diseases like alcohol use disorders (AUD). Epigenetic mechanisms have been recently proposed to play a role in the cellular actions of alcohol via chromatin remodeling. Here we discuss interactions between stress and the pharmacological effects of alcohol, including the possibility that early exposure to, or withdrawal of, alcohol might induce stressful effects of their own. A specific aim is to describe novel molecular mechanisms by which stress, alcohol or their combined presentation impact on the epigenome. A key question is why only a fraction of the population progresses from regular, non-problematic, alcohol use to AUD, despite suffering from similar alcohol exposure. It is important to analyze how environmental factors, most notably stress, interact with the epigenetic machinery to increase vulnerability for AUD. The knowledge derived from this endeavor will be critical for the development of preventive strategies and new, drug- or gene-based, therapies.
Modulation of the endocannabinoid system by sex hormones: Implications for Posttraumatic Stress Disorder Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-11 Luke John Ney, Allison Matthews, Raimondo Bruno, Kim Louise Felmingham
The endocannabinoid system is an increasingly recognised pharmacological target for treating stress and anxiety disorders, including post-traumatic stress disorder (PTSD). Recent preclinical developments have implicated the endocannabinoid system in stress responses, emotional memories and fear extinction, all critical to PTSD aetiology. However, preclinical research in endocannabinoid biology has neglected the influential role of sex hormone differences on PTSD symptomology, which is particularly important given that PTSD is twice as common in women as in men. In this review, we compile and consider the evidence that the endocannabinoid system is influenced by ovarian hormones, with application to stress disorders such as PTSD. It is clear that therapeutic modulation of the endocannabinoid system needs to be approached with awareness of ovarian hormonal influences, and knowledge of these influences may enhance treatment outcomes for female PTSD populations.
Food intake and addictive-like eating behaviors: time to think about the circadian clock(s) Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-07 Jorge Mendoza
Compulsive feeding has been considered as an addicted-like behavior with similarities to drug addiction. Food intake is brain controlled involving a balance between metabolic and hedonic pathways that modulate respectively how much and what is eaten. Pathological conditions such as compulsive feeding or an eating addiction can interfere with this balance and obesity may develop. Daily feeding times are also centrally controlled by the circadian clock in the suprachiasmatic nucleus. Disruptions of this body clock (e.g., social jet-lag, shift work) lead to eating and metabolic disorders. The circadian pacemaker is intricately connected with the metabolic and hedonic centers controlling feeding, and most importantly, some of these nuclei have clock activity. When the brain circadian system is compromised in eating disorders, such perturbations may be in part the causes of compulsive feeding, night eating and addictive-like eating behavior. Therefore, food intake is regulated by the central circadian-metabolic-hedonic network, which is functionally interconnected to avoid perturbing the eating behavior physiology.
Prenatal exposure to environmental insults and enhanced risk of developing Schizophrenia and Autism Spectrum Disorder: Focus on biological pathways and epigenetic mechanisms Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-04 Nadia Cattane, Juliet Richetto, Annamaria Cattaneoa
When considering neurodevelopmental disorders (NDDs), Schizophrenia (SZ) and Autism Spectrum Disorder (ASD) are considered to be among the most severe in term of prevalence, morbidity and impact on the society.Similar features and overlapping symptoms have been observed at multiple levels, suggesting common pathophysiological bases. Indeed, recent genome-wide association studies (GWAS) and epidemiological data report shared vulnerability genes and environmental triggers across the two disorders. In this review, we will discuss the possible biological mechanisms, including glutamatergic and GABAergic neurotransmissions, inflammatory signals and oxidative stress related systems, which are targeted by adverse environmental exposures and that have been associated with the development of SZ and ASD. We will also discuss the emerging role of the gut microbiome as possible interplay between environment, immune system and brain development. Finally, we will describe the involvement of epigenetic mechanisms in the maintenance of long-lasting effects of adverse environments early in life. This will allow us to better understand the pathophysiology of these NDDs, and also to identify novel targets for future treatment strategies.
Puberty and the human brain: insights into adolescent development Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-07-01 Nandita Vijayakumar, Zdena Op de Macks, Elizabeth A. Shirtcliff, Jennifer H. Pfeifer
Alongside the exponential flourish of research on age-related trajectories of human brain development during childhood and adolescence in the past two decades, there has been an increase in the body of work examining the association between pubertal development and brain maturation. This review systematically examines empirical research on puberty-related structural and functional brain development in humans, with the aim of identifying convergent patterns of associations. We emphasize longitudinal studies, and discuss pervasive but oft-overlooked methodological issues that may be contributing to inconsistent findings and hindering progress (e.g., conflating distinct pubertal indices and different measurement instruments). We also briefly evaluate support for prominent models of adolescent neurodevelopment that hypothesize puberty-related changes in brain regions involved in affective and motivational processes. For the field to progress, replication studies are needed to help resolve current inconsistencies and gain a clearer understanding of pubertal associations with brain development in humans, knowledge that is crucial to make sense of the changes in psychosocial functioning, risk behavior, and mental health during adolescence.
Commentary on fear extinction in the human brain: A meta-analysis of fMRI studies in healthy participants Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-30 Morriss Jayne, Hoare Shannon, M. van Reekum Carien
The recent meta-analysis by Fullana et al. (2018) is both timely and significant, providing a vital milestone towards understanding the neural networks involved in threat extinction in humans. Fullana et al. (2018) examined both threat extinction and recall separately using sophisticated meta-analytic methods based on raw contrast maps. Importantly, the meta-analysis highlighted a lack of consistent activation across studies for key neural “players” in the threat extinction circuit: the amygdala and ventromedial prefrontal cortex (vmPFC). In the current commentary, we highlight reasons for which this key circuitry may not have resulted from this meta-analysis, and call for a ‘gold standard’ in the examination of threat extinction using fMRI.
Purinergic modulation of glutamate transmission: An expanding role in stress-linked neuropathology Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-28 J. Mayhew, B.A. Graham, Knut Biber, M. Nilsson, F.R. Walker
Chronic stress has been extensively linked to disturbances in glutamatergic signalling. Emerging from this field of research is a considerable number of studies identifying the ability of purines at the pre-, post-, and peri-synaptic levels to tune glutamatergic neurotransmission. While the evidence describing purinergic control of glutamate has continued to grow, there has been relatively little attention given to how chronic stress modulates purinergic functions. The available research on this topic has demonstrated that chronic stress can not only disturb purinergic receptors involved in the regulation of glutamate neurotransmission, but also perturb glial-dependent purinergic signalling. This review will provide a detailed examining of the complex literature relating to glutamatergic-purinergic interactions with a focus on both neuronal and glial contributions. Once these detailed interactions have been described and contextualised, we will integrate recent findings from the field of stress research.
The role of the anterior insula in social norm compliance and enforcement: evidence from coordinate-based and functional connectivity meta-analyses Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-26 Gabriele Bellucci, Chunliang Feng, Julia Camilleri, Simon B. Eickhoff, Frank Krueger
Economic games —trust (TG) and ultimatum game (UG)— combined with fMRI have shown the importance of the anterior insula (AI) in social normative behaviors. However, whether different AI subregions are engaged in different cognitive and affective processes for social norm compliance and norm enforcement during social exchange remains elusive. Here, we investigated the role of the dorsal AI (dAI) and ventral AI (vAI), combining a coordinate-based meta-analysis of fMRI studies using the TG and UG with meta-analytic task-based and task-free connectivity analyses. Our findings showed that the right dAI and vAI were the only common brain regions consistently activated across games. These clusters were part of two functionally distinguishable connectivity networks associated with cognitive (dAI) and emotional (vAI) processes. In conclusion, we propose that dAI mediates cognitive processes that generate expectancy for norm compliance, whereas vAI mediates aversive feelings that generate motivation to norm enforcement. The identified functional differentiation of the right AI in the social domain contributes to a better understanding of its role in basic and clinical neuroscience.
A systematic review and meta-analysis of structural magnetic resonance imaging studies investigating cognitive and social activity levels in older adults Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-27 M. Anatürk, N. Demnitz, K.P. Ebmeier, C.E. Sexton
Population aging has prompted considerable interest in identifying modifiable factors that may help protect the brain and its functions. Collectively, epidemiological studies show that leisure activities with high mental and social demands are linked with better cognition in old age. The extent to which socio-intellectual activities relate to the brain’s structure is, however, not yet fully understood. This systematic review and meta-analysis summarizes magnetic resonance imaging studies that have investigated whether cognitive and social activities correlate with measures of gray and white matter volume, white matter microstructure and white matter lesions. Across eighteen included studies (total n = 8429), activity levels were associated with whole-brain white matter volume, white matter lesions and regional gray matter volume, although effect sizes were small. No associations were found for global gray matter volume and the evidence concerning white matter microstructure was inconclusive. While the causality of the reviewed associations needs to be established, our findings implicate socio-intellectual activity levels as promising targets for interventions aimed at promoting healthy brain aging.
Strategies for integrated analysis in Imaging Genetics studies Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-23 Natàlia Vilor-Tejedor, Silvia Alemany, Alejandro Cáceres, Mariona Bustamante, Jesús Pujol, Jordi Sunyer, Juan R. González
Imaging Genetics (IG) integrates neuroimaging and genomic data from the same individual, deepening our knowledge of the biological mechanisms behind neurodevelopmental domains and neurological disorders. Although the literature on IG has exponentially grown over the past years, the majority of studies have mainly analyzed associations between candidate brain regions and individual genetic variants. However, this strategy is not designed to deal with the complexity of neurobiological mechanisms underlying behavioral and neurodevelopmental domains. Moreover, larger sample sizes and increased multidimensionality of this type of data represents a challenge for standardizing modeling procedures in IG research. This review provides a systematic update of the methods and strategies currently used in IG studies, and serves as an analytical framework for researchers working in this field. To complement the functionalities of the Neuroconductor framework, we also describe existing R packages that implement these methodologies. In addition, we present an overview of how these methodological approaches are applied in integrating neuroimaging and genetic data.
Executive Dysfunction in Parkinson’s Disease: A Meta-Analysis on the Wisconsin Card Sorting Test Literature Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-23 Florian Lange, Carolin Brückner, Aylin Knebel, Caroline Seer, Bruno Kopp
Executive dysfunctions are a frequently described non-motor symptom in patients with Parkinson’s disease (PD). However, the nature, extent, variability, and determinants of executive dysfunctions in PD are still poorly understood. To improve the characterization of executive dysfunctions in PD, we conducted a meta-analysis of the studies administering the Wisconsin Card Sorting Test (WCST) to patients with PD and healthy controls. We included k = 161 studies, which allowed us to precisely estimate the size of PD-related WCST deficits and to run powerful tests for potential moderators of these deficits. We found robust WCST deficits in PD, which were medium-to-large in size. These deficits were most pronounced in patients tested after withdrawal from dopaminergic medication and in samples characterized by severe motor impairment and long disease duration. Substantial WCST impairment was also detected in non-demented, non-depressed, and never-medicated patients with PD as well as after conservatively correcting for publication bias. Based on these findings, impaired WCST performance can be considered as a major hallmark of executive dysfunction in PD.
Meta-analytic evidence for a core problem solving network across multiple representational domains Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-23 Jessica E. Bartley, Emily R. Boeving, Michael C. Riedel, Katherine L. Bottenhorn, Taylor Salo, Simon B. Eickhoff, Eric Brewe, Matthew T. Sutherland, Angela R. Laird
Problem solving is a complex skill engaging multi-stepped reasoning processes to find unknown solutions. The breadth of real-world contexts requiring problem solving is mirrored by a similarly broad, yet unfocused neuroimaging literature, and the domain-general or context-specific brain networks associated with problem solving are not well understood. To more fully characterize those brain networks, we performed activation likelihood estimation meta-analysis on 280 neuroimaging problem solving experiments reporting 3,166 foci from 1,919 individuals across 131 papers. The general map of problem solving revealed broad fronto-cingulo-parietal convergence, regions similarly identified when considering separate mathematical, verbal, and visuospatial problem solving domain-specific analyses. Conjunction analysis revealed a common network supporting problem solving across diverse contexts, and difference maps distinguished functionally-selective sub-networks specific to task type. Our results suggest cooperation between representationally specialized sub-network and whole-brain systems provide a neural basis for problem solving, with the core network contributing general purpose resources to perform cognitive operations and manage problem demand. Further characterization of cross-network dynamics could inform neuroeducational studies on problem solving skill development.
Working definitions, subjective and objective assessments and experimental paradigms in a study exploring social withdrawal in schizophrenia and Alzheimer’s disease Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-24 Nic. J.A. van der Wee, Amy C. Bilderbeck, Maria Cabello, Jose L. Ayuso-Mateos, Ilya M.J. Saris, Erik J. Giltay, Brenda WJH. Penninx, Celso Arango, Anke Post, Stefano Porcelli
Social withdrawal is one of the first and common signs of early social dysfunction in a number of important neuropsychiatric disorders, likely because of the enormous amount and complexity of brain processes required to initiate and maintain social relationships (Adolphs, 2009). The Psychiatric Ratings using Intermediate Stratified Markers (PRISM) project focusses on the shared and unique neurobiological basis of social withdrawal in schizophrenia, Alzheimer and depression. In this paper, we discuss the working definition of social withdrawal for this study and the selection of objective and subjective rating scales to assess social withdrawal chosen or adapted for this project. We also discuss the MRI and EEG paradigms selected to study the systems and neural circuitry thought to underlie social functioning and more particularly to be involved in social withdrawal in humans, such as the social perception and the social affiliation networks. A number of behavioral paradigms were selected to assess complementary aspects of social cognition. Also, a digital phenotyping method (a smartphone application) was chosen to obtain real-life data.
Neuropeptide modulation of addiction: focus on galanin Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-24 Shannyn G. Genders, Karlene J. Scheller, Elvan Djouma
Addiction is a chronic, relapsing disorder characterised by the use of a substance or act to the point of compulsion. There are a number of medical treatments available for the intervention of these disorders, however, the effectiveness of current therapeutics is far from adequate. Neuropeptides are known to modulate addictive behaviours and may provide new therapeutic targets for the treatment of substance abuse. Accumulating evidence has suggested galanin as a potential important neuromodulator of addiction. Both human genetic studies and animal models have highlighted a role for this neuropeptide in affective disorders, as well as alcohol, nicotine, and opiate dependence. This review highlights the role of galanin and other primary neuropeptides implicated in modulating addiction to different drugs of abuse. Orexin, relaxin-3, corticotrophin-releasing factor, dynorphin and enkephalin, are also discussed given their involvement in mediating reward-seeking behaviour.
Overview of the clinical implementation of a study exploring social withdrawal in patients with schizophrenia and Alzheimer’s disease Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-22 Amy C. Bilderbeck, Brenda W.J.H. Penninx, Celso Arango, Nic van der Wee, René Kahn, Inge Winter-van Rossum, Anja Hayen, Martien J. Kas, Anke Post, Gerard R. Dawson
Trans-diagnostic, domain- or symptom-focused approaches have been heralded as advancing psychiatric research, but relatively few clinical research programmes have been undertaken to leverage their potential. In this manuscript we describe the approach and protocol for an exploratory study, PRISM (Psychiatric Ratings using Intermediate Stratified Markers), that will be conducted to explore the biomarkers in schizophrenia (SZ) and Alzheimer’s Disease (AD) that may be related to a common symptom, social withdrawal. Patient participants (N = 72 SZ and N = 72 AD study completers), will complete a series of fMRI, EEG, and behavioural paradigms, as well as contributing blood-derived (e.g. epigenetic) and smartphone data related to social behaviour. Self- as well as caregiver- and researcher-reported assessments will be provided to characterise social withdrawal. Normative data will also be collected from a group of healthy controls (N = 48 study completers), half of whom will be matched in terms of age and gender distribution to the SZ and AD group, respectively. Thus we will explore both differentiation and cross-diagnostic overlap in the biomarkers associated with different levels of social withdrawal in SZ and AD. In this way we aim to provide a deeper understanding of the biological underpinnings of symptomatology common to both disorders, and provide insights into novel treatment targets and future drug development approaches.
The Neurobiology of the Male Sexual Refractory Period Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-22 A. Seizert Curtis
Role of Kynurenine Pathway and its Metabolites in Mood Disorders: A Systematic Review and Meta-Analysis of Clinical Studies Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-22 Danilo Arnone, Smita Saraykar, Haitham Salem, Antonio L. Teixeira, Robert Dantzer, Sudhakar Selvaraj
Activation of the kynurenine pathway is one of the described mechanisms by which inflammation can induce depression. It involves multiple pathways including interference with the bioavailability of tryptophan central to the synthesis of the neurotransmitter serotonin. In this systematic review, we examine the relationship between kynurenine metabolites (kynurenine, kynurenic acid, tryptophan, quinolinic acid, the ratio of kynurenine and tryptophan) and mood disorders by conducting a meta-analysis. Fifty-six studies were identified, 21 met inclusion criteria and 14 were deemed suitable (9 investigating unipolar depression and 5 bipolar disorder). We found decreased levels of kynurenine in unipolar major depression vs. healthy controls but studies were significantly heterogeneous in nature. No significant differences were found in tryptophan levels or kynurenine/tryptophan ratios. Kynurenine metabolites are likely to play a role in major depression but an exact etiological role in mood disorder seem complex and requires further research.
Modulation of glucocorticoids by the serotonin transporter polymorphism: a narrative review Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-22 T.M. Klein Gunnewiek, J.R. Homberg, T. Kozicz
The biological background and consequences of serotonin transporter polymorphism-glucocorticoid relationship in individual differences in stress reactivity has been a major interest in neuropsychiatry research. Individual differences in glucocorticoid release have long been implicated in vulnerability to stress-related psychopathologies, like depression and anxiety in various species. Yet, it is largely elusive to what extent results from non-human primates and rodents translate to human findings. Based on our structured, comprehensive and non-hypothesis driven overview of this topic, we conclude that although gene-environment interaction studies have highlighted the importance of serotonin transporter polymorphism in modulating glucocorticoid release, there is compelling evidence that age, gender and ethnicity are significant factors too contributing to the equation. We conclude too that the way early life events modulate an individual’s stress reactivity as a function of serotonin transporter polymorphism is comparable between species. These data provide a rationale for the design of new, prospective translational studies into sex-specific gene-environment interactions across the lifespan with the goal of improving preventative efforts and optimizing (personalized) treatment in stress-related psychopathologies.
Early human brain development: Starring the subplate Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-20 Mijna Hadders-Algra
This review summarizes early human brain development on the basis of neuroanatomical data and functional connectomics. It indicates that the most significant changes in the brain occur during the second half of gestation and the first three months post-term, in particular in the cortical subplate and cerebellum. As the transient subplate pairs a high rate of intricate developmental changes and interactions with clear functional activity, two phases of development are distinguished: a) the transient cortical subplate phase, ending at 3 months post-term when the permanent circuitries in the primary motor, somatosensory and visual cortices have replaced the subplate; and subsequently, b) the phase in which the permanent circuitries dominate. In the association areas the subplate dissolves in the remainder of the first postnatal year. During both phases developmental changes are paralleled by continuous reconfigurations in network activity. The reviewed literature also suggests that disruption of subplate development may play a pivotal role in developmental disorders, such as cerebral palsy, autism spectrum disorders, attention deficit hyperactivity disorder and schizophrenia.
From controlled to compulsive drug-taking: The role of the habenula in addiction Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-21 Victor Mathis, Paul J. Kenny
Addiction is now recognized as a neurobiological and cognitive brain disorder and is generally viewed as a switch from recreational or voluntary to compulsive substance use despite aversive consequences. The habenula, composed of medial (MHb) and lateral (LHb) domains, has been implicated in regulating behavioral flexibility and anxiety-related behaviors and is considered a core component of the brain “anti-reward” system. These functions position the habenula to influence voluntary behaviors. Consistent with this view, emerging evidence points to alterations in habenula activity as important factors to contributing the loss of control over the use of drugs of abuse and the emergence of compulsive drug seeking behaviors. In this review, we will discuss the general functions of the MHb and LHb and describe how these functional properties allow this brain region to promote or suppress volitional behaviors. Then, we highlight mechanisms by which drugs of abuse may alter habenular activity, precipitating the emergence of addiction-relevant behavioral abnormalities.
Why cognitive event-related potentials (ERPs) should have a role in the management of alcohol disorders Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-21 Salvatore Campanella, Elisa Schroder, Hendrik Kajosch, Xavier Noel, Charles Kornreich
Alcohol dependence is currently one of the most serious public health problems. Indeed, 3-8% of all deaths worldwide are attributable to effects of alcohol consumption. Although the first step in alcohol dependence treatment is straightforward, the main problem for clinicians lies with the prevention of relapse, as 40-70% of patients who only undergo psychosocial therapy resume alcohol use within a year following treatment. This review of the literature regarding event-related potentials (ERPs) is focused on two major neurocognitive factors that partially account for the inability of many alcoholics to remain abstinent: attentional biases towards alcohol-related stimuli that increase the urge to drink, and impaired response inhibition towards these cues that makes it more difficult for alcoholics to resist the temptation to drink. On this basis, we propose new research avenues to better implement ERPs in the management of alcohol disorders, according to four main directions that relate to (1) the development of ERP serial recordings; (2) the promotion of a multi-component ERP approach; (3) the definition of multi-site guidelines; and (4) the use of more representative laboratory situations through the use of more compelling environments.
Episodic and working memory function in Primary Progressive Aphasia: A meta-analysis Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-18 Willem S. Eikelboom, Nikki Janssen, Lize C. Jiskoot, Esther van den Berg, Ardi Roelofs, Roy P.C. Kessels
Objective The distinction between Primary Progressive Aphasia (PPA) variants remains challenging for clinicians, especially for the non-fluent (nfv-PPA) and the logopenic variants (lv-PPA). Previous research suggests that memory tests might aid this differentiation. This meta-analysis compares memory function among PPA variants. Method Effects sizes were extracted from 41 studies (N = 849). Random-effects models were used to compare performance on episodic and working memory tests among PPA patients and healthy controls, and between the PPA variants. Results Memory deficits were frequently observed in PPA compared to controls, with large effect sizes for lv-PPA (Hedges’ g = -2.04 [-2.58 to -1.49]), nfv-PPA (Hedges’ g = -1.34 [-1.69 to -1.00]), and the semantic variant (sv-PPA; Hedges’ g = -1.23 [-1.50 to -0.97]). Sv-PPA showed primarily verbal memory deficits, whereas lv-PPA showed worse performance than nfv-PPA on both verbal and non-verbal memory tests. Conclusions Memory deficits were more pronounced in lv-PPA compared to nfv-PPA. This suggests that memory tests may be helpful to distinguish between these PPA variants.
Clinical use of semantic space models in psychiatry and neurology: A systematic review and meta-analysis Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-08 J.N. de Boer, A.E. Voppel, M.J.H. Begemann, H.G. Schnack, F. Wijnen, I.E.C. Sommer
Verbal communication disorders are a hallmark of many neurological and psychiatric illnesses. Recent developments in computational analysis provide objective characterizations of these language abnormalities. We conducted a meta-analysis assessing semantic space models as a diagnostic or prognostic tool in psychiatric or neurological disorders. Diagnostic test accuracy analyses revealed reasonable sensitivity and specificity and high overall efficacy in differentiating between patients and controls (n=1680: Hedges’ g =.73, p=.001). Analyses of full sentences (Hedges’ g =.95 p <.0001) revealed a higher efficacy than single words (Hedges’ g = .51, p <.0001). Specifically, models examining psychotic patients (Hedges’ g =.96, p=.003) and those with autism (Hedges’ g = .84, p <.0001) were highly effective. Our results show semantic space models are effective as a diagnostic tool in a variety of psychiatric and neurological disorders. The field is still exploratory in nature; techniques differ and models are only used to distinguish patients from healthy controls so far. Future research should aim to distinguish between disorders and perhaps explore newer semantic space tools like word2vec.
Understanding Sources of Adult Age Differences in Task Switching: Evidence from Behavioral and ERP Studies Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-06 Patrick D. Gajewski, Nicola K. Ferdinand, Jutta Kray, Michael Falkenstein
The task-switching paradigm is a valid tool to measure age-related changes in executive functions. It allows identifying the most vulnerable cognitive control processes affected by aging. This review provides an overview about the current evidence on behavioral and electrophysiological signatures of adult age differences in task switching with a focus on age-related changes in ERP correlates of three task-processing phases: (1) advanced task preparation as reflected by the cue-P3 and the CNV; (2) task implementation including P1 / N1, P2, N2, N450 / Ni as well as target-P3; and (3) response monitoring mechanisms as indicated by the Nc / CRN / MFN during correct responding and Ne / ERN in error trials. While most of these ERP correlates of executive control are reduced in older age, qualitative ERP differences between age groups are less consistent. We also report some recent findings from cognitive training research showing the potential for enhancement in task switching in older age. The results are discussed in the light of current models of cognitive control.
Understanding individual variability in symptoms and recovery following mTBI: a role for TMS-EEG? Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-06 Hannah L. Coyle, Jennie Ponsford, Kate E. Hoy
The pathophysiology associated with mild traumatic brain injury (mTBI) includes neurometabolic and cytoskeletal changes that have been shown to impair structural and functional connectivity. Evidence that persistent neuropsychological impairments post injury are linked to structural and functional connectivity changes is increasing. However, to date the relationship between connectivity changes, heterogeneity of persistent symptoms and recovery post mTBI has been poorly characterised. Recent innovations in neuroimaging provide new ways of exploring connectivity changes post mTBI. Namely, combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) offers several advantages over traditional approaches for studying connectivity changes post TBI. Its ability to perturb neural function in a controlled manner allows for measurement of causal interactions or effective connectivity between brain regions. We review the current literature assessing structural and functional connectivity following mTBI and outline the rationale for the use of TMS-EEG as an ideal tool for investigating the neural substrates of connectivity dysfunction and reorganisation post mTBI. The diagnostic, prognostic and potential therapeutic implications will also be explored.
Common social cognitive impairments do not mean common causes: A commentary on Cotter et al. (2018) Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-06 David Dodell-Feder, Laura T. Germine
Many clinical conditions, ranging from psychiatric to neurodegenerative illnesses, are associated with impairment in the processes by which we perceive, interpret, and respond to social information; a suite of abilities known as social cognition. Through a systematic review of meta-analyses, Cotter et al. (2018) present a compelling view of social cognitive deficits as a core phenotype of many clinical conditions. However, we caution against one potential interpretation of their findings, namely, that similar social cognitive outcomes are produced by similar causes. Specifically, we argue that while the outcome may look similar across clinical conditions (i.e., global social cognitive deficits), the cause and nature of those impairments are likely to differ, and, as a consequence, so too will its remediation. We advocate for the development of better methods for assessing social cognition, which may speak to the varying nature of social cognitive impairment across conditions. Ultimately, a better understanding of how social cognition is impaired will facilitate the development of more targeted, more effective treatments, that will improve patient care.
Early Life Stress, Air Pollution, Inflammation, and Disease: An Integrative Review and Immunologic Model of Social-Environmental Adversity and Lifespan Health Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2018-06-03 Hector A. Olvera Alvarez, Laura D. Kubzansky, Matthew J. Campen, George M. Slavich
Socially disadvantaged individuals are at greater risk for simultaneously being exposed to adverse social and environmental conditions. Although the mechanisms underlying joint effects remain unclear, one hypothesis is that toxic social and environmental exposures have synergistic effects on inflammatory processes that underlie the development of chronic diseases, including cardiovascular disease, diabetes, depression, and certain types of cancer. In the present review, we examine how exposure to two risk factors that commonly occur with social disadvantage—early life stress and air pollution—affect health. Specifically, we identify neuroimmunologic pathways that could link early life stress, inflammation, air pollution, and poor health, and use this information to propose an integrated, multi-level model that describes how these factors may interact and cause health disparity across individuals based on social disadvantage. This model highlights the importance of interdisciplinary research considering multiple exposures across domains and the potential for synergistic, cross-domain effects on health, and may help identify factors that could potentially be targeted to reduce disease risk and improve lifespan health.
Preclinical models of conduct disorder – principles and pharmacologic perspectives Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-05-26 Jozsef Haller
The translational value of preclinical research was recently enhanced by abnormal aggression models, which focus on deviant behaviors induced by the exposure of rodents to etiological factors of aggression-related psychopathologies. Prompted by similar trials in other psychiatric disorders, here we investigate models of abnormal aggression from the perspective of DSM5 criteria. After proposing principles based on which analogies can be established between psychopathology symptoms and rodent behavioral dysfunctions, we show that rodents submitted to abnormal aggression models fulfill basic criteria of aggression-related psychopathologies; moreover, some models can be considered specific to particular disorders e.g. conduct disorder. We also show that abnormal and species-typical aggressions differ in terms of both brain mechanisms and pharmacological responsiveness, which mimics differences observed in psychiatric disorders. We conclude that evaluating abnormal aggression models from a DSM5 perspective is not only possible but also worthwhile, and such models may contribute to the development of novel treatment strategies not only for aggression as a symptom but also for specific aggression-related disorders or multi-symptom clusters at least.
Behavioral and mechanistic insight into rodent empathy Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-06-14 Sivaani Sivaselvachandran, Erinn L. Acland, Salsabil Abdallah, Loren J. Martin
Empathy is a psychological construct that allows individuals to understand and share the emotions of others. The ability to share emotional states relies on basic social mechanisms, such as mimicry and emotional contagion, which are considered building blocks for empathy. Mimicking another’s emotional or physical state is essential for successful social interactions and is found in a number of animal species. For the current review we focus on emotional state sharing in rodents, a core feature of empathy that is often measured using pain and fear as proxies; we also discuss prosociality in rodents. The evidence for empathy in rodents shows that rats and mice consistently imitate arousal states and behaviors of conspecifics and will even sacrifice personal gain to relieve the distress of a conspecific. These behaviors support basic processes that are crucial for the survival of individual animals and give us insight into the neural mechanisms that govern empathy-related behaviors.
Genetic influences on conduct disorder Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-06-24 Jessica E. Salvatore, Danielle M. Dick
Conduct disorder (CD) is a moderately heritable psychiatric disorder of childhood and adolescence characterized by aggression toward people and animals, destruction of property, deceitfulness or theft, and serious violation of rules. Genome-wide scans using linkage and association methods have identified a number of suggestive genomic regions that are pending replication. A small number of candidate genes (e.g., GABRA2, MAOA, SLC6A4, AVPR1A) are associated with CD related phenotypes across independent studies; however, failures to replicate also exist. Studies of gene-environment interplay show that CD genetic predispositions also contribute to selection into higher-risk environments, and that environmental factors can alter the importance of CD genetic factors and differentially methylate CD candidate genes. The field’s understanding of CD etiology will benefit from larger, adequately powered studies in gene identification efforts; the incorporation of polygenic approaches in gene-environment interplay studies; attention to the mechanisms of risk from genes to brain to behavior; and the use of genetically informative data to test quasi-causal hypotheses about purported risk factors.
Gene x environment interactions in conduct disorder: Implications for future treatments Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-08-18 Nathalie E. Holz, Katrin Zohsel, Manfred Laucht, Tobias Banaschewski, Sarah Hohmann, Daniel Brandeis
Conduct disorder (CD) causes high financial and social costs, not only in affected families but across society, with only moderately effective treatments so far. There is consensus that CD is likely caused by the convergence of many different factors, including genetic and adverse environmental factors. There is ample evidence of gene-environment interactions in the etiology of CD on a behavioral level regarding genetically sensitive designs and candidate gene-driven approaches, most prominently and consistently represented by MAOA. However, conclusive indications of causal GxE patterns are largely lacking. Inconsistent findings, lack of replication and methodological limitations remain a major challenge. Likewise, research addressing the identification of affected brain pathways which reflect plausible biological mechanisms underlying GxE is still very sparse. Future research will have to take multilevel approaches into account, which combine genetic, environmental, epigenetic, personality, neural and hormone perspectives. A better understanding of relevant GxE patterns in the etiology of CD might enable researchers to design customized treatment options (e.g. biofeedback interventions) for specific subgroups of patients.
Psychiatric evaluation of youths with Disruptive Behavior Disorders and psychopathic traits: A critical review of assessment measures Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-09-25 Gabriele Masi, Annarita Milone, Paola Brovedani, Simone Pisano, Pietro Muratori
Disruptive Behavior Disorders (DBDs) are stable and impairing disorders, heterogeneous in presentation, developmental pathways, and treatment needs. Disentangling subtypes according to psychopathological dimensions is helpful for timely diagnoses, precise prognoses and tailored interventions. Psychopathic traits are relevant in subtyping DBDs with severe antisocial and aggressive behaviors. Three psychopathy dimensions have been found: 1) an affective dimension, the callous-unemotional (CU) trait, with lack of empathy and remorse, and with short-lived emotions; 2) an interpersonal dimension, the narcissistic domain, with manipulative abilities, superficial charm, egocentricity and grandiosity; 3) a behavioral dimension, the impulsivity or impulsive-irresponsibility, with irresponsibility, proneness to boredom, and novelty seeking. Recently, research suggests that youth with CU traits, similarly to adults with psychopathy, can present a low-anxious “primary” and high-anxious “secondary” variants. Our aim is to critically review the main measures of psychopathic traits, including the three main dimensions (with specific emphasis on CU traits), and the “primary/secondary” distinction, focusing on the assessment in clinical settings. An assessment procedure is proposed, based on previous literature and personal clinical experience.
Understanding heterogeneity in conduct disorder: A review of psychophysiological studies Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-09-28 Kostas A. Fanti
The present review is concerned with the role of different physiological systems (e.g., skin conductance, heart rate, electromyography, and the eye-bling startle reflex) in understanding heterogeneity in conduct disorder (CD). Four subtyping approaches are considered: age of onset, comorbid psychopathology, callous-unemotional traits, and proactive/reactive aggression. Empirical findings are discussed in terms of distinct theoretical perspectives that aim to explain CD behaviors based on physiological over-arousal, under-arousal, and empathy deficits. According to the studies reviewed, the callous-unemotional (CD + CU) and internalizing (CD + Internalizing) sub-types can best inform CD heterogeneity. Findings indicated that children in the CD + CU and CD + Internalizing subtypes score on opposite extremes on heart rate, skin conductance and startle reactivity measures. Heart rate variability and respiratory sinus arrhythmia dysfunctions, associated with emotional dysregulation, were more evident among children in the CD + Internalizing group, while dysfunctional facial electromyography activity, which has been linked with reduced empathy, with the CD + CU group. In conclusion, it might be important to redefine CD diagnostic criteria based on physiological heterogeneity to enable the identification of distinct subtypes of CD.
The link between aberrant hypothalamic–pituitary–adrenal axis activity during development and the emergence of aggression—Animal studies Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-10-14 Sophie E. Walker, Aurélie Papilloud, Damien Huzard, Carmen Sandi
Aggressive behavior is not uniform, including proactive and reactive forms of aggression. Aberrant functioning of the hypothalamic–pituitary–adrenal (HPA) axis is frequently associated with abnormal aggression. Here, we review the rodent literature in order to assess whether developmental abnormalities in the HPA axis can be causally linked with the emergence of abnormal aggression. We examine studies that involve genetic models and life challenges (e.g., early life stress, drug exposure) that course with developmental alterations in the HPA axis. Although the lack of systematic studies hinders development of an integrated model, existing evidence supports a U-shaped function regarding differences in HPA axis functioning during development and the emergence of aggressive phenotypes. Thus, developmentally low or high HPA axis reactivity are typically found to be aligned with the emergence of aggressive phenotypes; however, existing information is insufficient to causally link divergent HPA axis aberration with specific types of aggression. Progress in this field is needed to support interventions in children aimed at ameliorating social dysfunctions associated with aberrations in HPA axis function.
Classification and treatment of antisocial individuals: From behavior to biocognition Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-10-17 I.A. Brazil, J.D.M. van Dongen, J.H.R. Maes, R.B. Mars, A.R. Baskin-Sommers
Antisocial behavior is a heterogeneous construct that can be divided into subtypes, such as antisocial personality and psychopathy. The adverse consequences of antisocial behavior produce great burden for the perpetrators, victims, family members, and for society at-large. The pervasiveness of antisocial behavior highlights the importance of precisely characterizing subtypes of antisocial individuals and identifying specific factors that are etiologically related to such behaviors to inform the development of targeted treatments. The goals of the current review are (1) to briefly summarize research on the operationalization and assessment of antisocial personality and psychopathy; (2) to provide an overview of several existing treatments with the potential to influence antisocial personality and psychopathy; and (3) to present an approach that integrates and uses biological and cognitive measures as starting points to more precisely characterize and treat these individuals. A focus on integrating factors at multiple levels of analysis can uncover person-specific characteristics and highlight potential targets for treatment to alleviate the burden caused by antisocial behavior.
Neuro-cognitive system dysfunction and symptom sets: A review of fMRI studies in youth with conduct problems Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-10-26 R.J.R. Blair, K. Veroude, J.K. Buitelaar
In this paper, we review fMRI work on neuro-cognitive systems that are considered to be dysfunctional in individuals with conduct problems (i.e., individuals with Conduct Disorder (CD), Oppositional Defiant Disorder (ODD) or antisocial behavior without formal clinical diagnosis). These are: empathy, the acute threat response, reinforcement-based decision-making, response inhibition and the Default Mode Network. Evidence regarding the Default Mode Network is somewhat inconsistent and its functional role/the symptom sets consequent on its dysfunction remain underspecified. However, dysfunctions in the other four neuro-cognitive systems are associated with symptom sets seen in individuals with conduct problems.
The impact of chronic stress during adolescence on the development of aggressive behavior: A systematic review on the role of the dopaminergic system in rodents Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-11-05 Jorim J Tielbeek, Zeineb Al-Itejawi, Josjan Zijlmans, Tinca JC Polderman, Joshua W Buckholtz, Arne Popma
Pathological aggression, frequently observed in psychiatric patients and criminal subjects, poses a major burden on the health care and criminal justice system, necessitating better aetiological models to inform targets for prevention and intervention. Emerging evidence suggests that adverse experiences during development can cause long-lasting brain alterations associated with maladaptive behaviors, such as aggression. The present review discusses, mainly based on studies in rodents, whether disruption of the mesocorticolimbic dopamine system through chronic stress-exposure during adolescence predisposes to adult aggression. Our findings suggest that chronic stress in adolescence induces prefrontal cortex (PFC) hyperdopaminergia and ultimately leads to blunted prefrontal dopamine transmission in adulthood. This, in turn, disrupts the ability of the PFC to guide adaptive, long-term focused action selection by regulating mesolimbic dopamine signaling. We propose that, especially during the dynamic and transitional period of adolescence, exposure to chronic stress could lead to excessive adaptive change, which may result in an increased vulnerability to maladaptive aggression in adulthood. We discuss how these findings in rodents may translate to humans.
Clock genes, ADHD and aggression Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-11-09 Floriana Mogavero, Amanda Jager, Jeffrey C. Glennon
Attention deficit/hyperactivity disorder (ADHD) is frequently associated with comorbid aggression and sleep disturbances. The sleep/wake cycle is under the control of the circadian system which is moderated by clock genes. Clock genes can regulate the transcription of monoamine oxidase A, which is involved in the degradation of monoamines. Disturbances in monoamine interaction with clock genes in those with monoamine gene polymorphisms may regulate susceptibility of ADHD and comorbid aggression/sleep disturbances. While monoamines influence circadian rhythm and clock gene expression, circadian rhythm components modulate aggressive behavior, and altered clock genes expression have been associated with ADHD. We propose a mechanism by which circadian rhythm and clock gene expression may influence ADHD and comorbid aggression through the modulation of neurotransmitters. The role of clock genes in ADHD patients with comorbid aggression awaits further research; therefore we also indicate directions for future studies to help increase understanding of the underlying mechanisms in ADHD with comorbid aggression and sleep disturbances.
Association of trauma, Posttraumatic Stress Disorder and Conduct Disorder: A systematic review and meta-analysis Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-12-23 Anka Bernhard, Anne Martinelli, Katharina Ackermann, Daniel Saure, Christine M. Freitag
Objective To summarize findings of previous studies on the prevalence of trauma and Posttraumatic Stress Disorder (PTSD) in Conduct Disorder (CD). Method We conducted a systematic review and meta-analysis following the PRISMA guidelines. EBSCOhost, PubMed, CDSR and ARIF databases were searched in October 2016, employing relevant keywords. Results 19 studies met inclusion criteria. Meta-analysis resulted in a lifetime PTSD prevalence of 11% (95% CI: 7–17%) in children and adolescents with CD, 14% (95% CI: 12–15%) in adults with pre-existing CD and 32% (95% CI: 25–40%) in juvenile offenders with CD. Higher lifetime PTSD prevalence was observed in individuals with than without CD, and in females compared to males with CD. Conclusions Studies focusing on the association of trauma, PTSD and CD are still relatively rare. Possible comorbidity models are discussed considering psychological and biological risk factors in a comprehensive model. The high rate of PTSD in CD may be due to shared risk factors; furthermore, CD might increase the risk for comorbid PTSD due to CD inherent risk taking behavior. To study pathways of risk, especially longitudinal studies are necessary.
Towards an animal model of callousness Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2016-12-28 Julen Hernandez-Lallement, Marijn van Wingerden, Tobias Kalenscher
Callous-unemotional traits – the insensitivity to other’s welfare and well-being – are characterized by a lack of empathy. They are characteristic of psychopathy and can be found in other anti-social disorders, such as conduct disorder. Because of the increasing prevalence of anti-social disorders and the rising societal costs of violence and aggression, it is of great importance to elucidate the psychological and physiological mechanisms underlying callousness in the search for pharmacological treatments. One promising avenue is to create a relevant animal model to explore the neural bases of callousness. Here, we review recent advances in rodent models of pro-social choice that could be applied to probe the absence of pro-sociality as a proxy of callous behavior, and provide future directions for the exploration of the neural substrates of callousness.
The pharmacological treatment of aggression in children and adolescents with conduct disorder. Do callous—unemotional traits modulate the efficacy of medication? Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2017-01-27 Carla Balia, Sara Carucci, David Coghill, Alessandro Zuddas
Background Children and adolescents with conduct disorder (CD) show repetitive and persistent patterns of aggressive behaviour and the more severe forms are often associated with callous-unemotional (CU) traits. Objectives To systematically review and, where data are adequate, conduct meta-analyses on the efficacy of medication on aggression in children and adolescent with CD considering the impact of CU traits. Results Few studies have investigated patients with CD as primary diagnosis, and few of these have discriminated between different types of aggression or reported measures of CU traits. Methylphenidate and risperidone showed the largest effects on aggression in randomized controlled trials; other antipsychotics showed clinical efficacy on CD but this evidence is mainly revealed by open label trials. There is some low quality evidence to support a small effect of mood stabilizers and other agents. There were only two papers describing the effects of CU traits thus providing inconclusive results. Conclusion Considering heterogeneity of the disorder, more proof-of-concept clinical studies are needed to define effects of medication and role of CU traits.
Can laboratory animals violate behavioural norms? Towards a preclinical model of conduct disorder Neurosci. Biobehav. Rev. (IF 8.037) Pub Date : 2017-02-03 Simone Macrì, Francesca Zoratto, Flavia Chiarotti, Giovanni Laviola
Conduct disorder (CD), a disturbance characterised by excess rates of aggression – often associated with callousness, lack of empathy and shallow/deficient affect – is extremely prevalent (2–10%) in the juvenile population. CD symptoms are quantitative rather than qualitative in nature whereby, rather than exhibiting abnormal behaviours, CD patients indulge in normal behaviours at abnormal rates. Although genetic and environmental factors contribute to CD aetiology, their precise contribution is yet to be determined. Experimental animal models may aid discriminating genetic vs. environmental effects and designing innovative therapeutic approaches. Here we discuss a theoretical framework potentially favouring the design of experimental models of CD. We suggest that the latter shall recapitulate the “norm violation” typical of the human disorder across the core domains involved in CD: aggression, callousness, empathy and emotionality. We first review how these domains have been operationalised in preclinical models; we then suggest that these experimental paradigms shall be combined with appropriate statistical tools to identify a subset of individuals consistently characterised by abnormal values in CD-relevant phenotypes.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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