What have We Learned from “Perturbing” the Human Cortical Motor System with Transcranial Magnetic Stimulation?

The purpose of this paper is twofold. First, we will review different approaches that one can use with transcranial magnetic stimulation (TMS) to study both its effects on motor behavior and on neural connections in the human brain. Second, we will present evidence obtained in TMS-based studies showing that the dorsal premotor area (PMd), the ventral premotor area (PMv), the supplementary motor area (SMA), and the pre-supplementary motor area (pre-SMA) each have different roles to play in motor behavior. We highlight the importance of the PMd in response selection based on arbitrary cues and in the control of arm movements, the PMv in grasping and in the discrimination of bodily actions, the SMA in movement sequencing and in bimanual coordination, and the pre-SMA in cognitive control. We will also discuss ways in which TMS can be used to chart “true” cerebral reorganization in clinical populations and how TMS might be used as a therapeutic tool to facilitate motor recovery after stroke. We will end our review by discussing some of the methodological challenges and future directions for using this tool in basic and clinical neuroscience

Effects of Left Inferior Prefrontal Stimulation on Episodic Memory Formation: A Two-Stage fMRI—rTMS Study

Successful recovery of words from episodic memory relies strongly on semantic processes at the time of encoding. Evidence from several functional magnetic resonance imaging (fMRI) studies has shown that changes in neural activity in the left inferior prefrontal cortex (LIPFC) during semantic encoding predict subsequent memory performance. This evidence has been taken to suggest that LIPFC plays a critical role in memory formation. Functional neuroimaging findings, however, do not establish a causal brain-behavior relationship. To determine whether there is a causal link between LIPFC involvement at encoding and subsequent success in memory performance, we conducted a two-part study in which we first used fMRI to localize encoding-related activation in LIPFC and then employed repetitive transcranial magnetic stimulation (rTMS) to manipulate neural processes in LIPFC during semantic encoding. To demonstrate the neuroanatomical specificity of any observed effect and to control for nonspecific rTMS side effects, we also stimulated neural processes in two control sites. Using frameless stereotaxy, we positioned the stimulation coil to target (1) the LIPF region that was activated during fMRI (mean xyz = −48 35 5); (2) the homologous righthemisphere region; and (3) an additional left parietal control site. At each site, “stimulated” items (600 msec of 7-Hz rTMS with Cadwell Round Coil) were intermixed with items presented without concurrent stimulation. Subsequently, subjects performed a recognition memory task for the words encountered. We found support for the predicted causal brain-behavior relationship, which was specific to LIPFC. When comparing recognition scores for stimulated items, normalized for variations in performance on nonstimulated trials, we found that words encoded under LIPFC stimulation were subsequently recognized with higher accuracy than words encoded under stimulation in the two cortical control sites. By contrast, no performance difference emerged when the two control sites were compared with each other. Based on additional analyses of the rTMS effects observed directly at the time of encoding (i.e., on semantic-decision performance), we suggest that LIPFC stimulation may have produced its effect on recognition memory, at least in part, through the triggering of more extensive processing of the stimulated items and an ensuing gain in item distinctiveness. Physiological processes of facilitation probably also contributed to the observed memory benefit. Together, these findings suggest that LIPFC does play a causal role in episodic memory formation.Psycholog

Epigenetic clock as a correlate of anxiety

DNA methylation changes consistently throughout life and age-dependent alterations in DNA methylation can be used to estimate one’s epigenetic age. Post-mortem studies revealed higher epigenetic age in brains of patients with major depressive disorder, as compared with controls. Since MDD is highly correlated with anxiety, we hypothesized that symptoms of anxiety, as well as lower volume of grey matter (GM) in depression-related cortical regions, will be associated with faster epigenetic clock in a community-based sample of young adults. Participants included 88 young adults (53% men; 23–24 years of age) from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) who participated in its neuroimaging follow-up and provided saliva samples for epigenetic analysis. Epigenetic age was calculated according to Horvath (Horvath, 2013). Women had slower epigenetic clock than men (Cohen’s d = 0.48). In women (but not men), slower epigenetic clock was associated with less symptoms of anxiety. In the brain, women (but not men) with slower epigenetic clock had greater GM volume in the cerebral cortex (brain size-corrected; R2 = 0.07). Lobe-specific analyses showed that in women (but not men), slower epigenetic clock was associated with greater GM volume in frontal lobe (R2 = 0.16), and that GM volume in frontal lobe mediated the relationship between the speed of epigenetic clock and anxiety trait (ab = 0.15, SE = 0.15, 95% CI [0.007; 0.369]). These findings were not replicated, however, in a community-based sample of adolescents (n = 129; 49% men; 12–19 years of age), possibly due to the different method of tissue collection (blood vs. saliva) or additional sources of variability in the cohort of adolescents (puberty stages, socioeconomic status, prenatal exposure to maternal smoking during pregnancy)

Development of functional connectivity during adolescence:A longitudinal study using an action-observation paradigm

Successful interpersonal interactions rely on an ability to read the emotional states of others and to modulate one's own behavior in response. The actions of others serve as valuable social stimuli in this respect, offering the observer an insight into the actor's emotional state. Social cognition continues to mature throughout adolescence. Here we assess longitudinally the development of functional connectivity during early adolescence within two neural networks implicated in social cognition: one network of brain regions consistently engaged during action observation and another one associated with mentalizing. Using fMRI, we reveal a greater recruitment of the social-emotional network during the observation of angry hand actions in male relative to female adolescents. These findings are discussed in terms of known sex differences in adolescent social behavior

Machine Learning Patterns for Neuroimaging-Genetic Studies in the Cloud

International audienceBrain imaging is a natural intermediate phenotype to understand the link between genetic information and behavior or brain pathologies risk factors. Massive efforts have been made in the last few years to acquire high-dimensional neuroimaging and genetic data on large cohorts of subjects. The statistical analysis of such data is carried out with increasingly sophisticated techniques and represents a great computational challenge. Fortunately, increasing computational power in distributed architectures can be harnessed, if new neuroinformatics infrastructures are designed and training to use these new tools is provided. Combining a MapReduce framework (TomusBLOB) with machine learning algorithms (Scikit-learn library), we design a scalable analysis tool that can deal with non-parametric statistics on high-dimensional data. End-users describe the statistical procedure to perform and can then test the model on their own computers before running the very same code in the cloud at a larger scale. We illustrate the potential of our approach on real data with an experiment showing how the functional signal in subcortical brain regions can be significantly fit with genome-wide genotypes. This experiment demonstrates the scalability and the reliability of our framework in the cloud with a two weeks deployment on hundreds of virtual machines

The Superoanterior Fasciculus (SAF): A Novel White Matter Pathway in the Human Brain?

Fiber tractography (FT) using diffusion magnetic resonance imaging (dMRI) is widely used for investigating microstructural properties of white matter (WM) fiber-bundles and for mapping structural connections of the human brain. While studying the architectural configuration of the brain’s circuitry with FT is not without controversy, recent progress in acquisition, processing, modeling, analysis, and visualization of dMRI data pushes forward the reliability in reconstructing WM pathways. Despite being aware of the well-known pitfalls in analyzing dMRI data and several other limitations of FT discussed in recent literature, we present the superoanterior fasciculus (SAF), a novel bilateral fiber tract in the frontal region of the human brain that—to the best of our knowledge—has not been documented. The SAF has a similar shape to the anterior part of the cingulum bundle, but it is located more frontally. To minimize the possibility that these FT findings are based on acquisition or processing artifacts, different dMRI data sets and processing pipelines have been used to describe the SAF. Furthermore, we evaluated the configuration of the SAF with complementary methods, such as polarized light imaging (PLI) and human brain dissections. The FT results of the SAF demonstrate a long pathway, consistent across individuals, while the human dissections indicate fiber pathways connecting the postero-dorsal with the antero-dorsal cortices of the frontal lobe

GABRB1 Single Nucleotide Polymorphism Associated with Altered Brain Responses (but not Performance) during Measures of Impulsivity and Reward Sensitivity in Human Adolescents.

Variations in genes encoding several GABAA receptors have been associated with human drug and alcohol abuse. Among these, a number of human studies have suggested an association between GABRB1, the gene encoding GABAA receptor β1 subunits, with Alcohol dependence (AD), both on its own and comorbid with other substance dependence and psychiatric illnesses. In the present study, we hypothesized that the GABRB1 genetically-associated increased risk for developing alcoholism may be associated with impaired behavioral control and altered sensitivity to reward, as a consequence of altered brain function. Exploiting the IMAGEN database (Schumann et al., 2010), we explored in a human adolescent population whether possession of the minor (T) variant of the single nucleotide polymorphism (SNP) rs2044081 is associated with performance of tasks measuring aspects of impulsivity, and reward sensitivity that are implicated in drug and alcohol abuse. Allelic variation did not associate with altered performance in either a stop-signal task (SST), measuring one aspect of impulsivity, or a monetary incentive delay (MID) task assessing reward anticipation. However, increased functional magnetic resonance imaging (fMRI) blood-oxygen-level dependent (BOLD) response in the right hemisphere inferior frontal gyrus (IFG), left hemisphere caudate/insula and left hemisphere inferior temporal gyrus (ITG) during MID performance was higher in the minor (T) allelic group. In contrast, during SST performance, the BOLD response found in the right hemisphere supramarginal gyrus, right hemisphere lingual and left hemisphere inferior parietal gyrus indicated reduced responses in the minor genotype. We suggest that β1-containing GABAA receptors may play a role in excitability of brain regions important in controlling reward-related behavior, which may contribute to susceptibility to addictive behavior

The structure of psychopathology in adolescence and its common personality and cognitive correlates

The traditional view that mental disorders are distinct, categorical disorders has been challenged by evidence that disorders are highly comorbid and exist on a continuum (e.g., Caspi et al., 2014; Tackett et al., 2013). The first objective of this study was to use structural equation modeling to model the structure of psychopathology in an adolescent community-based sample (N = 2,144) including conduct disorder, attention-deficit/hyperactivity disorder (ADHD), oppositional-defiant disorder (ODD), obsessive-compulsive disorder, eating disorders, substance use, anxiety, depression, phobias, and other emotional symptoms, assessed at 16 years. The second objective was to identify common personality and cognitive correlates of psychopathology, assessed at 14 years. Results showed that psychopathology at 16 years fit 2 bifactor models equally well: (a) a bifactor model, reflecting a general psychopathology factor, as well as specific externalizing (representing mainly substance misuse and low ADHD) and internalizing factors; and (b) a bifactor model with a general psychopathology factor and 3 specific externalizing (representing mainly ADHD and ODD), substance use and internalizing factors. The general psychopathology factor was related to high disinhibition/impulsivity, low agreeableness, high neuroticism and hopelessness, high delay-discounting, poor response inhibition and low performance IQ. Substance use was specifically related to high novelty-seeking, sensation-seeking, extraversion, high verbal IQ, and risk-taking. Internalizing psychopathology was specifically related to high neuroticism, hopelessness and anxiety-sensitivity, low novelty-seeking and extraversion, and an attentional bias toward negatively valenced verbal stimuli. Findings reveal several nonspecific or transdiagnostic personality and cognitive factors that may be targeted in new interventions to potentially prevent the development of multiple psychopathologies

Personality, attentional biases towards emotional faces and symptoms of mental disorders in an adolescent sample

Objective To investigate the role of personality factors and attentional biases towards emotional faces, in establishing concurrent and prospective risk for mental disorder diagnosis in adolescence. Method Data were obtained as part of the IMAGEN study, conducted across 8 European sites, with a community sample of 2257 adolescents. At 14 years, participants completed an emotional variant of the dot-probe task, as well two personality measures, namely the Substance Use Risk Profile Scale and the revised NEO Personality Inventory. At 14 and 16 years, participants and their parents were interviewed to determine symptoms of mental disorders. Results Personality traits were general and specific risk indicators for mental disorders at 14 years. Increased specificity was obtained when investigating the likelihood of mental disorders over a 2-year period, with the Substance Use Risk Profile Scale showing incremental validity over the NEO Personality Inventory. Attentional biases to emotional faces did not characterise or predict mental disorders examined in the current sample. Discussion Personality traits can indicate concurrent and prospective risk for mental disorders in a community youth sample, and identify at-risk youth beyond the impact of baseline symptoms. This study does not support the hypothesis that attentional biases mediate the relationship between personality and psychopathology in a community sample. Task and sample characteristics that contribute to differing results among studies are discussed

Ventral striatum connectivity during reward anticipation in adolescent smokers

Substance misusers, including adolescent smokers, often have reduced reward system activity during processing of non-drug rewards. Using a psychophysiological interaction approach, we examined functional connectivity with the ventral striatum during reward anticipation in a large (N = 206) sample of adolescent smokers. Increased smoking frequency was associated with (1) increased connectivity with regions involved in saliency and valuation, including the orbitofrontal cortex and (2) reduced connectivity between the ventral striatum and regions associated with inhibition and risk aversion, including the right inferior frontal gyrus. These results demonstrate that functional connectivity during reward processing is relevant to adolescent addiction