Central neurogenetic signatures of the visuomotor integration system.

Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader-Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes-TBR1, SCN1A, MAGEL2, and CACNB4-to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes.

Brain tumour microstructure is associated with post-surgical cognition.

Brain tumour microstructure is potentially predictive of changes following treatment to cognitive functions subserved by the functional networks in which they are embedded. To test this hypothesis, intra-tumoural microstructure was quantified from diffusion-weighted MRI to identify which tumour subregions (if any) had a greater impact on participants' cognitive recovery after surgical resection. Additionally, we studied the role of tumour microstructure in the functional interaction between the tumour and the rest of the brain. Sixteen patients (22-56 years, 7 females) with brain tumours located in or near speech-eloquent areas of the brain were included in the analyses. Two different approaches were adopted for tumour segmentation from a multishell diffusion MRI acquisition: the first used a two-dimensional four group partition of feature space, whilst the second used data-driven clustering with Gaussian mixture modelling. For each approach, we assessed the capability of tumour microstructure to predict participants' cognitive outcomes after surgery and the strength of association between the BOLD signal of individual tumour subregions and the global BOLD signal. With both methodologies, the volumes of partially overlapped subregions within the tumour significantly predicted cognitive decline in verbal skills after surgery. We also found that these particular subregions were among those that showed greater functional interaction with the unaffected cortex. Our results indicate that tumour microstructure measured by MRI multishell diffusion is associated with cognitive recovery after surgery.

Robust estimation of fractal measures for characterizing the structural complexity of the human brain: optimization and reproducibility.

High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter structures can be characterized to quantify aspects of their shape, volume and topological complexity. In particular, methods based on fractal analysis have been applied in neuroimaging studies to quantify the structural complexity of the brain in both healthy and impaired conditions. The usefulness of such measures for characterizing individual differences in brain structure critically depends on their within-subject reproducibility in order to allow the robust detection of between-subject differences. This study analyzes key analytic parameters of three fractal-based methods that rely on the box-counting algorithm with the aim to maximize within-subject reproducibility of the fractal characterizations of different brain objects, including the pial surface, the cortical ribbon volume, the white matter volume and the gray matter/white matter boundary. Two separate datasets originating from different imaging centers were analyzed, comprising 50 subjects with three and 24 subjects with four successive scanning sessions per subject, respectively. The reproducibility of fractal measures was statistically assessed by computing their intra-class correlations. Results reveal differences between different fractal estimators and allow the identification of several parameters that are critical for high reproducibility. Highest reproducibility with intra-class correlations in the range of 0.9-0.95 is achieved with the correlation dimension. Further analyses of the fractal dimensions of parcellated cortical and subcortical gray matter regions suggest robustly estimated and region-specific patterns of individual variability. These results are valuable for defining appropriate parameter configurations when studying changes in fractal descriptors of human brain structure, for instance in studies of neurological diseases that do not allow repeated measurements or for disease-course longitudinal studies.

Functional asymmetries in early learning during right, left, and bimanual performance in right-handed subjects.

PURPOSE: To elucidate differences in activity and connectivity during early learning due to the performing hand. MATERIALS AND METHODS: Twenty right-handed subjects were recruited. The neural correlates of explicit visuospatial learning executed with the right, the left hand, and bimanually were investigated using functional magnetic resonance imaging. Connectivity analyses were carried out using the psychophysiological interactions model, considering right and left anterior putamen as index regions. RESULTS: A common neural network was found for the three tasks during learning. Main activity increases were located in posterior cingulate cortex, supplementary motor area, parietal cortex, anterior putamen, and cerebellum (IV-V), whereas activity decrements were observed in prefrontal regions. However, the left hand task showed a greater recruitment of left hippocampal areas when compared with the other tasks. In addition, enhanced connectivity between the right anterior putamen and motor cortical and cerebellar regions was found for the left hand when compared with the right hand task. CONCLUSION: An additional recruitment of brain regions and increased striato-cortical and striato-cerebellar functional connections is needed when early learning is performed with the nondominant hand. In addition, access to brain resources during learning may be directed by the dominant hand in the bimanual task.

Cortical hypoperfusion in Parkinson's disease assessed using arterial spin labeled perfusion MRI.

Alterations in cerebral perfusion and metabolism in Parkinson's disease have been assessed in several studies, using nuclear imaging techniques and more recently magnetic resonance imaging. However, to date there is no consensus in the literature regarding the extent and the magnitude of these alterations. In this work, arterial spin labeled perfusion MRI was employed to quantify absolute cerebral blood flow in a group of early-to-moderate Parkinson's disease patients and age-matched healthy controls. Perfusion comparisons between the two groups showed that Parkinson's disease is characterized by wide-spread cortical hypoperfusion. Subcortically, hypoperfusion was also found in the caudate nucleus. This pattern of hypoperfusion could be related to cognitive dysfunctions that have been previously observed even at the disease early stages. The present results were obtained by means of whole brain voxel-wise comparisons of absolute perfusion values, using statistical parametric mapping, thus avoiding the potentially biased global mean normalization procedure. In addition, this work demonstrates that between-group comparison of relative perfusion values after global mean normalization, introduced artifactual relative perfusion increases, where absolute perfusion was in fact preserved. This has implications for perfusion studies of other brain disorders.

Brain Activity and Functional Connectivity Patterns Associated With Fast and Slow Motor Sequence Learning in Late Middle Adulthood.

The human brain undergoes structural and functional changes across the lifespan. The study of motor sequence learning in elderly subjects is of particularly interest since previous findings in young adults might not replicate during later stages of adulthood. The present functional magnetic resonance imaging (fMRI) study assessed the performance, brain activity and functional connectivity patterns associated with motor sequence learning in late middle adulthood. For this purpose, a total of 25 subjects were evaluated during early stages of learning [i.e., fast learning (FL)]. A subset of these subjects (n = 11) was evaluated after extensive practice of a motor sequence [i.e., slow learning (SL) phase]. As expected, late middle adults improved motor performance from FL to SL. Learning-related brain activity patterns replicated most of the findings reported previously in young subjects except for the lack of hippocampal activity during FL and the involvement of cerebellum during SL. Regarding functional connectivity, precuneus and sensorimotor lobule VI of the cerebellum showed a central role during improvement of novel motor performance. In the sample of subjects evaluated, connectivity between the posterior putamen and parietal and frontal regions was significantly decreased with aging during SL. This age-related connectivity pattern may reflect losses in network efficiency when approaching late adulthood. Altogether, these results may have important applications, for instance, in motor rehabilitation programs.

Lifetime Mental Health Problems in Adult Lower Secondary Education: A Student Survey.

BACKGROUND/OBJECTIVE: Adult Lower Secondary Education is an education program for basic qualifications for the labor market. Our study aimed to compare lifetime mental health problems between current Adult Lower Secondary Education students and higher Vocational Education students, as the former constitutes a highly distinct and understudied group. METHODS: Findings were based on a cross-sectional self-report survey. Lifetime relative odds of occurrence of mental disorders [i.e., psychiatric disorders typically diagnosed in adults, learning difficulties or deficit hyperactivity disorder (ADHD)] were compared between Adult Lower Secondary Education students (n = 134) and Vocational Education students (n = 149). RESULTS: While the frequency of mental health problems was high in both groups, psychiatric disorders typically diagnosed in adults were more common in Adult Lower Secondary Education students than among other students. Vocational Education students reported higher rates of ADHD. CONCLUSION: There is a need for additional psychological resources for Adult Lower Secondary Education students, an educational level that is the last path for many to acquire a basic degree.

Continuous performance of a novel motor sequence leads to highly correlated striatal and hippocampal perfusion increases.

The time course of changes in regional cerebral perfusion during a continuous motor learning task performed with the right hand was monitored using the arterial spin labeling (ASL) technique at high field (3 T). ASL allowed measuring explicit learning related effects in neural activity elicited throughout a 6 minute task period. During this time learning took place as demonstrated by performance improvement. Comparing the initial and final learning phases, perfusion decreases were detected in most of the cortical regions recruited during early learning. More interestingly however perfusion increases were observed in a few cortical and subcortical regions of the contralateral hemisphere: the supplementary motor area, the primary somatosensory area, the posterior insula and posterior putamen, the hippocampus and bilaterally the retrosplenial cortex. Moreover, perfusion increases in the posterior putamen and hippocampus were highly correlated during the learning period. These results support the hypothesis that the striatum and hippocampus form interactive memory systems with parallel processing.

Implications of Unconnected Micro, Molecular, and Molar Level Research in Psychology: The Case of Executive Functions, Self-Regulation, and External Regulation.

The proliferation of research production in Psychology as a science has been increasing exponentially. This situation leads to the necessity of organizing the research production into different levels of analysis that make it possible to delimit each research domain. The objective of this analysis is to clearly distinguish the different levels of research: micro-analysis, molecular, and molar. Each level is presented, along with an analysis of its benefits and limitations. Next, this analysis is applied to the topics of Executive Functions, Self-Regulation, and External Regulation. Conclusions, limitations, and implications for future research are offered, with a view toward a better connection of research production across the different levels, and an allusion to ethical considerations.

Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: A systematic review and meta-analysis.

A systematic review with meta-analyses was performed to: 1) quantify the association between ADHD and risk of unintentional physical injuries in children/adolescents ("risk analysis"); 2) assess the effect of ADHD medications on this risk ("medication analysis"). We searched 114 databases through June 2017. For the risk analysis, studies reporting sex-controlled odds ratios (ORs) or hazard ratios (HRs) estimating the association between ADHD and injuries were combined. Pooled ORs (28 studies, 4,055,620 individuals without and 350,938 with ADHD) and HRs (4 studies, 901,891 individuals without and 20,363 with ADHD) were 1.53 (95% CI=1.40,1.67) and 1.39 (95% CI=1.06,1.83), respectively. For the medication analysis, we meta-analysed studies that avoided the confounding-by-indication bias [four studies with a self-controlled methodology and another comparing risk over time and groups (a "difference in differences" methodology)]. The pooled effect size was 0.879 (95% CI=0.838,0.922) (13,254 individuals with ADHD). ADHD is significantly associated with an increased risk of unintentional injuries and ADHD medications have a protective effect, at least in the short term, as indicated by self-controlled studies.

Risk of poisoning in children and adolescents with ADHD: a systematic review and meta-analysis.

Poisoning, a subtype of physical injury, is an important hazard in children and youth. Individuals with ADHD may be at higher risk of poisoning. Here, we conducted a systematic review and meta-analysis to quantify this risk. Furthermore, since physical injuries, likely share causal mechanisms with those of poisoning, we compared the relative risk of poisoning and injuries pooling studies reporting both. As per our pre-registered protocol (PROSPERO ID CRD42017079911), we searched 114 databases through November 2017. From a pool of 826 potentially relevant references, screened independently by two researchers, nine studies (84,756 individuals with and 1,398,946 without the disorder) were retained. We pooled hazard and odds ratios using Robust Variance Estimation, a meta-analytic method aimed to deal with non-independence of outcomes. We found that ADHD is associated with a significantly higher risk of poisoning (Relative Risk = 3.14, 95% Confidence Interval = 2.23 to 4.42). Results also indicated that the relative risk of poisoning is significantly higher than that of physical injuries when comparing individuals with and without ADHD (Beta coefficient = 0.686, 95% Confidence Interval = 0.166 to 1.206). These findings should inform clinical guidelines and public health programs aimed to reduce physical risks in children/adolescents with ADHD.

Motor sequence learning in the elderly: differential activity patterns as a function of hand modality.

Previous research on motor sequence learning (MSL) in the elderly has focused mainly on unilateral tasks, even though bilateral coordination might be impaired in this age group. In this fMRI study, 28 right-handed elderly subjects were recruited. The paradigm consisted of a Novel and a simple Control sequence executed with the right (R), left (L) and both hands (B). Behavioral performance (Accuracy[AC], Inter-tap Interval[ITI]) and associated brain activity were assessed during early learning. Behavioral performance in the Novel task was similar between unilateral conditions whereas in the bimanual condition more errors and slower motor execution were observed. Brain activity increases during learning showed differences between Conditions: R showed increased activity in pre-SMA, basal ganglia and left hippocampus while B showed activity increments mainly in posterior parietal cortex and cerebellum. L did not show any activity modulation during learning. Performance correlates for AC (related to spatial success) and ITI (related to accurate timing) shared a cortico-basal-cerebellar network. However, it was found that the ITI regressor presented additional significant correlations with activity in SMA and basal ganglia in R. The AC regressor showed additional significant correlations with activity in more extended thalamic and cerebellar areas in B. The present findings suggest that, behaviorally, the spatial and temporal components of MSL are impaired in elderly subjects when using both hands. Additionally, differential brain activity patterns were found across hand modalities. The results obtained reveal the existence of a highly specialized network in the dominant hand and identify areas specifically involved in bimanual coordination.

Risk of unintentional injuries in children and adolescents with ADHD and the impact of ADHD medications: protocol for a systematic review and meta-analysis.

INTRODUCTION: Attention-deficit hyperactivity disorder (ADHD) has been related to increased rates of unintentional injuries. However, the magnitude of the effect and to which extent variables such as sex, age or comorbidity can influence this relationship is unknown. Additionally, and importantly, it is unclear if, and to which degree, ADHD medications can decrease the number of unintentional injuries. Due to the amount of economic and social resources invested in the treatment of injuries, filling these gaps in the literature is highly relevant from a public health standpoint. Here, we present a protocol for a systematic review and meta-analysis to estimate the relationship between ADHD and unintentional injuries and assess the impact of pharmacological treatment for ADHD METHODS AND ANALYSIS: We will combine results from 114 bibliographic databases for studies relating ADHD and risk of injuries. Bibliographic searches and data extraction will be carried out independently by two researchers. The studies' risk of bias will be assessed using the Newcastle-Ottawa Scale. Articles reporting ORs or HRs of suffering an injury in ADHD compared with controls (or enough data to calculate them) will be combined using Robust Variance Estimation, a method that permits to include multiple non-independent outcomes in the analysis. All analyses will be carried out in Stata. Age, sex and comorbid conduct disorders will be considered as potential causes of variance and their effect analysed through meta-regression and subgroup analysis. Sensitivity analyses will exclude articles with longer follow-ups, non-stringent definitions of ADHD or controls and statistically uncontrolled/controlled outcomes. Studies implementing a self-controlled case series methodology to investigate if ADHD drugs reduce the risk of injuries will be combined with a generalised linear mixed model using the Poisson distribution and a log link function. REGISTRATION DETAILS: PROSPERO-Prospective Register of Systematic Reviews (CRD42017064967).

Dopaminergic modulation of the trade-off between probability and time in economic decision-making.

Studies on animals and humans have demonstrated the importance of dopamine in modulating decision-making processes. In this work, we have tested dopaminergic modulation of economic decision-making and its neural correlates by administering either placebo or metoclopramide, a dopamine D2-receptor antagonist, to healthy subjects, during a functional MRI study. The decision-making task combined probability and time delay with a fixed monetary reward. For individual behavioral characterization, we used the Probability Time Trade-off (PTT) economic model, which integrates the traditional trade-offs of reward magnitude-time and reward magnitude-probability into a single measurement, thereby quantifying the subjective value of a delayed and probabilistic outcome. A regression analysis between BOLD signal and the PTT model index permitted to identify the neural substrate encoding the subjective reward-value. Behaviorally, medication reduced the rate of temporal discounting over probability, reflected in medicated subjects being more prone to postpone the reward in order to increase the outcome probability. In addition, medicated subjects showed less activity during the task in the postcentral gyrus as well as frontomedian areas, whereas there were no differences in the ventromedial orbitofrontal cortex (VMOFC) between groups when coding the subjective value. The present study demonstrates by means of behavior and imaging that dopamine modulation alters the probability-time trade-off in human economic decision-making.

The neural substrate and functional integration of uncertainty in decision making: an information theory approach.

Decision making can be regarded as the outcome of cognitive processes leading to the selection of a course of action among several alternatives. Borrowing a central measurement from information theory, Shannon entropy, we quantified the uncertainties produced by decisions of participants within an economic decision task under different configurations of reward probability and time. These descriptors were used to obtain blood oxygen level-dependent (BOLD) signal correlates of uncertainty and two clusters codifying the Shannon entropy of task configurations were identified: a large cluster including parts of the right middle cingulate cortex (MCC) and left and right pre-supplementary motor areas (pre-SMA) and a small cluster at the left anterior thalamus. Subsequent functional connectivity analyses using the psycho-physiological interactions model identified areas involved in the functional integration of uncertainty. Results indicate that clusters mostly located at frontal and temporal cortices experienced an increased connectivity with the right MCC and left and right pre-SMA as the uncertainty was higher. Furthermore, pre-SMA was also functionally connected to a rich set of areas, most of them associative areas located at occipital and parietal lobes. This study provides a map of the human brain segregation and integration (i.e., neural substrate and functional connectivity respectively) of the uncertainty associated to an economic decision making paradigm.

Effects on resting cerebral blood flow and functional connectivity induced by metoclopramide: a perfusion MRI study in healthy volunteers.

BACKGROUND AND PURPOSE The substituted benzamide, metoclopramide, is a dopamine receptor antagonist and is widely prescribed in the symptomatic treatment of nausea and vomiting, although it can cause adverse motor and non-motor side effects. The effects of metoclopramide on brain metabolism have not been investigated to date. EXPERIMENTAL APPROACH To determine the effects of metoclopramide on brain function, cerebral perfusion changes after a single oral dose were assessed in healthy volunteers using magnetic resonance imaging (MRI) techniques. Arterial spin labelling (ASL) perfusion MRI was used to measure cerebral blood flow before and after metoclopramide. Blood haemodynamics in the vertebral and internal carotid arteries were evaluated using phase-contrast MRI. KEY RESULTS Metoclopramide altered haemodynamics in the carotid arteries and the cerebral perfusion. Perfusion increased bilaterally in the putamen, consistent with antagonism of dopamine D(2) receptors by metoclopramide and possibly related to its motor side effects. In contrast, reduced perfusion was observed in the insular cortices and anterior temporal lobes. In addition, functional connectivity between the insular cortex and the dorsolateral prefrontal cortex was decreased. These cortical changes affecting neural circuits between high-order association areas may underlie certain neuropsychiatric conditions occasionally reported after metoclopramide administration. CONCLUSIONS AND IMPLICATIONS The present results show the sensitivity of ASL to detect small changes in regional blood flow, closely related to brain function, after a single pharmacological challenge, highlighting the potential of this technique for human pharmacological studies.