FMRI Effective Connectivity and TMS Chronometry: Complementary Accounts of Causality in the Visuospatial Judgment Network

BACKGROUND: While traditionally quite distinct, functional neuroimaging (e.g. functional magnetic resonance imaging: fMRI) and functional interference techniques (e.g. transcranial magnetic stimulation: TMS) increasingly address similar questions of functional brain organization, including connectivity, interactions, and causality in the brain. Time-resolved TMS over multiple brain network nodes can elucidate the relative timings of functional relevance for behavior ("TMS chronometry"), while fMRI functional or effective connectivity (fMRI EC) can map task-specific interactions between brain regions based on the interrelation of measured signals. The current study empirically assessed the relation between these different methods. METHODOLOGY/PRINCIPAL FINDINGS: One group of 15 participants took part in two experiments: one fMRI EC study, and one TMS chronometry study, both of which used an established cognitive paradigm involving one visuospatial judgment task and one color judgment control task. Granger causality mapping (GCM), a data-driven variant of fMRI EC analysis, revealed a frontal-to-parietal flow of information, from inferior/middle frontal gyrus (MFG) to posterior parietal cortex (PPC). FMRI EC-guided Neuronavigated TMS had behavioral effects when applied to both PPC and to MFG, but the temporal pattern of these effects was similar for both stimulation sites. At first glance, this would seem in contradiction to the fMRI EC results. However, we discuss how TMS chronometry and fMRI EC are conceptually different and show how they can be complementary and mutually constraining, rather than contradictory, on the basis of our data. CONCLUSIONS/SIGNIFICANCE: The findings that fMRI EC could successfully localize functionally relevant TMS target regions on the single subject level, and conversely, that TMS confirmed an fMRI EC identified functional network to be behaviorally relevant, have important methodological and theoretical implications. Our results, in combination with data from earlier studies by our group (Sack et al., 2007, Cerebral Cortex), lead to informed speculations on complex brain mechanisms, and TMS disruption thereof, underlying visuospatial judgment. This first in-depth empirical and conceptual comparison of fMRI EC and TMS chronometry thereby shows the complementary insights offered by the two methods

Comparative quantitative analysis reveals preserved structural connectivity patterns in the human and macaque brain

The macaque brain serves as a model for the human brain, but its suitability is challenged by unique human features, including connectivity reconfigurations, which emerged during primate evolution. We perform a quantitative comparative analysis of the whole brain macroscale structural connectivity of the two species. Our findings suggest that the human and macaque brain as a whole are similarly wired. A region-wise analysis reveals many interspecies similarities of connectivity patterns, but also lack thereof, primarily involving cingulate and parietal regions. We unravel a common structural backbone in both species involving a highly overlapping set of regions. This structural backbone, important for mediating information across the brain, constitutes a feature of the primate brain persevering evolution. Our findings illustrate novel evolutionary aspects at the macroscale connectivity level, including the existence of common topological structures, and offer a quantitative translational bridge between macaque and human research

Human larynx motor cortices coordinate respiration for vocal-motor control.

Vocal flexibility is a hallmark of the human species, most particularly the capacity to speak and sing. This ability is supported in part by the evolution of a direct neural pathway linking the motor cortex to the brainstem nucleus that controls the larynx the primary sound source for communication. Early brain imaging studies demonstrated that larynx motor cortex at the dorsal end of the orofacial division of motor cortex (dLMC) integrated laryngeal and respiratory control, thereby coordinating two major muscular systems that are necessary for vocalization. Neurosurgical studies have since demonstrated the existence of a second larynx motor area at the ventral extent of the orofacial motor division (vLMC) of motor cortex. The vLMC has been presumed to be less relevant to speech motor control, but its functional role remains unknown. We employed a novel ultra-high field (7T) magnetic resonance imaging paradigm that combined singing and whistling simple melodies to localise the larynx motor cortices and test their involvement in respiratory motor control. Surprisingly, whistling activated both 'larynx areas' more strongly than singing despite the reduced involvement of the larynx during whistling. We provide further evidence for the existence of two larynx motor areas in the human brain, and the first evidence that laryngeal-respiratory integration is a shared property of both larynx motor areas. We outline explicit predictions about the descending motor pathways that give these cortical areas access to both the laryngeal and respiratory systems and discuss the implications for the evolution of speech

Human larynx motor cortices coordinate respiration for vocal-motor control

Vocal flexibility is a hallmark of the human species, most particularly the capacity to speak and sing. This ability is supported in part by the evolution of a direct neural pathway linking the motor cortex to the brainstem nucleus that controls the larynx the primary sound source for communication. Early brain imaging studies demonstrated that larynx motor cortex at the dorsal end of the orofacial division of motor cortex (dLMC) integrated laryngeal and respiratory control, thereby coordinating two major muscular systems that are necessary for vocalization. Neurosurgical studies have since demonstrated the existence of a second larynx motor area at the ventral extent of the orofacial motor division (vLMC) of motor cortex. The vLMC has been presumed to be less relevant to speech motor control, but its functional role remains unknown. We employed a novel ultra-high field (7T) magnetic resonance imaging paradigm that combined singing and whistling simple melodies to localise the larynx motor cortices and test their involvement in respiratory motor control. Surprisingly, whistling activated both ‘larynx areas’ more strongly than singing despite the reduced involvement of the larynx during whistling. We provide further evidence for the existence of two larynx motor areas in the human brain, and the first evidence that laryngeal-respiratory integration is a shared property of both larynx motor areas. We outline explicit predictions about the descending motor pathways that give these cortical areas access to both the laryngeal and respiratory systems and discuss the implications for the evolution of speech

Development curves of communication and social interaction in individuals with cerebral palsy

Aim: To determine development curves of communication and social interaction from childhood into adulthood for individuals with cerebral palsy (CP). Method: This Pediatric Rehabilitation Research in the Netherlands (PERRIN)-DECADE study longitudinally assessed 421 individuals with CP, aged from 1 to 20 years at baseline, after 13 years (n=121 at follow-up). Communication and social interactions were assessed using the Vineland Adaptive Behavior Scales. We estimated the average maximum performance limit (level) and age at which 90% of the limit was reached (age90) using nonlinear mixed-effects modeling. Results: One-hundred individuals without intellectual disability were aged 21 to 34 years at follow-up (39 females, 61 males) (mean age [SD] 28y 5mo [3y 11mo]). Limits of individuals without intellectual disability, regardless of Gross Motor Function Classification System (GMFCS) level, approached the maximum score and were significantly higher than those of individuals with intellectual disability. Ages90 ranged between 3 and 4 years for receptive communication, 6 and 7 years for expressive communication and interrelationships, 12 and 16 years for written communication, 13 and 16 years for play and leisure, and 14 and 16 years for coping. Twenty-one individuals with intellectual disability were between 21 and 27 years at follow-up (8 females, 13 males) (mean age [SD] 24y 7mo [1y 8mo]). Individuals with intellectual disability in GMFCS level V showed the least favourable development, but variation between individuals with intellectual disability was large. Interpretation: Individuals with CP and without intellectual disability show developmental curves of communication and social interactions similar to typically developing individuals, regardless of their level of motor function. Those with intellectual disability reach lower performance levels and vary largely in individual development. What this paper adds: Communication and social interactions in individuals with cerebral palsy without intellectual disability develop similarly to typically developing individuals. Communication and social interactions of individuals with intellectual disability develop less favourably and show large variation

Measuring Granger Causality between Cortical Regions from Voxelwise fMRI BOLD Signals with LASSO

Functional brain network studies using the Blood Oxygen-Level Dependent (BOLD) signal from functional Magnetic Resonance Imaging (fMRI) are becoming increasingly prevalent in research on the neural basis of human cognition. An important problem in functional brain network analysis is to understand directed functional interactions between brain regions during cognitive performance. This problem has important implications for understanding top-down influences from frontal and parietal control regions to visual occipital cortex in visuospatial attention, the goal motivating the present study. A common approach to measuring directed functional interactions between two brain regions is to first create nodal signals by averaging the BOLD signals of all the voxels in each region, and to then measure directed functional interactions between the nodal signals. Another approach, that avoids averaging, is to measure directed functional interactions between all pairwise combinations of voxels in the two regions. Here we employ an alternative approach that avoids the drawbacks of both averaging and pairwise voxel measures. In this approach, we first use the Least Absolute Shrinkage Selection Operator (LASSO) to pre-select voxels for analysis, then compute a Multivariate Vector AutoRegressive (MVAR) model from the time series of the selected voxels, and finally compute summary Granger Causality (GC) statistics from the model to represent directed interregional interactions. We demonstrate the effectiveness of this approach on both simulated and empirical fMRI data. We also show that averaging regional BOLD activity to create a nodal signal may lead to biased GC estimation of directed interregional interactions. The approach presented here makes it feasible to compute GC between brain regions without the need for averaging. Our results suggest that in the analysis of functional brain networks, careful consideration must be given to the way that network nodes and edges are defined because those definitions may have important implications for the validity of the analysis

The psychological effects of terrorism are moderated by cultural worldviews

Terrorism cannot be easily studied experimentally for obvious reasons. We report the results of a laboratory study (N = 149) testing the effect of cultural worldviews on feelings of threat and hostility toward Muslims in France that include in the design the deadly terrorist attack of January 7th 2015 in Paris as a naturally occurring independent variable. The results replicate past research by showing that in a natural context, people felt more threatened and more hostile toward Muslims after the terrorist attack than before. However, the reverse occurred in an experimental condition that made the French cultural worldview of colorblind equality salient: People felt less threatened and less hostile after the terrorist attack than before. These results provide, for the first time in the context of a real terrorist attack, support for Terror Management Theory's proposal that cultural worldviews are an effective buffer against terror

Cardiovascular disease risk in adults with spastic bilateral cerebral palsy

Objective: To explore: (i) cardiovascular disease risk factors and the 10-year clustered risk of a fatal cardiovascular event in adults with spastic bilateral cerebral palsy; and (ii) relationships between the 10-year risk and body fat, aerobic fitness and physical activity. Design: Cross-sectional study. Subjects: Forty-three adults with spastic bilateral cerebral palsy without severe cognitive impairment (mean age 36.6 years (standard deviation 6); 27 men). Methods: Biological and lifestyle-related risk factors and the 10-year risk according to the Systematic Coronary Risk Evaluation (SCORE) were assessed. Relationships were studied using multivariable linear regression analysis. Results: The following single risk factors were present: hypertension (n = 12), elevated total cholesterol (n = 3), low high-density lipoprotein cholesterol (n = 5; all men), high-risk waist circumference (n = 11), obesity (body mass index; n = 5; all men), reduced aerobic fitness (on average 80% of reference values), reduced level of everyday physical activity (on average 78% of reference values) and smoking (n=9). All participants had a 10-year risk <1%. Corrected for gender, participants with higher waist circumference (β = 0.28; p = 0.06) or body mass index (β=0.25; p = 0.08) tended to have a higher 10-year risk. Conclusion: In this relatively young adult sample of people with spastic bilateral cerebral palsy several single cardiovascular disease risk factors were present. The 10-year fatal cardiovascular disease risk was low, and higher body fat tended to be related to higher 10-year risk

Attention-dependent modulation of cortical taste circuits revealed by granger causality with signal-dependent noise

We show, for the first time, that in cortical areas, for example the insular, orbitofrontal, and lateral prefrontal cortex, there is signal-dependent noise in the fMRI blood-oxygen level dependent (BOLD) time series, with the variance of the noise increasing approximately linearly with the square of the signal. Classical Granger causal models are based on autoregressive models with time invariant covariance structure, and thus do not take this signal-dependent noise into account. To address this limitation, here we describe a Granger causal model with signal-dependent noise, and a novel, likelihood ratio test for causal inferences. We apply this approach to the data from an fMRI study to investigate the source of the top-down attentional control of taste intensity and taste pleasantness processing. The Granger causality with signal-dependent noise analysis reveals effects not identified by classical Granger causal analysis. In particular, there is a top-down effect from the posterior lateral prefrontal cortex to the insular taste cortex during attention to intensity but not to pleasantness, and there is a top-down effect from the anterior and posterior lateral prefrontal cortex to the orbitofrontal cortex during attention to pleasantness but not to intensity. In addition, there is stronger forward effective connectivity from the insular taste cortex to the orbitofrontal cortex during attention to pleasantness than during attention to intensity. These findings indicate the importance of explicitly modeling signal-dependent noise in functional neuroimaging, and reveal some of the processes involved in a biased activation theory of selective attention