Proof-of-principle phase II MRI studies in stroke

Background and purpose: Since the failure of a number of phase III trials of neuroprotection in ischemic stroke, the need for smaller phase II studies with MRI surrogates has emerged. There is, however, little information available about sample size requirements for such phase II trials and rarely enough patients in single studies to make robust estimates. We have formed an international collaborative group to assemble larger datasets and from these have generated sample size tables for MRI-based infarct expansion as the outcome measure. Methods: Twelve centers from Australia, Europe, and North America contributed data from patients with hemispheric ischemic stroke. Infarct expansion was defined from initial diffusion-weighted images and later fluid-attenuated inversion recover or T2 images. Sample size estimates were calculated from data on infarct expansion ratios treated as dichotomous or continuous variables. A nonparametric approach was used because the distribution of infarct expansion was resistant to all forms of transformation. Results: As an example, a 20% absolute reduction in infarct expansion ratio (< or = 1), 80% power, and alpha = 0.05 requires 99 patients in each arm. To achieve an equivalent effect size with a continuous approach requires 61 patients. Conclusions: These tables will be useful in planning phase II trials of therapy with the use of MRI outcome measures. For positive studies, biologically plausible surrogates such as these may provide a rationale for proceeding to phase III trials

The human arcuate fasciculus provides specific advantages to process complex sequential stimuli, not hierarchies in general

Hierarchies are sets or sequences of elements connected in the form of a rooted tree. They possess the key properties: (1) all elements are combined into one structure; (2) one element is superior to all others; and (3) no element is superior to itself (that is, there are no cycles, direct or indirect)” (Fitch & Martins, 2014). Defined as such, hierarchies exist in multiple domains. Linguistic syntax, and tonal and action sequences display a multi-layered set-of-sets organization. Moreover, social (e.g. family and company structures) and spatial hierarchies (e.g. landmark-based navigation) also display asymmetrical and multi-layered relations between different elements and sets of elements. Humans can represent the hierarchical structure in all these domains, and to extend their hierarchical depth when necessary. In the same way that we can extend any arbitrarily long sentence, we can also join any two arbitrarily complex social groups such as the armies of two countries to form a joint inter-national army (or inter-continental, inter-planetary, inter-galactic, etc.). Humans are especially capable of generating hierarchies. While we are able to assemble these kinds of structures in language, music and complex action (Fitch & Martins, 2014), analogous capacities are missing in other species (Fitch & Friederici, 2012), even though they can process simpler structures to some extent (Wilson, Marslen-Wilson, & Petkov, 2017). The cognitive and neural substrata supporting this capacity are a matter of active research and discussion. In neurolinguistics, this capacity is usually mapped to the ventral portions of Brodmann’s area 44 (BA44), and its interactions with the posterior Superior Temporal Sulcus (Fitch, 2017; Friederici, 2017; Milne et al., 2016). Interestingly, these two regions are connected by a fiber tract, called the Arcuate Fasciculus (AF), which is exceptionally well-developed in humans (Rilling et al., 2008). The available data suggests the hypothesis that the human ability to represent linguistic hierarchy evolved over a general sequence-processing machinery already available in the primate brain, to which a highly-developed AF was added (Wilson et al., 2017). Some extended this framework to music and action, where hierarchical processing also recruits regions within the Inferior Frontal Gyrus (Fadiga, Craighero, & D’Ausilio, 2009; Fitch & Martins, 2014). Here, we present a critical challenge to this hypothesis. Consider that there are two groups of domains in which humans can represent hierarchies. In the first, signals are composed of ordered sequences. Here, the serial order of the physical stimuli determines the perceived content or meaning (‘Mary likes John’ vs. ‘John Mary likes’). Even though linguistic hierarchies are not serial themselves, the signal through which they are communicated and decoded is. In the second group, the presentation order of the elements within the set does not necessarily determine the final structure (think of visual or spatial landscapes, or social structures). While the exact serial input order is crucial to determine the structure of ordered sequences, the same is not true for other hierarchical sets. This taxonomy is important because while BA44 and the AF seem important to process hierarchies within the first group, they are mostly absent in the second (Kumaran, Melo, & Düzel, 2012; Ligneul, Obeso, Ruff, & Dreher, 2016; Martins et al., 2014). The human ability to represent hierarchies in the visual, spatial and social domains is not supported by these mechanisms but rather by the hippocampus, medial Prefrontal cortex, and other structures. The same has been demonstrated for semantic hierarchies (Neville, et al, 2017). Taken together, these observations yield a logical puzzle: 1. Primates have a general system to process non-hierarchical sequences. 2. The emergence of the human BA44 and AF allowed for the capacity to represent hierarchies to evolve in language. 3. The human ability to represent hierarchies in some domains does not activate the brain areas connected via the AF. There are two ways to solve this puzzle: The first is to assume that the capacity to represent hierarchies evolved several times, once within language, and for other domains in other time periods. The second entails that the capacity to process hierarchies was first present in the visual, spatial and social domains and then specific changes in BA44 and AF made this capacity available for language (or in general for domains hinging on specific serial order of the input). In either case, BA 44 and AF seem to be important to process complex structured sequences, but not hierarchies in general. On the one hand, this neural system might be involved in the core generative capacity for hierarchical processing, but only in language. On the other hand, it might connect a previously available capacity to represent sets of sets with a robust capacity to parse sequential information. The latter would be especially important when sequences contain hierarchical relations between elements that are distant in the serial order

Interactions between cardiac activity and conscious somatosensory perception

Fluctuations in the heart's activity can modulate the access of external stimuli to consciousness. The link between perceptual awareness and cardiac signals has been investigated mainly in the visual and auditory domain. Here, we investigated whether the phase of the cardiac cycle and the prestimulus heart rate influence conscious somatosensory perception. We also tested how conscious detection of somatosensory stimuli affects the heart rate. Electrocardiograms (ECG) of 33 healthy volunteers were recorded while applying near‐threshold electrical pulses at a fixed intensity to the left index finger. Conscious detection was not uniformly distributed across the cardiac cycle but significantly higher in diastole than in systole. We found no evidence that the heart rate before a stimulus influenced its detection, but hits (correctly detected somatosensory stimuli) led to a more pronounced cardiac deceleration than misses. Our findings demonstrate interactions between cardiac activity and conscious somatosensory perception, which highlights the importance of internal bodily states for sensory processing beyond the auditory and visual domain

The impact of ischemic stroke on connectivity gradients

The functional organization of the brain can be represented as a low-dimensional space that reflects its macroscale hierarchy. The dimensions of this space, described as connectivity gradients, capture the similarity of areas' connections along a continuous space. Studying how pathological perturbations with known effects on functional connectivity affect these connectivity gradients provides support for their biological relevance. Previous work has shown that localized lesions cause widespread functional connectivity alterations in structurally intact areas, affecting a network of interconnected regions. By using acute stroke as a model of the effects of focal lesions on the connectome, we apply the connectivity gradient framework to depict how functional reorganization occurs throughout the brain, unrestricted by traditional definitions of functional network boundaries. We define a three-dimensional connectivity space template based on functional connectivity data from healthy controls. By projecting lesion locations into this space, we demonstrate that ischemic strokes result in dimension-specific alterations in functional connectivity over the first week after symptom onset. Specifically, changes in functional connectivity were captured along connectivity Gradients 1 and 3. The degree of functional connectivity change was associated with the distance from the lesion along these connectivity gradients (a measure of functional similarity) regardless of the anatomical distance from the lesion. Together, these results provide support for the biological validity of connectivity gradients and suggest a novel framework to characterize connectivity alterations after stroke

Neurophysiophenomenology – predicting emotional arousal from brain arousal in a virtual reality roller coaster

Arousal is a core affect constituted of both bodily and subjective states that prepares an agent to respond to events of the natural environment. While the peripheral physiological components of arousal have been examined also under naturalistic conditions, its neural correlates were suggested mainly on the basis of simplifed experimental designs.   We used virtual reality (VR) to present a highly immersive and contextually rich scenario of roller coaster rides to evoke naturalistic states of emotional arousal. Simultaneously, we recorded EEG to validate the suggested neural correlates of arousal in alpha frequency oscillations (8-12Hz) over temporo-parietal cortical areas. To fnd the complex link between these alpha components and the participants’ continuous subjective reports of arousal, we employed a set of complementary analytical methods coming from machine learning and deep learning

Intrinsic connectivity changes mediate the beneficial effect of cardiovascular exercise on sustained visual attention

Cardiovascular exercise (CE) is an evidence-based healthy lifestyle strategy. Yet, little is known about its effects on brain and cognition in young adults. Furthermore, evidence supporting a causal path linking CE to human cognitive performance via neuroplasticity is currently lacking. To understand the brain networks that mediate the CE-cognition relationship, we conducted a longitudinal, controlled trial with healthy human participants to compare the effects of a 2-week CE intervention against a non-CE control group on cognitive performance. Concomitantly, we used structural and functional magnetic resonance imaging to investigate the neural mechanisms mediating between CE and cognition. On the behavioral level, we found that CE improved sustained attention, but not processing speed or short-term memory. Using graph theoretical measures and statistical mediation analysis, we found that a localized increase in eigenvector centrality in the left middle frontal gyrus, probably reflecting changes within an attention-related network, conveyed the effect of CE on cognition. Finally, we found CE-induced changes in white matter microstructure that correlated with intrinsic connectivity changes (intermodal correlation). These results suggest that CE is a promising intervention strategy to improve sustained attention via brain plasticity in young, healthy adults

Dopaminergic modulation of local non-oscillatory activity and global-network properties in Parkinson’s disease: An EEG study

Dopaminergic medication for Parkinson’s disease (PD) modulates neuronal oscillations and functional connectivity (FC) across the basal ganglia-thalamic-cortical circuit. However, the non-oscillatory component of the neuronal activity, potentially indicating a state of excitation/inhibition balance, has not yet been investigated and previous studies have shown inconsistent changes of cortico-cortical connectivity as a response to dopaminergic medication. To further elucidate changes of regional non-oscillatory component of the neuronal power spectra, FC, and to determine which aspects of network organization obtained with graph theory respond to dopaminergic medication, we analyzed a resting-state electroencephalography (EEG) dataset including 15 PD patients during OFF and ON medication conditions. We found that the spectral slope, typically used to quantify the broadband non-oscillatory component of power spectra, steepened particularly in the left central region in the ON compared to OFF condition. In addition, using lagged coherence as a FC measure, we found that the FC in the beta frequency range between centro-parietal and frontal regions was enhanced in the ON compared to the OFF condition. After applying graph theory analysis, we observed that at the lower level of topology the node degree was increased, particularly in the centro-parietal area. Yet, results showed no significant difference in global topological organization between the two conditions: either in global efficiency or clustering coefficient for measuring global and local integration, respectively. Interestingly, we found a close association between local/global spectral slope and functional network global efficiency in the OFF condition, suggesting a crucial role of local non-oscillatory dynamics in forming the functional global integration which characterizes PD. These results provide further evidence and a more complete picture for the engagement of multiple cortical regions at various levels in response to dopaminergic medication in PD

Priming cardiovascular exercise improves complex motor skill learning by affecting the trajectory of learning-related brain plasticity

In recent years, mounting evidence from animal models and studies in humans has accumulated for the role of cardiovascular exercise (CE) in improving motor performance and learning. Both CE and motor learning may induce highly dynamic structural and functional brain changes, but how both processes interact to boost learning is presently unclear. Here, we hypothesized that subjects receiving CE would show a different pattern of learning-related brain plasticity compared to non-CE controls, which in turn associates with improved motor learning. To address this issue, we paired CE and motor learning sequentially in a randomized controlled trial with healthy human participants. Specifically, we compared the effects of a 2-week CE intervention against a non-CE control group on subsequent learning of a challenging dynamic balancing task (DBT) over 6 consecutive weeks. Structural and functional MRI measurements were conducted at regular 2-week time intervals to investigate dynamic brain changes during the experiment. The trajectory of learning-related changes in white matter microstructure beneath parieto-occipital and primary sensorimotor areas of the right hemisphere differed between the CE vs. non-CE groups, and these changes correlated with improved learning of the CE group. While group differences in sensorimotor white matter were already present immediately after CE and persisted during DBT learning, parieto-occipital effects gradually emerged during motor learning. Finally, we found that spontaneous neural activity at rest in gray matter spatially adjacent to white matter findings was also altered, therefore indicating a meaningful link between structural and functional plasticity. Collectively, these findings may lead to a better understanding of the neural mechanisms mediating the CE-learning link within the brain