Basile Pinsard

The challenge of mapping the human connectome based on diffusion tractography

Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations.Though tractography is widely used, it has not been systematically validated. Here, authors report results from 20 groups showing that many tractography algorithms produce both valid and invalid bundles.

Tractography-based connectomes are dominated by false-positive connections

Fiber tractography based on non-invasive diffusion imaging is at the heart of connectivity studies of the human brain. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain dataset with ground truth white matter tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. While most state-of-the-art algorithms reconstructed 90% of ground truth bundles to at least some extent, on average they produced four times more invalid than valid bundles. About half of the invalid bundles occurred systematically in the majority of submissions. Our results demonstrate fundamental ambiguities inherent to tract reconstruction methods based on diffusion orientation information, with critical consequences for the approach of diffusion tractography in particular and human connectivity studies in general.

Resting state networks' corticotopy: the dual intertwined rings architecture.

How does the brain integrate multiple sources of information to support normal sensorimotor and cognitive functions? To investigate this question we present an overall brain architecture (called “the dual intertwined rings architecture”) that relates the functional specialization of cortical networks to their spatial distribution over the cerebral cortex (or “corticotopy”). Recent results suggest that the resting state networks (RSNs) are organized into two large families: 1) a sensorimotor family that includes visual, somatic, and auditory areas and 2) a large association family that comprises parietal, temporal, and frontal regions and also includes the default mode network. We used two large databases of resting state fMRI data, from which we extracted 32 robust RSNs. We estimated: (1) the RSN functional roles by using a projection of the results on task based networks (TBNs) as referenced in large databases of fMRI activation studies; and (2) relationship of the RSNs with the Brodmann Areas. In both classifications, the 32 RSNs are organized into a remarkable architecture of two intertwined rings per hemisphere and so four rings linked by homotopic connections. The first ring forms a continuous ensemble and includes visual, somatic, and auditory cortices, with interspersed bimodal cortices (auditory-visual, visual-somatic and auditory-somatic, abbreviated as VSA ring). The second ring integrates distant parietal, temporal and frontal regions (PTF ring) through a network of association fiber tracts which closes the ring anatomically and ensures a functional continuity within the ring. The PTF ring relates association cortices specialized in attention, language and working memory, to the networks involved in motivation and biological regulation and rhythms. This “dual intertwined architecture” suggests a dual integrative process: the VSA ring performs fast real-time multimodal integration of sensorimotor information whereas the PTF ring performs multi-temporal integration (i.e., relates past, present, and future representations at different temporal scales).

Reactivation or transformation? Motor memory consolidation associated with cerebral activation time-locked to sleep spindles

Motor memory consolidation is thought to depend on sleep-dependent reactivation of brain areas recruited during learning. However, up to this point, there has been no direct evidence to support this assertion in humans, and the physiological processes supporting such reactivation are unknown. Here, simultaneous electroencephalographic and functional magnetic resonance imaging (EEG-fMRI) recordings were conducted during post-learning sleep to directly investigate the spindle-related reactivation of a memory trace formed during motor sequence learning (MSL), and its relationship to overnight enhancement in performance (reflecting consolidation). We show that brain regions within the striato-cerebello-cortical network recruited during training on the MSL task, and in particular the striatum, were also activated during sleep, time-locked to spindles. Interestingly, the consolidated trace in the striatum was not simply strengthened, but was transformed/reorganized from rostrodorsal (associative) to caudoventral (sensorimotor) subregions. Moreover, the degree of the reactivation was correlated with overnight improvements in performance. Altogether, the present findings demonstrate that striatal reactivation linked to sleep spindles in the post-learning night, is related to motor memory consolidation.

Transient synchronization of hippocampo-striato-thalamo-cortical networks during sleep spindle oscillations induces motor memory consolidation

ABSTRACT Sleep benefits motor memory consolidation. This mnemonic process is thought to be mediated by thalamo‐cortical spindle activity during NREM‐stage2 sleep episodes as well as changes in striatal and hippocampal activity. However, direct experimental evidence supporting the contribution of such sleep‐dependent physiological mechanisms to motor memory consolidation in humans is lacking. In the present study, we combined EEG and fMRI sleep recordings following practice of a motor sequence learning (MSL) task to determine whether spindle oscillations support sleep‐dependent motor memory consolidation by transiently synchronizing and coordinating specialized cortical and subcortical networks. To that end, we conducted EEG source reconstruction on spindle epochs in both cortical and subcortical regions using novel deep‐source localization techniques. Coherence‐based metrics were adopted to estimate functional connectivity between cortical and subcortical structures over specific frequency bands. Our findings not only confirm the critical and functional role of NREM‐stage2 sleep spindles in motor skill consolidation, but provide first‐time evidence that spindle oscillations [11–17 Hz] may be involved in sleep‐dependent motor memory consolidation by locally reactivating and functionally binding specific task‐relevant cortical and subcortical regions within networks including the hippocampus, putamen, thalamus and motor‐related cortical regions.

Re-stepping into the same river: competition problem rather than a reconsolidation failure in an established motor skill

Animal models suggest that consolidated memories return to their labile state when reactivated and need to be restabilized through reconsolidation processes to persist. Consistent with this notion, post-reactivation pharmacological protein synthesis blockage results in mnemonic failure in hippocampus-dependent memories. It has been proposed that, in humans, post-reactivation experience with a competitive task can also interfere with memory restabilization. However, several studies failed to induce performance deficit implementing this approach. Moreover, even upon effective post-reactivation interference, hindered performance may rapidly recover, raising the possibility of a retrieval rather than a storage deficit. Here, to address these issues in procedural memory domain, we used new learning to interfere with restabilization of motor memory acquired through training on a sequence of finger movements. Only immediate post-reactivation interference was associated with the loss of post-training delayed gains in performance, a hallmark of motor sequence memory consolidation. We also demonstrate that such performance deficit more likely indicates a genuine memory impairment rather than a retrieval failure. However, the reconsolidation view on a reactivation-induced plasticity is not supported. Instead, our results are in line with the integration model according to which new knowledge acquired during the interfering experience, is integrated through its consolidation creating memory competition.

Age-Related Shift in Neuro-Activation during a Word-Matching Task

Growing evidence from the neuroscience of aging suggests that executive function plays a pivotal role in maintaining semantic processing performance. However, the presumed age-related activation changes that sustain executive semantic processing remain poorly understood. The aim of this study was to explore the executive aspects of semantic processing during a word-matching task with regard to age-related neuro-functional reorganization, as well as to identify factors that influence executive control profiles. Twenty younger and 20 older participants underwent fMRI scanning. The experimental task was based on word-matching, wherein visual feedback was used to instruct participants to either maintain or switch a semantic-matching rule. Response time and correct responses were assessed for each group. A battery of cognitive tests was administrated to all participants and the older group was divided into two subgroups based on their cognitive control profiles. Even though the percentage of correct responses was equivalent in the task performance between both groups and within the older groups, neuro-functional activation differed in frontoparietal regions with regards to age and cognitive control profiles. A correlation between behavioral measures (correct responses and response times) and brain signal changes was found in the left inferior parietal region in older participants. Results indicate that the shift in age-related activation from frontal to parietal regions can be viewed as another form of neuro-functional reorganization. The greater reliance on inferior parietal regions in the older compared to the younger group suggests that the executive control system is still efficient and sustains semantic processing in the healthy aging brain. Additionally, cognitive control profiles underlie executive ability differences in healthy aging appear to be associated with specific neuro-functional reorganization throughout frontal and parietal regions. These findings demonstrate that changes in neural support for executive semantic processing during a word-matching task are not only influenced by age, but also by cognitive control profile.

Age-Related Brain Activation Changes during Rule Repetition in Word-Matching

Objective: The purpose of this study was to explore the age-related brain activation changes during a word-matching semantic-category-based task, which required either repeating or changing a semantic rule to be applied. In order to do so, a word-semantic rule-based task was adapted from the Wisconsin Sorting Card Test, involving the repeated feedback-driven selection of given pairs of words based on semantic category-based criteria. Method: Forty healthy adults (20 younger and 20 older) performed a word-matching task while undergoing a fMRI scan in which they were required to pair a target word with another word from a group of three words. The required pairing is based on three word-pair semantic rules which correspond to different levels of semantic control demands: functional relatedness, moderately typical-relatedness (which were considered as low control demands), and atypical-relatedness (high control demands). The sorting period consisted of a continuous execution of the same sorting rule and an inferred trial-by-trial feedback was given. Results: Behavioral performance revealed increases in response times and decreases of correct responses according to the level of semantic control demands (functional vs. typical vs. atypical) for both age groups (younger and older) reflecting graded differences in the repetition of the application of a given semantic rule. Neuroimaging findings of significant brain activation showed two main results: (1) Greater task-related activation changes for the repetition of the application of atypical rules relative to typical and functional rules, and (2) Changes (older > younger) in the inferior prefrontal regions for functional rules and more extensive and bilateral activations for typical and atypical rules. Regarding the inter-semantic rules comparison, only task-related activation differences were observed for functional > typical (e.g., inferior parietal and temporal regions bilaterally) and atypical > typical (e.g., prefrontal, inferior parietal, posterior temporal, and subcortical regions). Conclusion: These results suggest that healthy cognitive aging relies on the adaptive changes of inferior prefrontal resources involved in the repetitive execution of semantic rules, thus reflecting graded differences in support of task demands.

Consolidation alters motor sequence-specific distributed representations

FMRI studies investigating the acquisition of sequential motor skills in humans have revealed learning-related functional reorganizations of the cortico-striatal and cortico-cerebellar motor systems in link with the hippocampus. Yet, the functional significance of these activity level changes is not fully understood as they convey the evolution of both sequence-specific knowledge and unspecific task expertise. Moreover, these changes do not specifically assess the occurrence of learning-related plasticity. To address these issues, we investigated local circuits tuning to sequence-specific information using multivariate distances between patterns evoked by consolidated or newly acquired motor sequences production. Results reveal that representations in dorsolateral striatum, prefrontal and secondary motor cortices are greater when executing consolidated sequences than untrained ones. By contrast, sequence representations in the hippocampus and dorsomedial striatum are less engaged. Our findings show, for the first time in humans, that complementary sequence-specific motor representations evolve distinctively during critical phases of skill acquisition and consolidation.

COMPARATIVE LONGITUDINAL CHANGE OF FUNCTIONAL CONNECTIVITY, DIFFUSION AND STRUCTURAL MRI MARKERS IN A PRODROMAL/MILD ALZHEIMER’S DISEASE POPULATION

eal, QC, Canada; Montreal Neurological Institute, Montreal, QC, Canada; Universit e de Montr eal, Montr eal, QC, Canada; 9 Centre for Studies on Prevention of Alzheimer’s Disease (StoP-AD Centre), Douglas Mental Health Institute, Verdun, QC, Canada. Contact e-mail: tharick.alipascoal@mail.mcgill.ca Background: Although individuals presenting abnormalities of both amyloid-b (Ab) deposition and neuronal injury are especially vulnerable to disease progression, the regional association of these two pathologies as a determinant of cognitive decline remains unclear. Here, we tested, at voxel level, whether co-localized interactions between abnormal Ab and brain hypometabolism determine subsequent cognitive decline in individuals with mild cognitive impairment (MCI).Methods:In order to test this framework, we assessed 309 amnesticMCI individuals formADNI cohort who underwent [F]florbetapir and [F]FDG positron emission tomography (PET) at baseline and a general cognitive performance testing (mini-mental state examination (MMSE)) at baseline and at 2-year follow-up visits (Table 1). First, cut-off analysis at every voxel was performed for both ligands, contrasting cognitively normal (n1⁄4209) and Alzheimer’s disease (AD) (n1⁄481) individuals, based on the best operating point of the receiver operating characteristic (ROC) curve. Second, parametrical maps of normality and abnormality at every voxel were generated for both ligands using the aforementioned cut-off maps for each MCI individual. Finally, using Voxel-stats, a voxel-based interaction model was built to assess the brain regions in which the coexistence of an abnormal [F]florbetapir and [F]FDG standardized uptake ratios (SUVR) interacted to determine an increased rate of cognitive decline over 2 years, as described in the formula: DMMSE 1⁄4 b0 + b1(florbetapir SUVR (0,1)) + b2(FDG SUVR(0,1)) + b3(florbetapir SUVR (0,1)*FDG SUVR (0,1)) + covariates + error. The statistical parametric maps were adjusted for age, gender, education, APOE ε4 status, baselineMMSEand corrected formultiple testing at a threshold ofP< 0.05.Results:The voxel-based interactionmodel revealed that a synergistic effect between abnormal [F]florbetapir and [F]FDG SUVRs in the precuneus and posterior cingulate cortices determined a faster rate of cognitive decline in amnestic MCI individuals (P < 0.05) (Figure 1). Conclusions:Our results support the notion that the regional synergism between brain Ab and metabolic injury is associated with subsequent clinical progression in patients with MCI.