SeSBAT: Single Subject Brain Analysis Toolbox. Application to Huntington's Disease as a Preliminary Study

Magnetic resonance imaging (MRI) biomarkers require complex processing routines that are time-consuming and labor-intensive for clinical users. The Single Subject Brain Analysis Toolbox (SeSBAT) is a fully automated MATLAB toolbox with a graphical user interface (GUI) that offers standardized and optimized protocols for the pre-processing and analysis of anatomical MRI data at the single-subject level. In this study, the two-fold strategy provided by SeSBAT is illustrated through its application on a cohort of 42 patients with Huntington's disease (HD), in pre-manifest and early manifest stages, as a suitable model of neurodegenerative processes. On the one hand, hypothesis-driven analysis can be used to extract biomarkers of neurodegeneration in specific brain regions of interest (ROI-based analysis). On the other hand, an exploratory voxel-based morphometry (VBM) approach can detect volume changes due to neurodegeneration throughout the whole brain (whole-brain analysis). That illustration reveals the potential of SeSBAT in providing potential prognostic biomarkers in neurodegenerative processes in clinics, which could be critical to overcoming the limitations of current qualitative evaluation strategies, and thus improve the diagnosis and monitoring of neurodegenerative disorders. Furthermore, the importance of the availability of tools for characterization at the single-subject level has been emphasized, as there is high interindividual variability in the pattern of neurodegeneration. Thus, tools like SeSBAT could pave the way towards more effective and personalized medicine

Words as anchors: known words facilitate statistical learning

Can even a handful of newly learned words help to find further word candidates in a novel spoken language? This study shows that the statistical segmentation of words from speech stream by adults is facilitated by the presence of known words in the stream. This facilitatory effect is immediate as the known words were acquired only minutes before the onset of the speech stream. Our results demonstrate an interplay between top-down lexical segmentation and bottom-up statistical learning, in line with infant research suggesting that integration of multiple cues facilitates early language learning. The ability to simultaneously benefit from both types of word segmentation cues appears to be present through adulthood and can thus contribute to second language learning

Neural mechanisms underlying adaptive actions after slips

An increase in cognitive control has been systematically observed in responses produced immediately after the commission of an error. Such responses show a delay in reaction time (post-error slowing) and an increase in accuracy. To characterize the neurophysiological mechanism involved in the adaptation of cognitive control, we examined oscillatory electrical brain activity by electroencephalogram and its corresponding neural network by event-related functional magnetic resonance imaging in three experiments. We identified a new oscillatory thetabeta component related to the degree of post-error slowing in the correct responses following an erroneous trial. Additionally, we found that the activity of the right dorsolateral prefrontal cortex, the right inferior frontal cortex, and the right superior frontal cortex was correlated with the degree of caution shown in the trial following the commission of an error. Given the overlap between this brain network and the regions activated by the need to inhibit motor responses in a stop-signal manipulation, we conclude that the increase in cognitive control observed after the commission of an error is implemented through the participation of an inhibitory mechanism

Feedback-related Brain Potential Activity Complies with Basic Assumptions of Associative Learning Theory

Feedback-related negativity (FRN) is an ERP component that distinguishes positive from negative feedback. FRN has been hypothesized to be the product of an error signal that may be used to adjust future behavior. In addition, associative learning models assume that the trial-to-trial learning of cueoutcome mappings involves the minimization of an error term. This study evaluated whether FRN is a possible electrophysiological correlate of this error term in a predictive learning task where human subjects were asked to learn different cueoutcome relationships. Specifically, we evaluated the sensitivity of the FRN to the course of learning when different stimuli interact or compete to become a predictor of certain outcomes. Importantly, some of these cues were blocked by more informative or predictive cues (i.e., the blocking effect). Interestingly, the present results show that both learning and blocking affect the amplitude of the FRN component. Furthermore, independent analyses of positive and negative feedback event-related signals showed that the learning effect was restricted to the ERP component elicited by positive feedback. The blocking test showed differences in the FRN magnitude between a predictive and a blocked cue. Overall, the present results show that ERPs that are related to feedback processing correspond to the main predictions of associative learning models.

Functional neuroanatomy of meaning acquisition from context

An important issue in language learning is how new words are integrated in the brain representations that sustain language processing. To identify the brain regions involved in meaning acquisition and word learning, we conducted a functional magnetic resonance imaging study. Young participants were required to deduce the meaning of a novel word presented within increasingly constrained sentence contexts that were read silently during the scanning session. Inconsistent contexts were also presented in which no meaning could be assigned to the novel word. Participants showed meaning acquisition in the consistent but not in the inconsistent condition. A distributed brain network was identified comprising the left anterior inferior frontal gyrus (BA 45), the middle temporal gyrus (BA 21), the parahippocampal gyrus, and several subcortical structures (the thalamus and the striatum). Drawing on previous neuroimaging evidence, we tentatively identify the roles of these brain areas in the retrieval, selection, and encoding of the meaning

Speech segmentation is facilitated by visual cues

Evidence from infant studies indicates that language learning can be facilitated by multimodal cues. We extended this observation to adult language learning by studying the effects of simultaneous visual cues (nonassociated object images) on speech segmentation performance. Our results indicate that segmentation of new words from a continuous speech stream is facilitated by simultaneous visual input that it is presented at or near syllables that exhibit the low transitional probability indicative of word boundaries. This indicates that temporal audio-visual contiguity helps in directing attention to word boundaries at the earliest stages of language learning. Off-boundary or arrhythmic picture sequences did not affect segmentation performance, suggesting that the language learning system can effectively disregard noninformative visual information. Detection of temporal contiguity between multimodal stimuli may be useful in both infants and second-language learners not only for facilitating speech segmentation, but also for detecting word-object relationships in natural environments

Implicit but not explicit extinction to threat‐conditioned stimulus prevents spontaneous recovery of threat‐potentiated startle responses in humans

INTRODUCTION: It has long been posited that threat learning operates and forms under an affective and a cognitive learning system that is supported by different brain circuits. A primary drawback in exposure‐based therapies is the high rate of relapse that occurs when higher order areas fail to inhibit responses driven by the defensive circuit. It has been shown that implicit exposure of fearful stimuli leads to a long‐lasting reduction in avoidance behavior in patients with phobia. Despite the potential benefits of this approach in the treatment of phobias and posttraumatic stress disorder, implicit extinction is still underinvestigated. METHODS: Two groups of healthy participants were threat conditioned. The following day, extinction training was conducted using a stereoscope. One group of participants was explicitly exposed with the threat‐conditioned image, while the other group was implicitly exposed using a continuous flash suppression (CFS) technique. On the third day, we tested the spontaneous recovery of defensive responses using explicit presentations of the images. RESULTS: On the third day, we found that only the implicit extinction group showed reduced spontaneous recovery of defensive responses to the threat‐conditioned stimulus, measured by threat‐potentiated startle responses but not by the electrodermal activity. CONCLUSION: Our results suggest that implicit extinction using CFS might facilitate the modulation of the affective component of fearful memories, attenuating its expression after 24 hr. The limitations of the CFS technique using threatful stimuli urge the development of new strategies to improve implicit presentations and circumvent such limitations. Our study encourages further investigations of implicit extinction as a potential therapeutic target to further advance exposure‐based psychotherapies

Neurocognitive signatures of phonemic sequencing in expert backward speakers

Despite its prolific growth, neurolinguistic research on phonemic sequencing has largely neglected the study of individuals with highly developed skills in this domain. To bridge this gap, we report multidimensional signatures of two experts in backward speech, that is, the capacity to produce utterances by reversing the order of phonemes while retaining their identity. Our approach included behavioral assessments of backward and forward speech alongside neuroimaging measures of voxel-based morphometry, diffusion tensor imaging, and resting-state functional connectivity. Relative to controls, both backward speakers exhibited behavioral advantages for reversing words and sentences of varying complexity, irrespective of working memory skills. These patterns were accompanied by increased grey matter volume, higher mean diffusivity, and enhanced functional connectivity along dorsal and ventral stream regions mediating phonological and other linguistic operations, with complementary support of areas subserving associative-visual and domain-general processes. Still, the specific loci of these neural patterns differed between both subjects, suggesting individual variability in the correlates of expert backward speech. Taken together, our results offer new vistas on the domain of phonemic sequencing, while illuminating neuroplastic patterns underlying extraordinary language abilities

Tau Protein is Associated with Longitudinal Memory Decline in Cognitively Healthy Subjects with Normal Alzheimer's Disease Cerebrospinal Fluid Biomarker Levels

Background: We investigated a sample of cognitively healthy subjects with normal Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker levels to identify the earliest variables related to longitudinal memory changes. Objective: Employing a new highly demanding learning and memory test (the Ancient Farming Equipment Test; AFE-T), we aimed to investigate whether a biomarker related to neurodegeneration (i.e., CSF tau) was associated with longitudinal memory decline. Methods: Thirty-two cognitively and biologically normal (CBN) subjects underwent MRI, neuropsychological assessment, and the AFE-T at baseline and 18 months later. To explore the relationship between cognitive performance and relevant factors, a linear model was set up. For a secondary analysis that further explore the effect of tau, the subjects were divided into CBN-Tau↓ (tau  228.64 pg/ml; n = 16). We also performed voxel-based morphometry (VBM) to identify regions of grey matter volume that would predict both baseline and longitudinal cognitive performance. Results: Our main finding was an association between CSF tau and longitudinal memory decline measured with AFE-T (B = -0.17, p < 0.05; r = -0.414; p < 0.01), and further analyses showed different evolvement between subgroups, with an accelerated decline in individuals with higher tau (F(1,31) = 8.37; p < 0.01). VBM results suggested that AFE-T performance is related to grey matter volume in a medial temporal, middle frontal, and posterior cerebellar network at baseline, and that there are strategic brain areas driving the longitudinal cognitive changes. Conclusions: The present findings provide evidence for structural and biological markers linked to cognitive aging by highlighting the role of tau, a marker of neurodegeneration, which can be related with the earliest memory changes in healthy subjects

Specific patterns of brain alterations underlie distinct clinical profiles in Huntington's disease

Huntington's disease (HD) is a genetic neurodegenerative disease which involves a triad of motor, cognitive and psychiatric disturbances. However, there is great variability in the prominence of each type of symptom across individuals. The neurobiological basis of such variability remains poorly understood but would be crucial for better tailored treatments. Multivariate multimodal neuroimaging approaches have been successful in disentangling these profiles in other disorders. Thus we applied for the first time such approach to HD. We studied the relationship between HD symptom domains and multimodal measures sensitive to grey and white matter structural alterations. Forty-three HD gene carriers (23 manifest and 20 premanifest individuals) were scanned and underwent behavioural assessments evaluating motor, cognitive and psychiatric domains. We conducted a multimodal analysis integrating different structural neuroimaging modalities measuring grey matter volume, cortical thickness and white matter diffusion indices - fractional anisotropy and radial diffusivity. All neuroimaging measures were entered into a linked independent component analysis in order to obtain multimodal components reflecting common inter-subject variation across imaging modalities. The relationship between multimodal neuroimaging independent components and behavioural measures was analysed using multiple linear regression. We found that cognitive and motor symptoms shared a common neurobiological basis, whereas the psychiatric domain presented a differentiated neural signature. Behavioural measures of different symptom domains correlated with different neuroimaging components, both the brain regions involved and the neuroimaging modalities most prominently associated with each type of symptom showing differences. More severe cognitive and motor signs together were associated with a multimodal component consisting in a pattern of reduced grey matter, cortical thickness and white matter integrity in cognitive and motor related networks. In contrast, depressive symptoms were associated with a component mainly characterised by reduced cortical thickness pattern in limbic and paralimbic regions. In conclusion, using a multivariate multimodal approach we were able to disentangle the neurobiological substrates of two distinct symptom profiles in HD: one characterised by cognitive and motor features dissociated from a psychiatric profile. These results open a new view on a disease classically considered as a uniform entity and initiates a new avenue for further research considering these qualitative individual differences