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Apathy, a prevalent feature in neurological disorders including Huntington's disease (HD), is characterized by a reduction in goal-directed behavior across cognitive, auto-activation (i.e., self-activating thoughts/behavior), and emotional domains. Nonetheless, current diagnostic criteria are incapable of distinguishing multidimensional apathy profiles. Meanwhile, the short-Lille Apathy Rating Scale (LARS-s) bears potential as an operative diagnostic tool to disentangle apathy dimensions in clinical practice. The present study thereby examines the psychometric properties and factor structure of the LARS-s to tap into apathy profiles and their underlying neural correlates in HD.Forty HD individuals were scanned and evaluated for apathy using the LARS-s, assessed for reliability and validity in HD, and the short-Problem Behavior Assessment (PBA-s). To study the dimensional structure of apathy, principal component analysis (PCA) of the LARS-s was implemented. Resulting factors were associated with gray matter volume through whole-brain voxel-based morphometry.The LARS-s demonstrated satisfactory psychometric properties, sharing convergent validity with PBA-s apathy and discriminant validity against depression. PCA resulted in three factors representative of apathy profiles across cognitive, auto-activation, and emotional domains. Anatomically, global apathy was significantly related with large-scale motor, cognitive, and limbic networks. Exploratory analyses of apathy profiles revealed correspondence between each factor and distinct cortical and subcortical nodes.The LARS-s is capable of capturing the multidimensional spectrum of apathy. At the same time, apathy profiles in HD are underpinned by functionally diverse neural networks. Such findings promote the continued study of apathy domains to pinpoint personalized therapeutic targets in neurologic disorders in addition to HD.

BackgroundDespite its impact on daily life, impulsivity in Huntington’s disease (HD) is understudied as a neuropsychiatric symptom. Our aim is to characterize temporal impulsivity in HD, evaluated through a Delay Discounting (DD) task, and to disentangle the underlying white matter correlates in HD.MethodsForty-seven HD individuals and thirty-six healthy controls conducted a DD task and complementary Sensitivity to Punishment and Sensitivity to Reward (SR) Questionnaire. Diffusion-tensor imaging was employed to characterize the structural connectivity of two limbic tracts: the uncinate fasciculus (UF) and the accumbofrontal tract (NAcc-OFC). Multiple linear regression analyses were applied to analyze the relationship between impulsive behavior and white-matter microstructural integrity.ResultsAltered structural connectivity in both the NAcc-OFC and UF in HD individuals was observed. Moreover, the variability in structural connectivity of these tracts was associated with the individual differences in temporal impulsivity. Specifically, increased structural connectivity in the right NAcc-OFC predicted increased temporal impulsivity, while reduced connectivity in the left UF was associated with higher temporal impulsivity scores.LimitationsOther cognitive mechanisms and white matter tracts may play a role in temporal impulsivity.ConclusionsThis study provides evidence that individual differences observed in impulsivity may be explained by variability in limbic fronto-striatal tracts. We emphasize the importance of investigating the spectrum of impulsivity in HD, less prevalent than other psychiatric features, but impacting the quality of life of patients and their caregivers.

Purpose Our aim was to study the microstructural architecture of the contralateral hippocampus to the affected side in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) and its relation with surgical outcome. Method We included 33 consecutive patients evaluated in our epilepsy surgery program during a five-year period. They underwent a presurgical MRI with volumetric T1 and diffusion weighted sequences. 22 patients with TLE-HS (13 women, 12 right TLE-HS) were finally selected. Median follow-up after surgery was 6.25 years (4.5–8.83 years). We segmented the hippocampal subfields of the contralateral hippocampus using FreeSurfer and calculated the fractional anisotropy (FA) and the mean diffusivity (MD) of each subfield. We also scanned 18 healthy age-matched controls. Results After surgery, 50 % of the patients (n = 11) remained seizure-free (SF) following surgery. Comparing non-SF to SF patients, the MD showed increased values of the CA1 (p = 0.035), the molecular layer (p = 0.010) and the dentate gyrus (p = 0.041) in the healthy hippocampus. Using a cut-off point for a survival analysis, we found that patients with lower values of MD of the molecular layer and the CA1 remained SF during long-term post-operative follow-up (p Conclusions The contralateral hippocampal internal microstructure may have be implicated in post-surgery seizure freedom in patients with TLE-HS.

Significant advances have been made by identifying the levels of synchrony of the underlying dynamics of a given brain state. This research has demonstrated that non-conscious dynamics tend to be more synchronous than in conscious states, which are more asynchronous. Here we go beyond this dichotomy to demonstrate that different brain states are underpinned by dissociable spatiotemporal dynamics. We investigated human neuroimaging data from different brain states (resting state, meditation, deep sleep and disorders of consciousness after coma). The model-free approach was based on Kuramoto’s turbulence framework using coupled oscillators. This was extended by a measure of the information cascade across spatial scales. Complementarily, the model-based approach used exhaustive in silico perturbations of whole-brain models fitted to these measures. This allowed studying of the information encoding capabilities in given brain states. Overall, this framework demonstrates that elements from turbulence theory provide excellent tools for describing and differentiating between brain states. A.E is supported by the HBP SGA3 Human Brain Project Specific Grant Agreement 3 (grant agreement no. 945539), funded by the EU H2020 FET Flagship programme. Y.S.P is supported by European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant 896354. G.D. is supported by the Spanish national research project (ref. PID2019-105772GB-I00 MCIU AEI) funded by the Spanish Ministry of Science, Innovation and Universities (MCIU), State Research Agency (AEI). M.L.K is supported by the Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117), and Centre for Eudaimonia and Human Flourishing at Linacre College funded by the Pettit and Carlsberg Foundations. The study was supported by the University and University Hospital of Liège, the Belgian National Funds for Scientific Research (FRS-FNRS), the European Space Agency (ESA) and the Belgian Federal Science Policy Office (BELSPO) in the framework of the PRODEX Programme, the BIAL Foundation, the Mind Science Foundation, the fund Generet of the King Baudouin Foundation, the Mind-Care foundation and AstraZeneca Foundation, the National Natural Science Foundation of China (Joint Research Project 81471100) and the European Foundation of Biomedical Research FERB Onlus. R.P is research fellow, O.G is research associate, and S.L is research director at FRS-FNRS. The authors thank all the patients and participants, and the entire staff of the Radiodiagnostic and Nuclear departments of the University Hospital of Liège.

Background Surgery may render temporal lobe epilepsy (TLE) patients seizure-free. However, TLE is a heterogenous entity and surgical prognosis varies between patients. Network-based biomarkers have been shown to be altered in TLE patients and hold promise for classifying TLE subtypes and improving pre-surgical prognosis. The aim of the present study is to investigate a network-based biomarker, the weighted degree of connectivity (wDC), on an individual level, and its relation to TLE subtypes and surgical prognosis. Methods Thirty unilateral TLE patients undergoing the same surgical procedure (anterior temporal resection) and 18 healthy controls were included. All patients were followed-up in the same center for a mean time of 6.85 years and classified as seizure-free (SF) and non seizure-free (non-SF). Using pre-surgical resting state functional MRI, whole brain wDC values for patients and controls were calculated. Then, we divided both temporal lobes in three Regions-of-interest (ROIs) -mesial, pole and lateral- as these areas are known to behave differently in seizure onset and propagation, delimiting different TLE profiles. The wDC values for the defined ROIs of each individual patient were compared with the healthy group. Results After surgery, 14 TLE patients remained SF. As a group, patients had higher wDC than controls in both the temporal pole (p p p p Conclusions This study provides a network-based presurgical biomarker that could pave the way towards personalized prediction. In patients with TLE undergoing anterior temporal resections, having an increased wDC at rest could be a signature of the epileptogenic area, and could help identifying those patients who would benefit most from surgery.

Recently, significant advances have been made by identifying the levels of synchronicity of the underlying dynamics of a given brain state. This research has demonstrated that unconscious dynamics tend to be more synchronous than those found in conscious states, which are more asynchronous. Here we go beyond this dichotomy to demonstrate that the different brain states are always underpinned by spatiotemporal chaos but with dissociable turbulent dynamics. We investigated human neuroimaging data from different brain states (resting state, meditation, deep sleep, and disorders of consciousness after coma) and were able to distinguish between them using complementary model-free and model-based measures of turbulent information transmission. Our model-free approach used recent advances describing a measure of information cascade across spatial scales using tools from turbulence theory. Complementarily, our model-based approach used exhaustive in silico perturbations of whole-brain models fitted to the empirical neuroimaging data, which allowed us to study the information encoding capabilities of the brain states. Overall, the current framework demonstrates that different levels of turbulent dynamics are fundamental for describing and differentiating between brain states.

Background HD is a suitable model to monitor the whole neurodegeneration process. Huntington’s disease (HD) affects primarily the striatum, but loss of white matter (WM) integrity and iron homeostasis disruption have been also described. These anomalies together with metabolite profiles could unveil the pathophysiologic mechanisms involved. Aims To assess the temporal and spatial progression of neurodegeneration on both anterior thalamic radiations (ATR). Methods Thirty-one HD gene carriers and twenty-four controls underwent neuropsychological evaluation and were scanned at 3T-MRI unit. A multimodal study was conducted to measure relaxometry, diffusivity and spectroscopy as proxies of iron, WM microstructure and metabolite composition, respectively. Three statistical approaches (average, segmental, along-the-tract) were performed, with MANOVA and post-hoc Tukey test to evaluate differences among groups and Pearson test to assess correlations. Results ATR disintegration began in premanifest individuals and progressed in extent and severity in manifest patients. WM damage was more extensive in the right ATR that could translate a higher vulnerability and showed a spatial gradient from subcortical to deep WM in favour of the dying-back hypothesis. Iron was increased in the left ATR in premanifest individuals that might uncover a dysregulated myelination or an abnormal ferritin accumulation. NAA and creatine decreased exclusively in manifest patients suggesting neuronal loss and mitochondrial dysfunction. Furthermore, imaging parameters could be used as biomarkers given their links with clinical scores. Conclusions The complex neurodegeneration pattern of ATR in HD can help to understand the pathophysiological mechanisms underlying HD progression. The multimodal approach and along-the-tract analysis allow for a more comprehensive evaluation of neurodegeneration.

In the past decades, there has been a growing scientific interest in characterizing neural correlates of meditation training. Nonetheless, the mechanisms underlying meditation remain elusive. In the present work, we investigated meditation-related changes in structural and functional connectivities (SC and FC, respectively). For this purpose, we scanned experienced meditators and control (naive) subjects using magnetic resonance imaging (MRI) to acquire structural and functional data during two conditions, resting-state and meditation (focused attention on breathing). In this way, we aimed to characterize and distinguish both short-term and long-term modifications in the brain’s structure and function. First, we performed a network-based analysis of anatomical connectivity. Then, to analyze the fMRI data, we calculated whole-brain effective connectivity (EC) estimates, relying on a dynamical network model to replicate BOLD signals’ spatio-temporal structure, akin to FC with lagged correlations. We compared the estimated EC, FC, and SC links as features to train classifiers to predict behavioral conditions and group identity. The whole-brain SC analysis revealed strengthened anatomical connectivity across large-scale networks for meditators compared to controls. We found that differences in SC were reflected in the functional domain as well. We demonstrated through a machine-learning approach that EC features were more informative than FC and SC solely. Using EC features we reached high performance for the condition-based classification within each group and moderately high accuracies when comparing the two groups in each condition. Moreover, we showed that the most informative EC links that discriminated between meditators and controls involved the same large-scale networks previously found to have increased anatomical connectivity. Overall, the results of our whole-brain model-based approach revealed a mechanism underlying meditation by providing causal relationships at the structure-function level.

Background We identify cognitive impairment and MRI structural brain changes in long-term oligodendroglial tumor survivors treated with radiation therapy (RT) alone (21%) or with chemotherapy (CT) (79%). Methods Oligodendroglial tumor patients (based on the World Health Organization [WHO] 2007 classification) who completed RT ± CT at least 2 years before the study initiation, were classified into 3 groups according to the time treatment was completed: Group 1 = 2–5 years (n = 22), Group 2 = 6–10 years (n = 13), and Group 3 >10 years (n = 13). All patients had a cross-sectional neuropsychological evaluation (n = 48) and a longitudinal volumetric analysis (gray matter [GM; n = 34]) between postsurgical and last follow-up MRI. White matter (WM) changes on MRI were assessed using a qualitative scale. Results There were no differences regarding tumor or treatment-related characteristics between groups. Six of 22 patients (27.3%) in Group 1; 5/13 (38.5%) in Group 2; and 9/13 (69.2%) in Group 3 had cognitive impairment that was considered severe in 3/22 patients (13.6%) in Group 1; 4/13 (30.8%) in Group 2; and 6/13 (46.2%) in Group 3. Patients in Groups 2 and 3 showed significant GM atrophy and more leukoencephalopathy than Group 1. Cognitive deficits were associated with brain atrophy and WM changes. Conclusions Long-term oligodendroglial tumor survivors who underwent standard RT ± CT treatment, mainly >5 years of its completion, present cognitive impairment, especially on memory and executive functions, associated with late GM and WM damage, thus highlighting the need of developing future strategies in patients with oligodendroglial tumor and long expected survival.

Background Apathy, a common neuropsychiatric disturbance in Huntington's disease (HD), is subserved by a complex neurobiological network. However, no study has yet employed a whole-brain approach to examine underlying regional vulnerabilities that may precipitate apathy changes over time. Objectives To identify whole-brain gray matter volume (GMV) vulnerabilities that may predict longitudinal apathy development in HD. Methods Forty-five HD individuals (31 female) were scanned and evaluated for apathy and other neuropsychiatric features using the short-Problem Behavior Assessment for a maximum total of six longitudinal visits (including baseline). In order to identify regions where changes in GMV may describe changes in apathy, we performed longitudinal voxel-based morphometry (VBM) on those 33 participants with a magnetic resonance imaging (MRI) scan on their second visit at 18 +/- 6 months follow-up (78 MRI datasets). We next employed a generalized linear mixed-effects model (N = 45) to elucidate whether initial and specific GMV may predict apathy development over time. Results Utilizing longitudinal VBM, we revealed a relationship between increases in apathy and specific GMV atrophy in the right middle cingulate cortex (MCC). Furthermore, vulnerability in the right MCC volume at baseline successfully predicted the severity and progression of apathy over time. Conclusions This study highlights that individual differences in apathy in HD may be explained by variability in atrophy and initial vulnerabilities in the right MCC, a region implicated in action-initiation. These findings thus serve to facilitate the prediction of an apathetic profile, permitting targeted, time-sensitive interventions in neurodegenerative disease with potential implications in otherwise healthy populations. (c) 2021 International Parkinson and Movement Disorder Society

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. Fil: Torres Prioris, María José. Universidad de Málaga; España Fil: López Barroso, Diana. Universidad de Málaga; España Fil: Càmara, Estela. Universidad de Málaga; España Fil: Fittipaldi, María Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt; Argentina Fil: Sedeño, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Instituto de Neurología Cognitiva. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt | Fundación Favaloro. Instituto de Neurociencia Cognitiva y Traslacional. Fundación Ineco Rosario Sede del Incyt; Argentina Fil: Ibañez, Agustin Mariano. Universidad de San Andrés; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Autónoma del Caribe; Colombia. University of California; Estados Unidos. Universidad Adolfo Ibañez; Chile Fil: Berthier, Marcelo L.. Universidad de Málaga; España Fil: García, Adolfo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Cuyo; Argentina. Universidad de San Andrés; Argentina. University of California; Estados Unidos. Universidad de Santiago de Chile; Chile

Abstract. The dopamine (DA) system has been implicated in the mediation of cost/benefit evaluations involved in the intertemporal choices between immediate and delayed rewards. This involvement was further investigated in two studies of normal participants that had to decide between a smaller immediate and a larger delayed reward in a series of 27 decisions.In study 1 the dopamine D2/D3 receptor agonist pramipexole or placebo were administered in a double-blind cross-over protocol prior to the decisions. In study 2 the same experiment was conducted in two groups of normal participants that were homozygous for either the 7repeat or the 4 repeat variant of the exon III polymorphism of the Dopamine D4 receptor gene. Dopaminergic involvement is highlighted by the results.

Cognitive decline accompanying the clinically more salient motor symptoms of Hunting- ton's disease (HD) has been widely noted and can precede motor symptoms onset. Less clear is how such decline bears on language functions in everyday life, though a small number of experimental studies have revealed difficulties with the application of rule- based aspects of language in early stages of the disease. Here we aimed to determine whether there is a systematic linguistic profile that characterizes spontaneous narrative speech in both pre-manifest and/or early manifest HD, and how it is related to striatal degeneration and neuropsychological profiles. Twenty-eight early-stage patients (19 manifest and 9 gene-carriers in the pre-manifest stage), matched with 28 controls, participated in a story-telling task. Speech was blindly scored by independent raters ac- cording to fine-grained linguistic variables distributed over 5 domains for which composite scores were computed (Quantitative, Fluency, Reference, Connectivity, and Concordance). Voxel-based morphometry (VBM) was used to link specific brain degeneration patterns to loci of linguistic decline. In all of these domains, significant differences were observed between groups. Deficits in Reference and Connectivity were seen in the pre-manifest stage, where no other neuropsychological impairment was detected. Among HD patients, there was a significant positive correlation only between the values in the Quantitative domain and gray matter volume bilaterally in the putamen and pallidum. These results fill the gap of qualitative data of spontaneous narrative speech in HD and reveal that HD is characterized by systematic linguistic impairments leading to dysfluencies and disorga- nization in core domains of grammatical organization. This includes the referential use of noun phrases and the embedding of clauses, which mediate crucial dimensions of meaning in language in its normal social use. Moreover, such impairment is seen prior to motor symptoms onset and when standardized neuropsychological test profiles are otherwise normal

Huntington's disease is a neurodegenerative disorder characterized by a triad of motor, cognitive and psychiatric disturbances. There is great variability regarding the prominence and evolution of each type of clinical sign. One possible source of phenotypic heterogeneity could be the more prominent degeneration of specific brain circuits. The scope of this review is to highlight the most recent neuroimaging studies that have analysed the relationship between brain changes and motor, cognitive and psychiatric alterations in Huntington's disease.The results from recent neuroimaging studies are heterogeneous. Although there is a great overlap between the different regions associated with each symptomatic domain, there is some degree of differentiation. For example, the motor network is associated with motor impairment, whereas the ventral striatum is especially involved in emotional deficits related with psychiatric problems.Motor, cognitive and psychiatric impairments are associated with structural and functional brain biomarkers. However, the specificity of the regions involved remains unknown, because these studies focused on specific regions and symptoms. In order to tease apart the neural substrates that underlie the phenotypic heterogeneity in Huntington's disease, multivariate approaches combining brain and behavioural measures related to all symptomatic domains should be considered in the future.

Our aim was to study the microstructural architecture of the contralateral hippocampus to the affected side in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) and its relation with surgical outcome.We included 33 consecutive patients evaluated in our epilepsy surgery program during a five-year period. They underwent a presurgical MRI with volumetric T1 and diffusion weighted sequences. 22 patients with TLE-HS (13 women, 12 right TLE-HS) were finally selected. Median follow-up after surgery was 6.25 years (4.5-8.83 years). We segmented the hippocampal subfields of the contralateral hippocampus using FreeSurfer and calculated the fractional anisotropy (FA) and the mean diffusivity (MD) of each subfield. We also scanned 18 healthy age-matched controls.After surgery, 50 % of the patients (n = 11) remained seizure-free (SF) following surgery. Comparing non-SF to SF patients, the MD showed increased values of the CA1 (p = 0.035), the molecular layer (p = 0.010) and the dentate gyrus (p = 0.041) in the healthy hippocampus. Using a cut-off point for a survival analysis, we found that patients with lower values of MD of the molecular layer and the CA1 remained SF during long-term post-operative follow-up (p0.0001).The contralateral hippocampal internal microstructure may have be implicated in post-surgery seizure freedom in patients with TLE-HS.

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(down arrow) (tau < 228.64 pg/ml; n= 16) and CBN-Tau(up arrow) (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

Background: Apathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited. Objectives: To disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease. Methods: Forty-six Huntington's disease individuals (premanifest (N = 22) and manifest (N = 24)) and 35 healthy controls were scanned at 3-tesla and underwent apathy evaluation using the short-Problem Behavior Assessment and short-Lille Apathy Rating Scale, with the latter being characterized into three apathy domains, namely emotional, cognitive, and auto-activation deficit. Diffusion tensor imaging was used to study whether individual differences in specific cortico-striatal tracts predicted global apathy and its subdomains. Results: We elucidate that apathy profiles may develop along differential timelines, with the auto-activation deficit domain manifesting prior to motor onset. Furthermore, diffusion tensor imaging revealed that inter-individual variability in the disruption of discrete cortico-striatal tracts might explain the heterogeneous severity of apathy profiles. Specifically, higher levels of auto-activation deficit symptoms significantly correlated with increased mean diffusivity in the right uncinate fasciculus. Conversely, those with severe cognitive apathy demonstrated increased mean diffusivity in the right frontostriatal tract and left dorsolateral prefrontal cortex to caudate nucleus tract. Conclusions: The current study provides evidence that white matter correlates associated with emotional, cognitive, and auto-activation subtypes may elucidate the heterogeneous nature of apathy in Huntington's disease, as such opening a door for individualized pharmacological management of apathy as a multidimensional syndrome in other neurodegenerative disorders. Keywords: Apathy, Diffusion MRI, Huntington's disease, Individual differences, Neurodegeneration, White matter microstructure

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.

In the last decade, several studies have investigated the neuroplastic changes induced by long-term musical training. Here we investigated structural brain differences in expert pianists compared to non-musician controls, as well as the effect of the age of onset (AoO) of piano playing. Differences with non-musicians and the effect of sensitive periods in musicians have been studied previously, but importantly, this is the first time in which the age of onset of music-training was assessed in a group of musicians playing the same instrument, while controlling for the amount of practice. We recruited a homogeneous group of expert pianists who differed in their AoO but not in their lifetime or present amount of training, and compared them to an age-matched group of non-musicians. A subset of the pianists also completed a scale-playing task in order to control for performance skill level differences. Voxel-based morphometry analysis was used to examine gray-matter differences at the whole-brain level. Pianists showed greater gray matter (GM) volume in bilateral putamen (extending also to hippocampus and amygdala), right thalamus, bilateral lingual gyri and left superior temporal gyrus, but a GM volume shrinkage in the right supramarginal, right superior temporal and right postcentral gyri, when compared to non-musician controls. These results reveal a complex pattern of plastic effects due to sustained musical training: a network involved in reinforcement learning showed increased GM volume, while areas related to sensorimotor control, auditory processing and score-reading presented a reduction in the volume of GM. Behaviorally, early-onset pianists showed higher temporal precision in their piano performance than late-onset pianists, especially in the left hand. Furthermore, early onset of piano playing was associated with smaller GM volume in the right putamen and better piano performance (mainly in the left hand). Our results, therefore, reveal for the first time in a single large dataset of healthy pianists the link between onset of musical practice, behavioral performance, and putaminal gray matter structure. In summary, skill-related plastic adaptations may include decreases and increases in GM volume, dependent on an optimization of the system caused by an early start of musical training. We believe our findings enrich the plasticity discourse and shed light on the neural basis of expert skill acquisition.

Novel rehabilitation interventions have improved motor recovery by induction of neural plasticity in individuals with stroke. Of these, Music-supported therapy (MST) is based on music training designed to restore motor deficits. Music training requires multimodal processing, involving the integration and co-operation of visual, motor, auditory, affective and cognitive systems. The main objective of this study was to assess, in a group of 20 individuals suffering from chronic stroke, the motor, cognitive, emotional and neuroplastic effects of MST. Using functional magnetic resonance imaging (fMRI) we observed a clear restitution of both activity and connectivity among auditory-motor regions of the affected hemisphere. Importantly, no differences were observed in this functional network in a healthy control group, ruling out possible confounds such as repeated imaging testing. Moreover, this increase in activity and connectivity between auditory and motor regions was accompanied by a functional improvement of the paretic hand. The present results confirm MST as a viable intervention to improve motor function in chronic stroke individuals.

It has long been posited that threat learning operates and forms under an affective and a cognitive learning system that are supported by different brain circuits. A primary drawback in exposure-based therapies is the high rate of relapse when higher order inhibitory structures failed to inhibit the emotional responses driven by the defensive circuit. It has been shown that implicit exposure of fearful stimuli leads to a long-lasting reduction of avoidance behavior in patients with phobia through the facilitation of fear processing areas in the absence of subjective fear. Despite the potential benefits of this approach in the treatment of phobias and PTSD, implicit exposure to fearful stimuli is still under-investigated. Here, we used unconscious presentation of threat-conditioned stimuli in healthy humans, using a continuous flash suppression technique. We found that implicit exposure of a conditioned stimulus reduced, on the following day, defensive responses to the conditioned stimulus measured by threat-potentiated startle responses but not by the electrodermal activity. Our results suggest that implicit exposure using CFS might facilitate the modulation of the affective component of fearful memories, representing an important therapeutic target to further advance exposure-based psychotherapies.

A cognitive stimulating lifestyle has been observed to confer cognitive benefits in multiple neurodegenerative diseases. However, the underlying neurobiological basis of this phenomenon remains unclear. Huntington's disease can provide a suitable model to study the effects and neural mechanisms of cognitive engagement in neurodegeneration. In this study, we investigate the effect of lifestyle factors such as education, occupation and engagement in cognitive activities in Huntington's disease gene carriers on cognitive performance and age of onset as well as the underlying neural changes sustaining these effects, measured by magnetic resonance imaging. Specifically, we analyzed both gray matter volume and the strength of connectivity of the executive control resting-state network. High levels of cognitive engagement were significantly associated with more preserved executive functions, a delay in the appearance of symptoms, reduced volume loss of the left precuneus and the bilateral caudate and a modulation of connectivity strength of anterior cingulate cortex and left angular gyrus with the executive control network. These findings suggest that a cognitively stimulating lifestyle may promote brain maintenance by modulating the executive control resting-state network and conferring protection against neurodegeneration, which results in a delayed onset of symptoms and improved performance in executive functions.

The ability to learn to use new words is thought to depend on the integrity of the left dorsal temporo-frontal speech processing pathway. We tested this assumption in a chronic aphasic individual (AA) with an extensive left temporal lesion using a new-word learning paradigm. She exhibited severe phonological problems and Magnetic Resonance Imaging (MRI) suggested a complete disconnection of this left-sided white-matter pathway comprising the arcuate fasciculus (AF). Diffusion imaging tractography confirmed the disconnection of the direct segment and the posterior indirect segment of her left AF, essential components of the left dorsal speech processing pathway. Despite her left-hemispheric damage and moderate aphasia, AA learned to name and maintain the novel words in her active vocabulary on par with healthy controls up to 6 months after learning. This exceeds previous demonstrations of word learning ability in aphasia. Interestingly, AA's preserved word learning ability was modality-specific as it was observed exclusively for written words. Functional magnetic resonance imaging (fMRI) revealed that in contrast to normals, AA showed a significantly right-lateralized activation pattern in the temporal and parietal regions when engaged in reading. Moreover, learning of visually presented novel word–picture pairs also activated the right temporal lobe in AA. Both AA and the controls showed increased activation during learning of novel versus familiar word–picture pairs in the hippocampus, an area critical for associative learning. AA's structural and functional imaging results suggest that in a literate person, a right-hemispheric network can provide an effective alternative route for learning of novel active vocabulary. Importantly, AA's previously undetected word learning ability translated directly into therapy, as she could use written input also to successfully re-learn and maintain familiar words that she had lost due to her left hemisphere lesion.

In this study, we sought to dissociate event-related potentials (ERPs) and the oscillatory activity associated with signals indicating feedback about performance (outcome-based behavioral adjustment) and the signals indicating the need to change or maintain a task set (rule-based behavioral adjustment). With this purpose in mind, we noninvasively recorded electroencephalographic signals, using a modified version of the Wisconsin card sorting task, in which feedback processing and task switching could be studied separately. A similar late positive component was observed for the switch and correct feedback signals on the first trials of a series, but feedback-related negativity was observed only for incorrect feedback. Moreover, whereas theta power showed a significant increase after a switch cue and after the first positive feedback of a new series, a selective frontal beta-gamma increase was observed exclusively in the first positive feedback (i.e., after the selection of the new rule). Importantly, for the switch cue, beta-alpha activity was suppressed rather than increased. This clear dissociation between the cue and feedback stimuli in task switching emphasizes the need to accurately study brain oscillatory activity to disentangle the role of different cognitive control processes.

Primary objective: Music-Supported Therapy (MST) has been developed recently in order to improve the use of the affected upper extremity after stroke. This study investigated the neuroplastic mechanisms underlying effectiveness in a patient with chronic stroke. Methods: MST uses musical instruments, a midi piano and an electronic drum set emitting piano sounds, to retrain fine and gross movements of the paretic upper extremity. Data are presented from a patient with a chronic stroke (20 months poststroke) with residual right-sided hemiparesis who took part in 20 MST sessions over the course of 4 weeks. Results: Post-therapy, a marked improvement of movement quality, assessed by 3D movement analysis, was observed. Moreover, functional magnetic resonance imaging (fMRI) of a sequential hand movement revealed distinct therapy-related changes in the form of a reduction of excess contralateral and ipsilateral activations. This was accompanied by changes in cortical excitability evidenced by transcranial magnetic stimulation (TMS). Functional MRI in a music listening task suggests that one of the effects of MST is the task-dependent coupling of auditory and motor cortical areas. Conclusions: The MST appears to be a useful neurorehabilitation tool in patients with chronic stroke and leads to neural reorganization in the sensorimotor cortex.

The present study combined behavioral measures and diffusion tensor imaging to investigate the neuroanatomical basis of language learning in relation to phonological working memory (WM). Participants were exposed to simplified artificial languages under WM constraints. The results underscore the role of the rehearsal subcomponent of WM in successful speech segmentation and rule learning. Moreover, when rehearsal was blocked task performance was correlated to the white matter microstructure of the left ventral pathway connecting frontal and temporal language-related cortical areas through the extreme/external capsule. This ventral pathway may therefore play an important additional role in language learning when the main dorsal pathway-dependent rehearsal mechanisms are not available.

Pramipexole is widely prescribed to treat Parkinson's disease. It has been found to cause impulse control disorders such as pathological gambling. To examine how pramipexole modulates the network of reward anticipation, we carried out a pharmacological functional magnetic resonance imaging study with a double‐blind, within‐subject design. During the anticipation of monetary rewards, pramipexole increased the activity of the nucleus accumbens (NAcc), enhanced the interaction between the NAcc and the anterior insula, but weakened the interaction between the NAcc and the prefrontal cortex. These results suggest that pramipexole may exaggerate incentive and affective responses to possible rewards, but reduce the top‐down control of impulses, leading to an increase in impulsive behaviors. This imbalance between the prefrontal‐striatum connectivity and the insula‐striatum connectivity may represent the neural mechanism of pathological gambling caused by pramipexole. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.

How are adult second language learners able to segment words and map them to referents in the new language? The present study explores this unresolved issue by using a new multimodal learning paradigm that tracks the first steps in learning new words and their mappings to visual referents. It encompasses a continuous audiovisual stream in which transitional probability of syllables is the only acoustic cue available to segment the stream into words, and a visual stream of object images that accompanies the novel words. The objects are systematically varied in terms of constancy of word-picture association and meaningfulness. The results indicated good word-referent mapping and word segmentation after short exposure to the audiovisual stream. Mapping words with pictures was more effective when the visual referents were meaningful objects. In word segmentation, the consistency of the word-picture association affected segmentation performance. The effect of associative strength on segmentation performance was most prominent with meaningful objects, albeit associative strength did not interact significantly with meaningfulness. The present results suggest that word segmentation and word-referent mapping are closely related processes: word segmentation is affected by the consistency of the mapping relationship and both segmentation and mapping can be accomplished under the same short exposure.

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.

People's sensitivity to reinforcing stimuli such as monetary gains and losses shows a wide interindividual variation that might in part be determined by genetic differences. Because of the established role of the dopaminergic system in the neural encoding of rewards and negative events, we investigated young healthy volunteers being homozygous for either the Valine or Methionine variant of the catechol-O-methyltransferase (COMT) codon 158 polymorphism as well as homozygous for the C or T variant of the SNP -521 polymorphism of the dopamine D4 receptor. Participants took part in a gambling paradigm featuring unexpectedly high monetary gains and losses in addition to standard gains/losses of expected magnitude while undergoing functional magnetic resonance imaging at 3 T. Valence-related brain activations were seen in the ventral striatum, the anterior cingulate cortex, and the inferior parietal cortex. These activations were modulated by the COMT polymorphism with greater effects for valine/valine participants but not by the D4 receptor polymorphism. By contrast, magnitude-related effects in the anterior insula and the cingulate cortex were modulated by the D4 receptor polymorphism with larger responses for the CC variant. These findings emphasize the differential contribution of genetic variants in the dopaminergic system to various aspects of reward processing.

The present investigation was devoted to unraveling the time-course and brain regions involved in speech segmentation, which is one of the first processes necessary for learning a new language in adults and infants. A specific brain electrical pattern resembling the N400 language component was identified as an indicator of speech segmentation of candidate words. This N400 trace was clearly elicited after a short exposure to the words of the new language and showed a decrease in amplitude with longer exposure. Two brain regions were observed to be active during this process: the posterior superior temporal gyrus and the superior part of the ventral premotor cortex. We interpret these findings as evidence for the existence of an auditory–motor interface that is responsible for isolating possible candidate words when learning a new language in adults.

Dynamic adaptations of one's behavior by means of performance monitoring are a central function of the human executive system, that underlies considerable interindividual variation. Converging evidence from electrophysiological and neuroimaging studies in both animals and humans hints at the importance of the dopaminergic system for the regulation of performance monitoring. Here, we studied the impact of two polymorphisms affecting dopaminergic functioning in the prefrontal cortex [catechol-O-methyltransferase (COMT) Val108/158Met and dopamine D4 receptor (DRD4) single-nucleotide polymorphism (SNP)-521] on neurophysiological correlates of performance monitoring. We applied a modified version of a standard flanker task with an embedded stop-signal task to tap into the different functions involved, particularly error monitoring, conflict detection and inhibitory processes. Participants homozygous for the DRD4Tallele produced an increased error-related negativity after both choice errors and failed inhibitions compared withC-homozygotes. This was associated with pronounced compensatory behavior reflected in higher post-error slowing. No group differences were seen in the incompatibility N2, suggesting distinct effects of the DRD4 polymorphism on error monitoring processes. Additionally, participants homozygous for the COMTValallele, with a thereby diminished prefrontal dopaminergic level, revealed increased prefrontal processing related to inhibitory functions, reflected in the enhanced stop-signal-related components N2 and P3a. The results extend previous findings from mainly behavioral and neuroimaging data on the relationship between dopaminergic genes and executive functions and present possible underlying mechanisms for the previously suggested association between these dopaminergic polymorphisms and psychiatric disorders as schizophrenia or attention deficit hyperactivity disorder.

Introduccion El dolor es una experiencia subjetiva dificilmente evaluable por su variada expresion. Actualmente, la resonancia magnetica funcional (RMf) permite objetivar la respuesta cerebral al estimulo doloroso. Objetivo Evaluar la respuesta cerebral al dolor en pacientes con dolor cronico esencial generalizado diagnosticados de fibromialgia (FM). Sujetos y metodos Se administro un estimulo doloroso por presion mecanica a 15 pacientes con FM y 11 controles durante la adquisicion de RMf. Se realizaron diversos ensayos de activacion variando la presion ejercida sobre una superficie de 1 cm 2 del dedo pulgar. Resultados Durante la adquisicion de RMf, la aplicacion de una presion mecanica de 4 kg no ocasiono molestias relevantes en ningun sujeto control. Contrariamente, todos los pacientes, excepto uno, refirieron dolor moderado-grave con este estimulo. La RMf puso de manifiesto que, con poca presion (4 y 5 kg), es excepcional la activacion de regiones distintas al area sensitivomotora primaria contralateral al dedo estimulado en los sujetos control. Sin embargo, 5 pacientes (p = 0,027), a 4 kg de presion, y 7 (p = 0,030), a 5 kg, activaron las regiones cerebrales conocidas como mediadoras de la respuesta al dolor (area sensitivomotora primaria, corteza parietal, insula y region del cingulo anterior). Conclusiones Los resultados sugieren que una proporcion significativa de pacientes diagnosticados de FM y con bajo umbral doloroso presentan una consistente respuesta cerebral al dolor con estimulos mecanicos de baja intensidad, mientras que en otra parte de los casos el cerebro responde de forma similar a los sujetos control.