Neuroanatomical correlates of musicianship in left-handers.

BACKGROUND: Left-handedness is a condition that reverses the typical left cerebral dominance of motor control to an atypical right dominance. The impact of this distinct control - and its associated neuroanatomical peculiarities - on other cognitive functions such as music processing or playing a musical instrument remains unexplored. Previous studies in right-handed population have linked musicianship to a larger volume in the (right) auditory cortex and a larger volume in the (right) arcuate fasciculus. RESULTS: In our study, we reveal that left-handed musicians (n = 55), in comparison to left-handed non-musicians (n = 75), exhibit a larger gray matter volume in both the left and right Heschl's gyrus, critical for auditory processing. They also present a higher number of streamlines across the anterior segment of the right arcuate fasciculus. Importantly, atypical hemispheric lateralization of speech (notably prevalent among left-handers) was associated to a rightward asymmetry of the AF, in contrast to the leftward asymmetry exhibited by the typically lateralized. CONCLUSIONS: These findings suggest that left-handed musicians share similar neuroanatomical characteristics with their right-handed counterparts. However, atypical lateralization of speech might potentiate the right audiomotor pathway, which has been associated with musicianship and better musical skills. This may help explain why musicians are more prevalent among left-handers and shed light on their cognitive advantages.

The Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that arises from the cells lining the tubes of the kidney. The tumor immune microenvironment (TIME) of ccRCC is a complex interplay of various immune cells, cytokines, and signaling pathways. One of the critical features of the ccRCC TIME is the presence of infiltrating immune cells, including T cells, B cells, natural killer cells, dendritic cells, and myeloid-derived suppressor cells. Among these cells, CD8+ T cells are particularly important in controlling tumor growth by recognizing and killing cancer cells. However, the TIME of ccRCC is also characterized by an immunosuppressive environment that hinders the function of immune cells. Several mechanisms contribute to the immunosuppressive nature of the ccRCC TIME. For instance, ccRCC cells produce cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-ß), which suppress immune cell activation and promote the differentiation of regulatory T cells (Tregs). Tregs, in turn, dampen the activity of effector T cells and promote tumor growth. In addition, ccRCC cells can express programmed death-ligand 1 (PD-L1), which interacts with the programmed cell death protein 1 (PD-1) receptor on T cells to inhibit their function. In addition, other immune checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte activation gene 3 (LAG-3), also contribute to the immunosuppressive milieu of the ccRCC TIME. Finally, the hypoxic and nutrient-poor microenvironment of ccRCC can stimulate the production of immunosuppressive metabolites, such as adenosine and kynurenine, which further impair the function of immune cells. Understanding the complex interplay between tumor cells and the immune system in the ccRCC TIME is crucial for developing effective immunotherapies to treat this disease.

The manifestation of individual differences in sensitivity to punishment during resting state is modulated by eye state.

Structural and functional neuroimaging studies have shown that brain areas associated with fear and anxiety (defensive system areas) are modulated by individual differences in sensitivity to punishment (SP). However, little is known about how SP is related to brain functional connectivity and the factors that modulate this relationship. In this study, we investigated whether a simple methodological manipulation, such as performing a resting state with eyes open or eyes closed, can modulate the manifestation of individual differences in SP. To this end, we performed an exploratory fMRI resting state study in which a group of participants (n = 88) performed a resting state with eyes closed and another group (n = 56) performed a resting state with eyes open. All participants completed the Sensitivity to Punishment and Sensitivity to Reward Questionnaire. Seed-based functional connectivity analyses were performed in the amygdala, hippocampus, and periaqueductal gray (PAG). Our results showed that the relationship between SP and left amygdala-precuneus and left hippocampus-precuneus functional connectivity was modulated by eye state. Moreover, in the eyes open group, SP was negatively related to the functional connectivity between the PAG and amygdala and between the PAG and left hippocampus, and it was positively related to the functional connectivity between the amygdala and hippocampus. Together, our results may suggest underlying differences in the connectivity between anxiety-related areas based on eye state, which in turn would affect the manifestation of individual differences in SP.

Sustained and transient gray matter volume changes after n-back training: A VBM study.

Working memory training causes functional adaptations in the brain, which include changes in activation and functional connectivity that remain stable over time. Few studies have investigated gray matter (GM) changes after working memory training, and they have produced heterogeneous results without clarifying the stable effects of training. The present study was designed to test for sustained and transient anatomic changes after only 200 min of working memory training. The voxel-based morphometry technique was used in order to investigate the GM changes produced by a brief single n-back training, immediately and 5 weeks after finishing it. The sample was composed by 59 human participants who underwent MRI scanning and were assigned to either a training group or a passive control group. Results showed sustained GM volume enlargement in the right superior parietal cortex and a transient GM decrease in the right putamen. The brain adaptation in the right superior parietal cortex was stronger in individuals who showed greater improvements in performance. The results provide further evidence that a brief working memory training is able to produce brain plasticity in structures related to the trained task.

Left-handed musicians show a higher probability of atypical cerebral dominance for language.

Music processing and right hemispheric language lateralization share a common network in the right auditory cortex and its frontal connections. Given that the development of hemispheric language dominance takes place over several years, this study tested whether musicianship could increase the probability of observing right language dominance in left-handers. Using a classic fMRI language paradigm, results showed that atypical lateralization was more predominant in musicians (40%) than in nonmusicians (5%). Comparison of left-handers with typical left and atypical right lateralization revealed that: (a) atypical cases presented a thicker right pars triangularis and more gyrified left Heschl's gyrus; and (b) the right pars triangularis of atypical cases showed a stronger intra-hemispheric functional connectivity with the right angular gyrus, but a weaker interhemispheric functional connectivity with part of the left Broca's area. Thus, musicianship is the first known factor related to a higher prevalence of atypical language dominance in healthy left-handed individuals. We suggest that differences in the frontal and temporal cortex might act as shared predisposing factors to both musicianship and atypical language lateralization.

Resting-state fMRI detects the effects of learning in short term: A visual search training study.

Can resting-state functional connectivity (rs-FC) detect the impact of learning on the brain in the short term? To test this possibility, we have combined task-FC and rs-FC tested before and after a 30-min visual search training. Forty-two healthy adults (20 men) divided into no-contact control and trained groups completed the study. We studied the connectivity between four different regions of the brain involved in visual search: the primary visual area, the right posterior parietal cortex (rPPC), the right dorsolateral prefrontal cortex (rDLPFC), and the dorsal anterior cingulate cortex (dACC). Task-FC showed increased connectivity between the rPPC and rDLPFC and between the dACC and rDLPFC from pretraining to posttraining for both the control group and the trained group, suggesting that connectivity between these areas increased with task repetition. In rs-FC, we found enhanced connectivity between these regions in the trained group after training, especially in those with better learning. Whole brain independent component analyses did not reveal any change in main networks after training. These results imply that rs-FC may not only predict individual differences in task performance, but rs-FC might also serve to monitor the impact of learning on the brain after short periods of cognitive training, localizing them in brain areas specifically involved in training.

Reward network connectivity "at rest" is associated with reward sensitivity in healthy adults: A resting-state fMRI study.

The behavioral approach system (BAS), based on reinforcement sensitivity theory (RST), is a neurobehavioral system responsible for detecting and promoting motivated behaviors towards appetitive stimuli. Anatomically, the frontostriatal system has been proposed as the core of the BAS, mainly the ventral tegmental area and the ventral striatum and their dopaminergic connections with medial prefrontal structures. The RST also proposes the personality trait of reward sensitivity as a measurable construct of stable individual differences in BAS activity. However, the relationship between this trait and brain connectivity "at rest" has been poorly studied, mainly because previous investigations have focused on studying brain activity under reward-related contingency paradigms. Here, we analyzed the influence of reward sensitivity on the resting-state functional connectivity (rs-FC) between BAS-related areas by correlating the BOLD time series with the scores on the Sensitivity to Reward (SR) scale in a sample of 89 healthy young adults. Rs-FC between regions of interest were all significant. Results also revealed a positive association between SR scores and the rs-FC between the VTA and the ventromedial prefrontal cortex, and between the latter structure and the anterior cingulate cortex. These results suggest that reward sensitivity could be associated with different resting-state activity in the mesocortical pathway.

Separate Contribution of Striatum Volume and Pitch Discrimination to Individual Differences in Music Reward.

Individual differences in the level of pleasure induced by music have been associated with the response of the striatum and differences in functional connectivity between the striatum and the auditory cortex. In this study, we tested whether individual differences in music reward are related to the structure of the striatum and the ability to discriminate pitch. We acquired a 3-D magnetization-prepared rapid-acquisition gradient-echo image for 32 musicians and 26 nonmusicians who completed a music-reward questionnaire and a test of pitch discrimination. The analysis of both groups together showed that sensitivity to music reward correlated negatively with the volume of both the caudate and nucleus accumbens and correlated positively with pitch-discrimination abilities. Moreover, musicianship, pitch discrimination, and caudate volume significantly predicted individual differences in music reward. These results are consistent with the proposal that individual differences in music reward depend on the interplay between auditory abilities and the reward network.

Effect of cytomegalovirus infection and leukocyte immunoglobulin like receptor B1 polymorphisms on receptor expression in peripheral blood mononuclear cells.

Leukocyte immunoglobulin like receptor B1 (LILRB1) plays a significant role in a number of infectious, autoimmune, cardiovascular, and oncologic disorders. LILRB1 expression varies between individuals and may be associated with polymorphisms on the regulatory region of the LILRB1 gene, as well as to previous cytomegalovirus infection. In this study, the contribution of these two factors to LILRB1 expression in peripheral blood mononuclear cells of healthy young adults was analyzed. LILRB1 expression in NK cells, T cells, B cells and monocytes was significantly stronger in individuals who had had cytomegalovirus infection than in those who had not (P < 0.001, P < 0.001, P < 0.01, and P < 0.001, respectively). Overall, no differences in LILRB1 expression were observed between individuals with and without GAA haplotypes of the LILRB1 regulatory region. However, when analyzed according to cytomegalovirus infection status, significant differences in LILRB1+ NK cells were observed. A higher proportion of LILRB1+ cells was found in GAA+ than in GAA- individuals who had not been infected (P < 0.01), whereas GAA- individuals had a larger proportion of LILRB1+ cells than GAA+ individuals who were cytomegalovirus positive (P < 0.01). In conclusion, cytomegalovirus infection has a major effect on LILRB1 expression in NK and other mononuclear cells and polymorphisms in the LILRB1 regulatory region appear to have a modulatory influence over this effect.

Modulation of Functional Connectivity in Auditory-Motor Networks in Musicians Compared with Nonmusicians.

Correlation of spontaneous fluctuations at rest between anatomically distinct brain areas are proposed to reflect the profile of individual a priori cognitive biases, coded as synaptic efficacies in cortical networks. Here, we investigate functional connectivity at rest (rs-FC) in musicians and nonmusicians to test for differences in auditory, motor, and audiomotor connectivity. As expected, musicians had stronger rs-FC between the right auditory cortex (AC) and the right ventral premotor cortex than nonmusicians, and this stronger rs-FC was greater in musicians with more years of practice. We also found reduced rs-FC between the motor areas that control both hands in musicians compared with nonmusicians, which was more evident in the musicians whose instrument required bimanual coordination and as a function of hours of practice. Finally, we replicated previous morphometric data to show an increased volume in the right AC in musicians, which was greater in those with earlier musical training, and that this anatomic feature was in turn related to greater rs-FC between auditory and motor systems. These results show that functional coupling within the motor system and between motor and auditory areas is modulated as a function of musical training, suggesting a link between anatomic and functional brain features.

The dynamic imprint of word learning on the dorsal language pathway.

According to Hickok and Poeppel (2007), the acquisition of new vocabulary rests on the dorsal language pathway connecting auditory and motor areas. The present study tested this hypothesis longitudinally by measuring BOLD signal changes during a verbal repetition task and modulation of resting state functional connectivity (rs-FC) in the dorsal stream. Thirty-five healthy participants, divided into trained and control groups, completed fMRI sessions on days 1, 10, and 24. Between days 1 and 10, the trained group learned 84 new pseudowords associated with 84 native words. Task-related fMRI results showed a reduced activity in the IFG and STG while processing the learned vocabulary after training, returning to initial values two weeks later. Moreover, rs-fMRI analysis showed stronger rs-FC between the IFG and STG in the trained group than in the control group after learning, especially on day 24. These neural changes were more evident in participants with a larger vocabulary. Discussion focuses on the prominent role of the dorsal stream in vocabulary acquisition. Even when their meaning was known, newly learned words were again processed through the dorsal stream two weeks after learning, with the increase in rs-FC between auditory and motor areas being a relevant long-term imprint of vocabulary learning.

Complexity analysis of cortical surface detects changes in future Alzheimer's disease converters.

Alzheimer's disease (AD) is a neurological disorder that creates neurodegenerative changes at several structural and functional levels in human brain tissue. The fractal dimension (FD) is a quantitative parameter that characterizes the morphometric variability of the human brain. In this study, we investigate spherical harmonic-based FD (SHFD), thickness, and local gyrification index (LGI) to assess whether they identify cortical surface abnormalities toward the conversion to AD. We study 33 AD patients, 122 mild cognitive impairment (MCI) patients (50 MCI converters and 29 MCI nonconverters), and 32 healthy controls (HC). SHFD, thickness, and LGI methodology allowed us to perform not only global level but also local level assessments in each cortical surface vertex. First, we found that global SHFD decreased in AD and future MCI converters compared to HC, and in MCI converters compared to MCI nonconverters. Second, we found that local white matter SHFD was reduced in AD compared to HC and MCI mainly in medial temporal lobe. Third, local white-matter SHFD was significantly reduced in MCI converters compared to MCI nonconverters in distributed areas, including the medial frontal lobe. Thickness and LGI metrics presented a reduction in AD compared to HC. Thickness was significantly reduced in MCI converters compared to healthy controls in entorhinal cortex and lateral temporal. In summary, SHFD was the only surface measure showing differences between MCI individuals that will convert or remain stable in the next 4 years. We suggest that SHFD may be an optimal complement to thickness loss analysis in monitoring longitudinal changes in preclinical and clinical stages of AD. Hum Brain Mapp 38:5905-5918, 2017. © 2017 Wiley Periodicals, Inc.

Hippocampal dysfunction is associated with memory impairment in multiple sclerosis: A volumetric and functional connectivity study.

BACKGROUND: Previous studies have suggested a relationship between neuroanatomical and neurofunctional hippocampal alterations and episodic memory impairments in multiple sclerosis (MS) patients. OBJECTIVE: We examined hippocampus volume and functional connectivity (FC) changes in MS patients with different episodic memory capabilities. METHODS: Hippocampal subfield volume and FC changes were compared in two subgroups of MS patients with and without episodic memory impairment (multiple sclerosis impaired (MSi) and multiple sclerosis preserved (MSp), respectively) and healthy controls (HC). A discriminant function (DF) analysis was used to identify which of these neuroanatomical and neurofunctional parameters were the most relevant components of the mnemonic profiles of HC, MSp, and MSi. RESULTS: MSi showed reduced volume in several hippocampal subfields compared to MSp and HC. Ordinal gradation (MSi > MSp > HC) was also observed for FC between the posterior hippocampus and several cortical areas. DF-based analyses revealed that reduced right fimbria volume and enhanced FC at the right posterior hippocampus were the main neural signatures of the episodic memory impairments observed in the MSi group. CONCLUSION: Before any sign of episodic memory alterations (MSp), FC increased on several pathways that connect the hippocampus with cortical areas. These changes further increased when the several hippocampal volumes reduced and memory deficits appeared (MSi).

The Modulation of the Startle Reflex as Predictor of Alcohol Use Disorders in a Sample of Heavy Drinkers: A 4-Year Follow-Up Study.

BACKGROUND: Previous studies demonstrated that patients with alcohol use disorders (AUDs) show altered startle reflex responses to alcohol-related stimuli. However, there is little information about the role of these altered responses in the development of AUDs. This study examined the startle reflex response to different visual stimuli and the role of these patterns in the development of AUDs in a 4-year follow-up. METHODS: Two hundred and thirty-nine (nondependent) heavy-drinking participants were selected. In the baseline period, the startle reflex responses to alcohol-related, aversive, appetitive, and neutral pictures were assessed. Startle reflex responses to these pictures were used as predictive variables. Status drinking (alcohol dependence and nondependence) assessed at 4-year follow-up was used as outcome measure. RESULTS: At the 4-year follow-up assessment, 46% of participants fulfilled DSM-IV alcohol abuse or dependence criteria. Alcohol dependence status was predicted by an attenuated startle reflex response to alcohol-related and aversive pictures. CONCLUSIONS: This study revealed that an attenuated modulation of startle reflex response to alcohol-related and aversive stimuli could be used as a clinical marker to predict the development of AUDs in participants with previous alcohol consumption.

Reduced activity in functional networks during reward processing is modulated by abstinence in cocaine addicts.

Cocaine addiction is characterized by alterations in motivational and cognitive processes. Recent studies have shown that some alterations present in cocaine users may be related to the activity of large functional networks. The aim of this study was to investigate how these functional networks are modulated by non-drug rewarding stimuli in cocaine-dependent individuals. Twenty abstinent cocaine-dependent and 21 healthy matched male controls viewed erotic and neutral pictures while undergoing a functional magnetic resonance imaging scan. Group independent component analysis was then performed in order to investigate how functional networks were modulated by reward in cocaine addicts. The results showed that cocaine addicts, compared with healthy controls, displayed diminished modulation of the left frontoparietal network in response to erotic pictures, specifically when they were unpredicted. Additionally, a positive correlation between the length of cocaine abstinence and the modulation of the left frontoparietal network by unpredicted erotic images was found. In agreement with current addiction models, our results suggest that cocaine addiction contributes to reduce sensitivity to rewarding stimuli and that abstinence may mitigate this effect.

Exploring Neural Efficiency in Multiple Sclerosis Patients during the Symbol Digit Modalities Test: A Functional Magnetic Resonance Imaging Study.

BACKGROUND: Reduced information-processing speed (IPS) is a primary cognitive deficit of multiple sclerosis (MS) patients. The neural efficiency hypothesis describes an inverse relationship between cognitive performance in a task and the amount of cognitive resources devoted to it. Previous studies have shown that the neural efficiency hypothesis provides an appropriate framework to explore cognitive dysfunction in neurological patients. OBJECTIVE: The aim of this study was to explore the neural efficiency hypothesis regarding IPS capabilities in cognitively preserved MS patients. METHODS: 16 MS patients and 17 healthy controls (HCs) were enrolled and neuropsychologically assessed. All participants also performed a functional magnetic resonance imaging (fMRI)-adapted version of the Symbol Digit Modalities Test (SDMT) at different interstimulus intervals (ISI: 1.5, 2, and 2.5 s). RESULTS: MS patients only displayed lower SDMT performance when the ISI was set at 1.5 s. However, MS patients' normal SDMT performance at larger ISIs was achieved at the cost of increased brain activation, hence revealing that they were less cognitively efficient than the HCs. Regression analyses confirmed this conclusion by showing an opposite relationship between SDMT performance and the amount of neural resources recruited in the HC and MS groups. Thus, while a positive relationship between both variables was observed in MS patients, this correlation was negative for the HC group. CONCLUSIONS: MS patients require more cognitive resources than HCs to achieve a normal SDMT performance, then revealing that they are less efficient regarding IPS capabilities.

Hand gestures as visual prosody: BOLD responses to audio-visual alignment are modulated by the communicative nature of the stimuli.

During public addresses, speakers accompany their discourse with spontaneous hand gestures (beats) that are tightly synchronized with the prosodic contour of the discourse. It has been proposed that speech and beat gestures originate from a common underlying linguistic process whereby both speech prosody and beats serve to emphasize relevant information. We hypothesized that breaking the consistency between beats and prosody by temporal desynchronization, would modulate activity of brain areas sensitive to speech-gesture integration. To this aim, we measured BOLD responses as participants watched a natural discourse where the speaker used beat gestures. In order to identify brain areas specifically involved in processing hand gestures with communicative intention, beat synchrony was evaluated against arbitrary visual cues bearing equivalent rhythmic and spatial properties as the gestures. Our results revealed that left MTG and IFG were specifically sensitive to speech synchronized with beats, compared to the arbitrary vision-speech pairing. Our results suggest that listeners confer beats a function of visual prosody, complementary to the prosodic structure of speech. We conclude that the emphasizing function of beat gestures in speech perception is instantiated through a specialized brain network sensitive to the communicative intent conveyed by a speaker with his/her hands.

Bilingualism at the core of the brain. Structural differences between bilinguals and monolinguals revealed by subcortical shape analysis.

Naturally acquiring a language shapes the human brain through a long-lasting learning and practice process. This is supported by previous studies showing that managing more than one language from early childhood has an impact on brain structure and function. However, to what extent bilingual individuals present neuroanatomical peculiarities at the subcortical level with respect to monolinguals is yet not well understood, despite the key role of subcortical gray matter for a number of language functions, including monitoring of speech production and language control - two processes especially solicited by bilinguals. Here we addressed this issue by performing a subcortical surface-based analysis in a sample of monolinguals and simultaneous bilinguals (N=88) that only differed in their language experience from birth. This analysis allowed us to study with great anatomical precision the potential differences in morphology of key subcortical structures, namely, the caudate, accumbens, putamen, globus pallidus and thalamus. Vertexwise analyses revealed significantly expanded subcortical structures for bilinguals compared to monolinguals, localized in bilateral putamen and thalamus, as well as in the left globus pallidus and right caudate nucleus. A topographical interpretation of our results suggests that a more complex phonological system in bilinguals may lead to a greater development of a subcortical brain network involved in monitoring articulatory processes.

Characterizing individual differences in reward sensitivity from the brain networks involved in response inhibition.

A "disinhibited" cognitive profile has been proposed for individuals with high reward sensitivity, characterized by increased engagement in goal-directed responses and reduced processing of negative or unexpected cues, which impairs adequate behavioral regulation after feedback in these individuals. This pattern is manifested through deficits in inhibitory control and/or increases in RT variability. In the present work, we aimed to test whether this profile is associated with the activity of functional networks during a stop-signal task using independent component analysis (ICA). Sixty-one participants underwent fMRI while performing a stop-signal task, during which a manual response had to be inhibited. ICA was used to mainly replicate the functional networks involved in the task (Zhang and Li, 2012): two motor networks involved in the go response, the left and right fronto-parietal networks for stopping, a midline error-processing network, and the default-mode network (DMN), which was further subdivided into its anterior and posterior parts. Reward sensitivity was mainly associated with greater activity of motor networks, reduced activity in the midline network during correct stop trials and, behaviorally, increased RT variability. All these variables explained 36% of variance of the SR scores. This pattern of associations suggests that reward sensitivity involves greater motor engagement in the dominant response, more distractibility and reduced processing of salient or unexpected events, which may lead to disinhibited behavior.

Reduced posterior parietal cortex activation after training on a visual search task.

Gaining experience on a cognitive task improves behavioral performance and is thought to enhance brain efficiency. Despite the body of literature already published on the effects of training on brain activation, less research has been carried out on visual search attention processes under well controlled conditions. Thirty-six healthy adults divided into trained and control groups completed a pre-post letter-based visual search task fMRI study in one day. Twelve letters were used as targets and ten as distractors. The trained group completed a training session (840 trials) with half the targets between scans. The effects of training were studied at the behavioral and brain levels by controlling for repetition effects using both between-subjects (trained vs. control groups) and within-subject (trained vs. untrained targets) controls. The trained participants reduced their response speed by 31% as a result of training, maintaining their accuracy scores, whereas the control group hardly changed. Neural results revealed that brain changes associated with visual search training were circumscribed to reduced activation in the posterior parietal cortex (PPC) when controlling for group, and they included inferior occipital areas when controlling for targets. The observed behavioral and brain changes are discussed in relation to automatic behavior development. The observed training-related decreases could be associated with increased neural efficiency in specific key regions for task performance.