Uremic Toxins and Inflammation: Metabolic Pathways Affected in Non-Dialysis-Dependent Stage 5 Chronic Kidney Disease.

Chronic kidney disease (CKD) affects approximately 12% of the global population, posing a significant health threat. Inflammation plays a crucial role in the uremic phenotype of non-dialysis-dependent (NDD) stage 5 CKD, contributing to elevated cardiovascular and overall mortality in affected individuals. This study aimed to explore novel metabolic pathways in this population using semi-targeted metabolomics, which allowed us to quantify numerous metabolites with known identities before data acquisition through an in-house polar compound library. In a prospective observational design with 50 patients, blood samples collected before the initial hemodialysis session underwent liquid chromatography and high-resolution mass spectrometer analysis. Univariate (Mann-Whitney test) and multivariate (logistic regression with LASSO regularization) methods identified metabolomic variables associated with inflammation. Notably, adenosine-5'-phosphosulfate (APS), dimethylglycine, pyruvate, lactate, and 2-ketobutyric acid exhibited significant differences in the presence of inflammation. Cholic acid, homogentisic acid, and 2-phenylpropionic acid displayed opposing patterns. Multivariate analysis indicated increased inflammation risk with certain metabolites (N-Butyrylglycine, dimethylglycine, 2-Oxoisopentanoic acid, and pyruvate), while others (homogentisic acid, 2-Phenylpropionic acid, and 2-Methylglutaric acid) suggested decreased probability. These findings unveil potential inflammation-associated biomarkers related to defective mitochondrial fatty acid beta oxidation and branched-chain amino acid breakdown in NDD stage 5 CKD, shedding light on cellular energy production and offering insights for further clinical validation.

Early response competition over the motor cortex underlies proactive control of error correction.

Response inhibition is a fundamental brain function that must be flexible enough to incorporate proactive goal-directed demands, along with reactive, automatic and well consolidated behaviors. However, whether proactive inhibitory processes can be explained by response competition, rather than by active top-down inhibitory control, remains still unclear. Using a modified version of the Eriksen flanker task, we examined the behavioral and electrophysiological correlates elicited by manipulating the degree of inhibitory control in a task that involved the fast amendment of errors. We observed that restraining or encouraging the correction of errors did not affect the behavioral and neural correlates associated to reactive inhibition. We rather found that an early, sustained and bilateral activation, of both the correct and the incorrect response, was required for an effective proactive inhibitory control. Selective unilateral patterns of response preparation were instead associated with defective response suppression. Our results provide behavioral and electrophysiological evidence of a simultaneous dual pre-activation of two motor commands, likely underlying a global operating mechanism suggesting competition or lateral inhibition to govern the amendment of errors. These findings are consistent with the response inhibitory processes already observed in speed-accuracy tradeoff studies, and hint at a decisive role of early response competition to determine the success of multiple-choice action selection.

Causal modulation of right hemisphere fronto-parietal phase synchrony with Transcranial Magnetic Stimulation during a conscious visual detection task.

Correlational evidence in non-human primates has reported increases of fronto-parietal high-beta (22-30 Hz) synchrony during the top-down allocation of visuo-spatial attention. But may inter-regional synchronization at this specific frequency band provide a causal mechanism by which top-down attentional processes facilitate conscious visual perception? To address this question, we analyzed electroencephalographic (EEG) signals from a group of healthy participants who performed a conscious visual detection task while we delivered brief (4 pulses) rhythmic (30 Hz) or random bursts of Transcranial Magnetic Stimulation (TMS) to the right Frontal Eye Field (FEF) prior to the onset of a lateralized target. We report increases of inter-regional synchronization in the high-beta band (25-35 Hz) between the electrode closest to the stimulated region (the right FEF) and right parietal EEG leads, and increases of local inter-trial coherence within the same frequency band over bilateral parietal EEG contacts, both driven by rhythmic but not random TMS patterns. Such increases were accompained by improvements of conscious visual sensitivity for left visual targets in the rhythmic but not the random TMS condition. These outcomes suggest that high-beta inter-regional synchrony can be modulated non-invasively and that high-beta oscillatory activity across the right dorsal fronto-parietal network may contribute to the facilitation of conscious visual perception. Our work supports future applications of non-invasive brain stimulation to restore impaired visually-guided behaviors by operating on top-down attentional modulatory mechanisms.

Integrating when and what information in the left parietal lobe allows language rule generalization.

A crucial aspect when learning a language is discovering the rules that govern how words are combined in order to convey meanings. Because rules are characterized by sequential co-occurrences between elements (e.g., "These cupcakes are unbelievable"), tracking the statistical relationships between these elements is fundamental. However, purely bottom-up statistical learning alone cannot fully account for the ability to create abstract rule representations that can be generalized, a paramount requirement of linguistic rules. Here, we provide evidence that, after the statistical relations between words have been extracted, the engagement of goal-directed attention is key to enable rule generalization. Incidental learning performance during a rule-learning task on an artificial language revealed a progressive shift from statistical learning to goal-directed attention. In addition, and consistent with the recruitment of attention, functional MRI (fMRI) analyses of late learning stages showed left parietal activity within a broad bilateral dorsal frontoparietal network. Critically, repetitive transcranial magnetic stimulation (rTMS) on participants' peak of activation within the left parietal cortex impaired their ability to generalize learned rules to a structurally analogous new language. No stimulation or rTMS on a nonrelevant brain region did not have the same interfering effect on generalization. Performance on an additional attentional task showed that this rTMS on the parietal site hindered participants' ability to integrate "what" (stimulus identity) and "when" (stimulus timing) information about an expected target. The present findings suggest that learning rules from speech is a two-stage process: following statistical learning, goal-directed attention-involving left parietal regions-integrates "what" and "when" stimulus information to facilitate rapid rule generalization.

Entrainment of local synchrony reveals a causal role for high-beta right frontal oscillations in human visual consciousness.

Prior evidence supports a critical role of oscillatory activity in visual cognition, but are cerebral oscillations simply correlated or causally linked to our ability to consciously acknowledge the presence of a target in our visual field? Here, EEG signals were recorded on humans performing a visual detection task, while they received brief patterns of rhythmic or random transcranial magnetic stimulation (TMS) delivered to the right Frontal Eye Field (FEF) prior to the onset of a lateralized target. TMS entrained oscillations, i.e., increased high-beta power and phase alignment (the latter to a higher extent for rhythmic high-beta patterns than random patterns) while also boosting visual detection sensitivity. Considering post-hoc only those participants in which rhythmic stimulation enhanced visual detection, the magnitude of high-beta entrainment correlated with left visual performance increases. Our study provides evidence in favor of a causal link between high-beta oscillatory activity in the Frontal Eye Field and visual detection. Furthermore, it supports future applications of brain stimulation to manipulate local synchrony and improve or restore impaired visual behaviors.

Unexpected Improvement of Hand Motor Function with a Left Temporoparietal Low-Frequency Repetitive Transcranial Magnetic Stimulation Regime Suppressing Auditory Hallucinations in a Brainstem Chronic Stroke Patient.

We here report paradoxical hand function recovery in a 61-year-old male tetra-paretic chronic patient following a stroke of the brainstem (with highly degraded right and abolished left-hand finger flexion/extension disabling him to manipulate objects) who experienced insidious auditory hallucinations (AHs) 4 years after such event. Symptomatic treatment for AHs was provided with periodical double sessions of low-frequency repetitive transcranial magnetic stimulation (rTMS) (daily 1 Hz, 2 × 1,200 pulses interleaved by 1 h interval) delivered to the left temporoparietal junction across two periods of 5 and 3 weeks, respectively. At the end of each stimulation period, AHs disappeared completely. Most surprisingly and totally unexpectedly, the patient experienced beneficial improvements of long-lasting impairments in his right-hand function. Detailed examination of onset and offset of rTMS stimulation regimes strongly suggests a temporal relation with the remission and re-appearance of AHs and also with a fragile but clinically meaningful improvements of right (but not left) hand function contingent to the accrual of stimulation sessions. On the basis of post-recovery magnetic resonance imaging structural and functional evidence, mechanistic hypotheses that could subtend such unexpected motor recovery are critically discussed.

Transcranial magnetic stimulation in basic and clinical neuroscience: A comprehensive review of fundamental principles and novel insights.

Non-invasive brain stimulation methods, such as Transcranial Magnetic Stimulation (TMS), are widely used worldwide to make causality-based inferences about brain-behavior interactions. TMS-based clinical applications have been shown promising to treat neurological or psychiatric diseases. TMS works by inducing non-invasively electric currents in localized cortical regions thus modulating their excitability levels and ongoing activity patterns depending on stimulation settings: frequency, number of pulses, train duration and intertrain intervals. Proper use of TMS in the fundamental and clinical neuroscience research requires a deep understanding of its operational principles, risks, potential and limitations. In this article we present the principles through which TMS is thought to operate. Readers will be provided with the bases to be able to understand and critically discuss TMS studies and design hypothesis driven TMS applications for basic and clinical neuroscience. Moreover, some recently identified physiological phenomena which that can dramatically influence the efficacy and magnitude of TMS impact and technological and methodological developments to guide TMS interventions that are becoming mainstream in the field will be also reviewed.

Local entrainment of oscillatory activity induced by direct brain stimulation in humans.

In a quest for direct evidence of oscillation entrainment, we analyzed intracerebral electroencephalographic recordings obtained during intracranial electrical stimulation in a cohort of three medication-resistant epilepsy patients tested pre-surgically. Spectral analyses of non-epileptogenic cerebral sites stimulated directly with high frequency electrical bursts yielded episodic local enhancements of frequency-specific rhythmic activity, phase-locked to each individual pulse. These outcomes reveal an entrainment of physiological oscillatory activity within a frequency band dictated by the rhythm of the stimulation source. Our results support future uses of rhythmic stimulation to elucidate the causal contributions of synchrony to specific aspects of human cognition and to further develop the therapeutic manipulation of dysfunctional rhythmic activity subtending the symptoms of some neuropsychiatric conditions.

Microstructure of the superior longitudinal fasciculus predicts stimulation-induced interference with on-line motor control.

A cortical visuomotor network, comprising the medial intraparietal sulcus (mIPS) and the dorsal premotor area (PMd), encodes the sensorimotor transformations required for the on-line control of reaching movements. How information is transmitted between these two regions and which pathways are involved, are less clear. Here, we use a multimodal approach combining repetitive transcranial magnetic stimulation (rTMS) and diffusion tensor imaging (DTI) to investigate whether structural connectivity in the 'reaching' circuit is associated to variations in the ability to control and update a movement. We induced a transient disruption of the neural processes underlying on-line motor adjustments by applying 1Hz rTMS over the mIPS. After the stimulation protocol, participants globally showed a reduction of the number of corrective trajectories during a reaching task that included unexpected visual perturbations. A voxel-based analysis revealed that participants exhibiting higher fractional anisotropy (FA) in the second branch of the superior longitudinal fasciculus (SLF II) suffered less rTMS-induced behavioral impact. These results indicate that the microstructural features of the white matter bundles within the parieto-frontal 'reaching' circuit play a prominent role when action reprogramming is interfered. Moreover, our study suggests that the structural alignment and cohesion of the white matter tracts might be used as a predictor to characterize the extent of motor impairments.

Overactivation of the supplementary motor area in chronic stroke patients.

Stroke induces a loss of neural function, but it triggers a complex amount of mechanisms to compensate the associated functional impairment. The present study aims to increase our understanding of the functional reshape of the motor system observed in chronic stroke patients during the preparation and the execution of movements. A cohort of 14 chronic stroke patients with a mild-to-moderate hemiparesis and 14 matched healthy controls were included in this study. Participants were asked to perform a bimanual reaction time task synchronizing alternated responses to the presentation of a visual cue. We used Laplacian-transformed EEG activity (LT-EEG) recorded at the locations Cz and C3/C4 to study the response-locked components associated with the motor system activity during the performance of this task. Behaviorally, patients showed larger variable errors than controls in synchronizing the frequency of execution of responses to the interstimulus interval, as well as slower responses compared with controls. LT-EEG analysis showed that whereas control participants increased their supplementary motor area (SMA) activity during the preparation of all responses, patients only showed an increment of activity over this area during their first response of the sequence. More interestingly, patients showed a clear increment of the LT-EEG activity associated with SMA shortly after motor responses as compared to the control participants. Finally, patients showed a hand-dependent inhibitory activity over motor areas ipsilateral to the response hand. Overall, our findings reveal drastic differences in the temporal dynamics of the LT-EEG components associated with the activity over motor and premotor cortices in chronic stroke patients compared with matched control participants during alternated hand responses.

Conscious brain-to-brain communication in humans using non-invasive technologies.

Human sensory and motor systems provide the natural means for the exchange of information between individuals, and, hence, the basis for human civilization. The recent development of brain-computer interfaces (BCI) has provided an important element for the creation of brain-to-brain communication systems, and precise brain stimulation techniques are now available for the realization of non-invasive computer-brain interfaces (CBI). These technologies, BCI and CBI, can be combined to realize the vision of non-invasive, computer-mediated brain-to-brain (B2B) communication between subjects (hyperinteraction). Here we demonstrate the conscious transmission of information between human brains through the intact scalp and without intervention of motor or peripheral sensory systems. Pseudo-random binary streams encoding words were transmitted between the minds of emitter and receiver subjects separated by great distances, representing the realization of the first human brain-to-brain interface. In a series of experiments, we established internet-mediated B2B communication by combining a BCI based on voluntary motor imagery-controlled electroencephalographic (EEG) changes with a CBI inducing the conscious perception of phosphenes (light flashes) through neuronavigated, robotized transcranial magnetic stimulation (TMS), with special care taken to block sensory (tactile, visual or auditory) cues. Our results provide a critical proof-of-principle demonstration for the development of conscious B2B communication technologies. More fully developed, related implementations will open new research venues in cognitive, social and clinical neuroscience and the scientific study of consciousness. We envision that hyperinteraction technologies will eventually have a profound impact on the social structure of our civilization and raise important ethical issues.

Linking motor-related brain potentials and velocity profiles in multi-joint arm reaching movements.

The study of the movement related brain potentials (MRPBs) needs accurate technical approaches to disentangle the specific patterns of bran activity during the preparation and execution of movements. During the last forty years, synchronizing the electromyographic activation (EMG) of the muscle with electrophysiological recordings (EEG) has been commonly ussed for these purposes. However, new clinical approaches in the study of motor diseases and rehabilitation suggest the demand of new paradigms that might go further into the study of the brain activity associated with the kinematics of movements. As a response to this call, we have used a 3-D hand-tracking system with the aim to record continuously the position of an ultrasonic sender attached to the hand during the performance of multi-joint self-paced movements. We synchronized time-series of position and velocity of the sender with the EEG recordings, obtaining specific patterns of brain activity as a function of the fluctuations of the kinematics during natural movement performance. Additionally, the distribution of the brain activity during the preparation and execution phases of movements was similar that reported previously using the EMG, suggesting the validity of our technique. We claim that this paradigm could be usable in patients because of its simplicity and the potential knowledge that can be extracted from clinical protocols.

Plasticity in the sensorimotor cortex induced by Music-supported therapy in stroke patients: a TMS study.

Playing a musical instrument demands the engagement of different neural systems. Recent studies about the musician's brain and musical training highlight that this activity requires the close interaction between motor and somatosensory systems. Moreover, neuroplastic changes have been reported in motor-related areas after short and long-term musical training. Because of its capacity to promote neuroplastic changes, music has been used in the context of stroke neurorehabilitation. The majority of patients suffering from a stroke have motor impairments, preventing them to live independently. Thus, there is an increasing demand for effective restorative interventions for neurological deficits. Music-supported Therapy (MST) has been recently developed to restore motor deficits. We report data of a selected sample of stroke patients who have been enrolled in a MST program (1 month intense music learning). Prior to and after the therapy, patients were evaluated with different behavioral motor tests. Transcranial Magnetic Stimulation (TMS) was applied to evaluate changes in the sensorimotor representations underlying the motor gains observed. Several parameters of excitability of the motor cortex were assessed as well as the cortical somatotopic representation of a muscle in the affected hand. Our results revealed that participants obtained significant motor improvements in the paretic hand and those changes were accompanied by changes in the excitability of the motor cortex. Thus, MST leads to neuroplastic changes in the motor cortex of stroke patients which may explain its efficacy.

Negative reward expectations in Borderline Personality Disorder patients: neurophysiological evidence.

Borderline Personality Disorder (BPD) patients present profound disturbances in affect regulation and impulse control which could reflect a dysfunction in reward-related processes. The current study investigated these processes in a sample of 18 BPD patients and 18 matched healthy controls, using an event-related brain potentials methodology. Results revealed a reduction in the amplitude of the Feedback-Related Negativity of BPD patients, which is a neurophysiological index of the impact of negative feedback in reward-related tasks. This reduction, in the effect of negative feedback in BPD patients, was accompanied by a different behavioral pattern of risk choice compared to healthy participants. These findings confirm a dysfunctional reward system in BDP patients, which might compromise their capacity to build positive expectations of future rewards and decision making.

Sensorimotor plasticity after music-supported therapy in chronic stroke patients revealed by transcranial magnetic stimulation.

BACKGROUND: Several recently developed therapies targeting motor disabilities in stroke sufferers have shown to be more effective than standard neurorehabilitation approaches. In this context, several basic studies demonstrated that music training produces rapid neuroplastic changes in motor-related brain areas. Music-supported therapy has been recently developed as a new motor rehabilitation intervention. METHODS AND RESULTS: In order to explore the plasticity effects of music-supported therapy, this therapeutic intervention was applied to twenty chronic stroke patients. Before and after the music-supported therapy, transcranial magnetic stimulation was applied for the assessment of excitability changes in the motor cortex and a 3D movement analyzer was used for the assessment of motor performance parameters such as velocity, acceleration and smoothness in a set of diadochokinetic movement tasks. Our results suggest that the music-supported therapy produces changes in cortical plasticity leading the improvement of the subjects' motor performance. CONCLUSION: Our findings represent the first evidence of the neurophysiological changes induced by this therapy in chronic stroke patients, and their link with the amelioration of motor performance. Further studies are needed to confirm our observations.

Prognostic value of cortically induced motor evoked activity by TMS in chronic stroke: caveats from a revealing single clinical case.

BACKGROUND: We report the case of a chronic stroke patient (62 months after injury) showing total absence of motor activity evoked by transcranial magnetic stimulation (TMS) of spared regions of the left motor cortex, but near-to-complete recovery of motor abilities in the affected hand. CASE PRESENTATION: Multimodal investigations included detailed TMS based motor mapping, motor evoked potentials (MEP), and Cortical Silent period (CSP) as well as functional magnetic resonance imaging (fMRI) of motor activity, MRI based lesion analysis and Diffusion Tensor Imaging (DTI) Tractography of corticospinal tract (CST). Anatomical analysis revealed a left hemisphere subinsular lesion interrupting the descending left CST at the level of the internal capsule. The absence of MEPs after intense TMS pulses to the ipsilesional M1, and the reversible suppression of ongoing electromyographic (EMG) activity (indexed by CSP) demonstrate a weak modulation of subcortical systems by the ipsilesional left frontal cortex, but an inability to induce efficient descending volleys from those cortical locations to right hand and forearm muscles. Functional MRI recordings under grasping and finger tapping patterns involving the affected hand showed slight signs of subcortical recruitment, as compared to the unaffected hand and hemisphere, as well as the expected cortical activations. CONCLUSIONS: The potential sources of motor voluntary activity for the affected hand in absence of MEPs are discussed. We conclude that multimodal analysis may contribute to a more accurate prognosis of stroke patients.

The involvement of audio-motor coupling in the music-supported therapy applied to stroke patients.

Music-supported therapy (MST) has been developed recently to improve the use of the affected upper extremity after stroke. MST uses musical instruments, an electronic piano and an electronic drum set emitting piano sounds, to retrain fine and gross movements of the paretic upper extremity. In this paper, we first describe the rationale underlying MST, and we review the previous studies conducted on acute and chronic stroke patients using this new neurorehabilitation approach. Second, we address the neural mechanisms involved in the motor movement improvements observed in acute and chronic stroke patients. Third, we provide some recent studies on the involvement of auditory-motor coupling in the MST in chronic stroke patients using functional neuroimaging. Finally, these ideas are discussed and focused on understanding the dynamics involved in the neural circuit underlying audio-motor coupling and how functional connectivity could help to explain the neuroplastic changes observed after therapy in stroke patients.