Neuroscience: Boosting the brain.

A therapeutic effect of vagus nerve stimulation has been reported for a wide range of neurological, medical and psychiatric conditions. New research provides evidence that this effect results from extensive increase of physiological arousal and brain activation.

Anatomical bases of fast parietal grasp control in humans: A diffusion-MRI tractography study.

The dorso-posterior parietal cortex (DPPC) is a major node of the grasp/manipulation control network. It is assumed to act as an optimal forward estimator that continuously integrates efferent outflows and afferent inflows to modulate the ongoing motor command. In agreement with this view, a recent per-operative study, in humans, identified functional sites within DPPC that: (i) instantly disrupt hand movements when electrically stimulated; (ii) receive short-latency somatosensory afferences from intrinsic hand muscles. Based on these results, it was speculated that DPPC is part of a rapid grasp control loop that receives direct inputs from the hand-territory of the primary somatosensory cortex (S1) and sends direct projections to the hand-territory of the primary motor cortex (M1). However, evidence supporting this hypothesis is weak and partial. To date, projections from DPPC to M1 grasp zone have been identified in monkeys and have been postulated to exist in humans based on clinical and transcranial magnetic studies. This work uses diffusion-MRI tractography in two samples of right- (n = 50) and left-handed (n = 25) subjects randomly selected from the Human Connectome Project. It aims to determine whether direct connections exist between DPPC and the hand control sectors of the primary sensorimotor regions. The parietal region of interest, related to hand control (hereafter designated DPPChand), was defined permissively as the 95% confidence area of the parietal sites that were found to disrupt hand movements in the previously evoked per-operative study. In both hemispheres, irrespective of handedness, we found dense ipsilateral connections between a restricted part of DPPChand and focal sectors within the pre and postcentral gyrus. These sectors, corresponding to the hand territories of M1 and S1, targeted the same parietal zone (spatial overlap > 92%). As a sensitivity control, we searched for potential connections between the angular gyrus (AG) and the pre and postcentral regions. No robust pathways were found. Streamline densities identified using AG as the starting seed represented less than 5 % of the streamline densities identified from DPPChand. Together, these results support the existence of a direct sensory-parietal-motor loop suited for fast manual control and more generally, for any task requiring rapid integration of distal sensorimotor signals.

Cerebellar lesions at a young age predict poorer long-term functional recovery.

Early studies on long-term functional recovery after motor and premotor lesions showed better outcomes in younger monkeys than in older monkeys. This finding led to the widespread belief that brain injuries cause less impairment in children than adults. However, this view has limitations and a large body of evidence now indicates that cerebral damages can be more harmful when inflicted at young age, during critical periods of neural development. To date, this issue has been mainly investigated in the context of focal and diffuse cortical lesions. Much less is known about the potential influence of early cerebellar damages. Several studies exist in survivor of posterior fossa tumours. However, in these studies, critical confounders were not always considered and contradictory conclusions were provided. We studied the impact or early cerebellar damage on long-term functional recovery in three groups of 15 posterior fossa survivors, comparable with respect to their tumour characteristics (type, size and location) but operated at different ages: young (≤7 years), middle (>7 and ≤13 years) and older (>13 years). Daily (health-related quality of life scale, performance status scale), motor (International Cooperative Ataxia Rating Scale, Pegboard Purdue Test) and cognitive (full-scale intelligence quotient) functioning were assessed. A general linear model controlling for age at surgery, radiotherapy, preservation of deep cerebellar nuclei, tumour volume and delay between surgery and assessment was used to investigate significant variations in outcome measures. Early age at surgery, lesion of deep cerebellar nuclei and postoperative radiotherapy had a significant, independent negative influence on long-term recovery. Tumour volume and delay between surgery and assessment had no statistically detectable impact. The negative influence of early age at surgery was significant in all domains: daily functioning (health-related quality of life scale, performance status scale), motor functioning (International Cooperative Ataxia Rating Scale, Pegboard Purdue Test) and cognitive functioning (full-scale intelligence quotient). These results support the existence of an early critical period of development during which the cerebellar 'learning machine' is of critical importance. Although the extent to which the early deficits here observed can be reversed needs now to be established, our data plead for the implementation of prompt and intense rehabilitation interventions in children operated before 7 years of age.

Awake brain surgery in children-a single-center experience.

INTRODUCTION: Awake brain surgery (ABS) represents a rare surgical procedure in children as age and psychological aspects, which are considered to interfere with its feasibility and psychological outcome and limit its application. Only few pediatric case series have been reported so far, indicating a more complex translation of this surgical approach to children. However, the advances in neuropsychological testing and monitoring may have a substantial impact on ameliorating the eligibility of children undergoing awake procedures. This study addresses the condition of ABS in a pediatric cohort, focusing on its practicability and diversified outcome aspects. METHODS: We performed a retrospective review and prospective outcome analysis of pediatric patients with CNS lesions undergoing ABS between 2005 and 2018, completed at the University of Lyon, France. RESULTS: Eighteen children were considered for ABS with respect to the eloquent location of their CNS lesions documented in their pre-operative MRI. Seventeen of them underwent asleep-awake-asleep brain surgery. The cohort included 5 males and 12 females. The median age at surgery was 14.8 years, (range 9.4 to 17.6 years). Intraoperative testing included electrocortical stimulation while pursuing speech or motor activity. Most of the lesions were intrinsic tumors of glial origin. A complete tumor removal was achieved in 11 patients (65%). Post-operative neurological deficits were transiently observed in 2 patients, whereas severe psychological reactions occurred in 1 child. Persistent attention deficits were found in 2 patients. One patient experienced an infectious complication requiring antibiotic treatment. Two patients died during follow-up due to tumor progression. The mean duration of follow up was 22.2 months (range 3.4 to 46.8 months). CONCLUSIONS: ABS was shown to be beneficial in terms of efficient tumor resection besides simultaneous preservation of neurological functions. Psychological preparation of the families and the children is essential to increase the number and age range of patients, who can benefit from this technique. Neuropsychological testing before and after surgery is essential to determine cognitive outcome, which can be altered in a minority of patients.

Psychological aspects of awake brain surgery in children-interests and risks.

Awake brain surgery (ABS) in children remains a subject of controversial debate for the potential psychological limitations that are related to this type of procedure. However, the tolerance and benefits of ABS in adults advocate for increased application of ABS in children. In this study, we report the psychological assessment, evaluation algorithm, and outcome of pediatric patients, who underwent ABS for surgical treatment of lesions in eloquent areas. Psychological selection criteria and the specifications of psychological support are described. A retrospective review and analysis of psychological assessment and psychological outcome of pediatric patients, who underwent ABS between 2005 and 2018 at the Department of pediatric neurosurgery, University of Lyon, France, was performed. Long-term psychological outcomes are reported. ABS was proposed to 18 children aged between 9 and 17 years and their families. After psychological evaluation of the individual patient and their familial surrounding, five boys and 12 girls (n = 17) were accounted eligible for ABS. They underwent asleep-awake-asleep brain surgery with intraoperative testing. In 16 cases, ABS could be performed as planned. Psychological alterations were postoperatively observed in 3 patients, symptoms of a post-traumatic stress disorder in 1 patient. The precise preoperative evaluation of the risk-benefit ratio in children plays a crucial role in anticipating a good psychological outcome. Professional psychological preparation and support of the child and his or her family are the key elements for successful completion of ABS.

Superstitious beliefs and the associative mind.

Persistence of superstitions in the modern era could be justified by considering them as a by-product of the brain's capacity to detect associations and make assumptions about cause-effect relationships. This ability, which supports predictive behaviour, directly relates to associative learning. We tested whether variability in superstitious behaviour reflects individual variability in the efficiency of mechanisms akin to habit learning. Forty-eight individuals performed a Serial Reaction Time Task (SRTT) or an Implicit Cuing Task (ICT). In the SRTT, participants were exposed to a hidden sequence and progressively learnt to optimize responses, a process akin to skill learning. In the ICT participants met with a hidden association, which (if detected) provided a benefit (cf. habit learning). An index of superstitious beliefs was also collected. A correlation emerged between susceptibility to personal superstitions and performance at the ICT only. This novel finding is discussed in view of current ideas on how superstitions are instated.

How did I get so late so soon? A review of time processing and management in autism.

While the definition of Autism Spectrum Disorder (ASD) does not include any explicit criteria concerning difficulties of time perception or management, there is growing evidence of atypical temporal perception in individuals with ASD. This review synthesizes the evidence and gaps of the current literature on time processing in ASD. After a brief overview of clinical findings and available assessment tools, we synthetize outcomes of studies evaluating time perception at second and infra-second level, and then, recent literature on the circadian timing system. Findings point that all levels of time processing are atypical in autism (i.e. millisecond, interval and circadian timing). We discuss how time perception abnormalities and ASD core symptoms might intertwine and offer a new perspective for future research on this topic. We advocate the need to systematically assess temporal perception in ASD, and to include these aspects in global functional assessments before intervention. Implementing early intervention techniques to remediate time perception alterations in children with ASD may substantially improve their developmental trajectory.

Awake brain surgery in children-review of the literature and state-of-the-art.

OBJECTIVE: Awake brain surgery (ABS) is poorly reported in children as it is considered having limited indications due to age and neuropsychological aspects interfering with its feasibility and psychological outcome. The aim of this article is to review the current state-of-the-art of ABS in children and to offer an objective summary of the published literature on diversified outcome aspects of pediatric awake procedures. METHODS: A literature review was performed using the MEDLINE (PubMed) electronic database applying the following MeSH terms to the keyword search within titles and abstracts: "awake brain surgery children," "awake brain surgery pediatric," "awake craniotomy children," "awake craniotomy pediatric," and "awake surgery children." Of the initial 753 results obtained from these keyword searches, a full text screening of 51 publications was performed, ultimately resulting in 18 eligible articles for this review. RESULTS: A total of 18 full text articles reporting the results of 50 patients were included in the analysis. Sixteen of the 18 studies were retrospective studies, comprising 7 case series, 9 case reports, and 2 reviews. Eleven studies were conducted from anesthesiological (25 patients) and 7 from neurosurgical (25 patients) departments. Most of the patients underwent ABS for supratentorial lesions (26 patients), followed by epilepsy surgery (16 patients) and deep brain stimulation (DBS) (8 patients). The median age was 15 years (range 8-17 years). Persistent deficits occurred in 6 patients, (12%), corresponding to minor motor palsies (4%) and neuropsychological concerns (8%). An awake procedure was aborted in 2 patients (4%) due to cooperation failure and anxiety, respectively. CONCLUSIONS: Despite well-documented beneficial aspects, ABS remains mainly limited to adults. This review confirms a reliable tolerability of ABS in selected children; however, recommendations and guidelines for its standardized implementation in this patient group are pending. Recommendations and guidelines may address diagnostic workup and intra-operative handling besides criteria of eligibility, psychological preparation, and coordinated neuropsychological testing in order to routinely offer ABS to children.

Willingness towards cognitive engagement: a preliminary study based on a behavioural entropy approach.

Faced with a novel task some people enthusiastically embark in it and work with determination, while others soon lose interest and progressively reduce their efforts. Although cognitive neuroscience has explored the behavioural and neural features of apathy, the why's and how's of positive engagement are only starting to be understood. Stemming from the observation that the left hemisphere is commonly associated to a proactive ('do something') disposition, we run a preliminary study exploring the possibility that individual variability in eagerness to engage in cognitive tasks could reflect a preferred left- or right-hemisphere functioning mode. We adapted a task based on response-independent reinforcement and used entropy to characterize the degree of involvement, diversification, and predictability of responses. Entropy was higher in women, who were overall more active, less dependent on instructions, and never reduced their engagement during the task. Conversely, men showed lower entropy, took longer pauses, and became significantly less active by the end of the allotted time, renewing their efforts mainly in response to negative incentives. These findings are discussed in the light of neurobiological data on gender differences in behaviour.

Selective Inhibition of Volitional Hand Movements after Stimulation of the Dorsoposterior Parietal Cortex in Humans.

Inhibition is a central component of motor control. Although current models emphasize the involvement of frontal networks [1, 2], indirect evidence suggests a potential contribution of the posterior parietal cortex (PPC). This region is active during inhibition of upper-limb movements to undesired targets [3], and its stimulation with single magnetic pulses can depress motor-evoked potentials [4, 5]. Also, it has been speculated that alien hand movements caused by focal parietal lesions reflect a release of inhibition from PPC to M1 [6]. Considering these observations, we instructed 16 patients undergoing awake brain surgery to perform continuous hand movements while electrical stimulation was applied over PPC. Within a restricted dorsoposterior area, we identified focal sites where stimulation prevented movement initiation and instantly inhibited ongoing responses (which restarted promptly at stimulation offset). Inhibition was selective of the instructed response. It did not affect speech, hand movements passively generated through muscle electrical stimulation, or the ability to initiate spontaneous actions with other body segments (e.g., the feet). When a patient inadvertently performed a bilateral movement, a bilateral inhibition was found. When asked to produce unilateral movements, this patient presented a contralesional but not ipsilateral inhibition. This selectivity contrasted sharply with the unspecific inhibitions reported by previous studies within frontal regions, where speech and all limbs are typically affected (as we here confirm in a subset of patients) [7-10]. These results provide direct evidence that a specific area in the dorsoposterior parietal cortex can inhibit volitional upper-limb responses with high selectivity.

Restoring consciousness with vagus nerve stimulation.

Patients lying in a vegetative state present severe impairments of consciousness [1] caused by lesions in the cortex, the brainstem, the thalamus and the white matter [2]. There is agreement that this condition may involve disconnections in long-range cortico-cortical and thalamo-cortical pathways [3]. Hence, in the vegetative state cortical activity is 'deafferented' from subcortical modulation and/or principally disrupted between fronto-parietal regions. Some patients in a vegetative state recover while others persistently remain in such a state. The neural signature of spontaneous recovery is linked to increased thalamo-cortical activity and improved fronto-parietal functional connectivity [3]. The likelihood of consciousness recovery depends on the extent of brain damage and patients' etiology, but after one year of unresponsive behavior, chances become low [1]. There is thus a need to explore novel ways of repairing lost consciousness. Here we report beneficial effects of vagus nerve stimulation on consciousness level of a single patient in a vegetative state, including improved behavioral responsiveness and enhanced brain connectivity patterns.

Revealing humans' sensorimotor functions with electrical cortical stimulation.

Direct electrical stimulation (DES) of the human brain has been used by neurosurgeons for almost a century. Although this procedure serves only clinical purposes, it generates data that have a great scientific interest. Had DES not been employed, our comprehension of the organization of the sensorimotor systems involved in movement execution, language production, the emergence of action intentionality or the subjective feeling of movement awareness would have been greatly undermined. This does not mean, of course, that DES is a gold standard devoid of limitations and that other approaches are not of primary importance, including electrophysiology, modelling, neuroimaging or psychophysics in patients and healthy subjects. Rather, this indicates that the contribution of DES cannot be restricted, in humans, to the ubiquitous concepts of homunculus and somatotopy. DES is a fundamental tool in our attempt to understand the human brain because it represents a unique method for mapping sensorimotor pathways and interfering with the functioning of localized neural populations during the performance of well-defined behavioural tasks.

Dissociable contribution of the parietal and frontal cortex to coding movement direction and amplitude.

To reach for an object, we must convert its spatial location into an appropriate motor command, merging movement direction and amplitude. In humans, it has been suggested that this visuo-motor transformation occurs in a dorsomedial parieto-frontal pathway, although the causal contribution of the areas constituting the "reaching circuit" remains unknown. Here we used transcranial magnetic stimulation (TMS) in healthy volunteers to disrupt the function of either the medial intraparietal area (mIPS) or dorsal premotor cortex (PMd), in each hemisphere. The task consisted in performing step-tracking movements with the right wrist towards targets located in different directions and eccentricities; targets were either visible for the whole trial (Target-ON) or flashed for 200 ms (Target-OFF). Left and right mIPS disruption led to errors in the initial direction of movements performed towards contralateral targets. These errors were corrected online in the Target-ON condition but when the target was flashed for 200 ms, mIPS TMS manifested as a larger endpoint spreading. In contrast, left PMd virtual lesions led to higher acceleration and velocity peaks-two parameters typically used to probe the planned movement amplitude-irrespective of the target position, hemifield and presentation condition; in the Target-OFF condition, left PMd TMS induced overshooting and increased the endpoint dispersion along the axis of the target direction. These results indicate that left PMd intervenes in coding amplitude during movement preparation. The critical TMS timings leading to errors in direction and amplitude were different, namely 160-100 ms before movement onset for mIPS and 100-40 ms for left PMd. TMS applied over right PMd had no significant effect. These results demonstrate that, during motor preparation, direction and amplitude of goal-directed movements are processed by different cortical areas, at distinct timings, and according to a specific hemispheric organization.

Movement-related discharge in the macaque globus pallidus during high-frequency stimulation of the subthalamic nucleus.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) has largely replaced ablative therapies for Parkinson's disease. Because of the similar efficacies of the two treatments, it has been proposed that DBS acts by creating an "informational lesion," whereby pathologic neuronal firing patterns are replaced by low-entropy, stimulus-entrained firing patterns. The informational lesion hypothesis, in its current form, states that DBS blocks the transmission of all information from the basal ganglia, including both pathologic firing patterns and normal, task-related modulations in activity. We tested this prediction in two healthy rhesus macaques by recording single-unit spiking activity from the globus pallidus (232 neurons) while the animals completed choice reaction time reaching movements with and without STN-DBS. Despite strong effects of DBS on the activity of most pallidal cells, reach-related modulations in firing rate were equally prevalent in the DBS-on and DBS-off states. This remained true even when the analysis was restricted to cells affected significantly by DBS. In addition, the overall form and timing of perimovement modulations in firing rate were preserved between DBS-on and DBS-off states in the majority of neurons (66%). Active movement and DBS had largely additive effects on the firing rate of most neurons, indicating an orthogonal relationship in which both inputs contribute independently to the overall firing rate of pallidal neurons. These findings suggest that STN-DBS does not act as an indiscriminate informational lesion but rather as a filter that permits task-related modulations in activity while, presumably, eliminating the pathological firing associated with parkinsonism.

The dorsal medial frontal cortex mediates automatic motor inhibition in uncertain contexts: evidence from combined fMRI and EEG studies.

Response inhibition is commonly thought to rely on voluntary, reactive, selective, and relatively slow prefrontal mechanisms. In contrast, we suggest here that response inhibition is achieved automatically, nonselectively, within very short delays in uncertain environments. We modified a classical go/nogo protocol to probe context-dependent inhibitory mechanisms. Because no single neuroimaging method can definitely disentangle neural excitation and inhibition, we combined fMRI and EEG recordings in healthy humans. Any stimulus (go or nogo) presented in an uncertain context requiring action restraint was found to evoke activity changes in the supplementary motor complex (SMC) with respect to a control condition in which no response inhibition was required. These changes included: (1) An increase in event-related BOLD activity, (2) an attenuation of the early (170 ms) event related potential generated by a single, consistent source isolated by advanced blind source separation, and (3) an increase in the evoked-EEG Alpha power of this source. Considered together, these results suggest that the BOLD signal evoked by any stimulus in the SMC when the situation is unpredictable can be driven by automatic, nonselective, context-dependent inhibitory activities. This finding reveals the paradoxical mechanisms by which voluntary control of action may be achieved. The ability to provide controlled responses in unpredictable environments would require setting-up the automatic self-inhibitory circuitry within the SMC. Conversely, enabling automatic behavior when the environment becomes predictable would require top-down control to deactivate anticipatorily and temporarily the inhibitory set.

Neural representations of ethologically relevant hand/mouth synergies in the human precentral gyrus.

Complex motor responses are often thought to result from the combination of elemental movements represented at different neural sites. However, in monkeys, evidence indicates that some behaviors with critical ethological value, such as self-feeding, are represented as motor primitives in the precentral gyrus (PrG). In humans, such primitives have not yet been described. This could reflect well-known interspecies differences in the organization of sensorimotor regions (including PrG) or the difficulty of identifying complex neural representations in peroperative settings. To settle this alternative, we focused on the neural bases of hand/mouth synergies, a prominent example of human behavior with high ethological value. By recording motor- and somatosensory-evoked potentials in the PrG of patients undergoing brain surgery (2-60 y), we show that two complex nested neural representations can mediate hand/mouth actions within this structure: (i) a motor representation, resembling self-feeding, where electrical stimulation causes the closing hand to approach the opening mouth, and (ii) a motor-sensory representation, likely associated with perioral exploration, where cross-signal integration is accomplished at a cortical site that generates hand/arm actions while receiving mouth sensory inputs. The first finding extends to humans' previous observations in monkeys. The second provides evidence that complex neural representations also exist for perioral exploration, a finely tuned skill requiring the combination of motor and sensory signals within a common control loop. These representations likely underlie the ability of human children and newborns to accurately produce coordinated hand/mouth movements, in an otherwise general context of motor immaturity.

Re-establishing the merits of electrical brain stimulation.

During the past decades, direct electrical stimulation (DES) has been a key method not only in determining the organization of brain networks mediating movement, language, and cognition but also in establishing many central concepts of modern neuroscience, such as the electrical nature of neural transmission, the localization of brain functions, and the homuncular arrangement of sensorimotor areas. However, recent criticisms have questioned the utility of DES and argued that data collected with this technique may be flawed and unreliable. As with every other neuroscientific method, DES does have limitations. However, existing evidence argues strongly for its validity and usefulness by demonstrating that DES produces highly specific outcomes at well-defined anatomical sites and significantly minimizes postoperative deficits in brain-damaged patients.

Searching for the neural correlates of conscious intention.

It is typically assumed that the conscious experience of wanting to move is not the driving force for motor planning, but the secondary consequence of the unconscious neural processes preparing the movement. A recent study by Schneider et al. [Schneider, L., Houdayer, E., Bai, O., & Hallett, M. What we think before a voluntary movement. Journal of Cognitive Neuroscience, 25, 822-829, 2013] seems consistent with this dominant view by showing that the brain can be preparing to make voluntary movements not only "prior to the conscious appreciation that this is happening" but also "while subjects are thinking about something else." However, an alternative hypothesis exists. It is supported by several lines of evidence and suggests that the early neural signals recorded by Schneider et al. (and others) do not reflect movement preparation per se, but rather a buildup in neural activity that ultimately leads to the emergence of a conscious intention to move. According to this view, the conscious experience of wanting to move is not the consequence but the cause of movement initiation.

A common optimization principle for motor execution in healthy subjects and parkinsonian patients.

Recent research on Parkinson's disease (PD) has emphasized that parkinsonian movement, although bradykinetic, shares many attributes with healthy behavior. This observation led to the suggestion that bradykinesia in PD could be due to a reduction in motor motivation. This hypothesis can be tested in the framework of optimal control theory, which accounts for many characteristics of healthy human movement while providing a link between the motor behavior and a cost/benefit trade-off. This approach offers the opportunity to interpret movement deficits of PD patients in the light of a computational theory of normal motor control. We studied 14 PD patients with bilateral subthalamic nucleus (STN) stimulation and 16 age-matched healthy controls, and tested whether reaching movements were governed by similar rules in these two groups. A single optimal control model accounted for the reaching movements of healthy subjects and PD patients, whatever the condition of STN stimulation (on or off). The choice of movement speed was explained in all subjects by the existence of a preset dynamic range for the motor signals. This range was idiosyncratic and applied to all movements regardless of their amplitude. In PD patients this dynamic range was abnormally narrow and correlated with bradykinesia. STN stimulation reduced bradykinesia and widened this range in all patients, but did not restore it to a normal value. These results, consistent with the motor motivation hypothesis, suggest that constrained optimization of motor effort is the main determinant of movement planning (choice of speed) and movement production, in both healthy and PD subjects.