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•Premotor, motor and parietal areas play a differential role in correction of reaches.•Dorsal premotor cortex provides the earlier command signal to update motor plans.•Posterior ...parietal cortex is mostly involved on a continuous estimate of limb kinematics.•Same cortical assemblies encode composition and corrections of movement.•Original and new motor plans for hand movements can coexist in the cerebral cortex.
The ability of human and non-human primates to make fast corrections to hand movement trajectories after a sudden shift in the target’s location is a key feature of visuo-motor behavior. In healthy individuals, hand movements smoothly adapt to a change in target location without needing to complete the movement to the first target location, as typical of parietal patients. This finding indicates that the nervous system continuously monitors the visual scene and is able to integrate new information in order to produce an efficient motor response. In this paper, we review the kinematics, reaction times and muscle activity observed during the online correction of hand movements as well as the underlying neurophysiological processes studied through single-cell neural recordings in monkeys. Brain stimulation, lesion and imaging studies in humans are also discussed. We demonstrate that while online correction mechanisms strongly depend on the activity of a parieto-frontal network of which the posterior parietal cortex is a crucial node, these mechanisms proceed smoothly and are similar to what is observed during simple point-to-point movements. Online correction of hand movements would rely on feedforward and feedback mechanisms in the parietal cortex, as part of the activity within the fronto-parietal network for the planning and execution of visuo-motor tasks.
The ability to act jointly with others is a hallmark of primate evolution and is fundamental for human development. In recent years, the study of coordination strategies between individuals ...performing joint actions has received growing attention. However, when, in the course of post-natal development, this cognitive-motor function emerges is still unknown. Here, we studied dyads of peers aged 6–9 years, as well as adult subjects, while they performed a task where the same action, namely, exerting hand force on an isometric joystick to move a visual cursor from a central toward a peripheral target, was performed in a “solo” and in a social “cooperative” context. The results revealed that during joint action planning, an attempt to synchronize one's own action with that of a partner emerges at 7 years of age, together with a reduction in the duration and variability of the reaction times. A critical time is 8 years, when “solo” performance reaches a high level of accuracy. From this age, another coordination strategy, based on the online monitoring of the peer's behavior, seems to be implemented during the execution of joint action. The motor and cognitive development occurring during childhood are discussed as possible mechanisms mediating, respectively, the capability and the propensity to take into account the peer's behavior for implementing a common action plan.
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•We examined the ability of 6- to 9-year old children to act jointly in an isometric task.•Synchronization between peers emerged during joint action planning at 7 years age.•Coordination strategies during joint action performance emerged at 8 years age.•Successful coordination was, at least in part, based on the online monitoring of the peer's behavior.
Visuomotor deficits in parietal patients suffering from Optic Ataxia (OA) have been so far studied during natural reaching movements. We aimed at understanding if these disorders are also present ...when more abstract visuomotor transformations are involved. A patient with unilateral OA was tested during both standard reaches and isometric actions, therefore in the absence of hand displacement. Isometric action was affected similarly to standard reaches, with endpoint errors to visual targets that were found in both central and peripheral vision. The dissociation of perceptual and motor components of errors highlighted the existence of field, hand and hemispace effects, which depended on the type of error investigated. A generalization of the reaching disorder to learned isometric conditions would suggest that lesions of posterior parietal cortex (PPC) affect sensory-motor transformations not only for standard reaches, but also when visual signals need to be aligned with information from hand force receptors, therefore regardless of the specific remapping required to generate the directional motor output. The isometric impairment emerged with high and similar severity regardless of whether targets were in central or peripheral vision. Since under all isometric conditions gaze and hand position were decoupled, the spatial correspondence between the hand and the gaze seems to play a critical role in this syndrome. This indicates that regardless of the action to be performed and the specific remapping required, there exists in PPC an abstract representation of the directional motor output, where the computation of eye–hand alignment by parietal neurons plays a crucial role.
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•A patient with unilateral Optic Ataxia (OA) was tested during isometric actions.•OA appears to generalize to isometric actions, both in central and peripheral vision.•The existence of field and hand effects depends on the type of error investigated.•OA is more severe when gaze and hand position are decoupled.
Daily life often requires the coordination of our actions with those of another partner. After 50 years (1968-2018) of behavioral neurophysiology of motor control, the neural mechanisms that allow ...such coordination in primates are unknown. We studied this issue by recording cell activity simultaneously from dorsal premotor cortex (PMd) of two male interacting monkeys trained to coordinate their hand forces to achieve a common goal. We found a population of "joint-action cells" that discharged preferentially when monkeys cooperated in the task. This modulation was predictive in nature, because in most cells neural activity led in time the changes of the "own" and of the "other" behavior. These neurons encoded the joint-performance more accurately than "canonical action-related cells", activated by the action per se, regardless of the individual versus interactive context. A decoding of joint-action was obtained by combining the two brains' activities, using cells with directional properties distinguished from those associated to the "solo" behaviors. Action observation-related activity studied when one monkey observed the consequences of the partner's behavior, i.e., the cursor's motion on the screen, did not sharpen the accuracy of joint-action cells' representation, suggesting that it plays no major role in encoding joint-action. When monkeys performed with a non-interactive partner, such as a computer, joint-action cells' representation of the other (non-cooperative) behavior was significantly degraded. These findings provide evidence of how premotor neurons integrate the time-varying representation of the self-action with that of a co-actor, thus offering a neural substrate for successful visuomotor coordination between individuals.
The neural bases of intersubject motor coordination were studied by recording cell activity simultaneously from the frontal cortex of two interacting monkeys, trained to coordinate their hand forces to achieve a common goal. We found a new class of cells, preferentially active when the monkeys cooperated, rather than when the same action was performed individually. These "joint-action neurons" offered a neural representation of joint-behaviors by far more accurate than that provided by the "canonical action-related cells", modulated by the action per se regardless of the individual/interactive context. A neural representation of joint-performance was obtained by combining the activity recorded from the two brains. Our findings offer the first evidence concerning neural mechanisms subtending interactive visuomotor coordination between co-acting agents.
Major achievements of primate evolution are skilled hand-object interaction and tool use, both in part dependent on parietal cortex expansion. We recorded spiking activity from macaque inferior ...parietal cortex during directional manipulation of an isometric tool, which required the application of hand forces to control a cursor's motion on a screen. In areas PFG/PF, the activity of ∼ 70% neurons was modulated by the hand force necessary to implement the desired target motion, reflecting an inverse model, rather than by the intended motion of the visual cursor (forward model). The population vector matched the direction and amplitude of the instantaneous force increments over time. When exposed to a new force condition, that obliged the monkey to change the force output to successfully bring the cursor to the final target, the activity of a consistent subpopulation of neurons changed in an orderly fashion and, at the end of a "Wash-out" session, retained memory of the new learned association, at the service of predictive control of force. Our findings suggest that areas PFG/PF represent a crucial node of the distributed control of hand force, by encoding instantaneous force variations and serving as a memory reservoir of hand dynamics required for object manipulation and tool use. This is coherent with previous studies in humans showing the following: (1) impaired adaptation to a new force field under TMS parietal perturbation; (2) defective control of direction of hand force after parietal lesion; and (3) fMRI activation of parietal cortex during object manipulation requiring control of fine hand forces.
Skilled object manipulation and tool use are major achievements of primate evolution, both largely dependent on posterior parietal cortex (PPC) expansion. Neurophysiological and fMRI studies in macaque and humans had documented a crucial role of PPC in encoding the hand kinematics underlying these functions, leaving to premotor and motor areas the role of specifying the underlying hand forces. We recorded spiking activity from macaque PPC during manipulation of an isometric tool and found that population activity is not only modulated by the dynamic hand force and its change over time, but also retains memory of the exerted force, as a reservoir to guide of future hand action. This suggests parallel parietal encoding of hand dynamics and kinematics during object manipulation.
Abstract
STUDY QUESTION
Can high resolution array-CGH analysis on a cohort of women showing a primary ovarian insufficiency (POI) phenotype in young age identify copy number variants (CNVs) with a ...deleterious effect on ovarian function?
SUMMARY ANSWER
This approach has proved effective to clarify the role of CNVs in POI pathogenesis and to better unveil both novel candidate genes and pathogenic mechanisms.
WHAT IS KNOWN ALREADY
POI describes the progression toward the cessation of ovarian function before the age of 40 years. Genetic causes are highly heterogeneous and despite several genes being associated with ovarian failure, most of genetic basis of POI still needs to be elucidated.
STUDY DESIGN, SIZE, DURATION
The current study included 67 46,XX patients with early onset POI (<19 years) and 134 control females recruited between 2012 and 2016 at the Medical Cytogenetics and Molecular Genetics Lab, IRCCS Istituto Auxologico Italiano.
PARTICIPANTS/MATERIALS, SETTING, METHODS
High resolution array-CGH analysis was carried out on POI patients’ DNA. Results of patients and female controls were analyzed to search for rare CNVs. All variants were validated and subjected to a gene content analysis and disease gene prioritization based on the present literature to find out new ovary candidate genes. Case-control study with statistical analysis was carried out to validate our approach and evaluate any ovary CNVs/gene enrichment. Characterization of particular CNVs with molecular and functional studies was performed to assess their pathogenic involvement in POI.
MAIN RESULTS AND THE ROLE OF CHANCE
We identified 37 ovary-related CNVs involving 44 genes with a role in ovary in 32 patients. All except one of the selected CNVs were not observed in the control group. Possible involvement of the CNVs in POI pathogenesis was further corroborated by a case-control analysis that showed a significant enrichment of ovary-related CNVs/genes in patients (P = 0.0132; P = 0.0126). Disease gene prioritization identified both previously reported POI genes (e.g. BMP15, DIAPH2, CPEB1, BNC1) and new candidates supported by transcript and functional studies, such as TP63 with a role in oocyte genomic integrity and VLDLR which is involved in steroidogenesis.
LARGE SCALE DATA
ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/); accession numbers SCV000787656 to SCV000787743.
LIMITATIONS, REASONS FOR CAUTION
This is a descriptive analysis for almost all of the CNVs identified. Inheritance studies of CNVs in some non-familial sporadic cases was not performed as the parents’ DNA samples were not available. Addionally, RT-qPCR analyses were carried out in few cases as RNA samples were not always available and the genes were not expressed in blood.
WIDER IMPLICATIONS OF THE FINDINGS
Our array-CGH screening turned out to be efficient in identifying different CNVs possibly implicated in disease onset, thus supporting the extremely wide genetic heterogeneity of POI. Since almost 50% of cases are negative rare ovary-related CNVs, array-CGH together with next generation sequencing might represent the most suitable approach to obtain a comprehensive genetic characterization of POI patients.
STUDY FUNDING/COMPETING INTEREST(S)
Supported by Italian Ministry of Health grants ‘Ricerca Corrente’ (08C203_2012) and ‘Ricerca Finalizzata’ (GR-2011-02351636, BIOEFFECT) to IRCCS Istituto Auxologico Italiano.
Humans and other primates share many decision biases, among them our subjective distortion of objective probabilities. When making choices between uncertain rewards we typically treat probabilities ...nonlinearly: overvaluing low probabilities of reward and undervaluing high ones. A growing body of evidence, however, points to a more flexible pattern of distortion than the classical inverse-S one, highlighting the effect of experimental conditions in shifting the weight assigned to probabilities, such as task feedback, learning, and attention. Here we investigated the role of sequence structure (the order in which gambles are presented in a choice task) in shaping the probability distortion patterns of rhesus macaques: we presented 2 male monkeys with binary choice sequences of MIXED or REPEATED gambles against safe rewards. Parametric modeling revealed that choices in each sequence type were guided by significantly different patterns of probability distortion: whereas we elicited the classical inverse-S-shaped probability distortion in pseudorandomly MIXED trial sequences of gamble-safe choices, we found the opposite pattern consisting of S-shaped distortion, with REPEATED sequences. We extended these results to binary choices between two gambles, without a safe option, and confirmed the unique influence of the sequence structure in which the animals make choices. Finally, we showed that the value of gambles experienced in the past had a significant impact on the subjective value of future ones, shaping probability distortion on a trial-by-trial basis. Together, our results suggest that differences in choice sequence are sufficient to reverse the direction of probability distortion.
Our lives are peppered with uncertain, probabilistic choices. Recent studies showed how such probabilities are subjectively distorted. In the present study, we show that probability distortions in macaque monkeys differ significantly between sequences in which single gambles are repeated (S-shaped distortion), as opposed to being pseudorandomly intermixed with other gambles (inverse-S-shaped distortion). Our findings challenge the idea of fixed probability distortions resulting from inflexible computations, and points to a more instantaneous evaluation of probabilistic information. Past trial outcomes appeared to drive the "gap" between probability distortions in different conditions. Our data suggest that, as in most adaptive systems, probability values are slowly but constantly updated from prior experience, driving measures of probability distortion to either side of the S/inverse-S debate.
Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) ...that is associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n = 355) or with unexplained anemia (n = 177), and 592 patients with overt MN. Ninety-two of 311 (30%) patients with ICUS carried a somatic genetic lesion that signaled CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of nonanemic and anemic community-dwelling individuals, respectively. Different mutation patterns and variant allele frequencies (VAFs) (clone metrics parameters) were observed in the conditions studied. Recurrent mutation patterns exhibited different VAFs associated with marrow dysplasia (0.17-0.48), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified 2 major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR, 1.8). In patients with CCUS, the 2 clusters had different risk of progression to MN (HR, 2.7). Within the MN-like cluster, distinct subsets with different risk of progression to MN were identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical for informing clinical decision-making in patients with clonal cytopenia.
•CCUS is a precursor condition for myeloid neoplasms with myelodysplasia with a highly variable risk of disease progression.•Clone metrics enables estimation of disease progression risk and may inform clinical decision making in patients with clonal cytopenia.
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•In PMd neural dynamics is shared across action execution and mere observation.•Task directional features are more accurately discriminated than action types.•Spatial aspects are encoded in PMd ...independently from specific behavioral demands.•PMd dynamics largely reflect higher cognitive-motor processes rather than strictly motor-related functions.
Studies of neural population dynamics of cell activity from monkey motor areas during reaching show that it mostly represents the generation and timing of motor behavior. We compared neural dynamics in dorsal premotor cortex (PMd) during the performance of a visuomotor task executed individually or cooperatively and during an observation task. In the visuomotor conditions, monkeys applied isometric forces on a joystick to guide a visual cursor in different directions, either alone or jointly with a conspecific. In the observation condition, they observed the cursor’s motion guided by the partner. We found that in PMd neural dynamics were widely shared across action execution and observation, with cursor motion directions more accurately discriminated than task types. This suggests that PMd encodes spatial aspects irrespective of specific behavioral demands. Furthermore, our results suggest that largest components of premotor population dynamics, which have previously been suggested to reflect a transformation from planning to movement execution, may rather reflect higher cognitive-motor processes, such as the covert representation of actions and goals shared across tasks that require movement and those that do not.
This study investigated how the experience of different reward distributions would shape the utility functions that can be inferred from economic choice. Despite the generally accepted notion that ...utility functions are not insensitive to external references, the exact way in which such changes take place remains largely unknown. Here we benefitted from the capacity to engage in thorough and prolonged empirical tests of economic choice by one of our evolutionary cousins, the rhesus macaque. We analyzed data from thousands of binary choices and found that the animals' preferences changed depending on the statistics of rewards experienced in the past (up to weeks) and that these changes could reflect monkeys' adapting their expectations of reward. The utility functions we elicited from their choices stretched and shifted over several months of sequential changes in the mean and range of rewards that the macaques experienced. However, this adaptation was usually incomplete, suggesting that – even after months - past experiences held weight when monkeys' assigned value to future rewards. Rather than having stable and fixed preferences assumed by normative economic models, our results demonstrate that rhesus macaques flexibly shape their preferences around the past and present statistics of their environment. That is, rather than relying on a singular reference-point, reference-dependent preferences are likely to capture a monkey's range of expectations.
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