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Retinal prosthesis technologies require that the visual system downstream of the retinal circuitry be capable of transmitting and elaborating visual signals. We studied the capability of plastic remodeling in late blind subjects implanted with the Argus II Retinal Prosthesis with psychophysics and functional MRI (fMRI). After surgery, six out of seven retinitis pigmentosa (RP) blind subjects were able to detect high-contrast stimuli using the prosthetic implant. However, direction discrimination to contrast modulated stimuli remained at chance level in all of them. No subject showed any improvement of contrast sensitivity in either eye when not using the Argus II. Before the implant, the Blood Oxygenation Level Dependent (BOLD) activity in V1 and the lateral geniculate nucleus (LGN) was very weak or absent. Surprisingly, after prolonged use of Argus II, BOLD responses to visual input were enhanced. This is, to our knowledge, the first study tracking the neural changes of visual areas in patients after retinal implant, revealing a capacity to respond to restored visual input even after years of deprivation. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA) is highly expressed in most prostate cancers (PCs). PET and CT imaging studies using 68 Ga-labeled PSMA ligands demonstrated the specific localization of 68 Ga in PC lesions and distant metastatic lesions. [ 68 Ga]Ga-PSMA-R2 ( 68 Ga-PSMA-R2) is a PSMA-targeted PET/CT radiotracer with potential diagnostic applications. Methods: PROfind (NCT03490032) was a phase 1/2, open-label, multicenter study of administration of 3 MBq/kg of 68 Ga-PSMA-R2 (from >150 to ≤250 MBq) in patients with biochemical recurrence (BCR) or metastatic PC (mPC). Participants underwent baseline conventional imaging (CT/MRI or bone scan) and PET/CT. Whole-body PET/CT imaging sequences were obtained between 20 min and 4 h after injection. Primary endpoints were safety and tolerability; secondary endpoints included biodistribution, potential lesion identification, pharmacokinetics, and dosimetry. Potential lesions were identified by 2 masked expert panels; a third panel evaluated the identified lesions. Results: Six patients with BCR were enrolled into phase 1, and 24 patients with BCR or mPC ( n = 12 each) into phase 2. Thirteen treatment-emergent adverse events were reported, including 1 serious adverse event (ileus), unrelated to drug administration. All adverse events were mild or moderate and deemed not related to 68 Ga-PSMA-R2. Peak blood concentration of 68 Ga-PSMA-R2 was typically observed approximately 5 min after injection, steadily decreasing over 6 h. Mean absorbed radiation dose was highest in the urinary bladder wall (0.120 mGy/MBq) and kidney (0.061 mGy/MBq). No other organ mean absorbed radiation dose exceeded 0.020 mGy/MBq. Mean absorbed radiation doses in the salivary and lacrimal glands were 0.016 and 0.008 mGy/MBq, respectively. Mean total body absorbed radiation dose was 0.014 mGy/MBq. Mean effective total body dose was 0.015 mSv/MBq (range, 0.012-0.018 mSv/MBq). 68 Ga-PSMA-R2 PET/CT detected 85 lesions in 22 participants at 1 h after injection and 103 lesions in 22 participants at 2 h after injection. Conventional imaging detected 49 lesions in 8 participants with mPC but none in participants with BCR. Conclusion: 68 Ga-PSMA-R2 was well tolerated, with no drug-related treatment-emergent adverse events. Safety and preliminary imaging performance data support further development of 68 Ga-PSMA-R2 as a diagnostic agent in patients with PC., (© 2025 by the Society of Nuclear Medicine and Molecular Imaging.)

When objects are grouped in space, humans can estimate numerosity more precisely than when they are randomly scattered. This phenomenon, called groupitizing, is thought to arise from the interplay of two components: the subitizing system which identifies both the number of subgroups and of items within each group, and the possibility to perform basic arithmetic operations on the subitized groups. Here we directly investigate the relative role of these two components in groupitizing via an interference (dual task) paradigm. Participants were required to estimate numerosities of grouped and ungrouped arrays while their attentional resources were fully available (single task) or while performing concurrent tasks loading auditory or visuo-spatial attention (both known to interfere with the subitizing process) as well as while performing arithmetic calculation. The attentional cost of performing any concurrent task was overall higher for grouped than ungrouped stimuli, supporting the idea that groupitizing relies on the recruitment of more than one attention-dependent mechanism. However, depriving visuo-spatial attention and preventing participants from performing calculations caused the strongest decrement in sensory precision for grouped numerosities indicating that these attentional components play a major role in groupitizing. These results are in line with the existence of an estimation mechanism that might operate across all numerical ranges, supplemented by attentional mechanisms (subitizing). This study shows that this attentional-demanding mechanism can be activated also when processing numerosities outside of the subitizing regime ( n > 4), provided that grouping cues are available and, in concert with calculation abilities, gives rise to the groupitizing phenomenon., Competing Interests: Competing Interests: The authors declare no conflict of interests., (© 2025 Paula A. Maldonado Moscoso, Giovanni Anobile, Giuseppe Maduli, Roberto Arrighi, and Elisa Castaldi.)

Perceptual adaptation has been widely used to infer the existence of numerosity detectors, enabling animals to quickly estimate the number of objects in a scene. Here, we investigated, in humans, whether numerosity adaptation is influenced by stimulus feature changes as previous research suggested that adaptation is reduced when the colour of adapting and test stimuli did not match. We tested whether such adaptation reduction is due to unspecific novelty effects or changes of stimuli identity. Numerosity adaptation was measured for stimuli matched or unmatched for low-level (colour, luminance, shape and motion) or high-level (letters' identity and face emotions) features. Robust numerosity adaptation occurred in all conditions, but it was reduced when adapting and test stimuli differed for colour, luminance and shape. However, no reduction was observed between moving and still stimuli, a readable change that did not affect the item's identity. Similarly, changes in letters' spatial rotations or face features did not affect adaptation magnitude. Overall, changes in stimulus identity defined by low-level features, rather than novelty in general, determined the strength of the adaptation effects, provided these changes were readily noticeable. These findings suggest that numerosity mechanisms operate on categorized items in addition to the total quantity of the set.

Objective: Navigated transcranial magnetic stimulation (nTMS) has seldom been used to study visuospatial (VS) circuits so far. Our work studied (I) VS functions in neurosurgical oncological patients by using repetitive nTMS (rnTMS), (II) the possible subcortical circuits underneath, and (III) the correspondence between nTMS and direct cortical stimulation (DCS) during awake procedures. Methods: We designed a monocentric prospective study, adopting a protocol to use rnTMS for preoperative planning, including VS functions for lesions potentially involving the VS network, including neurosurgical awake and asleep procedures. nTMS-based-DTI tractography allowed the visualization of subcortical circuits. Statistical analyses on nTMS/DCS points were performed. Clinical results were collected pre- and postoperatively. Results: Finally, 27 patients with primitive intra-axial brain lesions were enrolled between April 2023 and March 2024. Specific tests and an experimental integrated VS test (VISA) were used. The clinical evaluation (at 5 ± 7, 30 ± 10, 90 ± 10 days after surgery) documented 33% of patients with neglect in the left hemisphere four days after surgery and, during the 3-month follow-up, preservation of visuospatial function/clinical recovery (90.62% in MMSE, 98.86% in the bell test, 80% in the clock test, and 98% in the OCS test). The surgical strategy was modulated according to the nTMS map. Subcortical bundles were traced to identify those most involved in these functions: SFLII > SLFII > SLFI. A comparison of the nTMS and DCS points in awake surgery (n = 10 patients) documented a sensitivity (Se) of 12%, a specificity (Sp) of 91.21%, a positive predictive value (PPV) of 42%, a negative predictive value (NPV) of 66%, and an accuracy of ~63.7%. Conclusions: Based on our preliminary results, nTMS is advantageous for studying cognitive functions, minimising neurological impairment. Further analyses are needed to validate our data.

The objective assessment of cognitive processes is of critical importance to understanding the mechanisms underlying various mental functions and dysfunctions. In recent years, the technological innovations related to the eye-tracking industry made the time right to organically integrate pupillometry in the assessment of cognitive profiles. Here, we review evidence showing that pupillometry offers a uniquely sensitive biomarker of the functioning of several distinct networks, cognitive functions, emotional states, and individual differences in their instantiation. We outline why and how pupillometry can be effectively exploited to enrich current research and behavioral paradigms, including those designed for clinical testing. By making the cases of anxiety disorders (both generalized and specific - e.g., generalized anxiety vs. math anxiety) and substance use disorders, we then exemplify how pupillometry can be leveraged to obtain clinically meaningful variables. We finally conclude by arguing that measuring pupil size has the potential to complement more traditional, but coarse assessment methods, to return a more graded, objective, and physiologically informed picture of cognitive functioning., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The onco-functional balance represents the primary goal in neuro-oncology. The increasing use of navigated transcranial magnetic stimulation (nTMS) allows the noninvasive characterization of cortical functional anatomy, and its reliability for motor and language mapping has previously been validated. Calculation and arithmetic processing has not been studied with nTMS so far. In this study, the authors present their preliminary data concerning nTMS calculation., Methods: The authors designed a monocentric prospective study, adopting an internal protocol to use nTMS for preoperative planning, including arithmetic processing. When awake surgery was possible, according to the patients' conditions, nTMS points were used to guide direct cortical stimulation (DCS), i.e., the gold standard for cortical mapping. Navigated TMS-based tractography was used for surgical planning. Statistical analyses on the nTMS and DCS points were performed., Results: From February 2021 to October 2023, 61 procedures for nTMS calculation mapping were performed. The clinical evaluation, including pre- and postoperative evaluations (3 months after surgery), demonstrated a good clinical outcome with preservation of arithmetic function and recovery (92.8% of patients). Between the awake and asleep surgery groups, the postoperative clinical results were comparable at the 3-month follow-up, with > 90% of the patients achieving improved calculation function. The surgical strategy adopted was aimed at sparing nTMS positive points in asleep procedures, whereas nTMS and DCS positive points were not removed in awake procedures. Overall, 62% of the positive points for calculation functions were exposed by craniotomy and 85% were spared during surgery. None of the patients developed nTMS-related seizures. Diffusion tensor imaging fiber tracking based on nTMS positive points for calculation was used. The white matter fiber tracts involved in calculation functions were the arcuate fasciculus (56%) and frontal aslant tract (22%). When nTMS and DCS points were compared in awake surgery (n = 10 patients), a sensitivity of 31.71%, specificity of 85.76%, positive predictive value of 22.41%, negative predictive value of 90.64%, and accuracy of approximately 69% were achieved., Conclusions: Based on the authors' preliminary data, nTMS can be an advantageous tool to study cognitive functions, aimed at minimizing neurological impairment. The postoperative clinical outcome for patients who underwent operation with nTMS was very good. Considering these results, nTMS has proved to be a feasible method to map cognitive areas including those for calculation functions. Further analyses are needed to validate these data. Finally, other cognitive functions (e.g., visuospatial) may be explored with nTMS.

Developmental dyscalculia (DD) is a specific learning disability which prevents children from acquiring adequate numerical and arithmetical competences. We investigated whether difficulties in children with DD spread beyond the numerical domain and impact also their ability to perceive time. A group of 37 children/adolescent with and without DD were tested with an auditory categorization task measuring time perception thresholds in the sub-second (0.25-1 s) and supra-second (0.75-3 s) ranges. Results showed that auditory time perception was strongly impaired in children with DD at both time scales. The impairment remained even when age, non-verbal reasoning, and gender were regressed out. Overall, our results show that the difficulties of DD can affect magnitudes other than numerical and contribute to the increasing evidence that frames dyscalculia as a disorder affecting multiple neurocognitive and perceptual systems., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We recently showed that the gain of the pupillary light response depends on numerosity, with weaker responses to fewer items. Here we show that this effect holds when the stimuli are physically identical but are perceived as less numerous due to numerosity adaptation. Twenty-eight participants adapted to low (10 dots) or high (160 dots) numerosities and subsequently watched arrays of 10-40 dots, with variable or homogeneous dot size. Luminance was constant across all stimuli. Pupil size was measured with passive viewing, and the effects of adaptation were checked in a separate psychophysical session. We found that perceived numerosity was systematically lower, and pupillary light responses correspondingly smaller, following adaptation to high rather than low numerosities. This is consistent with numerosity being a primary visual feature, spontaneously encoded even when task irrelevant, and affecting automatic and unconscious behaviours like the pupillary light response., (© 2024. The Author(s).)

A precise neuropsychological assessment is of the utmost importance for neurosurgical patients undergoing the surgical excision of cerebral lesions. The assessment of mathematical abilities is usually limited to arithmetical operations while other fundamental visuo-spatial aspects closely linked to mathematics proficiency, such as the perception of numerical quantities and geometrical reasoning, are completely neglected. We evaluated these abilities with two objective and reproducible psychophysical tests, measuring numerosity perception and non-symbolic geometry, respectively. We tested sixteen neuro-oncological patients before the operation and six after the operation with classical neuropsychological tests and with two psychophysical tests. The scores of the classical neuropsychological tests were very heterogeneous, possibly due to the distinct location and histology of the tumors that might have spared (or not) brain areas subserving these abilities or allowed for plastic reorganization. Performance in the two non-symbolic tests reflected, on average, the presumed functional role of the lesioned areas, with participants with parietal and frontal lesions performing worse on these tests than patients with occipital and temporal lesions. Single-case analyses not only revealed some interesting exceptions to the group-level results (e.g., patients with parietal lesions performing well in the numerosity test), but also indicated that performance in the two tests was independent of non-verbal reasoning and visuo-spatial working memory. Our results highlight the importance of assessing non-symbolic numerical and geometrical abilities to complement typical neuropsychological batteries. However, they also suggest an avoidance of reliance on an excessively rigid localizationist approach when evaluating the neuropsychological profile of oncological patients.

Symmetry is an important and strong cue we rely on to organize the visual world. Although it is at the basis of objects segmentation in a visual scene, it can sometimes bias our perception. When asked to discriminate numerical quantities between symmetric and asymmetric arrays, individuals tend to underestimate the number of items in the symmetric stimuli. The reason for this underestimation is currently unknown. In this study we investigated whether the symmetry-induced numerosity underestimation depends on perceptual grouping mechanisms by depriving attentional resources. Twenty-six adults judged the numerosity of dot arrays arranged symmetrically or randomly, while ignoring a visual distractor (single task) or while simultaneously judging its color and orientation (dual-task). Diverting attention to the concurrent color-orientation conjunction task halved the symmetry-induced numerosity underestimation. Taken together these results showed that the bias in numerosity perception of symmetric arrays depends-at least partially-on attentional resources and suggested that it might originate from the recruitment of attentional dependent incremental grouping mechanisms., (© 2023. The Author(s).)

The moment we see a group of objects, we can appreciate its numerosity. Our numerical estimates can be imprecise for large sets (>4 items), but they become much faster and more accurate if items are clustered into groups compared to when they are randomly displaced. This phenomenon, termed groupitizing, is thought to leverage on the capacity to quickly identify groups from 1 to 4 items (subitizing) within larger sets, however evidence in support for this hypothesis is scarce. The present study searched for an electrophysiological signature of subitizing while participants estimated grouped numerosities exceeding this range by measuring event-related potential (ERP) responses to visual arrays of different numerosities and spatial configurations. The EEG signal was recorded while 22 participants performed a numerosity estimation task on arrays with numerosities in the subitizing (3 or 4) or estimation (6 or 8) ranges. In the latter case, items could be spatially arranged into subgroups (3 or 4) or randomly scattered. In both ranges, we observed a decrease in N1 peak latency as the number of items increased. Importantly, when items were arranged to form subgroups, we showed that the N1 peak latency reflected both changes in total numerosity and changes in the number of subgroups. However, this result was mainly driven by the number of subgroups to suggest that clustered elements might trigger the recruitment of the subitizing system at a relatively early stage. At a later stage, we found that P2p was mostly modulated by the total numerosity in the set, with much less sensitivity for the number of subgroups these might be segregated in. Overall, this experiment suggests that the N1 component is sensitive to both local and global parcelling of elements in a scene suggesting that it could be crucially involved in the emergence of the groupitizing advantage. On the other hand, the later P2p component seems to be much more bounded to the global aspects of the scene coding the total number of elements while being mostly blind to the number of subgroups in which elements are parsed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Caponi, Maldonado Moscoso, Castaldi, Arrighi and Grasso.)

To estimate the number of objects in an image, each element needs to be segregated as a single unit. Several principles guide the process of element identification, one of the strongest being symmetry. In the current study, we investigated how symmetry affects the ability to rapidly estimate the number of objects (numerosity). Participants judged the numerosity of asymmetric or symmetric arrays of various numerosities. The results show that the numerosity of symmetrical arrays was significantly underestimated at low numerosities, but the effect was greatly reduced at higher numerosities. Adding an additional axis of symmetry (double symmetry) further reduced perceived numerosity. The magnitude of the symmetry-driven underestimation was inversely correlated with autistic personality traits, consistent with previous work associating autistic traits with perceptual grouping. Overall, these results support the idea that perceived numerosity relies on object segmentation and grouping cues, with symmetry playing a key role., (© 2022. The Author(s).)

Many individuals, when faced with mathematical tasks or situations requiring arithmetic skills, experience exaggerated levels of anxiety. Mathematical anxiety (MA), in addition to causing discomfort, can lead to avoidance behaviors and then to underachievement. However, the factors inducing MA and how MA deploys its detrimental effects are still largely debated. There is evidence suggesting that MA affects working memory capacity by further diminishing its limited processing resources. An alternative account postulates that MA originates from a coarse early numerical cognition capacity, the perception of numerosity. In the current study, we measured MA, math abilities, numerosity perception and visuo-spatial working memory (VSWM) in a sample of neurotypical adults. Correlational analyses confirmed previous studies showing that high MA was associated with lower math scores and worse numerosity estimation precision. Conversely, MA turned out to be unrelated to VSWM capacities. Finally, partial correlations revealed that MA fully accounted for the relationship between numerosity estimation precision and math abilities, suggesting a key role for MA as a mediating factor between these two domains.

Numerical estimation of arrays of objects is faster and more accurate when items can be clustered into groups, a phenomenon termed "groupitizing." Grouping can facilitate segregation into subitizable "chunks," each easily estimated, then summed. The current study investigates whether spatial grouping of arrays drives specific neural responses during numerical estimation, reflecting strategies such as exact calculation and fact retrieval. Fourteen adults were scanned with fMRI while estimating either the numerosity or shape of arrays of items, either randomly distributed or spatially grouped. Numerosity estimation of both classes of stimuli elicited common activation of a right lateralized frontoparietal network. Grouped stimuli additionally recruited regions in the left hemisphere and bilaterally in the angular gyrus. Multivariate pattern analysis showed that classifiers trained with the pattern of neural activations read out from parietal regions, but not from the primary visual areas, can decode different numerosities both within and across spatial arrangements. The behavioral numerical acuity correlated with the decoding performance of the parietal but not with occipital regions. Overall, this experiment suggests that the estimation of grouped stimuli relies on the approximate number system for numerosity estimation, but additionally recruits regions involved in calculation., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Developmental dyscalculia (DD) is a specific learning disability affecting the development of numerical and arithmetical skills. The origin of DD is typically attributed to the suboptimal functioning of key regions within the dorsal visual stream (parietal cortex) which support numerical cognition. While DD individuals are often impaired in visual numerosity perception, the extent to which they also show a wider range of visual dysfunctions is poorly documented. In the current study we measured sensitivity to global motion (translational and flow), 2D static form (Glass patterns) and 3D structure from motion in adults with DD and control subjects. While sensitivity to global motion was comparable across groups, thresholds for static form and structure from motion were higher in the DD compared to the control group, irrespective of associated reading impairments. Glass pattern sensitivity predicted numerical abilities, and this relation could not be explained by recently reported differences in visual crowding. Since global form sensitivity has often been considered an index of ventral stream function, our findings could indicate a cortical dysfunction extending beyond the dorsal visual stream. Alternatively, they would fit with a role of parietal cortex in form perception under challenging conditions requiring multiple element integration., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To understand the number sense, we need to understand its function. We argue that numerosity estimation is fundamental not only for perception, but also preparation and control of action. We outline experiments that link numerosity estimation with action, pointing to a generalized numerosity system that serves both perception and action preparation.

Humans can quickly approximate how many objects are in a visual image, but no clear consensus has been achieved on the cognitive resources underlying this ability. Previous work has lent support to the notion that mechanisms which explicitly represent the locations of multiple objects in the visual scene within a mental map are critical for both visuo-spatial working memory and enumeration (at least for relatively small numbers of items). Regarding the cognitive underpinnings of large numerosity perception, an issue currently subject to much controversy is why numerosity estimates are often non-veridical (i.e., susceptible to biases from non-numerical quantities). Such biases have been found to be particularly pronounced in individuals with developmental dyscalculia (DD), a learning disability affecting the acquisition of arithmetic skills. Motivated by findings showing that DD individuals are also often impaired in visuo-spatial working memory, we hypothesized that resources supporting this type of working memory, which allow for the simultaneous identification of multiple objects, might also be critical for precise and unbiased perception of larger numerosities. We therefore tested whether loading working memory of healthy adult participants during discrimination of large numerosities would lead to increased interference from non-numerical quantities. Participants performed a numerosity discrimination task on multi-item arrays in which numerical and non-numerical stimulus dimensions varied congruently or incongruently relative to each other, either in isolation or in the context of a concurrent visuo-spatial or verbal working memory task. During performance of the visuo-spatial, but not verbal, working memory task, precision in numerosity discrimination decreased, participants' choices became strongly biased by item size, and the strength of this bias correlated with measures of arithmetical skills. Moreover, the interference between numerosity and working memory tasks was bidirectional, with number discrimination impacting visuo-spatial (but not verbal) performance. Overall, these results suggest that representing visual numerosity in a way that is unbiased by non-numerical quantities relies on processes which explicitly segregate/identify the locations of multiple objects that are shared with visuo-spatial (but not verbal) working memory. This shared resource may potentially be impaired in DD, explaining the observed co-occurrence of working memory and numerosity discrimination deficits in this clinical population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Castaldi, Piazza and Eger.)

Although luminance is the main determinant of pupil size, the amplitude of the pupillary light response is also modulated by stimulus appearance and attention. Here we ask whether perceived numerosity modulates the pupillary light response. Participants passively observed arrays of black or white dots of matched physical luminance but different physical or illusory numerosity. In half the patterns, pairs of dots were connected by lines to create dumbbell-like shapes, inducing an illusory underestimation of perceived numerosity; in the other half, connectors were either displaced or removed. Constriction to white arrays and dilation to black were stronger for patterns with higher perceived numerosity, either physical or illusory, with the strength of the pupillary light response scaling with the perceived numerosity of the arrays. Our results show that even without an explicit task, numerosity modulates a simple automatic reflex, suggesting that numerosity is a spontaneously encoded visual feature., (© 2021. The Author(s).)

While most animals have a sense of number, only humans have developed symbolic systems to describe and organize mathematical knowledge. Some studies suggest that human arithmetical knowledge may be rooted in an ancient mechanism dedicated to perceiving numerosity, but it is not known if formal geometry also relies on basic, non-symbolic mechanisms. Here we show that primary-school children who spontaneously detect and predict geometrical sequences (non-symbolic geometry) perform better in school-based geometry tests indexing formal geometric knowledge. Interestingly, numerosity discrimination thresholds also predicted and explained a specific portion of variance of formal geometrical scores. The relation between these two non-symbolic systems and formal geometry was not explained by age or verbal reasoning skills. Overall, the results are in line with the hypothesis that some human-specific, symbolic systems are rooted in non-symbolic mechanisms., (© 2021. The Author(s).)

Groupitizing is a recently described phenomenon of numerosity perception where clustering items of a set into smaller "subitizable" groups improves discrimination. Groupitizing is thought to be rooted on the subitizing system, with which it shares several properties: both phenomena accelerate counting and decrease estimation thresholds irrespective of stimulus format (for both simultaneous and sequential numerosity perception) and both rely on attention. As previous research on groupitizing has been almost completely limited to vision, the current study investigates whether it generalizes to other sensory modalities. Participants estimated the numerosity of a series of tones clustered either by proximity in time or by similarity in frequency. We found that compared with unstructured tone sequences, grouping lowered auditory estimation thresholds by up to 20%. The groupitizing advantage was similar across different grouping conditions, temporal proximity and tone frequency similarity. These results mirror the groupitizing effect for visual stimuli, suggesting that, like subitizing, groupitizing is an a-modal phenomenon., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Anobile, Castaldi, Maldonado Moscoso, Arrighi and Burr.)

The representation of space, time and number is believed to rely on a common encoding system developed to support action guidance. While the ecological advantage of such a shared system is evident when objects are located within the region of space we can act on (known as peri-personal space), it is less obvious in the case of objects located beyond our arms' reach. In the current study we investigated whether and to what extent the distance of the stimuli from the observer affects the perception of duration and numerosity. We first replicated Anelli et al.'s (2015) experiment by asking adult participants to perform a duration reproduction task with stimuli of different sizes displayed in the peri- or extra-personal space, and then applied the same paradigm to a non-symbolic numerosity estimation task. Results show that, independently of size, duration estimates were overestimated when visual stimuli were presented in the extra-personal space, replicating previous findings. A similar effect was also found for numerosity perception, however overestimation for far stimuli was much smaller in magnitude and was accounted by the difference in perceived size between stimuli presented in peripersonal or extrapersonal space. Overall, these results suggest that, while the processing of temporal information is robustly affected by the position of the stimuli in either the peri- or extra-personal space, numerosity perception is independent from stimulus distance. We speculate that, while time and numerosity may be encoded by a shared system in the peri-personal space (to optimize action execution), different and partially independent mechanisms may underlie the representation of time and numerosity in extra-personal space. Furthermore, these results suggest that investigating magnitude perception across spatial planes (where it is or is not possible to act) may unveil processing differences that would otherwise pass unnoticed., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Incoming sensory input provides information for the planning and execution of actions, which yield motor outcomes that are themselves sensory inputs. One dimension where action and perception strongly interact is numerosity perception. Many non-human animals can estimate approximately the number of external elements as well as their own actions, and neurons have been identified that respond to both. Recent psychophysical adaptation studies on humans also provide evidence for neural mechanisms responding to both the number of externally generated events and self-produced actions. Here we advance the idea that these strong connections may arise from dedicated sensorimotor mechanisms in the brain, part of a more generalized system interfacing action with the processing of other quantitative magnitudes such as space and time., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The demand for mental health services is projected to rapidly increase as a direct and indirect result of the COVID-19 pandemic. Given that young people are disproportionately disadvantaged by mental illness and will face further challenges related to the COVID-19 pandemic, it is crucial to deliver appropriate mental health care to young people as early as possible. Integrating digital health solutions into mental health service delivery pathways has the potential to greatly increase efficiencies, enabling the provision of "right care, first time." We propose an innovative digital health solution for demand management intended for use by primary youth mental health services, comprised of (1) a youth mental health model of care (ie, the Brain and Mind Centre Youth Model) and (2) a health information technology specifically designed to deliver this model of care (eg, the InnoWell Platform). We also propose an operational protocol of how this solution could be applied to primary youth mental health service delivery processes. By "flipping" the conventional service delivery models of majority in-clinic and minority web-delivered care to a model where web-delivered care is the default, this digital health solution offers a scalable way of delivering quality youth mental health care both in response to public health crises (such as the COVID-19 pandemic) and on an ongoing basis in the future., (©Tracey A Davenport, Vanessa Wan Sze Cheng, Frank Iorfino, Blake Hamilton, Eva Castaldi, Amy Burton, Elizabeth M Scott, Ian B Hickie. Originally published in JMIR Mental Health (http://mental.jmir.org), 15.12.2020.)

Human functional imaging has identified the middle part of the intraparietal sulcus (IPS) as an important brain substrate for different types of numerical tasks. This area is often equated with the macaque ventral intraparietal area (VIP) where neuronal selectivity for non-symbolic numerical stimuli (sets of items) is found. However, the low spatial resolution and whole-brain averaging analysis performed in most fMRI studies limit the extent to which an exact correspondence of activations in different numerical tasks with specific sub-regions of the IPS can be established. Here we acquired high-resolution 7T fMRI data in a group of human adults and related the activations in several numerical contrasts (implying different numerical stimuli and tasks) to anatomical and functional landmarks on the cortical surface. Our results reveal a functional heterogeneity within human intraparietal cortex where the retinotopic visual field maps in superior/medial parts of the IPS and superior parietal gyrus respond preferentially to the visual processing of concrete sets of items (over single Arabic numerals), whereas lateral/inferior parts of the IPS are predominantly recruited during numerical operations such as calculation and quantitative comparison. Since calculation and comparison-related activity fell mainly outside the retinotopic visual field maps considered the human functional equivalent of the monkey VIP/LIP complex, the areas most activated during such numerical operations in humans are likely different from VIP., (Copyright © 2020. Published by Elsevier Inc.)

Fast saccades are rapid automatic oculomotor responses to salient and ecologically important visual stimuli such as animals and faces. Discriminating the number of friends, foe, or prey may also have an evolutionary advantage. In this study, participants were asked to saccade rapidly towards the more numerous of two arrays. Participants could discriminate numerosities with high accuracy and great speed, as fast as 190 ms. Intermediate numerosities were more likely to elicit fast saccades than very low or very high numerosities. Reaction-times for vocal responses (collected in a separate experiment) were slower, did not depend on numerical range, and correlated only with the slow not the fast saccades, pointing to different systems. The short saccadic reaction-times we observe are surprising given that discrimination using numerosity estimation is thought to require a relatively complex neural circuit, with several relays of information through the parietal and prefrontal cortex. Our results suggest that fast numerosity-driven saccades may be generated on a single feed-forward pass of information recruiting a primitive system that cuts through the cortical hierarchy and rapidly transforms the numerosity information into a saccade command.

When asked to estimate the number of items in a visual array, educated adults and children are more precise and rapid if the items are clustered into small subgroups rather than randomly distributed. This phenomenon, termed "groupitizing", is thought to rely on the recruitment of the subitizing system (dedicated to the perception of very small numbers), with the aid of simple arithmetical calculations. The aim of current study is to verify whether the advantage for clustered stimuli does rely on subitizing, by manipulating attention, known to strongly affect attention. Participants estimated the numerosity of grouped or ungrouped arrays in condition of full attention or while attention was diverted with a dual-task. Depriving visual attention strongly decreased estimation precision of grouped but not of ungrouped arrays, as well as increasing the tendency for numerosity estimation to regress towards the mean. Additional explorative analyses suggested that calculation skills correlated with the estimation precision of grouped, but not of ungrouped, arrays. The results suggest that groupitizing is an attention-based process that leverages on the subitizing system. They also suggest that measuring numerosity estimation thresholds with grouped stimuli may be a sensitive correlate of math abilities.

Previous work has shown that when arrays of objects are grouped within clusters, participants can enumerate their numerosity more rapidly than when objects are randomly scattered, a phenomenon termed "groupitizing". Importantly, the magnitude of the grouping advantage correlates with math abilities in children. Here we show that sensory precision of numerosity estimation is also improved when grouping cues are available, by up to 20%. The grouping can be induced by color and/or spatial proximity, and occurs in temporal sequences as well as spatial arrays. The improvement is strongest for participants with the highest thresholds in the random, ungrouped conditions. Taken together with previous research, our data suggest that measurements correlations between numerosity estimation and formal math skills may be driven by grouping strategies, which require a minimal level of basic arithmetic.

Visual crowding refers to the inability to identify objects when surrounded by other similar items. Crowding-like mechanisms are thought to play a key role in numerical perception by determining the sensory mechanisms through which ensembles are perceived. Enhanced visual crowding might hence prevent the normal development of a system involved in segregating and perceiving discrete numbers of items and ultimately the acquisition of more abstract numerical skills. Here, we investigated whether excessive crowding occurs in developmental dyscalculia (DD), a neurodevelopmental disorder characterized by difficulty in learning the most basic numerical and arithmetical concepts, and whether it is found independently of associated major reading and attentional difficulties. We measured spatial crowding in two groups of adult individuals with DD and control subjects. In separate experiments, participants were asked to discriminate the orientation of a Gabor patch either in isolation or under spatial crowding. Orientation discrimination thresholds were comparable across groups when stimuli were shown in isolation, yet they were much higher for the DD group with respect to the control group when the target was crowded by closely neighbouring flanking gratings. The difficulty in discriminating orientation (as reflected by the combination of accuracy and reaction times) in the DD compared to the control group persisted over several larger target flanker distances. Finally, we found that the degree of such spatial crowding correlated with impairments in mathematical abilities even when controlling for visual attention and reading skills. These results suggest that excessive crowding effects might be a characteristic of DD, independent of other associated neurodevelopmental disorders.

Between 1-5:100 people worldwide have never experienced normotypic vision due to a condition called amblyopia, and about 1:4000 suffer from inherited retinal dystrophies that progressively lead to blindness. While a wide range of technologies and therapies are being developed to restore vision, a fundamental question still remains unanswered: would the adult visual brain retain a sufficient plastic potential to learn how to 'see' after a prolonged period of abnormal visual experience? In this review we summarize studies showing that the visual brain of sighted adults retains a type of developmental plasticity, called homeostatic plasticity, and this property has been recently exploited successfully for adult amblyopia recovery. Next, we discuss how the brain circuits reorganize when blindness occurs and when visual stimulation is partially restored by means of a 'bionic eye' in late blind adults with Retinitis Pigmentosa. The primary visual cortex in these patients slowly became activated by the artificial visual stimulation, indicating that sight restoration therapies can rely on a considerable degree of spared plasticity in adulthood., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Developmental dyscalculia (DD) is a developmental learning disability that manifests as a persistent difficulty in comprehending even the most basic numeric and arithmetic concepts, despite normal intelligence and schooling opportunities. Given the predominant use of numbers in modern society, this condition can pose major challenges in the sufferer's everyday life, both in personal and professional development. Since, to date, we still lack a universally recognized and psychometrically driven definition of DD, its diagnosis has been applied to a wide variety of cognitive profiles. In this chapter, we review the behavioral and neural characterization of DD as well as the different neurocognitive and etiologic accounts of this neurodevelopmental disorder. We underline the multicomponential nature of this heterogeneous disability: different aspects of mathematical competence can be affected by both the suboptimal recruitment of general cognitive functions supporting mathematical cognition (such as attention, memory, and cognitive control) and specific deficits in mastering numeric concepts and operations. Accordingly, both intervention paradigms focused on core numeric abilities and more comprehensive protocols targeting multiple neurocognitive systems have provided evidence for effective positive outcomes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: We evaluated the potential of magnetic resonance imaging in identifying signs of cortical visual processing with greater sensitivity than standard ophthalmological measures in patients with retinitis pigmentosa (RP) at advanced stages., Methods: Eight patients affected with RP with only bare light perception and weak or absent visual evoked potential (VEP) or electroretinogram (ERG) responses to flashes of light were tested. Visual impairment was evaluated by means of psychophysical testing, where patients were asked to discriminate the drifting direction of a contrast modulated grating. Patients underwent magnetic resonance imaging scanning, and the behavioral performance was correlated with both blood oxygenation level-dependent (BOLD) signal elicited by flashes of lights and cortical thickness measured in primary visual area., Results: Contrast sensitivity to drifting gratings of very low spatial and temporal frequency was greatly impaired, yet measurable in all patients. Weak luminance flashes elicited significant BOLD responses in the striate and extrastriate cortex, despite that the stimuli were not perceived during scanning. Importantly, patients with less severe impairment of contrast sensitivity showed stronger V1 BOLD responses. Striate cortical thickness did not correlate with visual sensitivity., Conclusions: BOLD responses provide a sensitive and reliable index of visual sparing more than VEPs or ERGs, which are often absent in RP patients. The minimal residual vision can be assessed by optimal visual stimulation in two alternative forced choice discrimination tasks and by BOLD responses. Imaging techniques provide useful information to monitor progressive vision loss., Translational Relevance: Functional magnetic resonance imaging might be a practical tool for assessing visual sparing, as it is more feasible and sensitive than psychophysical or ophthalmological testing., (Copyright 2019 The Authors.)

Humans and other animals base important decisions on estimates of number, and intraparietal cortex is thought to provide a crucial substrate of this ability. However, it remains debated whether an independent neuronal processing mechanism underlies this 'number sense', or whether number is instead judged indirectly on the basis of other quantitative features. We performed high-resolution 7 Tesla fMRI while adult human volunteers attended either to the numerosity or an orthogonal dimension (average item size) of visual dot arrays. Along the dorsal visual stream, numerosity explained a significant amount of variance in activation patterns, above and beyond non-numerical dimensions. Its representation was selectively amplified and progressively enhanced across the hierarchy when task relevant. Our results reveal a sensory extraction mechanism yielding information on numerosity separable from other dimensions already at early visual stages and suggest that later regions along the dorsal stream are most important for explicit manipulation of numerical quantity., Competing Interests: EC, MP, SD, AV, EE No competing interests declared, (© 2019, Castaldi et al.)

Dyscalculia, a specific learning disability that impacts arithmetical skills, has previously been associated to a deficit in the precision of the system that estimates the approximate number of objects in visual scenes (the so called 'number sense' system). However, because in tasks involving numerosity comparisons dyscalculics' judgements appears disproportionally affected by continuous quantitative dimensions (such as the size of the items), an alternative view linked dyscalculia to a domain-general difficulty in inhibiting task-irrelevant responses. To arbitrate between these views, we evaluated the degree of reciprocal interference between numerical and non-numerical quantitative dimensions in adult dyscalculics and matched controls. We used a novel stimulus set orthogonally varying in mean item size and numerosity, putting particular attention into matching both features' perceptual discriminability. Participants compared those stimuli based on each of the two dimensions. While control subjects showed no significant size interference when judging numerosity, dyscalculics' numerosity judgments were strongly biased by the unattended size dimension. Importantly however, both groups showed the same degree of interference from the unattended dimension when judging mean size. Moreover, only the ability to discard the irrelevant size information when comparing numerosity (but not the reverse) significantly predicted calculation ability across subjects. Overall, our results show that numerosity discrimination is less prone to interference than discrimination of another quantitative feature (mean item size) when the perceptual discriminability of these features is matched, as here in control subjects. By quantifying, for the first time, dyscalculic subjects' degree of interference on another orthogonal dimension of the same stimuli, we are able to exclude a domain-general inhibition deficit as explanation for their poor / biased numerical judgement. We suggest that enhanced reliance on non-numerical cues during numerosity discrimination can represent a strategy to cope with a less precise number sense., Competing Interests: The authors have declared that no competing interests exist.

Periventricular leukomalacia (PVL) is characterized by focal necrosis at the level of the periventricular white matter, often observed in preterm infants. PVL is frequently associated with motor impairment and with visual deficits affecting primary stages of visual processes as well as higher visual cognitive abilities. Here we describe six PVL subjects, with normal verbal IQ, showing orientation perception deficits in both the haptic and visual domains. Subjects were asked to compare the orientation of two stimuli presented simultaneously or sequentially, using both a two alternative forced choice (2AFC) orientation-discrimination and a matching procedure. Visual stimuli were oriented gratings or bars or collinear short lines embedded within a random pattern. Haptic stimuli comprised two rotatable wooden sticks. PVL patients performed at chance in discriminating the oblique orientation, both for visual and haptic stimuli. Moreover when asked to reproduce the oblique orientation, they often oriented the stimulus along the symmetric mirror orientation. The deficit generalized to stimuli varying in many low level features, was invariant for spatiotopic object orientation, and also occurred for sequential presentations. The deficit was specific to oblique orientations, and not for horizontal or vertical stimuli. These findings show that PVL can affect a specific network involved with the supramodal perception of mirror symmetry orientation., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Humans and other animals are able to make rough estimations of quantities using what has been termed the approximate number system (ANS). Much evidence suggests that sensitivity to numerosity correlates with symbolic math capacity, leading to the suggestion that the ANS may serve as a start-up tool to develop symbolic math. Many experiments have demonstrated that numerosity perception transcends the sensory modality of stimuli and their presentation format (sequential or simultaneous), but it remains an open question whether the relationship between numerosity and math generalizes over stimulus format and modality. Here we measured precision for estimating the numerosity of clouds of dots and sequences of flashes or clicks, as well as for paired comparisons of the numerosity of clouds of dots. Our results show that in children, formal math abilities correlate positively with sensitivity for estimation and paired-comparisons of the numerosity of visual arrays of dots. However, precision of numerosity estimation for sequences of flashes or sounds did not correlate with math, although sensitivities in all estimations tasks (for sequential or simultaneous stimuli) were strongly correlated with each other. In adults, we found no significant correlations between math scores and sensitivity to any of the psychophysical tasks. Taken together these results support the existence of a generalized number sense, and go on to demonstrate an intrinsic link between mathematics and perception of spatial, but not temporal numerosity. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Leibovich et al. opened up an important discussion on the nature and origins of numerosity perception. The authors rightly point out that non-numerical features of stimuli influence this ability. Despite these biases, there is evidence that from birth, humans perceive and represent numerosities, and not just non-numerical quantitative features such as item size, density, and convex hull.

Endothelial colony-forming cells (ECFCs) are promising candidates for cell therapy of ischemic diseases, as less than 10% of patients with an ischemic stroke are eligible for thrombolysis. We previously reported that erythropoietin priming of ECFCs increased their in vitro and in vivo angiogenic properties in mice with hindlimb ischemia. The present study used SPECT/CT to evaluate whether priming of ECFCs with erythropoietin could enhance their homing to the ischemic site after transient middle cerebral artery occlusion (MCAO) followed by reperfusion in rats and potentiate their protective or regenerative effect on blood-brain barrier (BBB) disruption, cerebral apoptosis, and cerebral blood flow (CBF)., Methods: Rats underwent a 1-h MCAO followed by reperfusion and then 1 d after MCAO received an intravenous injection of either PBS (control, n = 10), PBS-primed ECFCs (ECFC PBS , n = 13), or erythropoietin-primed ECFCs (ECFC EPO , n = 10). ECFC homing and the effect on BBB disruption, cerebral apoptosis, and CBF were evaluated by SPECT/CT up to 14 d after MCAO. The results were expressed as median ± interquartile range for ipsilateral-to-contralateral ratio of the activity in middle cerebral artery-vascularized territories in each hemisphere. Histologic evaluation of neuronal survival and astrocytic proliferation was performed on day 14., Results: Erythropoietin priming increased homing of ECFCs to the ischemic hemisphere (ECFC PBS , 111.0% ± 16.0%; ECFC EPO , 146.5% ± 13.3%). BBB disruption was significantly reduced (control, 387% ± 153%; ECFC PBS , 151% ± 46% [P < 0.05]; ECFC EPO , 112% ± 9% [P < 0.001]) and correlated negatively with ECFC homing (Pearson r = -0.6930, P = 0.0002). Cerebral apoptosis was significantly reduced (control, 161% ± 10%; ECFC PBS , 141% ± 9% [P < 0.05]; ECFC EPO ,118% ± 5% [P < 0.001]) and correlated negatively with ECFC homing (r = -0.7251, P < 0.0001). CBF was significantly restored with ECFCs and almost totally so with erythropoietin priming (control, 72% ± 2%; ECFC PBS , 90% ± 4% [P < 0.01]; ECFC EPO , 99% ± 4% [P < 0.001]) and correlated positively with ECFC homing (r = 0.7348, P < 0.0001). Immunoblocking against the CD146 receptor on ECFCs highlighted its notable role in ECFC homing with erythropoietin priming (ECFC EPO , 147% ± 14%, n = 4; ECFC EPO with antibody against CD146, 101% ± 12%, n = 4 [P < 0.05])., Conclusion: Priming with erythropoietin before cell transplantation is an efficient strategy to amplify the migratory and engraftment capacities of ECFCs and their beneficial impact on BBB disruption, apoptosis, and CBF., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Considerable recent work suggests that mathematical abilities in children correlate with the ability to estimate numerosity. Does math correlate only with numerosity estimation, or also with other similar tasks? We measured discrimination thresholds of school-age (6- to 12.5-years-old) children in 3 tasks: numerosity of patterns of relatively sparse, segregatable items (24 dots); numerosity of very dense textured patterns (250 dots); and discrimination of direction of motion. Thresholds in all tasks improved with age, but at different rates, implying the action of different mechanisms: In particular, in young children, thresholds were lower for sparse than textured patterns (the opposite of adults), suggesting earlier maturation of numerosity mechanisms. Importantly, numerosity thresholds for sparse stimuli correlated strongly with math skills, even after controlling for the influence of age, gender and nonverbal IQ. However, neither motion-direction discrimination nor numerosity discrimination of texture patterns showed a significant correlation with math abilities. These results provide further evidence that numerosity and texture-density are perceived by independent neural mechanisms, which develop at different rates; and importantly, only numerosity mechanisms are related to math. As developmental dyscalculia is characterized by a profound deficit in discriminating numerosity, it is fundamental to understand the mechanism behind the discrimination. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Packed school meals for children 3-10 years old were studied to evaluate the levels of di(2-ethylhexyl)phthalate (DEHP) and di-n-butylphthalate (DBP) and the influence of the packaging process on meal contamination, and their contribution to daily intake was estimated. The packaging consisted of polyethylene-coated aluminum (PE/Al) dishes thermally welded by a polyethyleneterephthalate-coated aluminum (PET/Al) foil. Foodstuffs before processing were analyzed, too. Total meals before packaging and after packaging were collected. It was found that 92% of foodstuffs employed in meal preparation contained DEHP, and 76% of them DBP, at detectable levels. In cooked foods before packaging the DEHP median concentration levels varied from 111.4 to 154.8 ng/g ww and those of DBP between 32.5 and 59.5 ng/g ww. In packed meals the DEHP median values ranged from 127.0 to 253.3 ng/g ww, and DBP median values varied from 44.1 to 80.5 ng/g ww. The mean increases of median concentrations of DEHP in cooked foods before and after packaging were 113 and 125% for DBP. For nursery and primary school children DEHP intake via school meals can raise on average the respective EFSA TDI by 18 and 12% and that of DBP by 50 and 30%.

Automatic synthesis of 4-[18F]fluorobenzaldehyde has been developed by a commercially available TRACERlab FX(F-N) synthesis module to be used as prosthetic group for amino-oxy functionalized peptide labelling in clinical routine application. In addition a handmade purification device (HPD) has been setup to perform automatic cartridge purification as well as to back-up the reactor where one-pot synthesis is not applicable. Cartridges for solid phase extraction such as C18, C8, phenyl has been tested to best perform purification as well as activity recovery. Radiochemical yield (RCY) at end of synthesis (EOS) was in average 67% after about 45 min (90% decay corrected at EOB). The RCY of the entire procedure was 54% with a radiochemical purity above 99%.