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Objective: For over half a century, studies of rare diseases using in-person cognitive tools have faced challenges, such as long study periods and small sample sizes (e.g. n = 10). The Montreal Cognitive Assessment (MoCA) was widely employed to assess mild cognitive impairment (MCI). We aimed to validate a modified online version of the MoCA in a large sample of a rare disease (population prevalence < .01%). Method: First, we analyzed 20 previous findings (n = 1,377), comparing the MoCA scores between large groups of neurotypically healthy (NH; n = 837) and cerebellar ataxia (CA; n = 540), where studies were conducted in-person. Second, we administered the MoCA in-person to a group of NH (n = 41) and a large group of CA (n = 103). Third, we administered a video conferencing version of the MoCA to NH (n = 38) and a large group of CA (n = 83). Results: We observed no performance differences between online and in-person MoCA administration in the NH and CA groups (p > .05, η2 = 0.001), supporting reliability. Additionally, our online CA group had lower MoCA scores than the NH group (p < .001, Hedges' g = 0.68). This result is consistent with previous studies, as demonstrated by our forest plot across 20 previous in-person findings, supporting construct validity. Conclusion: The results indicate that an online screening tool is valid in a large sample of individuals with CA. Online testing is not only time and cost-effective, but facilitates disease management and monitoring, ultimately enabling early detection of MCI.

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Parkinson's disease (PD) is primarily characterized by motor symptoms. Yet, many people with PD experience cognitive decline, which is often unnoticed by clinicians, although it may have a significant impact on quality of life. For over half a century, traditional in-person PD cognitive assessment lacked accessibility, scalability, and specificity due to its inherent limitations. In this review, we propose that novel methods of online cognitive assessment could potentially address these limitations. We first outline the challenges of traditional in-person cognitive testing in PD. We then summarize the existing literature on online cognitive testing in PD. Finally, we explore the advantages, but also the limitations, of three major processes involved in online PD cognitive testing: recruitment and sampling methods, measurement and participation, and disease monitoring and management. Taking the limitations into account, we aim to highlight the potential of online cognitive testing as a more accessible and efficient approach to cognitive testing in PD.

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[This corrects the article DOI: 10.3389/fnhum.2023.1325215.].

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Humans exhibit complex mathematical skills attributed to the exceptional enlargement of neocortical regions throughout evolution. In the current work, we initiated a novel exploration of the ancient subcortical neural network essential for mathematical cognition. Using a neuropsychological approach, we report that degeneration of two subcortical structures, the cerebellum and basal ganglia, impairs performance in symbolic arithmetic. We identify distinct computational impairments in male and female participants with cerebellar degeneration (CD) or Parkinson's disease (PD). The CD group exhibited a disproportionate cost when the arithmetic sum increased, suggesting that the cerebellum is critical for iterative procedures required for calculations. The PD group showed a disproportionate cost for equations with increasing addends, suggesting that the basal ganglia are critical for chaining multiple operations. In Experiment 2, the two patient groups exhibited intact practice gains for repeated equations at odds with an alternative hypothesis that these impairments were related to memory retrieval. Notably, we discuss how the counting and chaining operations relate to cerebellar and basal ganglia function in other task domains (e.g., motor processes). Overall, we provide a novel perspective on how the cerebellum and basal ganglia contribute to symbolic arithmetic. Our studies demonstrate the constraints on the computational role of two subcortical regions in higher cognition.

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Researchers often attribute higher cognition to the enlargement of cortical regions throughout evolution, reflecting the belief that humans sit at the top of the cognitive pyramid. Implicitly, this approach assumes that the subcortex is of secondary importance for higher-order cognition. While it is now recognized that subcortical regions can be involved in various cognitive domains, it remains unclear how they contribute to computations essential for higher-level cognitive processes such as endogenous attention and numerical cognition. Herein, we identify three models of subcortical-cortical relations in these cognitive processes: (i) subcortical regions are not involved in higher cognition; (ii) subcortical computations support elemental forms of higher cognition mainly in species without a developed cortex; and (iii) higher cognition depends on a whole-brain dynamic network, requiring integrated cortical and subcortical computations. Based on evolutionary theories and recent data, we propose the SEED hypothesis: the Subcortex is Essential for the Early Development of higher cognition. According to the five principles of the SEED hypothesis, subcortical computations are essential for the emergence of cognitive abilities that enable organisms to adapt to an ever-changing environment. We examine the implications of the SEED hypothesis from a multidisciplinary perspective to understand how the subcortex contributes to various forms of higher cognition.

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Neuropsychological testing has intrinsic challenges, including the recruitment of patients and their participation in research projects. To create a method capable of collecting multiple datapoints (across domains and participants) while imposing low demands on the patients, we have developed PONT (Protocol for Online Neuropsychological Testing). Using this platform, we recruited neurotypical controls, individuals with Parkinson's disease, and individuals with cerebellar ataxia and tested their cognitive status, motor symptoms, emotional well-being, social support, and personality traits. For each domain, we compared each group to previously published values from studies using more traditional methods. The results show that online testing using PONT is feasible, efficient, and produces results that are in line with results obtained from in-person testing. As such, we envision PONT as a promising bridge to more comprehensive, generalizable, and valid neuropsychological testing.

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There is a critical need for accessible neuropsychological testing for basic research and translational studies worldwide. Traditional in-person neuropsychological studies are inherently difficult to conduct because testing requires the recruitment and participation of individuals with neurological conditions. Consequently, studies are often based on small sample sizes, are highly time-consuming, and lack diversity. To address these challenges, in the last decade, the utilization of remote testing platforms has demonstrated promising results regarding the feasibility and efficiency of collecting patient data online. Herein, we tested the validity and generalizability of remote administration of the Montreal Cognitive Assessment (MoCA) test. We administered the MoCA to English and Hebrew speakers from three different populations: Parkinson's disease, Cerebellar Ataxia, and healthy controls via video conferencing. First, we found that the online MoCA scores do not differ from traditional in-person studies, demonstrating convergent validity. Second, the MoCA scores of both our online patient groups were lower than controls, demonstrating construct validity. Third, we did not find differences between the two language versions of the remote MoCA, supporting its generalizability to different languages and the efficiency of collecting binational data (USA and Israel). Given these results, future studies can utilize the remote MoCA, and potentially other remote neuropsychological tests to collect data more efficiently across multiple different patient populations, language versions, and nations.

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We introduce a novel perspective on how the cerebellum might contribute to cognition, hypothesizing that this structure supports dynamic transformations of mental representations. In support of this hypothesis, we report a series of neuropsychological experiments comparing the performance of individuals with degenerative cerebellar disorders on tasks that either entail continuous, movement-like mental operations or more discrete mental operations. In the domain of visual cognition, the cerebellar disorders group exhibited an impaired rate of mental rotation, an operation hypothesized to require the continuous manipulation of a visual representation. In contrast, the cerebellar disorders group showed a normal processing rate when scanning items in visual working memory, an operation hypothesized to require the maintenance and retrieval of remembered items. In the domain of mathematical cognition, the cerebellar disorders group was impaired at single-digit addition, an operation hypothesized to primarily require iterative manipulations along a mental number-line; this group was not impaired on arithmetic tasks linked to memory retrieval (e.g. single-digit multiplication). These results, obtained in tasks from two disparate domains, point to a potential constraint on the contribution of the cerebellum to cognitive tasks. Paralleling its role in motor control, the cerebellum may be essential for coordinating dynamic, movement-like transformations in a mental workspace.

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Humans exhibit complex arithmetic skills, often attributed to our exceptionally large neocortex. However, the past decade has provided ample evidence that the functional domain of the subcortex extends well beyond basic functions. Using a sensitive behavioral method, for the first time, we explored the contributions of lower-order visual monocular channels to symbolic arithmetic operations, addition and subtraction. The pattern of results from 4 different experiments provides converging evidence for a causal relation between mental arithmetic and primitive subcortical regions. The results have major implications for our understanding of the neuroevolutionary development of general numerical abilities-subcortical regions, which are shared across different species, are essential to complex numerical operations. In a bigger conceptual framework, these findings and others call for a shift from the modal view of the exclusive role of the neocortex in high-level cognition to a view that emphasizes the interplay between subcortical and cortical brain networks.

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A major challenge for neuropsychological research arises from the fact that we are dealing with a limited resource: the patients. Not only is it difficult to identify and recruit these individuals, but their ability to participate in research projects can be limited by their medical condition. As such, sample sizes are small, and considerable time (e.g., 2 years) is required to complete a study. To address limitations inherent to laboratory-based neuropsychological research, we developed a protocol for online neuropsychological testing (PONT). We describe the implementation of PONT and provide the required information and materials for recruiting participants, conducting remote neurological evaluations, and testing patients in an automated, self-administered manner. The protocol can be easily tailored to target a broad range of patient groups, especially those who can be contacted via support groups or multisite collaborations. To highlight the operation of PONT and describe some of the unique challenges that arise in online neuropsychological research, we summarize our experience using PONT in a research program involving individuals with Parkinson disease and spinocerebellar ataxia. In a 10-month period, by contacting 646 support group coordinators, we were able to assemble a participant pool with over 100 patients in each group from across the United States. Moreover, we completed six experiments (n > 300) exploring their performance on a range of tasks examining motor and cognitive abilities. The efficiency of PONT in terms of data collection, combined with the convenience it offers the participants, promises a new approach that can increase the impact of neuropsychological research.

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Scientific investigations have long emphasized the cortex's role in cognitive transfer and arithmetic abilities. To date, however, this assumption has not been thoroughly empirically investigated. Here we demonstrated that primitive mechanisms-lower visual channels-have a causal role in cognitive transfer of complex skills such as symbolic arithmetic. We found that exposing only one monocular channel to a visuospatial training resulted in a larger transfer effect in the trained monocular channel compared to the untrained monocular channel. Such cognitive transfer was found for both novel figural-spatial problems (near transfer) and novel subtraction problems (far transfer). Importantly, the benefits of the trained eye were not observed in old problems and in other tasks that did not involve visuospatial abilities (the Stroop task, a multiplication task). These results challenge the exclusive role of the cortex in cognitive transfer and complex arithmetic. In addition, the results suggest a new mechanism for the emergence of cognitive skills, that could be shared across different species.

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The literature has long emphasized the neocortex's role in the tangled phasic-alertness and temporal-expectancy processes. In this work, we examined whether subcortical, monocular mechanisms have a functional role in these processes. This was done by assessing phasic alertness and temporal expectancy independently using a cue-target eye-of-origin manipulation. Participants performed target detection tasks in which a central cue and its ensuing peripheral target were each presented either to the same eye or to a different eye. In Experiment 1, phasic alertness, independent of temporal expectancy, was manipulated by presenting an alerting cue prior to the target presentation. The alerting effect elicited by the cue lasted for a longer duration when the cue and target were presented to the same eye than when they were presented to different eyes, indicating the involvement of subcortical regions in phasic alertness. In Experiment 2, the cue's temporal predictability regarding the target's onset time was manipulated by changing the cue-target interval's foreperiod distribution. A modulation in temporal expectancy was found when both the cue and the target were presented to the same eye, demonstrating the importance of subcortical mechanisms in temporal expectancy. Together, the results demonstrate that monocular channels are functionally involved in both phasic alertness and temporal expectancy. This study suggests that both phasic alertness and temporal expectancy are functionally dependent on monocular channels of the visual stream, and highlights the importance of direct examination of primitive, subcortical regions in higher cognitive functioning (e.g., temporal expectancy).

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Human volitional orienting is typically assessed using Posner's endogenous cuing task. As a volitional process, the literature has long emphasized the role of neocortical structures in this higher cognitive function. Based on recent data, we explored the possibility that subcortical channels may have a functional role in volitional orienting as measured by a Posner cuing task in which a nonspatial feature of a centrally presented cue is predictively related to the location of the target. In addition, we have compared this typical cuing task to a "purer" version, which does not involve the probability manipulation. A sensitive behavioral method was used to probe the contribution of monocular channels (mostly subcortical) in the two types of endogenous orienting tasks. In both tasks, a spatially informative cue and its ensuing target were presented to the same or different eyes at varying cue-target intervals. In the typically used endogenous task, the onset of facilitation was apparent earlier when the cue and target were presented to the same eye. In contrast, in the "pure" task no difference was found between the two eye-of-origin conditions. These data support the notion that endogenous facilitation, as measured in the typical Posner cuing task, involves lower monocular regions. Hence, in the typical endogenous task, which was developed to explore "volitional" orienting, a simple associative learning mechanism might elicit monocular, rapid orienting responses. Notably, the typical volitional orienting paradigm might be contaminated by simple contingency benefits and thus may not provide a pure measure of volitional processes.

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The literature has long emphasized the role of higher cortical structures in endogenous orienting. Based on evolutionary explanation and previous data, we explored the possibility that lower monocular channels may also have a functional role in endogenous orienting of attention. Sensitive behavioral manipulation was used to probe the contribution of monocularly segregated regions in a simple cue - target detection task. A central spatially informative cue, and its ensuing target, were presented to the same or different eyes at varying cue-target intervals. Results indicated that the onset of endogenous orienting was apparent earlier when the cue and target were presented to the same eye. The data provides converging evidence for the notion that endogenous facilitation is modulated by monocular portions of the visual stream. This, in turn, suggests that higher cortical mechanisms are not exclusively responsible for endogenous orienting, and that a dynamic interaction between higher and lower neural levels, might be involved.

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The literature has long emphasized the role of the cerebral cortex in executive functions. Recently, however, several researchers have suggested that subcortical areas might also be involved in executive functions. The current study explored the possibility that subcortical mechanisms have a functional role in adaptive resolution of Stroop interference. We asked 20 participants to complete a cued task-switching Stroop task with variable cue-target intervals (CTI). Using a stereoscope, we manipulated which eye was shown the relevant dimension and which was shown the irrelevant dimension. This technique allowed us to examine the involvement of monocularly segregated - subcortical - regions of the visual processing stream. The interference effect was modulated by this eye-of-origin manipulation in the 0 CTI condition. This finding provides a novel indication for the notion that subcortical regions have a functional role in the resolution of Stroop interference. This indication suggests that cortical regions are not solely involved and that a dynamic interaction between cortical and subcortical regions is involved in executive functions.

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The literature has long emphasized the neocortex's role in volitional processes. In this work, we examined endogenous orienting in an evolutionarily older species, the archer fish, which lacks neocortex-like cells. We used Posner's classic endogenous cuing task, in which a centrally presented, spatially informative cue is followed by a target. The fish responded to the target by shooting a stream of water at it. Interestingly, the fish demonstrated a human-like "volitional" facilitation effect: their reaction times to targets that appeared on the side indicated by the precue were faster than their reaction times to targets on the opposite side. The fish also exhibited inhibition of return, an aftermath of orienting that commonly emerges only in reflexive orienting tasks in human participants. We believe that this pattern demonstrates the acquisition of an arbitrary connection between spatial orienting and a nonspatial feature of a centrally presented stimulus in nonprimate species. In the literature on human attention, orienting in response to such contingencies has been strongly associated with volitional control. We discuss the implications of these results for the evolution of orienting, and for the study of volitional processes in all species, including humans.

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