Changes in Brain Functional Connectivity Underlying the Space-Number Association.

Whether small number magnitudes are inherently represented as lying to the left of larger ones, the space-number association (SNA), is an important issue in mathematical cognition. In this fMRI study, we used a go/no-go implicit association task to investigate the brain activity and functional connectivity underlying the SNA. Arabic digits lower or higher than 5 and left- or right-pointing arrows were alternated as central targets. In a single-code task condition, participants responded to a specific number magnitude and to all arrows or to a specific arrow direction and to all number magnitudes. In a joint-code (JC) condition, responses were provided after congruent, for example, "go when a number is lower than 5 or an arrow points left," or incongruent, for example, "go when a number is lower than 5 or an arrow points right," SNAs. The SNA was only found in the JC condition, where responses were faster with congruent instructions. Analyses of fMRI functional connectivity showed that the SNA was matched with enhanced excitatory inputs from ACC, the left TPJ, and the left inferior frontal gyrus to the left and right intraparietal sulcus (IPS). Incongruent JC trials were associated with enhanced excitatory modulation from ACC to the left and right IPS. These results show that the SNA is associated with enhanced activation of top-down brain control and changes in the functional interaction between the left and right IPS. We conclude that the SNA does not depend on an inherent and bottom-up spatial coding of number magnitudes.

The time course of the spatial representation of 'past' and 'future' concepts: New evidence from the STEARC effect.

Humans use space to think of and communicate the flow of time. This spatial representation of time is influenced by cultural habits so that in left-to-right reading cultures, short durations and past events are mentally positioned to the left of long durations and future events. The STEARC effect (Space Temporal Association of Response Codes) shows a faster classification of short durations/past events with responses on the left side of space and of long durations/future events with responses on the right side. We have recently showed that during the classification of time durations, space is a late heuristic of time because in this case, the STEARC appears only when manual responses are slow, not when they are fast. Here, we wished to extend this observation to the semantic classification of words as referring to the 'past' or the 'future'. We hypothesised that the semantic processing of 'past' and 'future' concepts would have engaged slower decision processes than the classification of short versus long time durations. According to dual-route models of conflict tasks, if the task-dependent classification/decision process were to proceed relatively slowly, then the effects of direct activation of culturally preferred links between stimulus and response (S-R), i.e., past/left and future/right in the case of the present task, should attain higher amplitudes before the instruction-dependent correct response is selected. This would imply that, at variance with the faster classification of time durations, during the slower semantic classification of time concepts, in incongruent trials, the direct activation of culturally preferred S-R links should introduce significant reaction time (RT) costs and a corresponding STEARC at the fastest manual responses in the experiment too. The study's results confirmed this hypothesis and showed that in the classification of temporal words, the STEARC also increased as a function of the length of RTs. Taken together, the results from sensory duration and semantic classification STEARC tasks show that the occurrence, strength and time course of the STEARC varies significantly as a function of the speed and level of cognitive processing required in the task.

Exploring the Interplay of Working Memory, Apathy, and Mood/Emotional Factors.

BACKGROUND: Previous investigations on healthy humans showed conflicting evidence regarding the impact of mood on working memory performance. A systematic investigation of how mood affects apathy levels in healthy participants is currently missing. METHODS: We administered a visuospatial (VS) and a numerical (N) n-back task to a sample of 120 healthy individuals. In these participants, using a series of questionnaires, we also evaluated apathy, mood, working memory, perceived stress, PTSD symptoms caused by the COVID-19 pandemic outbreak, and general psychiatric symptoms. Successively, we investigated their performance in the n-back task as a function of scores to these questionnaires. RESULTS: Participants performed better in the N block than in the VS one. Their accuracy decreased as a function of the n-back difficulty. We reported no differences in working memory performance or apathy as a function of mood, stress, or PTSD symptoms. We found that phobic anxiety negatively predicted accuracy to the numerical n-back task and that subjects with greater anxiety and difficulty in regulating emotions also showed higher levels of withdrawal from the task. CONCLUSION: The study's results suggest that while mood did not significantly affect working memory performance, strong associations were found between WMQ scores and working memory capabilities.

Temperament and probabilistic predictive coding in visual-spatial attention.

Cholinergic (Ach), Noradrenergic (NE), and Dopaminergic (DA) pathways play an important role in the regulation of spatial attention. The same neurotransmitters are also responsible for inter-individual differences in temperamental traits. Here we explored whether biologically defined temperamental traits determine differences in the ability to orient spatial attention as a function of the probabilistic association between cues and targets. To this aim, we administered the Structure of Temperament Questionnaire (STQ-77) to a sample of 151 participants who also performed a Posner task with central endogenous predictive (80 % valid/20 % invalid) or non-predictive cues (50 % valid/50 % invalid). We found that only participants with high scores in Plasticity and Intellectual Endurance showed a selective abatement of attentional costs with non-predictive cues. In addition, stepwise regression showed that costs in the non-predictive condition were negatively predicted by scores in Plasticity and positively predicted by scores in Probabilistic Thinking. These results show that stable temperamental characteristics play an important role in defining the inter-individual differences in attentional behaviour, especially in the presence of different probabilistic organisations of the sensory environment. These findings emphasize the importance of considering temperamental and personality traits in social and professional environments where the ability to control one's attention is a crucial functional skill.

How time gets spatial: factors determining the stability and instability of the mental time line.

Left-to-right readers classify faster past events with motor responses on the left side of space and future events with responses on the right side. This suggests a left-to-right spatial organization in the mental representation of time. Here, we show that the significance and reliability of this representation are linked to the joint use of temporal and spatial codes in the task at hand. In a first unimanual Go/No-Go Implicit Association Test (IAT), attending selectively to "past" or to "future" words did not activate corresponding "left" or "right" spatial concepts and vice versa. In a second IAT, attending to both temporal (i.e., "past" and "future") words and spatial targets (i.e., "left" and "right") pointing arrows produced faster responses for congruent rather than incongruent combinations of temporal and spatial concepts in task instructions (e.g., congruent = "Go with past words and left-pointing arrows"; incongruent = "Go with past words and right-pointing arrows"). This effect increased markedly in a STEARC task where spatial codes defined the selection between "left-side" and "right-side" button presses that were associated with "past" and "future" words. Two control experiments showed only partial or unreliable space-time congruency effects when (a) participants attended to superordinate semantic codes that included both spatial "left"/"right" or temporal "past/future" subordinate codes; (b) a primary speeded response was assigned to one dimension (e.g., "past vs. future") and a nonspeeded one to the other dimension (e.g., "left" vs. "right"). These results help to define the conditions that trigger a stable and reliable spatial representation of time-related concepts.

Space is a late heuristic of elapsing time: New evidence from the STEARC effect.

To get a concrete representation of its intangible flow, culture frames elapsing time along spatially oriented mental or graphical lines, which are organised according to reading habits, from left to right in western cultures. One of the strongest evidence for this spatial representation of time is the STEARC effect (Spatial-Temporal Association of Response Codes), which consists of faster coding of "short" durations with motor responses in the left side of space and of "long" durations with responses in the right side. Here, we investigated the STEARC as a function of response speed in two different experiments in healthy participants. Surprisingly, in both sub- and supra-second ranges, we found the STEARC only when decisions on time durations were slow, while no spatial representation of time was present with fast decisions. This first demonstrates that space slowly takes over faster non-spatial processing of time flow and that it is possible to empirically separate the behavioural manifestations of the non-spatial and the nurtured spatial mechanisms of time coding.

A Reinforcement Meta-Learning framework of executive function and information demand.

Gathering information is crucial for maximizing fitness, but requires diverting resources from searching directly for primary rewards to actively exploring the environment. Optimal decision-making thus maximizes information while reducing effort costs, but little is known about the neuro-computational implementation of this tradeoff. We present a Reinforcement Meta-Learning (RML) computational model that solves the trade-off between the value and costs of gathering information. We implement the RML in a biologically plausible architecture that links catecholaminergic neuromodulators, the medial prefrontal cortex and topographically organized visual maps and show that it accounts for neural and behavioral findings on information demand motivated by instrumental incentives and intrinsic utility. Moreover, the utility function used by the RML, encoded by dopamine, is an approximation of variational free energy. Thus, the RML presents a biologically plausible mechanism for coordinating motivational, executive and sensory systems generate visual information gathering policies that minimize free energy.

Left and right temporal-parietal junctions (TPJs) as "match/mismatch" hedonic machines: A unifying account of TPJ function.

Experimental and theoretical studies have tried to gain insights into the involvement of the Temporal Parietal Junction (TPJ) in a broad range of cognitive functions like memory, attention, language, self-agency and theory of mind. Recent investigations have demonstrated the partition of the TPJ in discrete subsectors. Nonetheless, whether these subsectors play different roles or implement an overarching function remains debated. Here, based on a review of available evidence, we propose that the left TPJ codes both matches and mismatches between expected and actual sensory, motor, or cognitive events while the right TPJ codes mismatches. These operations help keeping track of statistical contingencies in personal, environmental, and conceptual space. We show that this hypothesis can account for the participation of the TPJ in disparate cognitive functions, including "humour", and explain: a) the higher incidence of spatial neglect in right brain damage; b) the different emotional reactions that follow left and right brain damage; c) the hemispheric lateralisation of optimistic bias mechanisms; d) the lateralisation of mechanisms that regulate routine and novelty behaviours. We propose that match and mismatch operations are aimed at approximating "free energy", in terms of the free energy principle of decision-making. By approximating "free energy", the match/mismatch TPJ system supports both information seeking to update one's own beliefs and the pleasure of being right in one's own' current choices. This renewed view of the TPJ has relevant clinical implications because the misfunctioning of TPJ-related "match" and "mismatch" circuits in unilateral brain damage can produce low-dimensional deficits of active-inference and predictive coding that can be associated with different neuropsychological disorders.

Splenial Callosal Disconnection in Right Hemianopic Patients Induces Right Visual-Spatial Neglect.

Posterior cerebral artery (PCA) territory infarction involving occipital cortical damage can give rise to contralateral homonymous hemianopia. Here, we report two rare cases of patients with lesions in the left hemisphere PCA territory who developed right visuo-spatial neglect. One patient suffered right hemianopia and right visuo-spatial neglect after a stroke that damaged the left primary visual cortex and the callosal splenial fibers. The other unique case is of a patient who had a brain tumor in the posterior cerebral region in the left hemisphere and initially exhibited only right hemianopia that developed into right visuo-spatial neglect after tumor resection that included the splenial fibers. These cases indicate that, as in cases with damage in the right PCA territory, lesions in the left PCA yield visuo-spatial neglect when the damage produces contralateral hemianopia and concomitant disconnection of the splenium of the corpus callosum, which interferes with the arrival of visual inputs from the intact right to the lesioned left hemisphere. These results also emphasize the necessity of sparing the splenial fibers in surgical interventions in patients who exhibit hemianopia.

Perceiving numerosity does not cause automatic shifts of spatial attention.

It is debated whether the representation of numbers is endowed with a directional-spatial component so that perceiving small-magnitude numbers triggers leftward shifts of attention and perceiving large-magnitude numbers rightward shifts. Contrary to initial findings, recent investigations have demonstrated that centrally presented small-magnitude and large-magnitude Arabic numbers do not cause leftward and rightward shifts of attention, respectively. Here we verified whether perceiving small or large non-symbolic numerosities (i.e., clouds of dots) drives attention to the left or the right side of space, respectively. In experiment 1, participants were presented with central small (1, 2) vs large-numerosity (8, 9) clouds of dots followed by an imperative target in the left or right side of space. In experiment 2, a central cloud of dots (i.e., five dots) was followed by the simultaneous presentation of two identical dot-clouds, one on the left and one on the right side of space. Lateral clouds were both lower (1, 2) or higher in numerosity (8, 9) than the central cloud. After a variable delay, one of the two lateral clouds turned red and participants had to signal the colour change through a unimanual response. We found that (a) in Experiment 1, the small vs large numerosity of the central cloud of dots did not speed up the detection of left vs right targets, respectively, (b) in Experiment 2, the detection of colour change was not faster in the left side of space when lateral clouds were smaller in numerosity than the central reference and in the right side when clouds were larger in numerosity. These findings show that perceiving non-symbolic numerosity does not cause automatic shifts of spatial attention and suggests no inherent association between the representation of numerosity and that of directional space.

Individual EEG profiling of attention deficits in left spatial neglect: A pilot study.

Electrophysiological group studies in brain-damaged patients can be run to capture the EEG correlates of specific cognitive impairments. Nonetheless, this procedure is not adequate to characterize the inter-individual variability present in major neuropsychological syndromes. We tested the possibility of getting a reliable individual EEG characterization of deficits of endogenous orienting of spatial attention in right-brain damaged (RBD) patients with left spatial neglect (N+). We used a single-trial topographical analysis (STTA; [39] of individual scalp EEG topographies recorded during leftward and rightward orienting of attention with central cues in RBD patients with and without (N-) neglect and in healthy controls (HC). We found that the STTA successfully decoded EEG signals related to leftward and rightward orienting in five out of the six N+, five out of the six N- patients and in all the six HC. In agreement with findings from conventional average-group studies, successful classifications of EEG signals in N+ were observed during the 400-800 ms period post-cue-onset, which reflects preserved voluntary engagement of attention resources (ADAN component). These results suggest the possibility of acquiring reliable individual EEG profiles of neglect patients.

Deficits of hierarchical predictive coding in left spatial neglect.

Right brain-damaged patients with unilateral spatial neglect fail to explore the left side of space. Recent EEG and clinical evidence suggests that neglect patients might suffer deficits in predictive coding, i.e. in identifying and exploiting probabilistic associations among sensory stimuli in the environment. To gain direct insights on this issue, we focussed on the hierarchical components of predictive coding. We recorded EEG responses evoked by central, left-side or right-side tones that were presented at the end of sequences of four central tones. Left-side and right-side deviant tones produce a pre-attentive Mismatch Negativity that reflects a lower-order prediction error for the 'Local' deviation of the tone at the end of the sequence. Higher-order prediction errors for the frequency of these deviations in the acoustic environment, i.e. 'Global' deviation, are marked by the P3 response. We show that when neglect patients are immersed in an acoustic environment characterized by frequent left-side deviant tones, they display no pre-attentive Mismatch Negativity both for left-side deviant tones and infrequent omissions of the last tone, while they have Mismatch Negativity for infrequent right-side deviant tones. In the same condition, neglect patients show no P300 response to 'Global' prediction errors for deviant tones, including those in the non-neglected right-side, and omissions. In contrast to this, when right-side deviant tones are predominant in the acoustic environment, neglect patients have pre-attentive Mismatch Negativity both for right-side deviant tones and infrequent omissions, while they display no Mismatch Negativity for infrequent left-side deviant tones. Most importantly, in the same condition neglect patients show enhanced P300 response to infrequent left-side deviant tones, notwithstanding that these tones evoked no pre-attentive Mismatch Negativity. This latter finding indicates that 'Global' predictions are independent of 'Local' error signals provided by the Mismatch Negativity. These results qualify deficits of predictive coding in the spatial neglect syndrome and show that neglect patients base their predictive behaviour only on statistical regularities that are related to the frequent occurrence of sensory events on the right side of space.

The Precentral Insular Cortical Network for Speech Articulation.

Apraxia of speech is a motor disorder characterized by the impaired ability to coordinate the sequential articulatory movements necessary to produce speech. The critical cortical area(s) involved in speech apraxia remain controversial because many of the previously reported cases had additional aphasic impairments, preventing localization of the specific cortical circuit necessary for the somatomotor execution of speech. Four patients with "pure speech apraxia" (i.e., who had no aphasic and orofacial motor impairments) are reported here. The critical lesion in all four patients involved, in the left hemisphere, the precentral gyrus of the insula (gyrus brevis III) and, to a lesser extent, the nearby areas with which it is strongly connected: the adjacent subcentral opercular cortex (part of secondary somatosensory cortex) and the most inferior part of the central sulcus where the orofacial musculature is represented. There was no damage to rostrally adjacent Broca's area in the inferior frontal gyrus. The present study demonstrates the critical circuit for the coordination of complex articulatory movements prior to and during the execution of the motor speech plans. Importantly, this specific cortical circuit is different from those that relate to the cognitive aspects of language production (e.g., Broca's area on the inferior frontal gyrus).

Forgetting Unwanted Memories: Active Forgetting and Implications for the Development of Psychological Disorders.

Intrusive memories are a common feature of many psychopathologies, and suppression-induced forgetting of unwanted memories appears as a critical ability to preserve mental health. In recent years, biological and cognitive studies converged in revealing that forgetting is due to active processes. Recent neurobiological studies provide evidence on the active role of main neurotransmitter systems in forgetting, suggesting that the brain actively works to suppress retrieval of unwanted memories. On the cognitive side, there is evidence that voluntary and involuntary processes (here termed "intentional" and "incidental" forgetting, respectively) contribute to active forgetting. In intentional forgetting, an inhibitory control mechanism suppresses awareness of unwanted memories at encoding or retrieval. In incidental forgetting, retrieval practice of some memories involuntarily suppresses the retrieval of other related memories. In this review we describe recent findings on deficits in active forgetting observed in psychopathologies, like post-traumatic stress disorder, depression, schizophrenia, and obsessive-compulsive disorder. Moreover, we report studies in which the role of neurotransmitter systems, known to be involved in the pathogenesis of mental disorders, has been investigated in active forgetting paradigms. The possibility that biological and cognitive mechanisms of active forgetting could be considered as hallmarks of the early onset of psychopathologies is also discussed.

A Scoping Review of Cognitive Training in Neurodegenerative Diseases via Computerized and Virtual Reality Tools: What We Know So Far.

Most prevalent neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease and multiple sclerosis are heterogeneous in their clinical profiles and underlying pathophysiology, although they typically share the presence of cognitive impairment that worsens significantly during the course of the disease. Viable pharmacological options for cognitive symptoms in these clinical conditions are currently lacking. In recent years, several studies have started to apply Computerized Cognitive Training (CCT) and Virtual Reality (VR) tools to try and contrast patients' cognitive decay over time. However, no in-depth literature review of the contribution of these promising therapeutic options across main neurodegenerative diseases has been conducted yet. The present paper reports the state-of-the-art of CCT and VR studies targeting cognitive impairment in most common neurodegenerative conditions. Our twofold aim is to point out the scientific evidence available so far and to support health professionals to consider these promising therapeutic tools when planning rehabilitative interventions, especially when the access to regular and frequent hospital consultations is not easy to be provided.

A Scoping Review of Neuromodulation Techniques in Neurodegenerative Diseases: A Useful Tool for Clinical Practice?

Background and Objectives: Neurodegenerative diseases that typically affect the elderly such as Alzheimer's disease, Parkinson's disease and frontotemporal dementia are typically characterised by significant cognitive impairment that worsens significantly over time. To date, viable pharmacological options for the cognitive symptoms in these clinical conditions are lacking. In recent years, various studies have employed neuromodulation techniques to try and contrast patients' decay. Materials and Methods: We conducted an in-depth literature review of the state-of-the-art of the contribution of these techniques across these neurodegenerative diseases. Results: The present review reports that neuromodulation techniques targeting cognitive impairment do not allow to draw yet any definitive conclusion about their clinical efficacy although preliminary evidence is very encouraging. Conclusions: Further and more robust studies should evaluate the potentialities and limitations of the application of these promising therapeutic tools to neurodegenerative diseases.

Number space is made by response space: Evidence from left spatial neglect.

Whether the semantic representation of numbers is endowed with an intrinsic spatial component, so that smaller numbers are inherently represented to the left of larger ones on a Mental Number Line (MNL), is a central matter of debate in numerical cognition. To gain an insight into this issue, we investigated the performance of right brain damaged patients with left spatial neglect (N+) in a bimanual Magnitude Comparison SNARC task and in a uni-manual Magnitude Comparison Go/No-Go task (i.e. "is the number smaller or larger than 5?"). While the first task requires the use of contrasting left/right spatial codes for response selection, the second task does not require the use of these codes. In line with previous evidence, in the SNARC task N+ patients displayed a significant asymmetry in Reaction Times (RTs), with slower RTs to number "4", that was immediately precedent to the numerical reference "5", with respect to the number "6", that immediately followed the same reference. This RTs asymmetry was correlated with lesion of white matter tracts, i.e. Fronto-Occipital-Fasciculus, that allows prefrontal Ba 8 and 46 to regulate the distribution of attention on sensory and memory traces in posterior occipital, temporal and parietal areas. In contrast, no similar RTs asymmetry was found in the Go/No-Go task. These findings suggest that while in the SNARC task numbers get mentally organised from left-to-right as a function of their increasing magnitude, so that N+ patients display a delay in the processing of number-magnitudes that are immediately smaller than a given numerical reference, in the Go/No-Go task no left-to-right organization is activated. These results support the idea that it is the use of contrasting left/right spatial codes, whether motor or conceptual, that triggers the generation of a spatially left-to-right organised MNL and that the representation of number magnitude is not endowed with an inherent spatial component.

How to trigger and keep stable directional Space-Number Associations (SNAs).

Humans are prone to mentally organise the ascending series of integers according to reading habits so that in western cultures small numbers are positioned to the left of larger ones on a mental number line. Despite 140 years since seminal observations by Sir Francis Galton (Galton, 1880a, b), the functional mechanisms that give rise to directional Space-Number Associations (SNAs) remain elusive. Here, we contrasted three different experimental conditions, each including a different version of a Go/No-Go task with intermixed numerical and arrow-targets (Shaki and Fischer, 2018; Pinto et al., 2019a). We show that directional SNAs are not "all or none" phenomena. We demonstrate that SNAs get progressively less noisy and more stable the more contrasting small/large magnitude-codes and contrasting left/right spatial-codes are explicitly and fully combined in the task set. The analyses of the time-course of space-number congruency effects showed that both the absence and presence of the SNA were independent of the speed of reaction times. In agreement with our original proposal (Aiello et al., 2012), these findings show that conceptualising the ascending series of integers in spatial terms depends on the use of spatial codes in the numerical task at hand rather than on the presence of an inherent spatial dimension in the semantic representation of numbers. This evidence suggests that directional SNAs, like the SNARC effect, are secondary to the primary transfer of spatial response codes to number stimuli, rather than deriving from a primary congruency or incongruence between independent spatial-response and spatial-number codes.

Pupil dilation during orienting of attention and conscious detection of visual targets in patients with left spatial neglect.

Right Brain-Damaged patients (RBD) with left spatial neglect (N+), are characterised by deficits in orienting and re-orienting attention to stimuli in the contralesional left side of space. In a recent ERPs study with visual stimuli (Lasaponara et al., 2018) we have pointed out that the pathological attentional bias of N+ is matched with exaggerated novelty reaction and contextual updating of targets in the right ipsilesional space and reduced novelty reaction and contextual updating of targets in the left contralesional space. To characterise further the attentional performance of N+, here we measured Pupil Dilation (PDil), which is a reliable marker of noradrenergic-locus coeruleus activity and response to unexpected events/rewards. Compared to Neutral and Valid targets, N+ patients displayed a pathological reduction of PDil in response to infrequent Invalid targets in the left side of space, while in Healthy Controls (HC) and RBD without neglect (N-) the same targets enhanced PDil with respect to Neutral and frequent Valid targets. Invalid targets in the right side of space enhanced PDil in all experimental groups. Interestingly, both N- and N+ showed a consistent number of target omissions both in the left and right side of space. With respect to seen targets, N- showed reduced PDil in response to unseen targets both in the left and right side of space. In contrast, N+ had reduced PDil in response to unseen targets in the left side of space though not in the right side, where seen and unseen targets evoked comparable levels of PDil. These results disclose, for the first time, the PDil correlates of spatial attention in left spatial neglect and suggest that the pathological attentional bias suffered by N+ might enhance the autonomic responses reflected in PDil to unseen ipsilesional stimuli. This enhancement can contribute to biasing contextual updating and predictive coding of stimuli in the ipsilesional space, thus worsening the pathological attentional bias of N+.