Transient Oscillations of Neural Firing Rate Associated With Routing of Evidence in a Perceptual Decision.

To form a perceptual decision, the brain must acquire samples of evidence from the environment and incorporate them in computations that mediate choice behavior. While much is known about the neural circuits that process sensory information and those that form decisions, less is known about the mechanisms that establish the functional linkage between them. We trained monkeys of both sexes to make difficult decisions about the net direction of visual motion under conditions that required trial-by-trial control of functional connectivity. In one condition, the motion appeared at different locations on different trials. In the other, two motion patches appeared, only one of which was informative. Neurons in the parietal cortex produced brief oscillations in their firing rate at the time routing was established: upon onset of the motion display when its location was unpredictable across trials, and upon onset of an attention cue that indicated in which of two locations an informative patch of dots would appear. The oscillation was absent when the stimulus location was fixed across trials. We interpret the oscillation as a manifestation of the mechanism that establishes the source and destination of flexibly routed information, but not the transmission of the information per se Significance Statement It has often been suggested that oscillations in neural activity might serve a role in routing information appropriately. We observe an oscillation in neural firing rate in the lateral intraparietal area consistent with such a role. The oscillations are transient. They coincide with the establishment of routing, but they do not appear to play a role in the transmission (or conveyance) of the routed information itself.

Multiple sclerosis-related fatigue lacks a unified definition: A narrative review.

Fatigue is the most common symptom in multiple sclerosis (MS). Although MS-related fatigue (MS-F) strongly affects quality of life and social performance of patients, there is currently a lack of knowledge about its pathophysiology, which in turns leads to poor objective diagnosis and management. Recent studies have attempted to explain potential etiologies as well as treatments for MS-F. However, it seems that without a consensus on its nature, these data could not provide a route to a successful approach. In this Article, we review definitions, epidemiology, risk factors and correlated comorbidities, pathophysiology, assessment methods, neuroimaging findings, and pharmacological and nonpharmacological treatments of MS-F. Further studies are warranted to define fatigue in MS patients more accurately, which could result in precise diagnosis and management.

Same principle, but different computations in representing time and space.

Time and space are two intertwined contexts that frame our cognition of the world and have shared mechanisms. A well-known theory on this case is "A Theory of Magnitude (ATOM)" which states that the perception of these two domains shares common mechanisms. However, evidence regarding shared computations of time and space is intermixed. To investigate this issue, we asked human subjects to reproduce time and distance intervals with saccadic eye movements in similarly designed tasks. We applied an observer model to both modalities and found underlying differences in the processing of time and space. While time and space computations are both probabilistic, adding priors to space perception minimally improved model performance, as opposed to time perception which was consistently better explained by Bayesian computations. We also showed that while both measurement and motor variability were smaller in distance than time reproduction, only the motor variability was correlated between them, as both tasks used saccadic eye movements for response. Our results suggest that time and space perception abide by the same algorithm but have different computational properties.

Perceptual learning of contrast discrimination in macaca mulatta.

Rhesus monkeys underwent training in a contrast discrimination task, in which grating stimuli were presented at parafoveal and peripheral visual field locations. Subjects had to compare a sample stimulus that had a fixed contrast of 30% to a test stimulus that varied in contrast from trial to trial. Extensive practice yielded improvements in contrast discrimination that were observed across the full range of test stimulus contrasts. These improvements occurred across multiple sessions, as well as across trials within individual sessions. The finer the contrast discriminations required, the longer it took for subjects to improve. Improvements in psychophysical performance resulted in the steepening of psychometric functions and/or shifts in the point of subjective equality towards the contrast of the sample stimulus. Enhancement in discrimination was especially pronounced around the contrast level of the sample stimulus, to which the subject was consistently exposed. The changes resulted in increased accuracy overall, lower discrimination thresholds, and faster response times. Partial transfer of learning, from vertically oriented training stimuli to horizontally oriented testing stimuli, was observed, while transfer to stimuli with different spatial frequencies was less pronounced. The results demonstrate the existence of perceptual learning in the contrast domain, whereby learning affects multiple performance-related psychophysical metrics.

Context-specific and context-invariant computations of interval timing.

Introduction: An accurate sense of time is crucial in flexible sensorimotor control and other cognitive functions. However, it remains unknown how multiple timing computations in different contexts interact to shape our behavior. Methods: We asked 41 healthy human subjects to perform timing tasks that differed in the sensorimotor domain (sensory timing vs. motor timing) and effector (hand vs. saccadic eye movement). To understand how these different behavioral contexts contribute to timing behavior, we applied a three-stage Bayesian model to behavioral data. Results: Our results demonstrate that the Bayesian model for each effector could not describe bias in the other effector. Similarly, in each task the model-predicted data could not describe bias in the other task. These findings suggest that the measurement stage of interval timing is context-specific in the sensorimotor and effector domains. We also showed that temporal precision is context-invariant in the effector domain, unlike temporal accuracy. Discussion: This combination of context-specific and context-invariant computations across sensorimotor and effector domains suggests overlapping and distributed computations as the underlying mechanism of timing in different contexts.

Working memory dysfunction differs between secondary progressive and relapsing multiple sclerosis: Effects of clinical phenotype, age, disease duration, and disability.

BACKGROUND: Cognitive dysfunction is relatively common in patients with multiple sclerosis (MS). Although it occurs in all stages and all phenotypes of MS, it is more prevalent in secondary progressive MS (SPMS) compared to relapsing MS (RMS). It is unclear whether the higher frequency of cognitive impairment in SPMS is linked to the progressive phenotype or other clinical factors. In this study, we compared working memory in patients with RMS, SPMS, and healthy subjects. We also investigated the effects of age, disease duration, and disability on working memory performance. METHODS: This case-control study enrolled 134 MS patients, 69 patients were diagnosed with RMS and 65 patients with SPMS, and 77 healthy control subjects. We designed two working memory tasks with different sets of stimuli (face vs. checkerboard) and different instructions (same or different vs. which one is the same). RESULTS: Accuracy was significantly more impaired in SPMS patients than in RMS patients and both groups were worse than healthy subjects. This finding was similar between both tasks. Age and overall cognitive functions (measured with MoCA) also affected accuracy, but disease duration and disability only affected accuracy in working memory task with checkerboard stimuli. CONCLUSION: MS patients are impaired in keeping the information in the visual working memory for a few seconds. Progressive phenotype significantly affected working memory accuracy, and this effect did not explain out with other demographic or clinical factors. Future studies are needed to reveal underlying mechanisms of working memory dysfunction in SPMS and working memory dysfunction as a biomarker of disease progression.

Patterns of attention deficit in relapsing and progressive phenotypes of multiple sclerosis.

Behavioral aspects and underlying pathology of attention deficit in multiple sclerosis (MS) remain unknown. This study aimed to clarify impairment of attention and its relationship with MS-related fatigue. Thirty-four relapse-remitting MS (RRMS), 35 secondary-progressive MS (SPMS) and 45 healthy controls (HC) were included. Results of psychophysics tasks (attention network test (ANT) and Posner spatial cueing test) and fatigue assessments (visual analogue scale and modified fatigue impact scale (MFIS)) were compared between groups. In ANT, attentional network effects were not different between MS phenotypes and HC. In Posner task, RRMS or SPMS patients did not benefit from valid cues unlike HC. RRMS and SPMS patients had less gain in exogenous trials with 62.5 ms cue-target interval time (CTIT) and endogenous trials with 250 ms CTIT, respectively. Total MFIS was the predictor of gain in 250 ms endogenous blocks and cognitive MFIS predicted orienting attentional effect. Executive attentional effect in RRMS patients with shorter disease duration and orienting attentional effect in longer diagnosed SPMS were correlated with MFIS scores. The pattern of attention deficit in MS differs between phenotypes. Exogenous attention is impaired in RRMS patients while SPMS patients have deficit in endogenous attention. Fatigue trait predicts impairment of endogenous and orienting attention in MS.

Aging decreases the precision of visual working memory.

OBJECTIVES: As individuals age, cognitive abilities such as working memory (WM), decline. In the current study, we investigated the effect of age on WM, and elucidated sources of errors. METHOD: A total of 102 healthy individuals, aged 18 to 71, participated in this research. We designed and administered a face-based visual WM task, collecting responses via a graded scale in a delayed match-to-sample reproduction task. RESULTS: The error of participants increased significantly as they aged. Our analysis revealed a significant age-related rise in the standard deviation of error distribution. However, there was no significant change in uniform probability with age. CONCLUSION: We found that WM performance declines through the lifespan. Investigating the sources of error, we found that the precision of WM decreased monotonously with age. The results also indicated that the probability of guessing the response as a measure of random response is not affected by age.

A mechanistic insight into sources of error of visual working memory in multiple sclerosis.

Working memory (WM) is one of the most affected cognitive domains in multiple sclerosis (MS), which is mainly studied by the previously established binary model for information storage (slot model). However, recent observations based on the continuous reproduction paradigms have shown that assuming dynamic allocation of WM resources (resource model) instead of the binary hypothesis will give more accurate predictions in WM assessment. Moreover, continuous reproduction paradigms allow for assessing the distribution of error in recalling information, providing new insights into the organization of the WM system. Hence, by utilizing two continuous reproduction paradigms, memory-guided localization (MGL) and analog recall task with sequential presentation, we investigated WM dysfunction in MS. Our results demonstrated an overall increase in recall error and decreased recall precision in MS. While sequential paradigms were better in distinguishing healthy control from relapsing-remitting MS, MGL were more accurate in discriminating MS subtypes (relapsing-remitting from secondary progressive), providing evidence about the underlying mechanisms of WM deficit in progressive states of the disease. Furthermore, computational modeling of the results from the sequential paradigm determined that imprecision in decoding information and swap error (mistakenly reporting the feature of other presented items) was responsible for WM dysfunction in MS. Overall, this study offered a sensitive measure for assessing WM deficit and provided new insight into the organization of the WM system in MS population.

Working memory is a system that temporarily stores and manipulates information used in tasks like decision-making and reasoning. Patients with multiple sclerosis ­ a condition that can affect the brain and spinal cord ­ often have impaired working memory, which can negatively affect their quality of life. Traditionally, working memory has been evaluated using tests that determine whether a patient can recall an item or not. In this approach, an incorrect response implies a complete absence of information regarding the specific item, resulting in a binary evaluation. More recently, researchers have shown that the precision of the memories people recall degrades gradually as they are asked to remember more things and that focusing on an item negatively affects recall precision for other items. This implies that working memory is reorganised flexibly between memorised items, a so-called 'resource model'. Unlike previous research, which favoured a binary model, Motahharynia et al. used a resource model to study visual working memory impairment in multiple sclerosis. The study participants consisted of healthy volunteers and patients with two subtypes of multiple sclerosis. Each participant completed one of two different types of test. In one, they were shown targets for short periods of time and then asked to pinpoint their position after they disappeared. In the other, participants were asked to memorise the orientation and colour of consecutively presented bars. The findings confirmed that multiple sclerosis patients had worse memory recall than people without the disease. However, computer modelling provided insights into the sources of error in working memory dysfunction, showing that the memory deficiency was due to imprecision in recalling information and 'swap errors', the phenomenon of mistakenly reporting the property of other memorised items. This rise in swap errors is likely due to an increase in unwanted signals, or noise, in the brains of multiple sclerosis patients. Motahharynia et al. have presented a sensitive way of measuring working memory deficiency. Importantly, the measurements were able to distinguish between different stages of multiple sclerosis. This could help doctors detect disease progression earlier, allowing for more timely and effective treatment interventions. This method could also be useful in the development and testing of drugs for therapy.

Effect of deep gray matter atrophy on information processing speed in early relapsing-remitting multiple sclerosis.

BACKGROUND: Cognitive dysfunction, including reduced Information processing speed (IPS), is relatively common in multiple sclerosis(MS). IPS deficits have profound effects on several aspects of patients' life. Previous studies showed that deep gray matter atrophy is highly correlated with overall cognitive impairment in MS. However, the effect of deep gray matter atrophy on IPS deficits is not well understood. In this study, we evaluated the effects of deep gray matter volume changes on IPS in people with early relapse-remitting MS (RRMS) compared to healthy control. METHODS: In this case-control study, we enrolled 63 case with RRMS and 36 healthy controls. All patients were diagnosed within 6 years. IPS was evaluated using the Integrated Cognitive Assessment (ICA) test. We also performed a 1.5T MRI to evaluate deep gray matter structures. RESULTS: People with RRMS had lower accuracy in the ICA test (p = .01). However, the reaction time did not significantly differ between RRMS and control groups (p = .6). Thalamus volume was significantly lower in the RRMS group with impaired IPS compared to the RRMS with normal IPS and control groups (p < 10-4). Other deep gray matter structures were not significantly different between the RRMS with impaired IPS group and the RRMS with normal IPS group. CONCLUSION: Some people with MS are impaired in IPS even in the early stages of the disease. Thalamic atrophy affected IPS in these patients, however atrophy in other deep gray matter structures, including caudate, putamen, globus pallidus, hippocampus, amygdala, accumbens, and cerebellum, were not significantly correlated with IPS impairment in early RRMS.

Thalamic asymmetry in Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a chronic neuroinflammatory disease that affects the central nervous system. Asymmetry is one of the finding in brain MRI of these patients, which is related to the debilitating symptoms of the disease. This study aimed to investigate and compare the thalamic asymmetry in MS patients and its relationship with other MRI and clinical findings of these patients. METHODS: This cross-sectional study conducted on 83 patients with relapse-remitting MS (RRMS), 43 patients with secondary progressive MS (SPMS), and 89 healthy controls. The volumes of total intracranial, total gray matter, total white matter, lesions, thalamus, and also the thalamic asymmetry indices were calculated. The 9-hole peg test (9-HPT) and Expanded Disability Status Scale (EDSS) were assessed as clinical findings. RESULTS: We showed that the normalized whole thalamic volume in healthy subjects was higher than MS patients (both RRMS and SPMS). Thalamic asymmetry index (TAI) was significantly different between RRMS patients and SPMS patients (p = 0.011). The absolute value of TAI was significantly lower in healthy subjects than in RRMS (p < 0.001) and SPMS patients (p < 0.001), and SPMS patients had a higher absolute TAI compared to RRMS patients (p = 0.037). CONCLUSIONS: In this cross-sectional study we showed a relationship between normalized whole thalamic volume and MS subtype. Also, we showed that the asymmetric indices of the thalamus can be related to the progression of the disease. Eventually, we showed that thalamic asymmetry can be related to the disease progression and subtype changes in MS.

The variation of functional connectivity and activity before and after thalamotomy surgery (review).

Ablation surgeries are utilized to treat certain brain disorders. Recently, these surgeries have become more prevalent using techniques such as magnetic resonance guided focused ultrasound (MRgFUS) ablation and Gamma knife thalamotomy (GKT). However, as the thalamus plays a critical role in cognitive functions, the potential impact of these surgeries on functional connectivity and cognition is a matter of concern. Various approaches have been developed to locate the target for ablation and also investigate changes in functional connectivity before and after surgery. Functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) are widely used methods for assessing changes in functional connectivity and activity in clinical research. In this Review, we summarize the use of fMRI and EEG in thalamotomy surgeries. Our analysis shows that thalamotomy surgery can result in changes in functional connectivity in motor-related, visuomotor, and default-mode networks, as detected by fMRI. EEG data also indicate a reduction in over-activities observed in the preoperative state.

Perceptual learning of fine contrast discrimination changes neuronal tuning and population coding in macaque V4.

Perceptual learning, the improvement in perceptual abilities with training, is thought to be mediated by an alteration of neuronal tuning. It remains poorly understood how tuning properties change as training progresses, whether improved stimulus tuning directly links to increased behavioural readout of sensory information, or how population coding mechanisms change with training. Here, we recorded continuously from multiple neuronal clusters in area V4 while macaque monkeys learned a fine contrast categorization task. Training increased neuronal coding abilities by shifting the steepest point of contrast response functions towards the categorization boundary. Population coding accuracy of difficult discriminations resulted largely from an increased information coding of individual channels, particularly for those channels that in early learning had larger ability for easy discriminations, but comparatively small encoding abilities for difficult discriminations. Population coding was also enhanced by specific changes in correlations. Neuronal activity became more indicative of upcoming choices with training.

Virtual Electrode Recording Tool for EXtracellular potentials (VERTEX): comparing multi-electrode recordings from simulated and biological mammalian cortical tissue.

Local field potentials (LFPs) sampled with extracellular electrodes are frequently used as a measure of population neuronal activity. However, relating such measurements to underlying neuronal behaviour and connectivity is non-trivial. To help study this link, we developed the Virtual Electrode Recording Tool for EXtracellular potentials (VERTEX). We first identified a reduced neuron model that retained the spatial and frequency filtering characteristics of extracellular potentials from neocortical neurons. We then developed VERTEX as an easy-to-use Matlab tool for simulating LFPs from large populations (>100,000 neurons). A VERTEX-based simulation successfully reproduced features of the LFPs from an in vitro multi-electrode array recording of macaque neocortical tissue. Our model, with virtual electrodes placed anywhere in 3D, allows direct comparisons with the in vitro recording setup. We envisage that VERTEX will stimulate experimentalists, clinicians, and computational neuroscientists to use models to understand the mechanisms underlying measured brain dynamics in health and disease.

Stimulus roving and flankers affect perceptual learning of contrast discrimination in Macaca mulatta.

'Stimulus roving' refers to a paradigm in which the properties of the stimuli to be discriminated vary from trial to trial, rather than being kept constant throughout a block of trials. Rhesus monkeys have previously been shown to improve their contrast discrimination performance on a non-roving task, in which they had to report the contrast of a test stimulus relative to that of a fixed-contrast sample stimulus. Human psychophysics studies indicate that roving stimuli yield little or no perceptual learning. Here, we investigate how stimulus roving influences perceptual learning in macaque monkeys and how the addition of flankers alters performance under roving conditions. Animals were initially trained on a contrast discrimination task under non-roving conditions until their performance levels stabilized. The introduction of roving contrast conditions resulted in a pronounced drop in performance, which suggested that subjects initially failed to heed the sample contrast and performed the task using an internal memory reference. With training, significant improvements occurred, demonstrating that learning is possible under roving conditions. To investigate the notion of flanker-induced perceptual learning, flanker stimuli (30% fixed-contrast iso-oriented collinear gratings) were presented jointly with central (roving) stimuli. Presentation of flanker stimuli yielded substantial performance improvements in one subject, but deteriorations in the other. Finally, after the removal of flankers, performance levels returned to their pre-flanker state in both subjects, indicating that the flanker-induced changes were contingent upon the continued presentation of flankers.

Attention-induced variance and noise correlation reduction in macaque V1 is mediated by NMDA receptors.

Attention improves perception by affecting different aspects of the neuronal code. It enhances firing rates, it reduces firing rate variability and noise correlations of neurons, and it alters the strength of oscillatory activity. Attention-induced rate enhancement in striate cortex requires cholinergic mechanisms. The neuropharmacological mechanisms responsible for attention-induced variance and noise correlation reduction or those supporting changes in oscillatory activity are unknown. We show that ionotropic glutamatergic receptor activation is required for attention-induced rate variance, noise correlation, and LFP gamma power reduction in macaque V1, but not for attention-induced rate modulations. NMDA receptors mediate attention-induced variance reduction and attention-induced noise correlation reduction. Our results demonstrate that attention improves sensory processing by a variety of mechanisms that are dissociable at the receptor level.