Transcutaneous Vagus Nerve Stimulation (tVNS) applications in cognitive aging: a review and commentary.

Differentiating healthy from pathological aging trajectories is extremely timely, as the global population faces an inversion where older adults will soon outnumber younger 5:1. Many cognitive functions (e.g., memory, executive functions, and processing speed) decline with age, a process that can begin as early as midlife, and which predicts subsequent diagnosis with dementia. Although dementia is a devastating and costly diagnosis, there remains limited evidence for medications, therapies, and devices that improve cognition or attenuate the transition into dementia. There is an urgent need to intervene early in neurodegenerative processes leading to dementia (e.g., depression and mild cognitive impairment). In this targeted review and commentary, we highlight transcutaneous Vagus Nerve Stimulation (tVNS) as a neurostimulation method with unique opportunities for applications in diseases of aging, reviewing recent literature, feasibility of use with remote data collection methods/telehealth, as well as limitations and conflicts in the literature. In particular, small sample sizes, uneven age distributions of participants, lack of standardized protocols, and oversampling of non-representative groups (e.g., older adults with no comorbid diagnoses) limit our understanding of the potential of this method. We offer recommendations for how to improve representativeness, statistical power, and generalizability of tVNS research by integrating remote data collection techniques.

Association between mental health symptoms and behavioral performance in younger vs. older online workers.

Background: The COVID-19 pandemic has been associated with increased rates of mental health problems, particularly in younger people. Objective: We quantified mental health of online workers before and during the COVID-19 pandemic, and cognition during the early stages of the pandemic in 2020. A pre-registered data analysis plan was completed, testing the following three hypotheses: reward-related behaviors will remain intact as age increases; cognitive performance will decline with age; mood symptoms will worsen during the pandemic compared to before. We also conducted exploratory analyses including Bayesian computational modeling of latent cognitive parameters. Methods: Self-report depression (Patient Health Questionnaire 8) and anxiety (General Anxiety Disorder 7) prevalence were compared from two samples of Amazon Mechanical Turk (MTurk) workers ages 18-76: pre-COVID 2018 (N = 799) and peri-COVID 2020 (N = 233). The peri-COVID sample also completed a browser-based neurocognitive test battery. Results: We found support for two out of three pre-registered hypotheses. Notably our hypothesis that mental health symptoms would increase in the peri-COVID sample compared to pre-COVID sample was not supported: both groups reported high mental health burden, especially younger online workers. Higher mental health symptoms were associated with negative impacts on cognitive performance (speed/accuracy tradeoffs) in the peri-COVID sample. We found support for two hypotheses: reaction time slows down with age in two of three attention tasks tested, whereas reward function and accuracy appear to be preserved with age. Conclusion: This study identified high mental health burden, particularly in younger online workers, and associated negative impacts on cognitive function.

Identification of psychiatric disorder subtypes from functional connectivity patterns in resting-state electroencephalography.

The understanding and treatment of psychiatric disorders, which are known to be neurobiologically and clinically heterogeneous, could benefit from the data-driven identification of disease subtypes. Here, we report the identification of two clinically relevant subtypes of post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) on the basis of robust and distinct functional connectivity patterns, prominently within the frontoparietal control network and the default mode network. We identified the disease subtypes by analysing, via unsupervised and supervised machine learning, the power-envelope-based connectivity of signals reconstructed from high-density resting-state electroencephalography in four datasets of patients with PTSD and MDD, and show that the subtypes are transferable across independent datasets recorded under different conditions. The subtype whose functional connectivity differed most from those of healthy controls was less responsive to psychotherapy treatment for PTSD and failed to respond to an antidepressant medication for MDD. By contrast, both subtypes responded equally well to two different forms of repetitive transcranial magnetic stimulation therapy for MDD. Our data-driven approach may constitute a generalizable solution for connectome-based diagnosis.

Damage to the Intraparietal Sulcus Impairs Magnitude Representations of Results of Complex Arithmetic Problems.

Past research investigating the role of the intraparietal sulcus (IPS) in numerical processes focused mainly on quantity and numerical comparisons as well on single digit arithmetic. The present study investigates the involvement of the IPS in estimating the results of multi-digit multiplication problems. For this purpose, the performance a 24-year-old female (JD) with brain damage in the left IPS was compared to an age-matched control group in the computation estimation task. When required to estimate whether the results of multi-digit multiplication problems are smaller or larger than given reference numbers, JD, in contrast to controls, did not show the common patterns of distance and size effects. Her strategy use was also atypical. Most control participants used both the approximated calculation strategy that involves rounding and calculation procedures and the sense of magnitude strategy that relies on an intuitive approximated magnitude representation of the results. In contrast, JD used only the former but not the latter strategy. Together, these findings suggest that the damage to the IPS impaired JD's representations of magnitude that play an important role in this computation estimation task.

An Electroencephalography Connectomic Profile of Posttraumatic Stress Disorder.

OBJECTIVE: The authors sought to identify brain regions whose frequency-specific, orthogonalized resting-state EEG power envelope connectivity differs between combat veterans with posttraumatic stress disorder (PTSD) and healthy combat-exposed veterans, and to determine the behavioral correlates of connectomic differences. METHODS: The authors first conducted a connectivity method validation study in healthy control subjects (N=36). They then conducted a two-site case-control study of veterans with and without PTSD who were deployed to Iraq and/or Afghanistan. Healthy individuals (N=95) and those meeting full or subthreshold criteria for PTSD (N=106) underwent 64-channel resting EEG (eyes open and closed), which was then source-localized and orthogonalized to mitigate effects of volume conduction. Correlation coefficients between band-limited source-space power envelopes of different regions of interest were then calculated and corrected for multiple comparisons. Post hoc correlations of connectomic abnormalities with clinical features and performance on cognitive tasks were conducted to investigate the relevance of the dysconnectivity findings. RESULTS: Seventy-four brain region connections were significantly reduced in PTSD (all in the eyes-open condition and predominantly using the theta carrier frequency). Underconnectivity of the orbital and anterior middle frontal gyri were most prominent. Performance differences in the digit span task mapped onto connectivity between 25 of the 74 brain region pairs, including within-network connections in the dorsal attention, frontoparietal control, and ventral attention networks. CONCLUSIONS: Robust PTSD-related abnormalities were evident in theta-band source-space orthogonalized power envelope connectivity, which furthermore related to cognitive deficits in these patients. These findings establish a clinically relevant connectomic profile of PTSD using a tool that facilitates the lower-cost clinical translation of network connectivity research.

Individual Patterns of Abnormality in Resting-State Functional Connectivity Reveal Two Data-Driven PTSD Subgroups.

OBJECTIVE: A major challenge in understanding and treating posttraumatic stress disorder (PTSD) is its clinical heterogeneity, which is likely determined by various neurobiological perturbations. This heterogeneity likely also reduces the effectiveness of standard group comparison approaches. The authors tested whether a statistical approach aimed at identifying individual-level neuroimaging abnormalities that are more prevalent in case subjects than in control subjects could reveal new clinically meaningful insights into the heterogeneity of PTSD. METHODS: Resting-state functional MRI data were recorded from 87 unmedicated PTSD case subjects and 105 war zone-exposed healthy control subjects. Abnormalities were modeled using tolerance intervals, which referenced the distribution of healthy control subjects as the "normative population." Out-of-norm functional connectivity values were examined for enrichment in cases and then used in a clustering analysis to identify biologically defined PTSD subgroups based on their abnormality profiles. RESULTS: The authors identified two subgroups among PTSD cases, each with a distinct pattern of functional connectivity abnormalities with respect to healthy control subjects. Subgroups differed clinically on levels of reexperiencing symptoms and improved case-control discriminability and were detectable using independently recorded resting-state EEG data. CONCLUSIONS: The results provide proof of concept for the utility of abnormality-based approaches for studying heterogeneity within clinical populations. Such approaches, applied not only to neuroimaging data, may allow detection of subpopulations with distinct biological signatures so that further clinical and mechanistic investigations can be focused on more biologically homogeneous subgroups.

Development of VM-REACT: Verbal memory RecAll computerized test.

When tracking the progression of neuropsychiatric or neurodegenerative diseases, assessment tools that enable repeated measures of cognition and require little examiner burden are increasingly important to develop. In the current study, we describe the development of the VM-REACT (Verbal Memory REcAll Computerized Test), which assesses verbal memory recall abilities using a computerized, automated version. Four different list versions of the test were applied on a cohort of 798 healthy adults (ages 20-80). Recall and learning scores were computed and compared to existing gender- and age-matched published norms for a similar paper-and-pencil test. Performance was similar to existing age-matched norms for all but the two oldest age groups. These adults (ages 60-80) outperformed their age-matched norms. Processing speed, initiation speed, and number of recall errors are also reported for each age group. Our findings suggest that VM-REACT can be utilized to study verbal memory abilities in a standardized and time efficient manner, and thus holds great promise for assessment in the 21st century.

Tactile enumeration: A case study of acalculia.

Enumeration is one of the building blocks of arithmetic and fingers are used as a counting tool in early steps. Subitizing-fast and accurate enumeration of small quantities-has been vastly studied in the visual modality, but less in the tactile modality. We explored tactile enumeration using fingers, and gray matter (GM) changes using voxel-based morphometry (VBM), in acalculia. We examined JD, a 22-year-old female with acalculia following a stroke to the left inferior parietal cortex. JD and a neurologically healthy normal comparison (NC) group reported how many fingers were stimulated. JD was tested at several time points, including at acute and chronic phases. Using the sensory intact hand for tactile enumeration, JD showed deficit in the acute phase, compared to the NC group, and improvement in the chronic phase of (1) the RT slope of enumerating up to four stimuli, (2) enumerating neighboring fingers, and (3) arithmetic fluency performance. Moreover, VBM analysis showed a larger GM volume for JD relative to the NC group in the right middle occipital cortex, most profoundly in the chronic phase. JD's performance serves as a first glance of tactile enumeration in acalculia. Pattern-recognition-based results support the suggestion of subitizing being the enumeration process when using one hand. Moreover, the increase in GM in the occipital cortex lays the groundwork for studying the innate and primitive ability to perceive and evaluate sizes or amounts-"sense of magnitude"- as a multisensory magnitude area and as part of a recovery path for deficits in basic numerical abilities.

Visual and Imagery Magnitude Comparisons Are Affected Following Left Parietal Lesion.

We describe Jane Dow (JD), a young right-handed female with acalculia following a cerebral infarction in the left intraparietal sulcus. We investigated automatic processing of different types of magnitudes that were presented visually or through imagery. We employed the size congruity task and the mental clock task that differ in stimuli presentation and in working memory load. In the size congruity task, for physical comparisons, JD presented a lack of facilitation effect, suggesting a deficit in the automatic processing of numerical values. In the mental clock task, JD performed as accurate as controls did but much slower. In both tasks, JD presented a steeper distance effect compared to controls, suggesting a deficit in a domain-general comparison process. Our findings present an atypical pattern of magnitude processing following a left parietal lesion that appears not only for visually presented stimuli but also for imagery-based magnitudes. These finding support recent theories suggesting different types of magnitudes are interconnected with each other.

Blood-Brain Barrier Disruption After Cardiopulmonary Bypass: Diagnosis and Correlation to Cognition.

BACKGROUND: Cardiopulmonary bypass (CPB) elicits a systemic inflammatory response that may impair blood-brain barrier (BBB) integrity. BBB disruption can currently be detected by dynamic contrast enhancement magnetic resonance imaging (MRI), reflected by an increase in the permeability constant (Ktrans). We aimed to determine (1) whether CPB induces BBB disruption, (2) duration until BBB disruption resolution, and (3) the obtainable correlation between BBB injury (location and intensity) and neurocognitive dysfunction. METHODS: Seven patients undergoing CPB with coronary artery bypass grafting (CABG) were assigned to serial cerebral designated MRI evaluations, preoperatively and on postoperative day (POD) 1 and 5. Examinations were analyzed for BBB disruption and microemboli using dynamic contrast enhancement MRI and diffusion-weighted imaging methods, respectively. Neuropsychologic tests were performed 1 day preoperatively and on POD 5. RESULTS: A significant local Ktrans increase (0.03 min-1 vs 0.07 min-1, p = 0.033) compatible with BBB disruption was evident in 5 patients (71%) on POD 1. Resolution was observed by POD 5 (mean, 0.012 min-1). The location of the disruption was most prominent in the frontal lobes (400% vs 150% Ktrans levels upsurge, p = 0.05). MRI evidence of microembolization was demonstrated in only 1 patient (14%). The postoperative global cognitive score was reduced in all patients (98.2 ± 12 vs 95.1 ± 11, p = 0.032), predominantly in executive and attention (frontal lobe-related) functions (91.8 ± 13 vs 86.9 ± 12, p = 0.042). The intensity of the dynamic contrast enhancement MRI BBB impairment correlated with the magnitude of cognition reduction (r = 0.69, p = 0.04). CONCLUSIONS: BBB disruption was evident in most patients, primarily in the frontal lobes. The location and intensity of the BBB disruption, rather than the microembolic load, correlated with postoperative neurocognitive dysfunction.

Flanking magnitudes: dissociation between numerosity and numerical value in a selective attention task.

The current research examined whether peripherally presented numerical information can affect the speed of number processing. In 2 experiments, participants were presented with a target matrix flanked by a distractor matrix and were asked to perform a comparative judgment (i.e., decide whether the target was larger or smaller than the reference 5). In Experiment 1, the target was symbolic (i.e., a single digit), and in Experiment 2, it was nonsymbolic (i.e., a random presentation of dots). In both experiments, flanker matrices had 2 dimensions-numerosity and numerical value-that were manipulated orthogonally to create stimulus congruent and stimulus incongruent conditions. Incongruent trials differed in the laterality between target and flanker (i.e., their location in relation to the reference 5). When responding to symbolic targets (Experiment 1), only the flanker's numerical value affected reaction times (RTs), whereas when responding to nonsymbolic targets (Experiment 2), only the flanker's numerosity affected RTs. In addition, the pattern of flanker interference differed between targets: For symbolic targets, laterality did not affect responses, whereas for nonsymbolic targets, laterality did affect responses. These results imply both symbolic and nonsymbolic magnitudes can be automatically activated; however, this activation is contingent upon their relevance to the task at hand. Implications of these results on the efficiency of the visual processing system and on numerical cognition are further discussed.

Tactile enumeration of small quantities using one hand.

Our study explores various aspects of enumerating small quantities in the tactile modality. Fingertips of one hand were stimulated by a vibro-tactile apparatus (for 100/800 ms). Between 1 and 5 stimuli were presented to the right or the left hand and applied to neighboring (e.g., thumb-index-middle) or non-neighboring (e.g., thumb-middle-pinkie) fingers. The results showed a moderate increase in RT up to 4 stimuli and then a decrease for 5 stimuli. Right hand stimulation evoked more accurate performance than left hand stimulation only under short exposures (100 ms). Importantly, when the stimuli were presented to neighboring fingers, the accuracy rate was higher and the RT was faster than when presented to non-neighboring fingers. We discuss the results and suggest that when the stimuli are presented to one hand the subitizing range is 4 rather than 3. Furthermore, the right hand advantage and the efficiency for neighboring fingers are further support for the association between number and spatial arrangement of the fingers.

Numerical-spatial representation affects spatial coding: binding errors across the numerical distance effect.

Does numerical-spatial representation affect feature binding? Studies of visual attention show that poor spatial coding leads to illusory conjunctions (ICs). In numerical cognition, it has been shown that numbers and space are not totally dissociated. This association underlies the numerical distance effect (DE): faster responses as the distance between the compared digits becomes larger (2 7 vs. 2 4). We used the DE to test whether numerical-spatial representation is available to visual processes that rely on spatial coding, such as feature binding. Participants reported the larger of two colored numbers. Both numerical distance (distances 2 and 5) and number-space congruity (e.g., congruent pair, 1 3; incongruent pair, 3 1) were analyzed. Results showed a higher proportion of ICs for distance 2 than for distance 5, providing strong evidence that numerical-spatial representation (1) entails a strong location code and (2) is available to visual processes that rely on location information.

Laterality briefed: laterality modulates performance in a numerosity-congruity task.

It is widely agreed that irrelevant numerical values are automatically activated. However, automatic and intentional activations may give rise to different numerical representations. We examined processing of symbolic and non-symbolic (i.e., numerosity) representations asking whether they differ in automatic and intentional processing. Participants were presented with two-dimensional displays containing repetitions of a digit and were asked to report, in different blocks, whether the digit or numerosity was smaller or larger than 5. Incongruent trials differed either in laterality between the relevant and irrelevant dimensions (i.e., the location of both dimensions in reference to the midpoint 5) or in numerical distance between dimensions. Congruency affected performance regardless of symbolic or non-symbolic presentation. For incongruent trials, laterality (not distance) affected performance, again regardless of presentation. This implies that automaticity does not mean similar processing of relevant and irrelevant dimensions. Specifically, the relevant dimension is processed elaborately whereas the irrelevant dimension is processed crudely.

Count me in! On the automaticity of numerosity processing.

Extraction of numerosity (i.e., enumeration) is an essential component of mathematical abilities. The current study asked how automatic is the processing of numerosity and whether automatic activation is task dependent. Participants were presented with displays containing a variable number of digits and were asked to pay attention to the number of digits or to their numerical value, in separate blocks. Effects of task were tested with a comparative judgment task and a parity judgment task. In the comparative judgment task, participants had to indicate whether the numerosity or the numerical value of the digits was smaller or larger than 5. In the parity judgment task, participants had to indicate whether this value was odd or even. Irrelevant numerical values modulated performance regardless of task. In contrast, irrelevant numerosities modulated performance only in the comparative judgment task. These results suggest that numerical value is activated automatically, whereas activation of numerosity is modulated by task. We suggest that the differences observed are related to different cognitive and neural mechanisms recruited by these tasks.