A modified neural circuit framework for semantic memory retrieval with implications for circuit modulation to treat verbal retrieval deficits.

Word finding difficulty is a frequent complaint in older age and disease states, but treatment options are lacking for such verbal retrieval deficits. Better understanding of the neurophysiological and neuroanatomical basis of verbal retrieval function may inform effective interventions. In this article, we review the current evidence of a neural retrieval circuit central to verbal production, including words and semantic memory, that involves the pre-supplementary motor area (pre-SMA), striatum (particularly caudate nucleus), and thalamus. We aim to offer a modified neural circuit framework expanded upon a memory retrieval model proposed in 2013 by Hart et al., as evidence from electrophysiological, functional brain imaging, and noninvasive electrical brain stimulation studies have provided additional pieces of information that converge on a shared neural circuit for retrieval of memory and words. We propose that both the left inferior frontal gyrus and fronto-polar regions should be included in the expanded circuit. All these regions have their respective functional roles during verbal retrieval, such as selection and inhibition during search, initiation and termination of search, maintenance of co-activation across cortical regions, as well as final activation of the retrieved information. We will also highlight the structural connectivity from and to the pre-SMA (e.g., frontal aslant tract and fronto-striatal tract) that facilitates communication between the regions within this circuit. Finally, we will discuss how this circuit and its correlated activity may be affected by disease states and how this circuit may serve as a novel target engagement for neuromodulatory treatment of verbal retrieval deficits.

Analyzing direct effects of education level and estimated IQ between cognitively intact Mexican Americans and Non-Hispanic whites on a confrontational naming task.

Confrontational naming is widely used in diagnosing neurodegenerative disorders like MCI and dementia, and previous research indicates that healthy Non-Hispanic Whites outperform Hispanics in such tasks. However, understanding the factors contributing to score differences among ethnic groups remains limited. This study focuses on cognitively intact Mexican Americans and Non-Hispanic White older adults from the TARCC Hispanic Cohort project. Hierarchical regression analyses reveal that sex, age, ethnicity, education level, and estimated IQ significantly predict performance on the Boston Naming Test (BNT). Notably, education level and estimated IQ more strongly influence BNT performance in Mexican Americans than in Non-Hispanic Whites. When controlling for education level, estimated IQ has a more pronounced impact on BNT performance in aging Mexican Americans compared to Non-Hispanic Whites. Conversely, after controlling for estimated IQ, the influence of education level is weaker for Mexican Americans than Non-Hispanic Whites. These findings emphasize the need for careful evaluation of confrontational naming task scores in diverse ethnic groups, emphasizing the critical role of education and estimated IQ in understanding performance disparities.

P3a amplitude to trauma-related stimuli reduced after successful trauma-focused PTSD treatment.

An elevated P3a amplitude to trauma-related stimuli is strongly associated with posttraumatic stress disorder (PTSD), yet little is known about whether this response to trauma-related stimuli is affected by treatment that decreases PTSD symptoms. As an analysis of secondary outcome measures from a randomized controlled trial, we investigated the latency and amplitude changes of the P3a in responses in a three-condition oddball visual task that included trauma-related (combat scenes) and trauma-unrelated (threatening animals) distractors. Fifty-five U.S. veterans diagnosed with combat-related PTSD were randomized to receive either active or sham repetitive transcranial magnetic stimulation (rTMS). All received cognitive processing therapy, CPT+A, which requires a written account of the index trauma. They were tested before and 6 months after protocol completion. P3a amplitude and response time decreases were driven largely by the changes in the responses to the trauma-related stimuli, and this decrease correlated to the decrease in PTSD symptoms. The amplitude changes were greater in those who received rTMS + CPT than in those who received sham rTMS + CPT, suggesting that rTMS plays beneficial role in reducing arousal and threat bias, which may allow for more effective engagement in trauma-focused PTSD treatment.

Auditory N2 Correlates of Treatment Response in Posttraumatic Stress Disorder.

Emotional processing and cognitive control are implicated as being dysfunctional in posttraumatic stress disorder (PTSD) and targeted in cognitive processing therapy (CPT), a trauma-focused treatment for PTSD. The N2 event-related potential has been interpreted in the context of emotional processing and cognitive control. In this analysis of secondary outcome measures from a randomized controlled trial, we investigated the latency and amplitude changes of the N2 in responses to task-relevant target tones and task-irrelevant distractor sounds (e.g., a trauma-related gunshot and a trauma-unrelated lion's roar) and the associations between these responses and PTSD symptom changes. United States military veterans (N = 60) diagnosed with combat-related PTSD were randomized to either active or sham repetitive transcranial magnetic stimulation (rTMS) and received a CPT intervention that included a written trauma account element (CPT+A). Participants were tested before and 6 months after protocol completion. Reduction in N2 amplitude to the gunshot stimulus was correlated with reductions in reexperiencing, |r| = .445, and hyperarousal measures, |r| = .364. In addition, in both groups, the latency of the N2 event-related potential to the distractors became longer with treatment and the N2 latency to the task-relevant stimulus became shorter, ηp 2  = .064, both of which are consistent with improved cognitive control. There were no between-group differences in N2 amplitude and latency. Normalized N2 latencies, reduced N2 amplitude to threatening distractors, and the correlation between N2 amplitude reduction and PTSD symptom reduction reflect improved cognitive control, consistent with the CPT+A objective of addressing patients' abilities to respond more appropriately to trauma triggers.

Identification of selection and inhibition components in a Go/NoGo task from EEG spectra using a machine learning classifier.

INTRODUCTION: Prior Go/NoGo studies have localized specific regions and EEG spectra for which traditional approaches have distinguished between Go and NoGo conditions. A more detailed characterization of the spatial distribution and timing of the synchronization of frequency bands would contribute substantially to the clarification of neural mechanisms that underlie performance of the Go/NoGo task. METHODS: The present study used a machine learning approach to learn the features that distinguish between ERSPs involved in selection and inhibition in a Go/NoGo task. A single-layer neural network classifier was used to predict task conditions for each subject to characterize ERSPs associated with Go versus NoGo trials. RESULTS: The final classifier accurately identified individual task conditions at an overall rate of 92%, estimated by fivefold cross-validation. The detailed accounting of EEG time-frequency patterns localized to brain regions (i.e., thalamus, pre-SMA, orbitofrontal cortex, and superior parietal cortex) corroborates and also elaborates upon previous findings from fMRI and EEG studies, and expands the information about EEG power changes in multiple frequency bands (i.e., primarily theta power increase, alpha decreases, and beta increases and decreases) within these regions underlying the selection and inhibition processes engaged in the Go and NoGo trials. CONCLUSION: This time-frequency-based classifier extends previous spatiotemporal findings and provides information about neural mechanisms underlying selection and inhibition processes engaged in Go and NoGo trials, respectively. This neural network classifier can be used to assess time-frequency patterns from an individual subject and thus may offer insight into therapeutic uses of neuromodulation in neural dysfunction.

Neurophysiology of threat processing bias in combat-related post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a debilitating condition that may develop after experiencing a traumatic event. Combat exposure increases an individual's chance of developing PTSD, making veterans especially susceptible to the disorder. PTSD is characterized by dysregulated emotional networks, memory deficits, and a hyperattentive response to perceived threatening stimuli. Recently, there have been a number of imaging studies that show structural and functional abnormalities associated with PTSD; however, there have been few studies utilizing electroencephalography (EEG). The goal of this study was to characterize **EEG brain dynamics in individuals with PTSD, in order to better understand the neurophysiological underpinnings of some of the salient features of PTSD, such as threat-processing bias. Veterans of Operation Enduring Freedom/Iraqi Freedom completed an implicit visual threat semantic memory recognition task with stimuli that varied on both category (animals, items, nature, and people) and feature (threatening and nonthreatening) membership, including trauma-related stimuli. Combat veterans with PTSD had slower reaction times for the threatening stimuli relative to the combat veterans without PTSD (VETC). There were trauma-specific effects in frontal regions, with theta band EEG power reductions for the threatening combat scenes in the PTSD patients compared to the VETC group. Additionally, a moderate negative correlation was observed between trauma-specific frontal theta power and hyperarousal symptoms as measured by clinically administered PTSD scale. These findings complement and extend current models of cortico-limbic dysfunction in PTSD. The moderate negative correlation between frontal theta power and hyperarousal endorsements suggests the utility of these measures as therapeutic markers of symptomatology in PTSD patients.

High-Definition Transcranial Direct Current Stimulation to Improve Verbal Retrieval Deficits in Chronic Traumatic Brain Injury.

Chronic verbal retrieval deficits have been noted in traumatic brain injury (TBI), but no U.S. Food and Drug Administration-approved interventions are available. The present study investigated whether 10 sessions of 20 min of 1 mA anodal high-definition transcranial direct current stimulation (HD-tDCS) targeting pre-supplementary motor area/dorsal anterior cingulate cortex (preSMA/dACC) compared with sham HD-tDCS would improve verbal retrieval deficits in TBI patients. Improvements in verbal retrieval processes were observed up to 8 weeks post-treatment. Thus, potential dysfunction to verbal retrieval circuitry in TBI appears amenable to remediation through electromodulation with HD tDCS to the preSMA/dACC. Although further studies clarifying mechanisms by which tDCS brought about these improvements will likely inform refinements in the application of this therapeutic technique, the findings suggest the efficacy of using HD-tDCS to target other systems vulnerable to TBI to improve functioning.

Conjoint differences in inhibitory control and processing speed in childhood to older adult cohorts: Discriminant functions from a Go/No-Go task.

To investigate differences in inhibitory control and processing speed over the life span, participants in 7- to 8-, 10- to 11-, 12- to 15-, 18- to 25-, and 54- to 80-year-old age cohorts completed a Go/No-Go task requiring varying levels of semantic categorization. Discriminant function analysis of correct rejection rates (CRRs), hit rates (HRs), and reaction times (RTs) revealed a function on which CRR loaded positively and RT loaded negatively, across categorization levels. Scores increased from youngest to the younger adult cohort and decreased for the older adult cohort. On a second function, CRR and RT loaded positively and HR loaded negatively across categorization levels. Scores were highest for the older adult cohort and higher for the youngest cohort than for the younger adult cohort. The results suggest change along 2 dimensions might underlie cognitive development: (a) combined increased inhibitory control and processing speed and (b) combined increased speed and decreased biased responding for better inhibitory control. In addition, 2 dimensions might underlie senescence: (a) combined decreased inhibitory control and processing speed and (b) combined decreased speed and increased biased responding for better inhibitory control. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Repetitive TMS to augment cognitive processing therapy in combat veterans of recent conflicts with PTSD: A randomized clinical trial.

BACKGROUND: The objective was to test whether repetitive Transcranial Magnetic Stimulation (rTMS) just prior to Cognitive Processing Therapy (CPT) would significantly improve the clinical outcome compared to sham rTMS prior to CPT in veterans with PTSD. METHODS: Veterans 18-60 years of age with current combat-related PTSD symptoms were randomized, using a 1:1 ratio in a parallel design, to active (rTMS+CPT) versus sham (sham+CPT) rTMS just prior to weekly CPT for 12-15 sessions. Blinded raters evaluated veterans at baseline, after the 5th and 9th treatments, and at 1, 3, and 6 months post-treatment. Clinician Administered PTSD Scale (CAPS) was the primary outcome measure with the PTSD Checklist (PCL) as a secondary outcome measure. The TMS coil (active or sham) was positioned over the right dorsolateral prefrontal cortex (110% MT, 1Hz continuously for 30min, 1800 pulses/treatment). RESULTS: Of the 515 individuals screened for the study, 103 participants were randomized to either active (n = 54) or sham rTMS (n = 49). Sixty-two participants (60%) completed treatment and 59 (57%) completed the 6-month assessment. The rTMS+CPT group showed greater symptom reductions from baseline on both CAPS and PCL across CPT sessions and follow-up assessments, t(df ≥ 325) ≤ -2.01, p ≤ 0.023, one-tailed and t(df ≥ 303) ≤ -2.14, p ≤ 0.017, one-tailed, respectively. LIMITATIONS: Participants were predominantly male and limited to one era of conflicts as well as those who could safely undergo rTMS. CONCLUSIONS: The addition of rTMS to CPT compared to sham with CPT produced significantly greater PTSD symptom reduction early in treatment and was sustained up to six months post-treatment.

Higher-order cognitive training effects on processing speed-related neural activity: a randomized trial.

Higher-order cognitive training has shown to enhance performance in older adults, but the neural mechanisms underlying performance enhancement have yet to be fully disambiguated. This randomized trial examined changes in processing speed and processing speed-related neural activity in older participants (57-71 years of age) who underwent cognitive training (CT, N = 12) compared with wait-listed (WLC, N = 15) or exercise-training active (AC, N = 14) controls. The cognitive training taught cognitive control functions of strategic attention, integrative reasoning, and innovation over 12 weeks. All 3 groups worked through a functional magnetic resonance imaging processing speed task during 3 sessions (baseline, mid-training, and post-training). Although all groups showed faster reaction times (RTs) across sessions, the CT group showed a significant increase, and the WLC and AC groups showed significant decreases across sessions in the association between RT and BOLD signal change within the left prefrontal cortex (PFC). Thus, cognitive training led to a change in processing speed-related neural activity where faster processing speed was associated with reduced PFC activation, fitting previously identified neural efficiency profiles.

Trial-Level Regressor Modulation for Functional Magnetic Resonance Imaging Designs Requiring Strict Periodicity of Stimulus Presentations: Illustrated Using a Go/No-Go Task.

Computer-based assessment of many cognitive processes (eg, anticipatory and response readiness processes) requires the use of invariant stimulus display times (SDT) and intertrial intervals (ITI). Although designs with invariant SDTs and ITIs have been used in functional magnetic resonance imaging (fMRI) research, such designs are problematic for fMRI studies because of collinearity issues. This study examined regressor modulation with trial-level reaction times (RT) as a method for improving signal detection in a go/no-go task with invariant SDTs and ITIs. The effects of modulating the go regressor were evaluated with respect to the detection of BOLD signal-change for the no-go condition. BOLD signal-change to no-go stimuli was examined when the go regressor was based on a (a) canonical hemodynamic response function (HRF), (b) RT-based amplitude-modulated (AM) HRF, and (c) RT-based amplitude and duration modulated (A&DM) HRF. Reaction time-based modulation reduced the collinearity between the go and no-go regressors, with A&DM producing the greatest reductions in correlations between the regressors, and greater reductions in the correlations between regressors were associated with longer mean RTs and greater RT variability. Reaction time-based modulation increased statistical power for detecting group-level no-go BOLD signal-change across a broad set of brain regions. The findings show the efficacy of using regressor modulation to increase power in detecting BOLD signal-change in fMRI studies in which circumstances dictate the use of temporally invariant stimulus presentations.

Cognitive Slowing in Gulf War Illness Predicts Executive Network Hyperconnectivity: Study in a Population-Representative Sample.

Cognitive slowing is a prevalent symptom observed in Gulf War Illness (GWI). The present study assessed the extent to which functional connectivity between dorsolateral prefrontal cortex (DLPFC) and other task-relevant brain regions was predictive of GWI-related cognitive slowing. GWI patients (n = 54) and healthy veteran controls (n = 29) were assessed on performance of a processing speed task (the Digit Symbol Substitution Task; DSST) while undergoing functional magnetic resonance imaging (fMRI). GWI patients were slower on the DSST relative to controls. Bilateral DLPFC connectivity with task-relevant nodes was altered in GWI patients compared to healthy controls during DSST performance. Moreover, hyperconnectivity in these networks predicted GWI-related increases in reaction time on the DSST, whereas hypoconnectivity did not. These results suggest that GWI-related cognitive slowing reflects reduced efficiency in cortical networks.

Common and differential electrophysiological mechanisms underlying semantic object memory retrieval probed by features presented in different stimulus types.

How the brain combines the neural representations of features that comprise an object in order to activate a coherent object memory is poorly understood, especially when the features are presented in different modalities (visual vs. auditory) and domains (verbal vs. nonverbal). We examined this question using three versions of a modified Semantic Object Retrieval Test, where object memory was probed by a feature presented as a written word, a spoken word, or a picture, followed by a second feature always presented as a visual word. Participants indicated whether each feature pair elicited retrieval of the memory of a particular object. Sixteen subjects completed one of the three versions (N=48 in total) while their EEG were recorded simultaneously. We analyzed EEG data in four separate frequency bands (delta: 1-4Hz, theta: 4-7Hz; alpha: 8-12Hz; beta: 13-19Hz) using a multivariate data-driven approach. We found that alpha power time-locked to response was modulated by both cross-modality (visual vs. auditory) and cross-domain (verbal vs. nonverbal) probing of semantic object memory. In addition, retrieval trials showed greater changes in all frequency bands compared to non-retrieval trials across all stimulus types in both response-locked and stimulus-locked analyses, suggesting dissociable neural subcomponents involved in binding object features to retrieve a memory. We conclude that these findings support both modality/domain-dependent and modality/domain-independent mechanisms during semantic object memory retrieval.

Investigating the neural bases for intra-subject cognitive efficiency changes using functional magnetic resonance imaging.

Several fMRI studies have examined brain regions mediating inter-subject variability in cognitive efficiency, but none have examined regions mediating intra-subject variability in efficiency. Thus, the present study was designed to identify brain regions involved in intra-subject variability in cognitive efficiency via participant-level correlations between trial-level reaction time (RT) and trial-level fMRI BOLD percent signal change on a processing speed task. On each trial, participants indicated whether a digit-symbol probe-pair was present or absent in an array of nine digit-symbol probe-pairs while fMRI data were collected. Deconvolution analyses, using RT time-series models (derived from the proportional scaling of an event-related hemodynamic response function model by trial-level RT), were used to evaluate relationships between trial-level RTs and BOLD percent signal change. Although task-related patterns of activation and deactivation were observed in regions including bilateral occipital, bilateral parietal, portions of the medial wall such as the precuneus, default mode network regions including anterior cingulate, posterior cingulate, bilateral temporal, right cerebellum, and right cuneus, RT-BOLD correlations were observed in a more circumscribed set of regions. Positive RT-BOLD correlations, where fast RTs were associated with lower BOLD percent signal change, were observed in regions including bilateral occipital, bilateral parietal, and the precuneus. RT-BOLD correlations were not observed in the default mode network indicating a smaller set of regions associated with intra-subject variability in cognitive efficiency. The results are discussed in terms of a distributed area of regions that mediate variability in the cognitive efficiency that might underlie processing speed differences between individuals.

Electrophysiological spatiotemporal dynamics during implicit visual threat processing.

Numerous studies have found evidence for corticolimbic theta band electroencephalographic (EEG) oscillations in the neural processing of visual stimuli perceived as threatening. However, varying temporal and topographical patterns have emerged, possibly due to varying arousal levels of the stimuli. In addition, recent studies suggest neural oscillations in delta, theta, alpha, and beta-band frequencies play a functional role in information processing in the brain. This study implemented a data-driven PCA based analysis investigating the spatiotemporal dynamics of electroencephalographic delta, theta, alpha, and beta-band frequencies during an implicit visual threat processing task. While controlling for the arousal dimension (the intensity of emotional activation), we found several spatial and temporal differences for threatening compared to nonthreatening visual images. We detected an early posterior increase in theta power followed by a later frontal increase in theta power, greatest for the threatening condition. There was also a consistent left lateralized beta desynchronization for the threatening condition. Our results provide support for a dynamic corticolimbic network, with theta and beta band activity indexing processes pivotal in visual threat processing.

Assessment of unconstrained cerebrovascular reactivity marker for large age-range FMRI studies.

Breath hold (BH), a commonly used task to measure cerebrovascular reactivity (CVR) in fMRI studies varies in outcome among individuals due to subject-physiology and/or BH-inspiration/expiration differences (i.e., performance). In prior age-related fMRI studies, smaller task-related BOLD response variability is observed among younger than older individuals. Also, a linear CVR versus task relationship exists in younger individuals which maybe useful to test the accuracy of CVR responses in older groups. Hence we hypothesized that subject-related physiological and/or BH differences, if present, may compromise CVR versus task linearity in older individuals. To test the hypothesis, empirical BH versus task relationships from motor and cognitive areas were obtained in younger (mean age = 26 years) and older (mean age = 58 years) human subjects. BH versus task linearity was observed only in the younger group, confirming our hypothesis. Further analysis indicated BH responses and its variability to be similar in both younger and older groups, suggesting that BH may not accurately represent CVR in a large age range. Using the resting state fluctuation of amplitude (RSFA) as an unconstrained alternative to BH, subject-wise correspondence between BH and RSFA was tested. Correlation between BH versus RSFA was significant within the motor but was not significant in the cognitive areas in the younger and was completely disrupted in both areas in the older subjects indicating that BH responses are constrained by subject-related physiology and/or performance-related differences. Contrasting BH to task, RSFA-task relationships were independent of age accompanied by age-related increases in CVR variability as measured by RSFA, not observed with BH. Together the results obtained indicate that RSFA accurately represents CVR in any age range avoiding multiple and yet unknown physiologic and task-related pitfalls of BH.

Inhibitory control gains from higher-order cognitive strategy training.

The present study examined the transfer of higher-order cognitive strategy training to inhibitory control. Middle school students enrolled in a comprehension- and reasoning-focused cognitive strategy training program and passive controls participated. The training program taught students a set of steps for inferring essential gist or themes from materials. Both before and after training or a comparable duration in the case of the passive controls, participants completed a semantically cued Go/No-Go task that was designed to assess the effects of depth of semantic processing on response inhibition and components of event-related potentials (ERP) related to response inhibition. Depth of semantic processing was manipulated by varying the level of semantic categorization required for response selection and inhibition. The SMART-trained group showed inhibitory control gains and changes in fronto-central P3 ERP amplitudes on inhibition trials; whereas, the control group did not. The results provide evidence of the transfer of higher-order cognitive strategy training to inhibitory control and modulation of ERPs associated with semantically cued inhibitory control. The findings are discussed in terms of implications for cognitive strategy training, models of cognitive abilities, and education.

Central Executive Dysfunction and Deferred Prefrontal Processing in Veterans with Gulf War Illness.

Gulf War Illness is associated with toxic exposure to cholinergic disruptive chemicals. The cholinergic system has been shown to mediate the central executive of working memory (WM). The current work proposes that impairment of the cholinergic system in Gulf War Illness patients (GWIPs) leads to behavioral and neural deficits of the central executive of WM. A large sample of GWIPs and matched controls (MCs) underwent functional magnetic resonance imaging during a varied-load working memory task. Compared to MCs, GWIPs showed a greater decline in performance as WM-demand increased. Functional imaging suggested that GWIPs evinced separate processing strategies, deferring prefrontal cortex activity from encoding to retrieval for high demand conditions. Greater activity during high-demand encoding predicted greater WM performance. Behavioral data suggest that WM executive strategies are impaired in GWIPs. Functional data further support this hypothesis and suggest that GWIPs utilize less effective strategies during high-demand WM.

Semantic processing and response inhibition.

The present study examined functional MRI (fMRI) BOLD signal changes in response to object categorization during response selection and inhibition. Young adults (N=16) completed a Go/NoGo task with varying object categorization requirements while fMRI data were recorded. Response inhibition elicited increased signal change in various brain regions, including medial frontal areas, compared with response selection. BOLD signal in an area within the right angular gyrus was increased when higher-order categorization was mandated. In addition, signal change during response inhibition varied with categorization requirements in the left inferior temporal gyrus (lIT). lIT-mediated response inhibition when inhibiting the response only required lower-order categorization, but lIT mediated both response selection and inhibition when selecting and inhibiting the response required higher-order categorization. The findings characterized mechanisms mediating response inhibition associated with semantic object categorization in the 'what' visual object memory system.

Threat as a feature in visual semantic object memory.

Threatening stimuli have been found to modulate visual processes related to perception and attention. The present functional magnetic resonance imaging (fMRI) study investigated whether threat modulates visual object recognition of man-made and naturally occurring categories of stimuli. Compared with nonthreatening pictures, threatening pictures of real items elicited larger fMRI BOLD signal changes in medial visual cortices extending inferiorly into the temporo-occipital (TO) "what" pathways. This region elicited greater signal changes for threatening items compared to nonthreatening from both the natural-occurring and man-made stimulus supraordinate categories, demonstrating a featural component to these visual processing areas. Two additional loci of signal changes within more lateral inferior TO areas (bilateral BA18 and 19 as well as the right ventral temporal lobe) were detected for a category-feature interaction, with stronger responses to man-made (category) threatening (feature) stimuli than to natural threats. The findings are discussed in terms of visual recognition of processing efficiently or rapidly groups of items that confer an advantage for survival.