Verbal retrieval deficits due to traumatic brain injury are associated with changes in event related potentials during a Go-NoGo task.

OBJECTIVE: Verbal retrieval (VR) deficits often occur after traumatic brain injury (TBI), but the mechanisms remain unclear. We examined how event-related potentials (ERPs) during a Go-NoGo task were associated with VR deficits. METHODS: Sixty veterans with a history of TBI underwent a neuropsychological battery and a Go-NoGo task with concurrent EEG recording. We compared task performance and ERP measures (N2, P3) between those with and those without persistent injury-related VR deficits. We then used generalized linear modeling to examine the relationship between ERP measures and scores on measures of executive function and processing speed. RESULTS: Go-NoGo task performance was comparable between the groups. Those with VR deficits had larger N2 amplitude in NoGo than in Go conditions. In participants with VR deficits, larger NoGo N2/P3 amplitude predicted faster processing speed. Furthermore, larger P3 amplitude and shorter P3 latency of the difference wave (NoGo - Go) predicted faster processing speed in those with VR deficits. CONCLUSIONS: Despite no difference in Go-NoGo task performance, ERP amplitude and latency measures associated with cognitive control during Go-NoGo distinguished TBI individuals with VR deficits from those without. SIGNIFICANCE: This study furthers our understanding of VR deficits in TBI and implicates potential application of ERP measures in monitoring and treating such deficits.

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.

Traumatic Brain Injury Characteristics Are Not Related to Neurocognitive Decline in Older Adults: A Nationwide Longitudinal Cohort Study.

OBJECTIVE: Evaluate whether traumatic brain injury (TBI) characteristics, age of injury, or recency of injury predicts the course of neurocognitive decline and/or increases conversion rates to mild cognitive impairment (MCI) or dementia. METHODS: Data were obtained from the National Alzheimer's Coordinating Center for participants 50-85 years old with 3-5 visits from 2015 to 2022, with or without TBI history (TBI+ = 508; TBI- = 2,382). Groups were stratified by self-reported TBI history (i.e., single TBI without loss of consciousness [LOC], single TBI with LOC, multiple TBI without LOC, and multiple TBI with LOC), age of most recent TBI, and recency of TBI. Mixed linear models compared neuropsychological composite trajectories (executive functioning/attention/speed, language, memory, and global), co-varying for age, gender, education, apolipoprotein E4 status, race/ethnicity, and baseline diagnosis (normal aging n = 1,720, MCI n = 749, or dementia n = 417). Logistic binary regression examined MCI/dementia conversion rates. RESULTS: There was a slightly higher frequency of MCI/dementia in those with multiple TBIs (50% to 60% with and without LOC, compared to 39% with no TBI) at baseline, but longitudinal trajectories were similar. TBI history, age of injury, or recency of injury did not impact neurocognitive trajectories or conversion rates to MCI/dementia (all p's > .01). CONCLUSIONS: TBI history, regardless of injury characteristics, age of injury, or recency of injury, did not worsen neurocognitive decline or MCI/dementia conversion. Additional longitudinal research in more diverse cohorts with a wider range of TBI severity is needed to evaluate the specific factors and possible mechanisms in which TBI may increase dementia risk.

Differences in electroencephalography oscillations between normal aging and mild cognitive impairment during semantic memory retrieval.

Semantic memory remains relatively stable with normal cognitive aging and declines in early stages of neurodegenerative disease. We measured electroencephalography (EEG) oscillatory correlates of semantic memory retrieval to examine the effects of normal and pathological aging. Twenty-nine cognitively healthy young adults (YA), 22 cognitively healthy aging adults (HA) and 20 patients with mild cognitive impairment (MCI) completed a semantic memory retrieval task with concurrent EEG recording in which they judged whether two words (features of objects) led to retrieval of an object (retrieval) or not (non-retrieval). Event-related power changes contrasting the two conditions (retrieval vs. non-retrieval) within theta, alpha, low-beta and high-beta EEG frequency bands were examined for normal aging (YA vs. HA) and pathological aging effects (HA vs. MCI). With no behavioural differences between the two normal age groups, we found later theta and alpha event-related power differences between conditions only in YA and a high-beta event-related power difference only in HA. For pathological aging effects, with reduced accuracy in MCI, we found different EEG patterns of early event-related beta power differences between conditions in MCI compared with HA and an event-related low-beta power difference only in HA. Beta oscillations were correlated with behavioural performance only in HA. We conclude that the aging brain relies on faster (beta) oscillations during the semantic memory task. With pathological aging, retrieval accuracy declines and pattern of beta oscillation changes. The findings provide insights about age-related neural mechanisms underlying semantic memory and have implications for early detection of pathological aging.

History of traumatic brain injury does not alter course of neurocognitive decline in older adults with and without cognitive impairment.

OBJECTIVE: Traumatic brain injury (TBI) history is associated with dementia risk, but it is unclear whether TBI history significantly hastens neurocognitive decline in older adults. METHOD: Data were derived from the National Alzheimer's Coordinating Center (NACC) data set. Participants with a history of TBI (TBI +; n = 1,467) were matched to individuals without a history of TBI (TBI-; n = 1,467) based on age (50-97, M = 71.61, SD = 8.40), sex, education, race, ethnicity, cognitive diagnosis, functional decline, number of Apolipoprotein ε4 (APOE ε4) alleles, and number of annual visits (3-6). Mixed linear models were used to assess longitudinal neuropsychological test composite scores of executive functioning/attention/speed, language, and memory in TBI + and TBI- participants. Interactions between TBI and demographics, APOE ε4 status, and cognitive diagnosis were also examined. RESULTS: Longitudinal neuropsychological functioning did not differ between TBI groups (p's > .001). There was a significant three-way interaction (age, TBI history, time) in language (F[20, 5750.1] = 3.133, p < .001) and memory performance (F[20, 6580.8] = 3.386, p < .001), but post hoc analyses revealed TBI history was not driving this relationship (all p's > .096). No significant interactions were observed between TBI history and sex, education, race/ethnicity, number of APOE ε4 alleles, or cognitive diagnosis (p's > .001). CONCLUSIONS: Findings suggest TBI history, regardless of demographic factors, APOE ε4 status, or cognitive diagnosis, does not alter the course of neurocognitive functioning later-in-life in older adults with or without cognitive impairment. Future clinicopathological longitudinal studies that well-characterize head injuries and the associated clinical course are needed to help clarify the mechanism in which TBI may increase dementia risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Microglia as a cellular target of diclofenac therapy in Alzheimer's disease.

Alzheimer's disease (AD) is an untreatable cause of dementia, and new therapeutic approaches are urgently needed. AD pathology is defined by extracellular amyloid plaques and intracellular neurofibrillary tangles. Research of the past decades has suggested that neuroinflammation plays a critical role in the pathophysiology of AD. This has led to the idea that anti-inflammatory treatments might be beneficial. Early studies investigated non-steroidal anti-inflammatory drugs (NSAIDS) such as indomethacin, celecoxib, ibuprofen, and naproxen, which had no benefit. More recently, protective effects of diclofenac and NSAIDs in the fenamate group have been reported. Diclofenac decreased the frequency of AD significantly compared to other NSAIDs in a large retrospective cohort study. Diclofenac and fenamates share similar chemical structures, and evidence from cell and mouse models suggests that they inhibit the release of pro-inflammatory mediators from microglia with leads to the reduction of AD pathology. Here, we review the potential role of diclofenac and NSAIDs in the fenamate group for targeting AD pathology with a focus on its potential effects on microglia.

Corrigendum: Case report: Improving verbal retrieval deficits with high definition transcranial direct current stimulation targeting the pre-supplementary motor area in a patient with chronic traumatic brain injury.

[This corrects the article DOI: 10.3389/fneur.2021.678518.].

High-definition transcranial direct current stimulation modulates theta response during a Go-NoGo task in traumatic brain injury.

OBJECTIVE: High Definition transcranial Direct Current Stimulation (HD-tDCS) has been shown to improve cognitive performance in individuals with chronic traumatic brain injury (TBI), although electrophysiological mechanisms remain unclear. METHODS: Veterans with TBI underwent active anodal (N = 15) vs sham (N = 10) HD-tDCS targeting the pre-supplementary motor area (pre-SMA). A Go-NoGo task was conducted simultaneously with electroencephalography (EEG) at baseline and after intervention completion. RESULTS: We found increased theta event-related spectral perturbation (ERSP) and inter-trial phase coherence (ITPC) during Go in the frontal midline electrodes overlying the pre-SMA after active HD-tDCS intervention, but not after sham. We also found increased theta phase coherence during Go between the frontal midline and left posterior regions after active HD-tDCS. A late increase in alpha-theta ERSP was found in the left central region after active HD-tDCS. Notably, lower baseline theta ERSP/ITPC in the frontal midline region predicted more post-intervention improvement in Go performance only in the active group. CONCLUSIONS: There are local and interregional oscillatory changes in response to HD-tDCS modulation in chronic TBI. SIGNIFICANCE: These findings may guide future research in utilizing EEG time-frequency metrics not only to measure interventional effects, but also in selecting candidates who may optimally respond to treatment.

Cognitive Decline in Older People with Multiple Sclerosis-A Narrative Review of the Literature.

Several important questions regarding cognitive aging and dementia in older people with multiple sclerosis (PwMS) are the focus of this narrative review: Do older PwMS have worse cognitive decline compared to older people without MS? Can older PwMS develop dementia or other neurodegenerative diseases such as Alzheimer's disease (AD) that may be accelerated due to MS? Are there any potential biomarkers that can help to determine the etiology of cognitive decline in older PwMS? What are the neural and cellular bases of cognitive aging and neurodegeneration in MS? Current evidence suggests that cognitive impairment in MS is distinguishable from that due to other neurodegenerative diseases, although older PwMS may present with accelerated cognitive decline. While dementia is prevalent in PwMS, there is currently no consensus on defining it. Cerebrospinal fluid and imaging biomarkers have the potential to identify disease processes linked to MS and other comorbidities-such as AD and vascular disease-in older PwMS, although more research is required. In conclusion, one should be aware that multiple underlying pathologies can coexist in older PwMS and cause cognitive decline. Future basic and clinical research will need to consider these complex factors to better understand the underlying pathophysiology, and to improve diagnostic accuracy.

EEG theta and alpha oscillations in early versus late mild cognitive impairment during a semantic Go/NoGo task.

Amnestic mild cognitive impairment (aMCI) is marked by episodic memory deficits, which can be used to classify individuals into early MCI (EMCI) and late MCI (LMCI). Although mounting evidence suggests that individuals with aMCI have additional cognitive alterations including deficits in cognitive control, few have examined if EMCI and LMCI differ on processes other than episodic memory. Using a semantic Go/NoGo task, we examined differences in cognitive control between EMCI and LMCI on behavioral (accuracy and reaction time) and neural (scalp-recorded event-related oscillations in theta and alpha band) measures. Although no behavioral differences were observed between the EMCI and LMCI groups, differences in neural oscillations were observed. The LMCI group had higher theta synchronization on Go trials at central electrodes compared to the EMCI group. In addition, the EMCI group showed differences in theta power at central electrodes and alpha power at central and centro-parietal electrodes between Go and NoGo trials, while the LMCI group did not exhibit such differences. These findings suggest that while behavioral differences may not be observable, neural changes underlying cognitive control processes may differentiate EMCI and LMCI stages and may be useful to understand the trajectory of aMCI in future studies.

Baseline delayed verbal recall predicts response to high definition transcranial direct current stimulation targeting the superior medial frontal cortex.

Anodal high definition transcranial direct current stimulation (HD-tDCS) targeting the pre-supplementary motor area/dorsal anterior cingulate cortex (pre-SMA/dACC) has recently been shown to improve verbal retrieval deficits in veterans with chronic traumatic brain injury (TBI) (Motes et al., 2020), but predictors of treatment response are unclear. We hypothesized that baseline delayed verbal recall, a sensitive measure for post-TBI chronic cognitive decline, would predict therapeutic effects of HD-tDCS targeting the pre-SMA/dACC for verbal retrieval deficits. Standardized verbal retrieval measures were administered at baseline, immediately after and 8 weeks after treatment completion. We applied mixed generalized linear modeling as a post-hoc subgroup analysis to the verbal retrieval scores that showed significant improvement in Motes at el. (2020) to examine effects of active stimulation across the groups with baseline-intact delayed recall (N = 10) and baseline-impaired delayed recall (N = 8), compared to sham (N = 7). Individuals with impaired baseline delayed recall showed significant improvement (compared to baseline) in both category fluency and color-word inhibition/switch, while individuals with intact delayed recall showed significant improvement only in color-word inhibition/switch. Baseline delayed verbal recall may therefore be considered as a predictor for future electromodulation studies targeting frontal structures to treat TBI-related verbal deficits.

Case Report: Improving Verbal Retrieval Deficits With High Definition Transcranial Direct Current Stimulation Targeting the Pre-Supplementary Motor Area in a Patient With Chronic Traumatic Brain Injury.

We report a patient who has cognitive sequalae including verbal retrieval deficits after severe traumatic brain injury (TBI). The cortico-caudate-thalamic circuit involving the pre-Supplementary Motor Area (pre-SMA) has been proposed to underlie verbal retrieval functions. We hypothesized that High Definition-transcranial Direct Current Stimulation (HD-tDCS) targeting the pre-SMA would selectively modulate this circuit to remediate verbal retrieval deficits. After the patient underwent 10 sessions of 20 min of 1 mA HD-tDCS targeting the pre-SMA, we documented significant improvements for verbal fluency and naming, and for working memory and executive function tasks that involve the frontal lobes. The effects persisted for up to 14 weeks after completion of HD-tDCS treatment. We also demonstrated normalization of the event-related potentials suggesting modulation of the underlying neural circuit. Our study implicates that region-specific non-invasive brain stimulation, such as HD-tDCS, serves as a potential individualized therapeutic tool to treat cognitive deficits by inducing longer-lasting neuroplasticity even in the chronic phase of TBI.

The Interconnections of Mal de Débarquement Syndrome and Vestibular Migraine.

OBJECTIVES/HYPOTHESIS: Mal de débarquement syndrome (MDDS) is characterized by a persistent rocking sensation, as though on a boat. It may occur following exposure to passive motion (motion-triggered MDDS [MT-MDDS]), or spontaneously (spontaneous-onset MDDS [SO-MDDS]). This study investigated the characteristics of MDDS patients with vestibular migraine (MDDS-VM) to those without (MDDS-O). STUDY DESIGN: Retrospective review. METHODS: Retrospective, single-center study of 62 patients with MDDS. Clinical characteristics, Dizziness Handicap Inventory (DHI), Migraine Disability Assessment Score (MIDAS), job impact, and optimal treatment(s) were studied. RESULTS: There were 23 MDDS-O (19 women), and 39 MDDS-VM (35 women) patients. Comparisons between MDDS-VM and MDDS-O showed significant differences in age of onset (41 vs. 52 years, P = .005), interictal visually induced dizziness (89.7% vs. 30.4%, P < .001), interictal head motion-induced dizziness (87.2% vs. 47.8%, P = .001), other vestibular sensations (59% vs. 13%, P < .001), interictal aural symptoms (25.6% vs. 0%, P = .008), number of interictal symptoms (4.3 vs. 2.3, P < .001), total DHI score (54.9 vs. 38.1, P = .005), DHI-P (physical domain) score (16.1 vs. 10, P = .004), DHI-F (functional domain) score (20.9 vs. 15.7, P = .016 MIDAS (4.6 vs. 32, P = .002), and job resignations (23.2% vs. 5%, P = .016). On the other hand, between-group comparisons for MT-MDDS and SO-MDDS did not reveal any significant differences whatsoever. For optimal treatment, venlafaxine was the most used (27.3%) in all groups. For MDDS-VM, antiepileptic drugs and migraine preventive vitamins were also useful in relieving symptoms. CONCLUSIONS: MDDS-VM patients appear to be more disabled than MDDS-O, in terms of severity of dizziness, job impact, and number of symptoms, but have good potential for improvement, particularly with migraine prophylactic treatment. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E1653-E1661, 2021.

Multimodal feature binding in object memory retrieval using event-related potentials: Implications for models of semantic memory.

To test the hypothesis that semantic processes are represented in multiple subsystems, we recorded electroencephalogram (EEG) as we elicited object memories using the modified Semantic Object Retrieval Test, during which an object feature, presented as a visual word [VW], an auditory word [AW], or a picture [Pic], was followed by a second feature always presented as a visual word. We performed both hypothesis-driven and data-driven analyses using event-related potentials (ERPs) time locked to the second stimulus. We replicated a previously reported left fronto-temporal ERP effect (750-1000 ms post-stimulus) in the VW task, and also found that this ERP component was only present during object memory retrieval in verbal (VW, AW) as opposed to non-verbal (Pic) stimulus types. We also found a right temporal ERP effect (850-1000 ms post-stimulus) that was present in auditory (AW) but not in visual (VW, Pic) stimulus types. In addition, we found an earlier left temporo-parietal ERP effect between 350 and 700 ms post-stimulus and a later midline parietal ERP effect between 700 and 1100 ms post-stimulus, present in all stimulus types, suggesting common neural mechanisms for object retrieval processes and object activation, respectively. These findings support multiple semantic subsystems that respond to varying stimulus modalities, and argue against an ultimate unitary amodal semantic analysis.

Event-related neural oscillation changes following reasoning training in individuals with Mild Cognitive Impairment.

Emerging evidence suggests cognitive training programs targeting higher-order reasoning may strengthen not only cognitive, but also neural functions in individuals with Mild Cognitive Impairment (MCI). However, research on direct measures of training-induced neural changes, derivable from electroencephalography (EEG), is limited. The current pilot study examined effects of Gist Reasoning training (n = 16) compared to New Learning training (n = 16) in older adults with amnestic MCI on measures of event-related neural oscillations (theta and alpha band power) corresponding to Go/NoGo tasks during basic and superordinate semantic categorization. EEG data were recorded while participants performed the Go/NoGo task pre- and post-training, and power in theta and alpha frequency bands was examined. Both groups were comparable at pre-training on all measures and both groups showed greater event-related theta synchronization post-training. Furthermore, the Gist Reasoning group had enhanced event-related desynchronization in low-frequency alpha band (8-10 Hz) on response inhibition (NoGo) trials and high-frequency alpha band (11-13 Hz) on response execution (Go) trials during superordinate categorization, relative to the New Learning group. These findings suggest that Gist Reasoning training in MCI impacted neural processing linked to strategic processing of Go and NoGo trials during the more complex superordinate categorization task. Targeting higher-order top-down cognitive processing seems to better harness residual neuroplastic potential in MCI. ClinicalTrials.gov ID: NCT02588209.

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).

Traumatic brain injury history is associated with an earlier age of dementia onset in autopsy-confirmed Alzheimer's disease.

OBJECTIVE: To evaluate whether a history of traumatic brain injury (TBI) with reported loss of consciousness (LOC) is a risk factor for earlier onset of Alzheimer's disease (AD) in an autopsy-confirmed sample. METHOD: Data from 2,133 participants with autopsy-confirmed AD (i.e., at least Braak neurofibrillary tangle stages III to VI and CERAD neuritic plaque score moderate to frequent) were obtained from the National Alzheimer's Coordinating Center (NACC). Participants were categorized by presence/absence of self-reported remote (i.e., >1 year prior to their first Alzheimer's Disease Center visit) history of TBI with LOC (TBI+ vs. TBI-). Analyses of Covariance (ANCOVA) controlling for sex, education, and race compared groups on clinician-estimated age of symptom onset and age of diagnosis. RESULTS: Average age of onset was 2.34 years earlier (p = .01) for the TBI+ group (n = 194) versus the TBI- group (n = 1900). Dementia was diagnosed on average 2.83 years earlier (p = .002) in the TBI+ group (n = 197) versus the TBI- group (n = 1936). Using more stringent neuropathological criteria (i.e., Braak stages V-VI and CERAD frequent), both age of AD onset and diagnosis were 3.6 years earlier in the TBI+ group (both p's < .001). CONCLUSIONS: History of TBI with reported LOC appears to be a risk factor for earlier AD onset. This is the first study to use autopsy-confirmed cases, supporting previous investigations that used clinical criteria for the diagnosis of AD. Further investigation as to possible underlying mechanisms of association is needed. (PsycINFO Database Record

Age effects on event-related potentials in individuals with amnestic Mild Cognitive Impairment during semantic categorization Go/NoGo tasks.

Both age and amnestic Mild Cognitive Impairment (aMCI), two major risk factors associated with Alzheimer's disease, have been associated with increased latency of event-related potentials, but how these factors interact has been less extensively evaluated. We examined the effects of age as a factor in 25 individuals with aMCI and in 25 age-matched normal controls (NC) during semantic categorization Go/NoGo tasks. We found that N2 latency was prolonged with increasing age in aMCI but not in the NC, and P3 latency was prolonged with increasing age in both groups. Furthermore, aMCI individuals showed significant prolongation in N2 latency compared to NC in the older age group, whereas such group differences were not observed in the younger age group. Our findings suggest that N2 latency corresponding to cognitive control is susceptible to a combination of age and disease effects, especially in older individuals, and thus may be useful in differentiating normal from pathological aging in this age group.